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Consultant in Endocrinology, Associate Professor
Department of Endocrinology
University of Medicine and Pharmacy Tg Mures

Florina Gliga, MD, PhD student

Corina Radu-Pop, MD, PhD

Consultant in Endocrinology
University Assistant
Department of Physiopathology
University of Medicine and Pharmacy
Tg Mures

Consultant in Endocrinology
University Assistant
Department of Endocrinology
University of Medicine and Pharmacy
Tg Mures

Gabriela Madaras, MD,PhD student

Zsuzsanna Szanto MD, PhD

Consultant in Endocrinology

Consultant in Endocrinology,
University Assistant
Department of Endocrinology
University of Medicine and Pharmacy
Tg Mures

Raluca Pop, MD, PhD student

Consultant in Endocrinology


CHAPTER I - INTRODUCTION IN ENDOCRINOLGY ........................................................................5
Mechanism of action and hormonal regulation systems .............................................................. 5
The chemical structure of hormones...........................................................................................7
The hormonal synthesis and transport ........................................................................................7
Hormone-receptor interaction .....................................................................................................8
Hormone receptors regulation ....................................................................................................9
Endocrine diseases ....................................................................................................................9
CHAPTER II - HIPOTHALAMUS AND PITUITARY GLAND.............................................................. 11
Hypophysiotropic Hormones..................................................................................................... 12
Other hypothalamic functions ................................................................................................... 14
Craniopharyngioma (CF) .......................................................................................................... 15
Congenital hypothalamic dysfunctions ...................................................................................... 16
Functional GnRH deficit............................................................................................................ 18
Neurohypophyseal hormones....................................................................................................... 19
Diabetes Insipidus (DI) ............................................................................................................. 20
The Syndrome of Inappropriate Secretion of ADH (SIADH)....................................................... 25
Adenophypophyseal hormones ................................................................................................ 26
Pituitary tumors ........................................................................................................................ 32
Prolactinomas .......................................................................................................................... 35
Acromegaly and gigantism ....................................................................................................... 38
Cushings disease .................................................................................................................... 41
TSH secreting pituitary adenoma.............................................................................................. 43
Gonadotropin-Secreting Pituitary Adenomas ............................................................................ 43
Alpha Subunit-Secreting Pituitary Adenomas............................................................................ 44
Nonfunctional Pituitary Adenomas............................................................................................ 44
Pituitary failure (PF) - Hypopituitarism....................................................................................... 44
Empty sella syndrome .............................................................................................................. 50
CHAPTER III - THE THYROID......................................................................................................... 51
Anatomy, histology and embryology ............................................................................................. 51
Thyroid hormone synthesis and secretion................................................................................. 52
Thyroid hormone metabolism ................................................................................................... 53
The thyroid hormone transport.................................................................................................. 53
Control of the thyroid hormone production ................................................................................ 54
Thyroid autoregulation.............................................................................................................. 55
The Thyroid Hormone Receptors and Mechanisms of Action .................................................... 55
Physiologic effects of the thyroid hormones .............................................................................. 56
Thyroid morphologic and functional evaluation ......................................................................... 57
Functional in vivo exploration.................................................................................................... 58
Hyperthyroidism and thyrotoxicosis .......................................................................................... 60
Hypothyroidism and thyroidites................................................................................................. 72
Chronic thyroiditis (Hashimoto thyroiditis, lymphocytic thyroiditis, CTH) .................................... 79
Subacute thyroiditis ( SAT) ....................................................................................................... 82
Other forms of thyroiditis .......................................................................................................... 83
Endemic goiter and other iodine deficit disorders ...................................................................... 83
Endemic cretinism (EC) and other forms of IDD........................................................................ 88
Thyroid neoplasia..................................................................................................................... 90
Euthyroid sick syndrome .......................................................................................................... 98
Thyroid hormone and TSH resistance syndromes..................................................................... 98
Thyroid disorders in pregnancy................................................................................................. 99
Anatomy, histology and embryology of the parathyroid glands .................................................... 102
Biosynthesis and secretion of PTH ............................................................................................. 102
Metabolism and assay of PTH.................................................................................................... 103

Mechanism of action and biologic effects of PTH .................................................................... 104

Primary Hyperparathyroidism (PHPT)..................................................................................... 104
Hypoparathyroidism (hPT)...................................................................................................... 111
Osteoporosis.............................................................................................................................. 116
Osteoporosis induced by endocrine disorders......................................................................... 118
Glucocorticoid-Induced Osteoporosis ..................................................................................... 119
Clinical manifestation ............................................................................................................. 120
Laboratory and paraclinical investigations............................................................................... 120
Treatment and prophylaxis of osteoporosis............................................................................. 122
CHAPTER V - ADRENAL GLAND.................................................................................................. 127
Anatomy, embryology and histology ........................................................................................... 127
Adrenal hormone biosynthesis................................................................................................ 128
The metabolism of adrenal hormones..................................................................................... 129
Circulation of adrenal hormones ............................................................................................. 130
The control of steroid hormone production and secretion ........................................................ 130
Molecular mechanisms of glucocorticoids and mineralocorticoids ........................................... 131
Biological effects of adrenal steroids....................................................................................... 132
Laboratory evaluation of adrenal gland hormones................................................................... 134
Cushing's syndrome (CS)....................................................................................................... 137
Disorders of adrenocortical insufficiency................................................................................. 144
Acute adrenal insufficiency..................................................................................................... 149
Congenital adrenal hyperplasia (CAH).................................................................................... 150
Primary aldosteronism............................................................................................................ 156
CHAPTER VI - ADRENAL MEDULLA ............................................................................................ 161
Anatomy, embryology and histology ........................................................................................... 161
Biosynthesis, secretion and circulation of catecholamines ...................................................... 161
Catecholamine Metabolism and Inactivation ........................................................................... 162
Catecholamines actions......................................................................................................... 162
Pheochromocytoma and paraganglioma................................................................................. 163
Adrenal incidentaloma............................................................................................................ 171
CHAPTER VII - DISORDERS OF SEX DEVELOPMENT (DSDs) ................................................... 173
Nomenclature and Classification of Disorders of Sex Development ............................................ 174
Ovotesticular DSD.................................................................................................................. 176
Defects in testosterone synthesis and action .......................................................................... 176
Turner syndrome.................................................................................................................... 177
Klinefelter's syndrome ............................................................................................................ 179
Normal puberty....................................................................................................................... 181
Precocious puberty................................................................................................................. 183
Delayed puberty ..................................................................................................................... 187
CHAPTER VIII - TESTIS................................................................................................................ 189
Morphological and functional exploration of the testis ................................................................. 191
Male Hypogonadism............................................................................................................... 192
Primary male hypogonadism .................................................................................................. 193
Cryptorchidism ....................................................................................................................... 196
Male sexual dysfunction ....................................................................................................... 198
Gynecomastia ........................................................................................................................ 201
Andropause and Partial Androgen Deficiency ......................................................................... 203
CHAPTER IX - OVARY.................................................................................................................. 205
Morpho-functional exploration of the ovary ............................................................................. 207
Female hypogonadism ............................................................................................................... 208
Hypergonadotropic hypogonadism (premature ovarian failure - POF) ..................................... 208
Amenorrhea ........................................................................................................................... 211
Premenstrual and intermenstrual syndrome (PMS)................................................................. 213
Benign mastopathy................................................................................................................. 214

Polycystic ovarian syndrome .................................................................................................. 217

Menopause ............................................................................................................................ 220
CHAPTER X - OBESITY................................................................................................................ 225
Etiopathogeny of Obesity ........................................................................................................... 227
Pathologic Consequences of Obesity ..................................................................................... 229
Management of the Obese Patient ......................................................................................... 230


Endocrinology is the science studying the endocrine glands and their hormones.
Even in the molecular biology and genetics era, endocrinologys main purpose
remains the study of the communication and signaling ways which control and
coordinate the function of many organs and processes.
The endocrine system releases hormones in the circulation. They are chemical
messengers capable of transmitting the information at distance to the peripheral
tissues to interact with specific receptors. The whole system is the subject of
complex regulations mechanism which coordinate the hormonal synthesis, release,
transport and metabolism in target cells, as well as the expression and activity of the
receptors or the cellular and nuclear signaling pathways.
The endocrine system is perfectly integrated with other major communication
systems the neural or the immune system. Its effects are:
the growth and maturation of the body,
sexual differentiation and reproduction,
energy metabolism and nutritional intake.
These categories of actions are not mutual exclusive, many of the hormones
having multiple effects for example, the thyroid hormones influence the maturation
as well as the metabolism or the homeostasis. For many of the biological responses
theres the need of integration of multiple hormonal pathways. A classic example is
the glycemic control which implicates the insulin a pancreatic peptide hormone as
well as counter regulation hormones: glucagon, cortisol, growth hormone and
epinephrine. Any pathological change of the glucose level is determined by a
dysregulation of at least one of the above mentioned hormones.
Mechanism of action and hormonal regulation systems
The hormones can act on target cells after their release from a gland in the
circulation (figure 1.1). There are other types of local action:
Paracrine - the substance released from a cell acts on a nearby cell in the
same tissue, for example the somatostatin released from pancreatic gamma
cells can inhibit the insulin release from beta cells.
Autocrine - a hormone acts on the same cell it was released from. This effect
can have a promotion role in tumor growth.
Intracrine - same as the autocrine one, without the hormone being released.
Neuroendocrine - the hormones which are produced in neural cells and
released in the circulation are called neurohormones.
The negative feedback is one of the fundamental concepts in endocrinology.
Each major hypothalamic-pituitary hormonal axis is governed by a feedback
control, with the purpose of maintaining peripheral hormonal values in narrow
ranges. For such a feed-back system we can describe:
the long loop - the peripheral hormone concentration can inhibit the release of
the pituitary or the releasing hypothalamic hormones.
the short loop - the pituitary hormones act on the hypothalamic releasing
hormones, inhibiting their secretion.

Figure 1. Different mechanisms of cell signaling.

The existence of such a feedback control has its importance for the diagnosis
as well as the treatment of endocrine disorders through the utilization of stimulatory
or inhibitory tests.
The secretion of certain endocrine glands (pancreas, parathyroid) is under
negative feedback control as well, but these glands are capable of responding to
modifications of some controllable variables glucose or calcium level.
Another regulation mechanism is the neurogenic one, which can influence
hormonal production both in the central and peripheral nervous system. Examples:
The hypothalamus receives nervous input which can determine
neurohormonal secretion at this level. These neurohormones will influence the
secretion of pituitary hormones and, by these means, the rest of the endocrine
The pineal gland can be considered the interface of the brain, cerebral fluid
and the cerebral circulation. It receives different photosensitive inputs via its
sympathetic innervations. This input will determine the transformation of
serotonin to melatonin, a substance capable of influencing the reproduction,
among other functions.
Due to its rich sympathetic innervations, the adrenal medulla can release
catecholamine under stress conditions.
Some hormones are regulated by the direct stimulation of their release via an
external factor. For example, some nutrients the rise of glucose in the pancreatic
beta cells is an important stimulus for the release of insulin.

The feed-back systems described above are superimposed on the hormonal

biorhythms which the body uses for its adjustment to the environment.
Considering their time loop, one can describe the following biorhythms:
- ultradian rhythm the LH and FSH pulsatile secretion,
- circadian rhythm 24hs the cortisol secretion,
- circatrigintan rhythm 30 days average ovulation,
- circumannual rhythm.
The chemical structure of hormones
Generally speaking, hormones can be derived from aminoacides,
polypeptides, cholesterol, phospholipids. Most of them are proteins, with a variable
number of aminoacides (from 4 to several hundred). Some hormones (insulin, for
example) consist of 2 subunits bounded by disulfide bonds via cysteine residues.
The anterior pituitary glycoprotein hormones have 2 polypeptide subunits bounded
by a glucidic one. There are hormones derived from one aminoacid, like tyrosine
the source of catecholamine and thyroid hormones - or tryptophan, the serotonin and
melatonin precursor. Some of them can function as neurotransmitters as well
The steroid hormones, secreted by the adrenal cortex and the gonads derive
from cholesterol, having a similar bidimensional structure. Their specificity is given
by the lateral chains and the spatial orientation. Hormones like the vitamin D and the
retinoic acid derive from cholesterol as well. Eicosanoides are hormones derived
from polyunsaturated fatty acids or phospholipids (prostaglandins, prostacycline,
The hormonal synthesis and transport
The peptide and protein hormones synthesis usually needs the transcription
of a single gene (exception and subunits of the glycoprotein pituitary hormones
which are each coded by a gene), splicing (the elimination of the introns), and the
translation in the endoplasmic reticulum followed by post-translational modifications.
A single gene can code multiple types of prohormones. Following the posttranslational modifications multiple active hormones can derive from a prohormone.
Unlike the peptide hormones, the steroid ones are synthesized in the
mitochondria and endoplasmic reticulum and dont need immediate gene expression.
Their synthesis can take place only in the presence of certain enzymes which act on
cholesterol and convert it to different steroids. In the cells where the steroid
synthesis takes place, the expression of the enzymes is under hormonal and/or other
factors control.
The thyroid and steroid hormones are less soluble in aqueous solutions than
the protein hormones or catecholamine. Over 90% of the insoluble hormones and a
certain proportion of the protein hormones circulate bounded to plasmatic proteins
(albumin or globulin). These ligand-protein complexes are an important reservoir for
the hormones and they provide an even distribution of the hormones. They protect
the small molecules from rapid inactivation or elimination via bile or urine. The free
fraction of the hormone is the active one. When the proteins needed for binding the
hormones are affected by liver diseases for example, only the total concentration of
the hormone differs, the free fraction remaining the same.
The rate of hormonal metabolism varies by a great amount. The
catecholamines secreted by the adrenal medulla have a half-life of a few seconds,

the protein hormones have a half-life of a few minute and the thyroid and steroid
hormones have a half-life of hours
Hormone-receptor interaction
There are 2 types of endocrine receptors:
Transmembrane receptors (for the water soluble hormones which cannot
cross the lipid membranes barrier) consist of several classes:
1. Receptor tyrosine kinase for example the insulin and IGF-1 receptors.
2. Receptor serine/treonine kinase for example the activin and inhibin
3. Receptor guanylate cyclase for the natriuretic atrial factor.
4. Ligand-gated ion channels acetylcholine receptors.
5. G protein coupled receptors receptors for epinephrine, glycoprotein
hormones, PTH, glucagon.
6. Cytokine receptors GH, PRL and leptin receptors.
In the first four categories fall bifunctional molecules that can act as enzymes
or ion channels, but can bind hormones as well. The last 2 categories of membrane
receptors need some intermediary molecules (G protein, other kinases Janus
tyrosine kinase - JAK) in order to transmit the information to second messengers.
The membrane receptors use, as second messengers, the following: AMPc,
diacylglycerol, phosphatidylinositol. They start a cascade reaction which ends with
the recruitment of nuclear proteins and regulation of transcription.
Nuclear receptors are used by the liposoluble hormones, small molecules
which can pass rapidly through the membrane either passively or with a transporting
protein. The ligands for these receptors arent coded. They belong to one of the
following categories:
Classic hormones:
Thyroid hormones,
Vitamins vitamin D, transretinoic or 9-cis retinoic acid,
Intermediary metabolism products fatty acids, bile acids,
Endobiotics (e.g., medicinals and toxins found in plants) and xenobiotics
(compounds that are not naturally occurring).
The steroid hormone receptors have a similar structure, which denotes the
existence of an ancient protein from which theyre derived. Some of them bind with
their ligand in the cytoplasm (glucocorticoid, progesterone, testosterone and
mineralocorticoid receptors) after which they undergo a homodimerization and enter
the nucleus and act as transcription factors. Other receptors (thyroid hormones,
estradiol, retinoic acid receptors) bind with their ligand directly in the nucleus and act
after heterodimerization.
The receptor has a highly conserved domain by which the dimers bind with
specific DNA sequences called HRE (hormone response elements). Some of the
steroid hormones and the thyroid hormones act also rapidly on target cells probably
through ion channels or membrane receptors.

Hormone receptors regulation

The function of the endocrine system depends a lot on tisular regulation which
takes place by modifying the number of the receptors upregulation or
downregulation or their sensitivity. The mechanism of this regulation could be:
The increase or decrease of the receptors synthesis.
Internalization of the membrane receptors after binding the ligand.
Decoupling of the receptor from the intracellular pathways
(desensitization) usually through receptor phosphorilation.
The regulation can be homologue through the direct effect of the ligands on
their receptors or heterologue when different hormones act on another hormonal
receptor (for example estrogen action on oxytocin receptors). The hormonereceptor interaction depends on the number of the receptors, the hormone
concentration and its affinity for the receptor. The affinity is the concentration of the
hormone for which half of the receptors are occupied. Normally only 5% of one cells
receptors are occupied and the maximum biologic response appears even when a
small fraction of the receptors are bonded. One could ask how come only a small
reduction in the number of receptors or the concentration of the hormone can have
great influence on the biological response. If the number of receptors decreases, the
odds of hormone binding are reduced as well, so well need a higher concentration to
have the same degree of receptor occupation.
Endocrine diseases
Endocrine diseases can be grouped in two categories: hormonal excess or
deficit. Besides these two there is also the alteration of the tissue response to the
hormone (resistance to their action), the tumors which affect different endocrine
glands or the iatrogenic administration of hormonal preparations.
1. Endocrine hypofunction can result from a wide variety of processes:
Destruction of the gland through autoimmune processes involving
one or more endocrine glands (pancreas, thyroid, gonads, adrenal
gland) or after trauma, infiltrative disease, tumors or hemorrhage.
Extraglandular diseases for example renal failure and inadequate
production of the 1, 25-(OH)2-colecalciferol.
Hormonal synthesis deficits GH deficit following the deletion or
mutation of the GH gene.
2. Endocrine hyperfunction:
Glandular hyperplasia followed by growth of the number of the cells
and of the hormonal secretion (for example hyperparathyroidism
caused by glandular hyperplasia).
Endocrine tumors for example the pituitary adenomas can
produce PRL, ACTH, GH, LH, FSH, rarely TSH.
Autoimmune diseases the classical example of the Basedow
disease during which the production of specific antibodies against
the TSH receptor causes its activation.
Ectopic secretion usually polypeptidic hormones ACTH or
3. Hormonal sensitivity disturbances:
Genetic: resistance to the hormones through receptor defects (for
example thyroid hormones, androgens, glucocorticoids, leptin, GH)

or intracellular signaling pathways disturbances like

pseudohypoparathyroidism defect in the coupling subunit of the G
Acquired the type 2 diabetes mellitus, the metabolic syndrome or
polycystic ovary syndrome all have insulin resistance as a
pathogenic pathway.
4. Endocrine tumors can determine either hormonal deficit or excess, through
destruction respectively secretion. They can also have local effects for
example the pituitary tumoral syndrome with intracranial hypertension,
ocular and neurological signs or the compression effects of big goiters.
5. Iatrogenic disturbances through deliberate or inadequate use of
hormonal preparations for example glucocorticoids administered in
excess for their anti-inflammatory effect can determine the Cushing



Neuroendocrinology is a branch of endocrinology which studies the interaction
between the nervous and the endocrine systems in order to obtain the integration of
neural activities (cognitive and noncognitive) with the metabolic and homeostasis
functions. The hypothalamic-pituitary gland unit represents the paradigm of the
interaction between the endocrine and the nervous system.
Anatomy, embryology, histology
The hypothalamus forms the floor and lateral walls of the third ventricle; it is
boarded in front by the optic chiasm, posterior by the mamillary bodies and superior
by the hypothalamic sulcus. Although being intracranial, the pituitary gland just like
the pineal gland is not intracerebral. The pituitary gland lies at the base of the skull
in the sella turcica of the sphenoid bone. Its anterior part, the tuberculum sellae, is
boarded by the posterior projections of the sphenoid wings the anterior clinoide
processes; its posterior wall, the dorsum sellae, forms the posterior clinoide
The pituitary gland is surrounded by dura mater; in its superior part we find
the diaphragma sellae with an opening of 5 mm, for the pituitary stalk. If this opening
is larger, the cerebral fluid can herniate inside the sella, causing the empty sella
syndrome. The optic chiasm is found 5-10 mm above the diaphragma sellae;
compression on the chiasm and visual field defects (bitemporal hemianopsia) appear
in pituitary tumor with supraselar extension.
The sphenoid sinus is placed in front and beneath the pituitary and the
cavernous sinus is placed laterally; in here we find the internal carotid arteries, the
oculomotor, trochlear , abducent and the maxillary and ophthalmic branches of the
trigeminal nerve.
The pituitary consists of 2 major parts: the anterior hypophysis and the
neurohypophysis. The anterior pituitary is divided in pars distalis, pars intermedia
and pars tuberalis. The neurohypophysis consists of the median eminence, pituitary
stalk and the posterior pituitary lobe.
In humans the pituitary gland weighs 500-900 mg and it measures around
15x10x6mm; during pregnancy it can double in size.
The embryology of the 2 parts of the hypophysis is different:
The anterior lobe derives from the Rathkes pouch an ectodermal
evagination of the oropharynx.
The neurohypophysis has a neural origin, deriving from the ventral
hypothalamus and the third ventricle; keeping connections with the
hypothalamic supraoptic and paraventricular nuclei.
The neurons of the neurohypophysis originate from the supraoptic and
paraventricular nuclei then go through the pituitary stalk and release vasopressin
and oxytocin in the posterior pituitary lobe. The neurons secreting the releasing
hormones originate in different hypothalamic nuclei, their axons reaching the median
eminence the place where the hormones or the releasing and inhibiting factors are
The blood supply is different for the 2 pituitary lobes. The anterior lobe has the
largest blood supply in the body, receiving 0.8ml/g/min. The arterial blood supply
derives from the internal carotid arteries, via the superior, median and inferior

hypophyseal arteries. The superior hypophyseal artery forms a capillary network in

the median eminence (the pituitary portal capillary network). From this venous
capillary network the long portal veins arise, along the pituitary stalk. They reach the
anterior lobe and form a second capillary network from which the blood is conducted
in the cavernous sinus. The capillaries in the anterior lobe are fenestrated, allowing
the neural hormones to enter the circulation. The median and inferior hypophyseal
arteries provide the blood supply for the pituitary stalk and the posterior lobe.
The venous drainage, through which the adenohypophyseal hormones reach the
circulation, is very variable, but from the cavernous sinus the blood reaches the
inferior and superior petrosal sinuses and then the jugular vein.
Hypophysiotropic Hormones
The great majority of anterior pituitary hormones are under stimulatory
hypothalamic control with 2 exceptions GH and especially PRL whose control is
mostly inhibitory. The hypophyseotropic hormones are secreted in a pulsatile
manner, sometimes with a circadian rhythm. Their synthesis takes place in the
parvocellular neurons and through the axons they reach the median eminence.
TRH (Thyrotropin-releasing hormone) is the smallest stimulatory peptidic
hormone (3 aminoacides) and is synthesized as a precursor with 242 aminoacides
which contains 6 copy of the TRH. Its origin is in the neurons from the medial part of
the paraventricular nucleus. Its secretion is stimulated by norepinephrine and
inhibited by serotonin; there is also a negative feed-back control through the thyroid
hormones levels. TRHs main function is to stimulate the release of TSH but its the
most important releasing factor for PRL. It is responsible for the PRL rise with or
without galactorrhea found sometimes in hypothyroidism. In healthy people TRH
does not influence the secretion of other hormones besides TSH and PRL, but it
stimulates the secretion of GH in acromegaly and of ACTH in some patients with
Cushings disease.
Synthetic TRH is used in the evaluation of the TSH reserve, the diagnosis of
acromegaly or hyperprolactinemia.
CRH (corticotrophin-releasing hormone), a 41 aminoacides peptide,
stimulates the release of ACTH, -endorphin, -lipotropin, MSH (melanocytestimulating hormone) and of other peptides derived from the POMC (pro-opiomelanocortin). CRH and vasopressin have a synergic effect on the release of ACTH.
The CRH secreting neurons are found in the anterior region of the paraventricular
nucleus. CRH is also secreted by the human placenta. Its secretory regulation is
achieved through different ways:
Negative feed-back: cortisol, ACTH, -endorphin;
Acetylcholine, dopamine, norepinephrine, epinephrine stimulate the
hypothalamic CRH secretion;
GABA inhibits the release of CRH;
Interleukin 1, 6, TNF (tumor necrosis factor-) stimulate both the synthesis
and the release of CRH, ACTH, and vasopressin. Synthetic CRH is used in
diagnosing the Cushing syndrome or the adrenal failure.
GnRH (Gonadotropin-releasing hormone) is a decapeptide whose main
function is to stimulate the release of pituitary LH and FSH. This is achieved through

differences in the size and frequency of GnRH release as well as feedback from
estrogens and androgens; low-frequency pulses favor FSH release while highfrequency pulses result in LH release.The embryological origin of GnRH secreting
neurons is the epithelial tissue of the nasal placode, which explains the Kallmann
syndrome (there is also anosmia). In the hypothalamus, these neurons can be found
in the preoptic area. For women the negative feed-back control can be found both in
the hypothalamus and the pituitary. In the hypothalamus, the estrogens regulate the
frequency and amplitude of the GnRH secretion; in the hypophysis the estrogens
modulate the pituitary hormones response to GnRH. In men, the testosterone has a
negative effect on the pulsatile secretion of GnRH.
Synthetic GnRH can be administered in a pulsatile manner in hypogonadotropic
hypogonadism caused by GnRH deficit. The depot GnRH agonist causes initially a
stimulation of the LH and FSH release and then a down-regulation of their own
receptors, causing the decrease of the pituitary hormones secretion. These agonists
can be used in some cancers (breast, prostate) or in the treatment of precocious
puberty. GnRH antagonists are used in the prevention of premature ovulation in
assisted reproduction, benign gynecological diseases (fibromatous uterus,
GHRH (Growth HormoneReleasing Hormone) has 44 aminoacides and
stimulates in a dose-dependent manner the GH secretion and causes sometimes a
light increase in the PRL level. Both IGF-1 and GH have a negative feed-back effect
on the GH secretion through lowering the GHRH and the rise of somatostatin. The
GHRH secreting neurons are located in the arcuate and ventromedial nuclei.
Serotonin activates the GHRH secretion and GH and GABA inhibit it. Non-sense
mutations in the GHRH receptor (GHRH-R) cause a rare familial form of GH deficit.
A different system of GH stimulation involves a peptide called Ghrelin which interacts
with a different receptor GH secretagogue receptor (GHS-R). The predominant
source of circulating ghrelin is the gastrointestinal tract, primarily from the stomach,
but also in smaller amounts from the intestine. ARNm molecules and GHS-R can be
found both in the hypothalamus and the pituitary. Ghrelin can increase the PRL,
ACTH, cortisol and aldosterone levels, but its main role appears to be in the
regulation of appetite and food intake.
Somatostatin (somatotropin releaseinhibiting factor) has 2 active forms:
one with 14 aminoacides (predominant in the CNS) and one with 28 aminoacides.
The first one inhibits the TSH and GH secretion, its origin being in the neurons of the
periventricular nucleus, above the optic chiasm and the arcuate and ventromedial
nuclei. The 28 aa form can be found in the D pancreatic cells, intestinal mucosa or
the thyroid C cells. Through paracrine and endocrine effects, the somatostatin
inhibits the secretion of:
VIP (vasoactive intestinal polypeptide).


The synthetic somatostatin analogues (octreotide for example, consisting of 8aa)

are used in the treatment of acromegaly, carcinoid tumors, pancreatic tumors and, as
a haemostatic agent in esophageal varices hemorrhage. The scintigraphy performed
using octreotid marked with different isotopes can be used in diagnosing the
neuroendocrine tumors.
PIF (Prolactin-Inhibitory Factor) is mainly represented by Dopamine. The
hypothalamic control of the PRL is mainly inhibitory. Dopamine-secreting neurons
(tuberoinfundibular dopaminergic system) are located in the arcuate nuclei, and their
axons terminate in the median eminence. In the lactotrope hypophyseal cells
dopamine binds with its receptors. Breaking the hypothalamic-pituitary connection
(pituitary stalk syndrome, hypothalamic lesion, blockade of the dopamine receptors
by some medication neuroleptics) will cause a rise in the PRL level. GABA and the
cholinergic pathways have an inhibiting effect on the PRL release.
PRF (Prolactin-Releasing Factor) is represented by TRH, but its role cant be
that important, since the physiologic stimulation of the PRL secretion
breastfeeding, stress, sleep isnt accompanied by a rise in the TRH or TSH level.
VIP and histidin-methionine (secreted along with VIP from a common precursor), two
hypothalamic peptides both stimulate the release of PRL. Serotonin can also
stimulate the PRL and serotonin antagonists reduce the PRL level.
Other hypothalamic functions
The hypothalamus is involved in many non-endocrine functions like body
temperature regulation, thirst, food intake. It is considered an integration centre for
the CNS, the vegetative and endocrine system. Hypothalamic function is regulated
both through hormonal signals (most frequently feed-back) and through nervous
inputs, with a variety of sources, mediated by neurotransmitters acetylcholine,
dopamine, norepinephrine, epinephrine, serotonin, GABA, endogenous opioids. In
the hypothalamus we can also find the superior vegetative centers cardio-vascular,
vasomotor, breathing. Sexual behavior, libido or some emotional states of anxiety,
anger, aggressivity are all regulated by multiple cerebral structures, among which the
hypothalamus seems to play an important role.
Table 1. The hypothalamic nuclei and their function and secretion
Paraventricular (PVN)
Lateral hypothalamus
Preoptic area

Neurohoromone or function
ADH, Oxytocin
magnocelullar neurons: ADH, Oxytocin
parvocellular neurons: TRH, CRH, VIP
Circadian rhythm and pineal function
GnRH, GHRH, Dopamine, Somatostatin
appetite regulation
GHRH, Somatostatin
satiety center
hunger center

Anterior hypothalamus
Posterior hypothalamus

thermoregulation cooling center

thirst center
thermoregulation heating center

Craniopharyngioma (CF)
Etiology and pathogenesis
The craniopharyngioma is the most frequent neoplasm of nonglial origin and it
is the tumor most often associated with hypothalamic-pituitary dysfunction. Its origin
is supposed to be from epithelial remains of the Rathkes pouch. The most frequent
localization is supraselar, but it can be found in the sella turcica, or, rarely, in the
nasopharynx or the third ventricle. CF has a first peak in incidence in childhood (6-14
years of age) and a second one in the fifth decade.
The tumor varies in size from small, solid, well defined masses to great
tumors, with multiple cysts which invade the sella turcica and the nearby regions.
Cystic degeneration (the liquid contains cholesterol crystals) is frequent. From the
pathologists view the epithelium is mucous, squamous or adamantoid, calcified in
70% of the cases. Malignant degeneration is rare, but possible, after multiple
recurrences and radiotherapy.
Signs and symptoms
The most frequent signs and symptoms of the CF are pituitary failure, visual
field defects, severe headache which can be associated with other signs of
intracranial hypertension (vomiting, papillary edema or optical atrophy).
In children:
o Growth retardation is constant and is associated with other signs of
pituitary growth failure
o Delayed puberty
o Central hypothyroidism and secondary adrenal failure
In adults:
o The most frequent symptom is sexual dysfunction amenorrhea
respectively erectile dysfunction
o Clinical signs of hypothyroidism and adrenal failure are associated
o Sometimes there are non-specific signs like depression without other signs
of endocrine dysfunction. This can be the result of frontal lobe and limbic
system extension of the tumor.
Both in childhood and adulthood neurohypohyseal dysfunctions can appear,
manifested both as diabetes insipidus or inadequate secretion of ADH.
Paraclinical and laboratory findings
Considering the pituitary failure dynamic tests are mandatory. PRL level can
be increased, decreased or normal depending on the location and the size of the
tumor. For positive diagnostic theres the need of imaging confirmation, either by CT
or MRI. In over 80% of the cases the tumor has cystic degeneration or calcifications
(these can be observed on the cranial radiograph scan).
It is mandatory to perform an ophthalmological exam, with visual field
determination before surgery.
Differential diagnosis

CF must be differentiated from all supraselar tumors:

optical gliomas,
systemic hystiocytosis or other infiltrative disorders like sarcoidosis
arachnoid cysts or other cystic lesions.

The treatment consists primary of surgical excision of the tumor. The small
tumors can be excised by transphenoidal approach, but the big ones need
craniotomy. Surgical treatment must be individualized extended resection can lead
to increased mortality. Conventional radiotherapy is indicated after surgery for
diminishing the risk of recurrence.
In case o recurrence, mostly due to cyst reaccumulation, there are the
following options:
drainage through stereotactic punction
the use of sclerosing substances with chemotherapeutic effect
intralesional radiotherapy.
Evolution, complications, prognostic.
The great majority of patients will have plurihormonal pituitary failure after
surgery which requires the correct substitution of all deficient hormonal axes.
Almost half of the patients develop morbid obesity due to the damage of the
ventromedial nucleus (with consequent increased parasympathetic activity and
hyperinsulinemia) and/or the paraventricular nuclei. Inhibiting the insulin secretion
can be beneficial.
There are sleep disturbances that can appear, caused by the dysregulation of
the circadian rhythm, going up to narcolepsy. These disturbances can sometimes be
treated with melatonin. An important complication can be the lesion of the thirst
center and liquid intake. In case theres a diabetes insipidus association, this can put
the life of the patient in danger.
Congenital hypothalamic dysfunctions
Kallmann syndrome and the congenital GnRH deficit (isolated hypogonadal
Kallmann syndrome is defined by the association of hypogonadotropic
hypogonadism with hypo- or anosmia due to the agenesis or hypoplasia of the
olfactory bulb. The congenital GnRH deficit refers to the absence of the GnRH
secretion in the hypothalamus or a defect in its action by receptor mutation in the
hypophysis. It is more frequent in males. Its characterized by the absence of
secondary sexual characteristics (underdeveloped musculature and the absence of
axillary and body hair). Boys have microphalus, cryptorchidism, small testicles and
the girls have primary amenorrhea.
There are other clinical findings:
median line defects cleft lip and palate;
deafness, optical atrophy;
renal anomalies;

linear growth is usually unaffected, the body has eunuchoidal proportions.

From the genetic point of view, the transmission is heterogeneous:
X linked recessive mutations or deletions of the KAL-1 gene in the
forms associating anosmia;
autosomal dominant mutations in the FGFR 1 gene;
autosomal recessive mutations in the GPR54 gene or the GnRH
receptor gene.
The hypogonadism in Kallmann syndrome is due to the lack of migration of
the GnRH secreting neurons from the nasal placode during embryologic
The diagnosis is suggested by the clinical findings amenorrhea and lack of
secondary sexual characteristics in females, delayed puberty in males and by the
reduced levels of the gonadotropes, estradiol in females and testosterone in males.
The MRI can demonstrate the absence of the olfactory bulb.
The treatment can be done with special pumps that deliver the GnRH in a
pulsatile manner and restore the pituitary function or with:
Testosterone or hCG in males,
Cyclic estro-progestative in females.
Bardet Biedl syndrome
It is a heterogenic genetic disease mutations in 10 different genes are
described and its defined by:
mental retardation,
renal anomalies,
hexadactily and brachidactily, rarely syndactily,
nephrogenic diabetes insipidus,
pigmented retinitis since childhood,
50-75% of the cases have a GnRH deficit.
Mutation in the leptin gene or leptin receptor gene
Leptin deficit causes a large range of hypothalamic disturbances, among which
hyperphagia, obesity and central hypogonadism. The decrease in GnRH secretion is
accompanied by the fall of LH and FSH synthesis and release.
Prader Willi syndrome (PWS)
PWS is caused by absence of the paternally derived PWS/Angelman syndrome
(AS) region of chromosome 15 by one of several genetic mechanisms (deletion,
uniparental disomy of maternal origin or imprinting defect). Clinical manifestation:
Central hypogonadism which can be restored by chronic pulsatile GnRH
Neonatal muscular hypotonia which improves with age;
Obesity caused by the hyperphagia, comportamental disorders and the
discreet mental retardation;
Diabetes mellitus type 2;
Small stature;
Dimorphic syndrome epicanthus, hypertelorism, acromicria.

Functional GnRH deficit

The extreme form of this entity is the anorexia nervosa, a disease with great
prevalence in female adolescents during puberty or young women. It has a very
complex etiology and pathogenesis in which there is a well defined psychological
and behavior component. Clinically, the diagnosis is made on the following 4 criteria:
1. The refusal to maintain a normal body weight (BMI under 17.5 kg/m2),
2. Intense fear of gaining weight or becoming fat,
3. Amenorrhea in postmenarcheal females,
4. Disturbed perception of one's body weight or shape,
Other clinical findings include hyperactivity, thermoregulation defects,
bradycardia, constipation, hypotension, dry skin, peripheral edema, parotid
hypertrophy. From the hormonal point of view we find a low LH and FSH, normal
TSH with low T3 and increased rT3 (euthyroid sick syndrome), high cortisol, low IGF1, leptin and DHEA. There are frequent medical complications heart disease,
osteopenia and osteoporosis, low final height, digestive disorders, impaired cognitive
function, electrolyte imbalances, hepatic disturbances which can lead to acute failure
and death. The treatment implies a great deal of patience, understanding and will
take place with the collaboration of a psychiatrist. Sometimes, in cases
unrespondent to treatment theres the need for total parenteral feeding, considering
the death risk.
Metabolic and endocrine dysfunctions can be corrected by weight increase,
but the amenorrhea can persist for several months. Theres always the need to make
a differential diagnosis with other organic diseases before establishing the anorexia
nervosa diagnosis. In cystic fibrosis, leukemia, nephrotic syndrome, thalasemia we
can often find amenorrhea and central hypogonadism. The differential diagnosis also
the debut of diabetes mellitus,
adrenal failure,
celiac disease or other inflammatory bowel diseases,
abdominal tumors,
CNS lesions.
Hypothalamic dysfunction has been observed in sustained intense stress and
in female athletes. Competitors in events such as gymnastics, ballet, marathon
running can show menstrual irregularities ranging from luteal phase defects to
amenorrhea. The rise of the PRL is frequent in the first category and the
osteoporosis is a constant complication. These patients have very low body fat - a
critical body fat level must be present in order to have a functioning reproductive


Neurohypophyseal hormones
The posterior pituitary is not a gland but only the distal axon terminals of the
magnocellular neurons located in supraoptic and paraventricular nuclei of the
Vasopressin and oxytocin are nonapeptides that are synthesized as part of a
larger precursor peptide, are packaged in neurosecretory granules and then travel
down the long axons through the stalk to the posterior pituitary. During transport,
peptide enzymes (peptidases) cleave the prohormone into vasopressin, oxytocin,
neurophysin, and a glycopeptide (for vasopressin only).
Antidiuretic hormone (ADH) and vasopressin (arginine vasopressin AVP)
represent the same hormone, both names reflecting its double function: regulation of
plasma osmolality and pressure.
The stimulation of AVP secretion is determined by elevation of plasma
osmolality (an increase as little as 1% is enough), reduction of plasma volume, but
also by acetylcholine, angiotensin II or rise of ambient temperature. The elevation of
both blood pressure and volume, reduction of plasma osmolality, noradrenalin, betaendorphins and decreasing external temperature inhibit AVP secretion.
In physiological point of view separate stimuli exist for osmolality and pressure
regulation in the secretion of AVP and also separate receptors in target organs:
- V1 receptors in blood vessels mediate vasoconstriction responsible for blood
pressure rise;
- V2 receptors in renal collecting tubules are involved in water retention, by
increasing free water flux from tubular lumen to interstitium. This flux
produces a rise of the urinary concentration and a decrease of the urinary
- V3 receptors in anterior pituitary: through them ADH is implicated in central
regulation of ACTH, enhancing the action of CRH to release ACTH.
The main antidiuretic action is realized via aquaporins, which act as water
channels and are intracellular organelles mediating rapid water transport across cell
membranes of collecting tubs according to osmotic gradient. Vasopressin regulates
directly the movement of intracytoplasmic aquaporin 2 to apical membrane of
collecting tubs, allowing water entrance into the cells.
Oxytocin secretion is stimulated by suckling, uterus dilatation, cervical
distension, acetylcholine, dopamine. In contrary, serotonin, alcohol and anxiety,
fever, pain act as inhibitors. Oxytocin has the role to stimulate pregnant uterus
contraction, especially at the end of pregnancy when uterine sensibility to oxytocin
may increase as much as 200-fold comparatively to a non pregnant uterus.
Estrogens increase, and progesterone reduces the sensitivity of the uterus for
oxytocin. The second physiological role of oxytocin is to stimulate milk ejection, and
data exist regarding its role as a behavioral modulator.
The synthetic preparation of oxytocin may be administered to induce
parturition in uterine atony or used in milk stasis in breast.


Diabetes Insipidus (DI)

Diabetes insipidus is a disease characterised by elimination of a large volume
of dilute, tasteless (insipid) and hypotonic urine. In physiological point of view
polyuria with dilute urine may be involved in two mechanisms in connection to AVP:
1. Central diabetes insipidus (hypothalamic or neurohypophyseal) the inability
to synthesize and/or release ADH.
2. Nephrogenic diabetes insipidus inappropriate renal response to ADH.
3. Gestational diabetes insipidus caused by excessive degradation of AVP by a
placental aminopetidase named oxitocinase or vasopressinase.
4. Primary polydipsic syndrome, characterised by the stimulation of thirst and
consequently by excessive liquid intake.
The etiology of central diabetes insipidus is:
1. Hereditary hereditary hypothalamic DI, autosomal dominant inheritance
onset in childhood, it appears to be due to a mutation in AVP gene, followed
by a premature apoptosis of magnocellular neurons. Wolframs syndrome or
DIDMOAD consists of DI associated to diabetes mellitus, optic atrophy and
deafness, may be transmitted autosomal recessive, dominant or
2. Tumoral solid or haematologic tumors: most frequently craniopharyngioma,
but suprasellar germinoma or pinealoma, as well as metastases of breast or
pulmonary tumors, or dissemination of lymphomas or leukemia.
3. Traumatic or postoperative: surgical interventions on pituitary sometimes may
injury axon terminations occurring transient DI, another time the lesion is in
hypothalamus and generates permanent DI.
4. Infiltrative histiocytosis, multifocal Hand-Schller-Christian disease,
sarcoidosis, Wegener granulomatosis etc.
5. Idiopathic it is now recognized that many cases of diabetes insipidus, that
were previously termed idiopathic and for which there was no specific
etiology, are probably due to lymphocytic infiltration of the neurohypophysis
on an autoimmune basis. X-rays may reveal enlargement of the pituitary stalk
as evidence of the lymphocytic invasion. There may be resolution of the
autoimmune response with time and the stalk may return to its normal size,
but the diabetes insipidus is usually permanent.
6. Essential hypernatremia or adipsic DI- a rare variant of diabetes insipidus
involves an absent osmoreceptor function, but an intact baroreceptor function.
In this form of diabetes insipidus, patients do not sense thirst and, therefore,
do not drink water. This results in an elevation of serum osmolality.
7. Cerebral anoxia (cerebral death) complex dysfunctions of the central
nervous system and DI are associated.
8. Gestational DI - can occur in a patient with normal pituitary and renal function,
when the level of cysteine aminopeptidase (vasopressinase), produced by the
placenta, is extraordinarily higher than in normal pregnancy. There may be
other associated pathology with the latter disease such as preeclampsia, fatty
liver, and coagulopathies. Diabetes insipidus in this situation also abates
when the pregnancy ends and may not recur with subsequent pregnancies.

Clinical manifestations
The characteristic symptomatology is persistent polyuria associated with
polydipsia. In humans a 3-4 liter/day polyuria is well tolerated. The patient is
requested to record a liquid balance in order to determine the amount of polyuria,
which may achieve 20 liters/day. Nocturia is regulary present and may cause
chronice fatigue syndrome.
The elevation of plasma osmolality due to hypotonic polyuria stimulates the
thirst center causing dipsic behaviour changes and ingestion of large amount of
liquids (especially cold) to avoid dehydration. If the morphofunctional integrity of the
thirst center is compromised or liquid ingestion is not possible for some reasons
(unconsciousness, coma, anesthesia), then hypertonic dehydration will develope,
manifested by fever, circulatory insufficiency, coma and death.
The clinical picture is completed by the manifestations of basic disease: visual
defects, headache, weight loss etc. Symptomatology may develop suddenly or
Laboratory and paraclinical findings
If diuresis exceeds 50 ml/kg/day, and urine density is under 1010, a thirst test
or a dehydration test must be performed. Biochemical evaluation at baseline
generally does not show any important modifications, because most of patients
consume enough liquids to avoid dehydration.
Dehydration test (liquid deprivation test, thirst probe) requires a serious followup of urine (OsmU) and plasma (OsmP) osmolality but also of general state of the
patient in condition of liquid restriction requiring hospitalization in an endocrinologic
service. A normal liquid intake is allowed for 12 hours before the test is started, but
avoiding excessive coffee, tea, salt, protein ingestion and smoking is recommended.
The steps of this test are the following:
1. Body weight measurement at the beginning of the test and serum
sodium and plasma osmolality (OsmP) determination
2. Liquid intake is not allowed and urine volume (Vu), density (Du) and
osmolality (OsmU) is registered for every urine probe.
3. If two successive values of OsmU differs with less than 10% and the
patient has lost 2% of body weight, Na+, OsmP and plasma
vasopressin are measured.
4. Synthetic desmopressin (ddAVP), a synthetic ADH-analogue is
administered in dose of 10-20 mcg intranasal or 1-2 mcg sc.
5. Vu, Du and OsmU is followed-up continuously for other 2-4 hours and
at the end of the test OsmP is determined once again.
6. The test may last 18 hours, but if the patient loses weight more than
3%, the test is interrupted.


Figure 2. The interpretation of dehydration test

Interpretation (figure 2):
In a person without DI, urine osmolality during dehydration test
increases (may achieve > 800 mOsm/kg H2O) and after ddAVP
administration OsmU elevation will be less than 10% of the value
prior to the administration.
In the complete form of central DI blood becomes hyperosmolar,
without OsmU elevation during liquid restriction, but an evident rise
of OmsU (generally above 50%) presents after ddAVP
In nephrogenic DI an increase of urine concentration capacity does
not exist after administration of ddAVP.
Measurements of plasma vasopressin by clinically available assays may help
in distinguishing nephrogenic diabetes insipidus (in which the level will be
unequivocally elevated) from other causes of diabetes insipidus.
Difficulties in the evaluation of the test may appear in differentiating partial DI
from primary polydipsia. Primary polydipsia will be associated with a rise in urine
osmolality, usually to above 500 mosmol/kg, and no response to exogenous ADH
since endogenous release is intact. Maximum concentrating ability is frequently
impaired in this disorder, resulting in a maximum urine osmolality that may reach 500
to 600 mosmol/kg, as compared to 800 mosmol/kg or more in normal subjects. This
acquired defect appears to be due to two effects of chronic polydipsia and polyuria:
partial wash out the medullary interstitial gradient; and downregulation of ADH
If dehydration test establishes a central DI, a pituitary-hypothalamus MRI must
be performed. Normally, posterior pituitary appears as a bright spot in T1-weighted
images which is missing in DI. The imagistic exploration may also reveal thickening
of pituitary stalk in infiltrative diseases or tumoral processes of this region.

Differential diagnosis
The syndrome of polyuria and polydipsia may appear as a consequence of
osmotic diuresis determined by glucosuria in diabetes mellitus or by excessive
urea excretion in hyperproteic diets.
Central DI must be differentiated from:
1. Nephrogenic DI, characterized by a reduced urine concentration capacity
as a consequence of a resistance to ADH, destruction of medullary interstitium or
reduction of NaCl reabsorption in Henles loop.
The hereditary form is caused by mutations of V2 receptors gene (Xlinked heterosomal recessive inheritance) or of the aquaporine 2 gene
(autosomal recessive inheritance). Contrary to the hereditary form of
central DI, these diseases manifest at birth with polyuria, fever,
constipation, vomiting, hypernatremia.
The aquired forms appear in:
Kidney diseases involving renal parenchyma: pyelonephritis,
polycystic renal disease, drepanocytosis, renal infarctions,
Reduced synthesis and/or function of aquaporine 2 as a
consequence of the inadequate binding of ADH to V2 receptors.
It can be described after administration of lithium carbonate,
demeclocycline, but also in hypercalcaemia and potassium
2. Primary polydipsia is characterized by a primary increase in water intake
and may develop:
in some psychiatric diseases such as schizophrenia, mania, obsessivecompulsive disorders it is named psychogenic polydipsia;
as a consequence of altered control of thirst osmoregulation dypsogenic DI mostly is idiopathic, but it may develop secondary to
multiple sclerosis, tubercular meningitis, trauma or tumors.

Clinical course, complications and prognosis.

A correct diagnosis and adequate treatment result in an excellent prognosis of
DI. Rarely, a urinary bladder hypertrophy or a secondary hydroureter may develop.
In case of a tumoral or infiltrative pathology, the prognosis and outcome of DI
are determined by the main disease.
A particular course is described in posttraumatic DI or after surgical
interventions on the hypothalamo-pituitary region. In this context DI may be:
- transient with sudden postoperative onset and short duration (a few days);
- persistent or permanent same onset but persists for months, years or an
undefined period;
- -triphasic evolution in pituitary stalk sections (fig. 3). Initial axonal shock
inhibits the release of any vasopressin, and there is a period of diabetes
insipidus that lasts for 5 to 10 days. Then, the severed axons in the posterior
pituitary become necrotic and there is uncontrolled release of vasopressin. If
excess fluid is administered during this time, the syndrome of
inappropriate antidiuretic hormone secretion is produced with hyponatremia.
This lasts for 5 to 10 days until all of the residual vasopressin leaks from the
axon terminals and there is a return of diabetes insipidus.

Figure 3. Triphasic evolution of posttraumatic DI

It is mandatory to treat the main cause of the disease. The access to water
should not be restricted, because most of the patients have intact thirst center and
the adequate liquid intake prevents dehydration.
The elective medication of central DI is a vasopressin analogue named
desmopressin (desamino, D-8 arginine vasopressin; ddAVP). Removal of amine at
position 1 increases the half-life (T1/2) of the compound and the replacement of Larginine at 8 position with D-arginine reduces markedly the pressor activity.
Consequently, the agent is highly selective for the V2 receptors and is about 2000
times more specific for antidiuresis than is the natural ADH. The therapeutic
response presents a great interindividual variability.
This medication may be administered:
- per os (tablets of 0.1 or 0.2 mg for 2-3 times/day) the effect appears within
30-60 minutes and it lasts for 8 hours,
- sublingual 60 or 120 micrograms, 3 times per day;
- intranasal instillation 10-20 micrograms for 2 times per day;
- parenteral solution ampulle of 1 ml with 4 mcg ddAVP/ml subcutaneous
(SC), intravenous (IV) or intramuscular (IM); it is 5-20 times more potent than
the intranasally administered dose. It is administered to unconscious patients
or in the perioperativ period.
Adjuvant medication is efficient only in partial forms where hypothalamic
reserve of ADH secreting neurons is conserved and these agents prolong the action
of vasopressin or the release of vasopressin:
- Chlorpropamide sulphonylurea derivate 250-500 mg/day with prudence to
elderly and children due to hypoglycemic effect;
- Carbamazepine (200-600 mg/day);
- Clofibrate (2-3 g/day);

Indomethacin 100 mg/day - enhances the ADH effect in the kidneys by

inhibiting the intrarenal prostaglandine synthesis.
In nephrogenic DI, besides the low-sodium diet, hydrochlorothiazide (50-100
mg/day) may be used with or without amiloride, a potassium-sparing diuretic to
prevent hypokalemia.
The Syndrome of Inappropriate Secretion of ADH (SIADH)
SIADH must be presumed in any patient presenting:
- Hyponatremia
- Plasma hypo-osmolality (reduced OsmP)
- Urine osmolality above 100 mOsm/kg;
- Urine Na above 40 mEq/;
- Normal acid-base equilibrium and potassium but sometimes decreased
plasma uric acid.
Excessive release of ADH leads to hyponatremia by exaggerate water
reabsorption in renal collecting tubules.
The principal causes of inappropriate secretion of AVP, in absence of
hypothyroidism and adrenal insufficiency are classified in four main categories:
1. Ectopic production of ADH, generally tumoral, in:
o carcinomas: bronchogenic, duodenal, pancreatic, uterine,
urinary bladder or prostate;
o thymomas;
o mesotheliomas
o lymphomas and leukemia.
2. Drug-induced:
o excessive administration of vasopressin, inclusive analogues
and oxytocin;
o chlorpropamide, carbamazepine, clofibrate;
o selective serotonin reuptake inhibitors;
o tricyclic antidepressants;
o monoamine oxidase inhibitors;
o Ecstasy;
o cisplatin, cyclophosphamide.
3. Lesions or disruption of the baroreceptor system including a series of
receptors in the chest and synapses in the brain.
o Pulmonary disorders: tuberculosis, empyema, pneumonia,
fungal infection, positive pressure ventilation.
o CNS disorders: infections, trauma, hemorrhage, degenerative or
inflammatory diseases.
4. Other etiologies:
o Acquired immune deficiency syndrome (AIDS);
o prolonged strenuous exercise marathon running: increase
secretion of vasopressin and excessive intake of hypotonic fluid;
o acute psychosis;
o hereditary form rare, as a consequence of gain of function
mutations in V2 receptor gene.


Clinical manifestations can be discrete or absent in mild forms (Na above 120
mEq/L). Nausea, vomiting, confusion, irritability, anorexia may appear. In severe
forms (Na below 110 mEq/L) the neurological involvement is constantly present:
areflexia, lethargy, epileptiform convulsions, but cardiac arrhythmias or coma by
water intoxication are also described.
In chronic forms the treatment requires liquid restriction and graduated
correction of hyponatremia (hypertonic saline solutions in association with loop
diuretics, such as Furosemid 20 mg are used), and administration of
Demeclocycline, a tetracycline derivate, in doses of 600-1200 mg/day or a V1 and V2
receptor antagonists, Conivaptan, (intravenous infusion, in hospitalized persons).
Tolvaptan is a selective V2 receptor antagonist that can be administered orally and is
approved to treat severe hyponatremia (serum Na < 125 mEq/L).
Hyponatremia must be corrected slowly (with approximately 10 mEq/L during
24 hours), because it carries a risk of osmotic demyelination. Brain shrinkage is
thought to be the cause of a syndrome of myelinolysis which was first described in
the ponshence the term central pontine myelinolysis. The syndrome consists of
neurologic deterioration over several days. Eventually, these patients may develop
pseudobulbar palsy with difficulty in swallowing and dysarthria, even leading to
quadriparesis. Recovery from this syndrome is variable.
Adenophypophyseal hormones
Anterior pituitary consists of a series of endocrine cells, classified in the past
in acidophils, basophils, and chromophobe cells. Immunohistochemical techniques
now permit classification of pituitary cells by their specific secretory product:
- somatotrophs approximately 50%, synthesize and secrete GH;
- lactotrophs, 10-25%, secrete PRL;
- corticotrophs, 15-25%, synthesize pro-opio-melanocortin (POMC);
- gonadotrophs, 10-25%, synthesize LH and FSH;
- thyrotrophs, 3-5%, secrete TSH,
- folliculostellate cells being considered nonsecreting cells.
The morphogenesis of anterior pituitary and the development of different type
of cells involve sequential expression of genes codifying various transcriptional
factors. Their role in pituitary development was elucidated by the description of
inactivating mutations determining hereditary syndromes of isolate or multiple
pituitary insufficiency (the lack of synthesis and/or secretion of one or more pituitary
tropins). For example, Pit1 transcriptional factor binds to a specific DNA segment
and determine the development and normal function of somatotroph, lactotroph and
thyreotroph cells. If mutation of the gene for this transcriptional factor occurs, loss of
these cells and consecutive hormonal deficiency of GH, PRL and TSH are
In biochemical point of view adenopituitary hormones may be:
- peptides: ACTH and relative peptides, GH and PRL;
- glycoproteins: TSH, LH, FSH.


ACTH (adrenocorticotropine hormone)

It is a 39-aminoacid peptide hormone, synthesized in corticotroph cells from a
common precursor POMC (241 aminoacids) with other peptides:
- amino terminal peptide;
- Joining peptide (JP);
- -lipotropin (-LPH).
The role of other peptides secreted simultaneously with ACTH was also
described. Thus -LPH, clivated in -lipotropin and -endorphin, stimulates
melanocytes and may contribute to the hyperpigmentation that appears with POMC
release. ACTH may be clivated in CLIP peptide (corticotropin-like intermediate lobe
peptide) and MSH (melanocyte-stimulating hormone).
The half-life of ACTH is very short, less than 10 minutes, and its secretion is
discrete pulsatile. The bioactive segment of ACTH consists of the first 18
aminoacids. In contrary a synthetic analogue containing the first 24 aminoacids
(cosyntropin) has a longer half-life than ACTH and it is used in practice to investigate
the function of adrenal cortex.
ACTH has the role to maintain the structure, shape and function of adrenal
cortex. It stimulates the secretion of cortisol, androgens and to a less degreee
mineralocorticoids in the adrenal cortex, through cAMP.
The secretion of ACTH has a circadian biorythm starting at about 4:00 AM
and achieving a peak at 7:00 AM, with a nocturnal narrow. Pulsatile secretion of
cortisol follows that of ACTH with a 5-10 minutes shift.
The regulation of ACTH is realized by:
- neurogen pathway mainly by CRH, the hypothalamic hormone which
assures circadian secretion but is activated by stress (physical trauma; psychic depression, anxiety; chemical hypoxia, acute
hypoglycaemia etc). AVP augments the efect of CRH.
- through negative feedback of peripheral cortisol or synthetic
glucocorticoid preparations by double effect: one directly on
corticotroph cells and one on hypothalamus. ACTH can supress its
own secretion (short feedback).
The ACTH level is measured by RIA and IRMA (immunoradiometric) assays,
the normal ACTH ranges between 8-52 pg/ml at 8:00 AM, and the evaluation of
plasma cortisol is required for a correct interpretation.
GH (growth hormone, STH, somatotroph hormone)
Somatotroph cells are the most numerous cells in the anterior pituitary, they
synthesize and secrete GH, a peptide made of 191 aminoacids and containing two
intramolecular disulphide bridges.
The half-life of GH is 20-50 minutes. The GH receptors located both in liver
and tissues are of transmembrane type, being similar with PRL or cytokine
receptors. Inactivating mutations in genes codifying these receptors cause Laron
dwarfism, characterized by resistance to GH action. An antagonist of GH receptors
(pegvisomant) is used in the treatment of acromegaly.
The major function of GH is to promote growth, a function which is realised in
the main part through IGF-1 (Insulin-like Growth Factor 1) known also as
somatomedin C. It circulates in the blood coupled to a high-affinity protein, IGFBP
(IGF binding protein) which influence the bioactivity of IGF-1.

The metabolic effects of GH:

- Protein metabolism: via IGF-1, GH increases protein synthesis by
enhancing the intracellular transport of aminoacids, stimulating directly
the transcription and translation of mRNA, simultaneusly with the
reduction of protein catabolism.
- Lipid metabolism stimulate lipolysis, rise of free-fatty-acids (AGL) and
plasma ketone bodies independent action from IGF-1.
- Carbohydrate metabolism increases peripheral resistance to insulin
and induces hyperglycemia and hyperinsulinism IGF-1 has an
inverse effect.
- Sodium and water retention independent from IGF-1.
The biologic effects of GH-IGF-1 axis are:
- to promote longitudinal growth in bones (before epiphysial closure) or
in width (perichondrial and periosteal); this is done by stimulating the
differentiation of prechondrocytes, the proliferation of chondrocytes and
by favouring osteogenesis.
- to stimulate calcitriol synthesis, promoting a positive calcium balance;
- to promote growth of the visceral organs (liver, spleen, thymus, thyroid)
but also the heart or tongue;
- to increase glomerular filtration;
- in derm: it stimulates hair growth, hypertrophy and hyperplasia of sweat
glands, derm thickening.
GH has a pulsatile secretion with a peak at night, immediately after sleep
onset. The GH secretory rate decreases by age, in adults reaching about 15% of the
pubertal value.
The regulation of GH secretion is realised by hypothalamic hormones: GHRH
and somatostatin, being integrated in a complex system of metabolic, hormonal and
neural factors.
Non-GHRH secretagogues act to release GH, not through the GHRH
receptor, but through a separate receptor, the growth hormone secretagogue
receptor (GHS-R). A number of synthetic secretagogues, both peptides and
nonpeptides, have been described. Ghrelin, a circulating peptide made by endocrine
cells in the stomach, is an endogenous ligand for GHS-R. Its location in the stomach
suggests a new mechanism for the regulation of the GH secretion.
The major physiologic, pharmacologic and pathologic factors that participate
in the regulation of GH secretion are showed in table 2.
Table 2. Factors affecting GH secretion
GH secretion

GH secretion


Elevated free fatty acids


Postprandial hyperglycaemia

Physical and psychologic stress


Relative hypoglycaemia
Insulin-induced hypoglycaemia
Hormons: ACTH, AVP, GHRH, estrogens,
alpha- adrenergic agonists (Clonidine),
dopamine agonists,
Beta-adrenergic antagonists (propranolol)
GABA agonists,
serotonin precursors
Potassium infusion, pyrogens (endotoxins)

Hormons: GH, somatostatin,

progesteron, glucorticoids
alfa-adrenergic antagonists
dopamine antagonists

Protein depletion


Anorexia nervosa

Hypo- and hyperthyroidism

Chronic renal failure

The measurement of plasma GH is performed by monoclonal or multiclonal

RIA or with dual monoclonal IRMA assays. In children values at baseline may
achieve 7-10 ng/mL and increase in puberty; in adulthood they does not exceed 2-5
ng/dml. A more accurate exploration of GH biological activity is IGF-1 and its binding
proteins (such as IGFBP 3) determination with RIA assay. Their serum concentration
is however influenced by nutrition state: malnutrition, cashexia or sepsis; these
situations are characterised by reduced values. Dinamic tests are described in the
chapters regarding GH pathology.
PRL (prolactin)
This hormone is synthesized in pituitary lactotroph cells. PRL is a polypeptide
hormone containing 198 aminoacids and being structurally related to GH and
placental lactogen hormone (hLP). In some pituitary adenomas a simultaneous
secretion of GH and PRL in the same cell is described as well. In the last months of
pregnancy and first postnatal months an evident hyperplasia of lactotroph cells
mediated by estrogens develops. A large precursor molecule secreted concomitently
may be responsable for 8-20% of the PRL imunoreactivity in healthy persons or in
those with pituitary tumors. The secretion of PRL is pulsatile, the most ample
pulsations occuring during sleep, especially in REM phase. Maximal plasma level is
observed between 4:00-6:00 AM. The half-life of PRL is 50 minutes.
PRL has the role to induce lactation in the postpartum period. During
pregnancy it prepares the mammary glands for milk secretion, along with other
hormones (estrogens, progesteron, cortisol, insulin, hLP). The reduction of estrogens
and progesterone immediately after delivery induces milk secretion. Although PRL
does not appear to play a physiologic role in the regulation of gonadal function,
hyperprolactinemia in humans leads to hypogonadism. In women, initially there is a
shortening of the luteal phase; subsequently, anovulation, oligomenorrhea or
amenorrhea, and infertility occur. In men, PRL excess leads to decreased testosterone synthesis and decreased spermatogenesis, which clinically present

as decreased libido, impotence, and infertility. The exact mechanisms of PRL

inhibition of gonadal function are unclear, but the principal one appears to be
alteration of hypothalamic-pituitary control of gonadotropin secretion.
PRL has also an immunomodulatory role, the extrapituitary synthesis of PRL
being located in T-lymphocytes.
Tabel 3. Factors affecting PRL secretion
PRL secretion

PRL secretion

Pregnancy, nursing,
nipple stimulation
Physical and psychologic stress
Hormons: TRH, estrogens, VIP
Dopamine antagonists(phenothiazines, haloperidol, risperidone
metoclopramide, reserpine, methyldopa, amoxapine, opioids)
Monoamine oxidase inhibitors
Cimetidine (intravenous)

Dopamine agonists
(levodopa, apomorphine,
bromocriptine, pergolid),

Pituitary tumors, pituitary stalk lesions, radiation


Spinal cord and chest wall lesions

Lymphocytic hypophysitis

Chronic renal failure, severe renal diseases

Pituitary destruction or


Hypothyroidism, Polycystic ovary syndrome

PRL secretion is controled by dopamine and TRH in hypothalamus. Contrary

to other pituitary hormones the control of PRL secretion is predominantly inhibitory,
which explains the appearance of hyperprolactinaemia as a main feature of the
syndrome of pituitary isolation due to surgical or traumatic section of the pituitary
stalk. A control also exists through internal negative feedback exerting by PRL on
dopaminergic neurons and a series of physiologic, pharmacologic and pathologic
factors influence PRL secretion table 3.
RIA, IRMA and ICMA assays measuring PRL level in basal conditions show
normal values between 10-20 ng/ml in women and 1-16 ng/ml in men.
TSH (thyrotropin, thyroid stimulating hormone)
It is a glycoprotein with two subunits: and . Alpha subunit contains 96
aminoacids The structure of the alpha subunit of TSH is identical to that of the other
glycoprotein molecules: LH, FSH and hCG (Human chorionic gonadotrophin). Beta30

subunit is responsable for the specificity of TSH action. The two subunits are
separately synthesized being codified by different genes, then they are assambled
and the heterodimer is than glycolised. Recombinant TSH is approved for use in
monitoring patients who have been treated for well-differentiated thyroid cancers.
The half-life of TSH is 50-60 minutes. It has a pulsatile secretion with a
reduced amplitude which does not create difficulties when hormonally assayed. It
has a circadian rhythm with a secretion peak registered at night. TSH circulates
without binding to any protein, and its receptors are found on thyrocytes. After
coupling adenilate cyclase is activated and enzymes implicated in thyroid hormone
synthesis are phosphorylated. TSH stimulates the iodine uptake by the thyroid cells
and also induces the thyroid hypertrophy and an increase in the vascularisation of
this gland.
The regulation of TSH secretion is realised partly in hypothalamus by
stimulation through TRH and inhibition by somatostatin and dopamine, and on the
other hand by the negative feed-back of peripheral thyroid hormones which act on
pituitary (short feed-back) and on hypothalamus (long feed-back).
The plasmatic measurement of TSH is realised with IRMA assay and its
normal range is 0.5-4.5 mU/L. TSH level is elevated immediately after birth, then it
remains constant during lifetime.
LH and FSH (pituitary gonadotroph hormones, luteinizing hormone and
follicle-stimulating hormone)
Similarly to TSH, both pituitary gonadotrophins are glycopeptides (synthesized
in one and the same cell), with two subunits and , the last assuring the specificity
of the action. Glycosilation is mandatory to maintain biological activity. Human
chorionic gonadotrophin (hCG) is structurally very similar with LH.
The half-life of LH is shorter (50 minutes) than that of FSH (220 minutes), and
consequently the secretional dinamics of LH is more rapid even if it is secreted by
the same cell.
LH and FSH bind to their own receptors on the ovary and testicle,
respectively, regulate gonadal function by stimulating the secretion of gonadal
steroids and gametogenesis.
In men LH binds to Leydig cells and stimulates testosterone synthesis.
Spermatozoa production requires both LH and FSH, respectively, the last being
coupled to its own receptors on Sertoli cells and seminiferous tubules cells.
In women the development of ovarian follicle is under FSH control (with
receptors on granulosa cells) but the synthesis of estrogens on this level has dual
control: FSH and LH. A sudden elevation of LH at the middle of menstrual cycle
(MC) induces ovulation and subsequently a continuous secretion of LH after
ovulation maintains an adequate secretion of progesterone in the lutheal phase.
Ovarian LH receptors are localised mainly on thecal cells of ovarian folllicles.
LH and FSH secretion is controlled by GnRH, which initiates puberty,
maintains basal secretion of LH and FSH, generates phasic release of
gonadotrophines necessary for ovulation. The secretion of LH and FSH is pulsatile
and ultradian (at about 90 minutes) under the influence of hypothalamic GnRH
pulsations. There are other factors involved in the regulation of hypothalamopituitary-gonadal axis (e.g. gonadal proteins with similar structure to TGF- and AMH
or MIF - anti mullerian hormone/mllerian-inhibiting factor):

Activine with the principal physiologic role to increase the sensibility

of ovarian granulosa cells to FSH;
- Follistatine, inhibine paracrine factors with inhibitory effect, especially
on FSH;
- Leptin, produced by adipocytes may determine gonadotrophine
suppression in caloric restriction.
The hypothalamo-pituitary-gonadal axis is activated during embrio-fetal period
but after birth pituitary gonadotrophines decrease and remain inhibited until puberty.
This supression is realised in the CNS by tonical inhibition of GnRH pulse generator;
pituitary gland maintains its sensibility to GnRH during the whole period. Puberty
coincides with the desinhibition of pulsatile secretion, reflected by nocturnal LH
elevation at first in boys and by the appearance of cyclic secretion of LH and FSH in
In adult women GnRH pulsatile frecvency varies during menstrual cycle.
GnRH stimulation, in combination with feedback regulation of ovarian hormones,
generates a cyclic secretion of LH and FSH (monthly biorhythm or circatrigintal) in
gonadotroph cells. During the menstrual cycle, estrogens provide a positive influence
on GnRH effects on LH and FSH secretion, and the rise in estrogen during the
follicular phase is the stimulus for the LH and FSH ovulatory surge. The reduction of
estrogens and progesterone in menopause is associated with the loss of their
inhibitory effect on gonadotrophines and consecutive elevation of LH and FSH.
In men the regulation of hypothalamo-pituitary-gonadal axis is more constant.
Testosterone has a negative feedback effect mainly on hypothalamus, the action
being mediated by the aromatisation of androgens into estrogens. In males a sudden
and dramatic decrease of androgens does not exist, as menopause in women, but a
progressive declination in testosterone synthesis with concomitant increase of LH
and FSH is described.
The measurement of LH and FSH is realised with RIA method, normal ranges
in men, and in follicular and lutheal phase in women being 5-25 mIU/mL for LH, and
1.5-15 mIU/mL for FSH. In women preovulatory LH achieves 60-100 mIU/mL and
FSH 60-80 mIU/mL.
Pituitary tumors
The most frequent etiology of intrasellar tumor mass is pituitary adenoma
(PA), a benign tumor risen from pituitary cells. Their origin is monoclonal, being
considerated true neoplasms on the base of aquired somatic mutation theory.
Numerous candidate genes in pituitary adenoma tumorigenesis exist. These tumors
may appear as a consequence of:
- activating mutations in genes such as: gsp (which codify alpha subunit
of protein G), PTTG (Pituitary tumor transforming gene), FGFR
(fibroblast growth factor receptor) etc.
- inactivating mutations in genes such as CDKN2A (cyclin dependent
kinase 2a).
Genetic syndromes with pituitary adenomas are:
1. MEN1 (Multiple Endocrine Neoplasia): syndrome caused by mutations
in MEN1 gene symptomatology: hyperparathyroidism, pituitary and
pancreatic tumors.

2. McCune Albright syndrome germinal mutations in gps gene

symptomatology: polyostotic fibrous dysplasia, GH and ACTH secreting
pituitary adenomas, premature puberty, dysmorphic syndrome and
pigmented skin patches.
3. Familial acromegaly unidentified gene yet, on 11q13 chromosome
4. Carney syndrome manifested as cardiac and skin myxomas,
acromegaly or Cushings disease.
In the pathogenesis of pituitary adenomas are implicated hereditary factors,
local hypothalamic factors (for example a rise in GHRH and CRH, activation of some
receptors or lose of dopaminergic inhibitory control), as well as pituitary factors (for
example the exacerbation of paracrine action of some growth factors and cytokines)
and environmental factors (estrogens, radiation) or factors related to the function of
target glands (peripheral glands deficiency thyroid, ovary and adrenal cortex).
The prevalence of pituitary adenomas, according to secretory types, varies
between 2 and 10 new cases per 100,000 inhabitants/year. Pituitary adenomas
represent about 15% of all intracranial neoplasms.
Adenomas are classified first of all according to their size in micro- (less than
1 cm) and macroadenomas (larger than 1 cm), respectively. The later can have
suprasellar extension or parasellar invasion.
Another classification of adenomas is based on their origins:
o lactotroph adenomas (prolactinomas): secrete PRL and have a
prevalence of 40%;
o somatotroph adenomas secrete GH and cause acromegaly or
gigantism (prevalence 10-15%);
o corticotroph adenomas, secrete ACTH and determine Cushings
disease (prevalence 10-15%);
o gonadotroph adenomas, secrete LH, FSH or alpha, beta subunits and
are clinically silent or determine hypogonadism (prevalence 15-20%);
o mammosomatotroph adenomas secrete PRL and GH;
o thyreotroph adenomas (TSH secreting pituitary adenoma)
hyperthyroidism (prevalence less than 1%).
There are also PA with plurihormonal secretion and nonfunctional adenomas,
such as oncocytoma or PA originated from folliculostellate cells.
Clinical manifestations
There are two major categories:
1. Endocrine syndrome pituitary deficiency (partial or total), diabetes
insipidus or syndrome of hypersecretion.
2. Neuro-ophthalmic syndrome:
- chronic, persistent, progressive headache, with retroorbital and bitemporal
localisation is met in pituitary macroadenoma by distension of sellar
diaphragm or bone invasion; may disappear when sellar diaphragm is
perforated but reappears when intracranial hypertension develops.
- acute headache accompanied by nausea, vomiting and alteration of
consciousness, appears in case of sudden growth of pituitary as a
consequence of infarction or hemorrhage inside a pituitary adenoma;
- optic chiasm syndrome with bitemporal hemianopia as a consequence of
nasal optic fiber compression at the optic chiasm level is the most frequent

visual field defect but other modifications of this type are also described,
related to tumor invasion and extension;
- visual impairment, scotomas, quadranopsies, uni- or bilateral sight loss,
stasis, papillar edema or retinal hemorrhages
- ptosis, diplopia, ophthalmoplegia, facial numbness caused by compression of
oculomotor nerve, palsy of IV, V and VI cranial nerves- in parasellar extension
of pituitary adenomas;
- temporal lobe epilepsy (uncinate seizures),
- anosmia, personality disturbances in case of frontal lobe involvement
- hypothalamic compression determines disturbances in temperature, sleep,
apetite (with obesity or cashexia) or thirst regulation, dysfunctions of
autonomous nervous system;
- rhinorea with cerebrospinal fluid in adenomas with inferior extension;
- hydrocephaly rare, in case of large, extensive tumors.
A pituitary tumor mass may also present as an accidental discovery, during a
cranial imagistic exploration for other reasons, and in this case the pituitary tumoral
mass is called incidentaloma.
Paraclinical investigations and laboratory
I. In case of clinically manifested endocrine syndrome (it is evaluated at every tumor
type) laboratory consists of plasma pituitary hormone levels determinations.
Hormonal hypersecretion is caused only by pituitary adenomas. Consequently, the
demonstration of hormonal hypersecretion identifies the sellar mass as a pituitary
adenoma and also identifies the type of adenoma. In the absence of clinical
manifestations the following screening tests became necesarry:
o A serum prolactin concentration >200 ng/mL generally identifies a
lactotroph adenoma; values that are between 20 and 200 ng/mL could
be due to a lactotroph adenoma or to any other sellar mass.
o IGF-1 level and GH during OGTT (oral glucose tolerance test) see
o Urinary free cortisol or plasma cortisol after inhibition with 1 mg
Dexamethasone see Cushings disease.
II. Imagistic investigations are mandatory for the positive diagnosis they
- Magnetic resonance imaging (MRI) is the single best imaging procedure for
most sellar masses, and there is usually no need to perform any other
imaging study. MRI shoud be focused on hypophyseo-hypothalamic system
(high resolution sections) and should be performed before and after
administration of contrast media agent with Gadolinium (Gadoliniumenhanced image).
- Computed tomography (CT) allows better visualisation of bone structures
sellar flour , clinoidal processes and if present, intratumoral calcifications.
- One can use positron emission tomography (PET), scintigraphy with
radioactive octreotid (octreoscan) or SPECT (single photon-emission
computed tomography).
- Sella turcica X-ray lateral incidence can evidentiate the enlargement of the
sella, wall erosion (lost continuity), double contour, dorsal wall verticalisation,
clinoidal hypertrophy. There are four grades in the development of a pituitary
tumor on Xray:

- I grade sella turcica with normal size, double contour

- II grade enlarged sella, with thin walls and posterior wall verticalisation;
III grade wall erosions;
- IV grade completely destroyed sella.
III. Neuro-ophthalmologic evaluation visual field examination, visual acuity, eyefundus examination and neurologic exam should be reccomended, especially in
pituitary macroadenomas with supra- or parasellar extension.
Differential diagnosis
There are several recognized causes of hyperplasia of the pituitary. These
may present as sellar masses and might be misdiagnosed as pituitary adenomas:
o Lactotroph hyperplasia during pregnancy,
o Thyrotroph and gonadotroph hyperplasia due to long-standing primary
hypothyroidism and primary hypogonadism, respectively,
o Somatotroph hyperplasia due to ectopic secretion of growth hormonereleasing hormone.
The differential diagnosis of pituitary adenomas is made with other pituitary
lesions or supra- and parasellar tumors:
o Benign tumors (craniopharyngioma, meningioma);
o Primary malignant tumors (germinal tumors, sarcomas, chordomas,
lymphomas), pituitary carcinoma is rare;
o Metastases to the hypothalamus and pituitary gland. They occur most
commonly with breast cancer in women and lung cancer in men,
o Cysts Rathke's cleft, arachnoid, and dermoid cysts can produce
sellar enlargement, possibly resulting in visual impairment, diabetes
insipidus, anterior pituitary hormonal deficiencies, and hydrocephalus.
o Arteriovenous fistulae of the cavernous sinus can cause modest
enlargement of the pituitary gland.
o Pituitary abscesses, which are rare, can occur in a normal or
pathologic pituitary glands
o Lymphocytic hypophysitis, sarcoidosis, histiocytosis.
Evolution, complications and treatment are individualised for every tumor
Etiology and pathogenesis
The PRL secreting adenoma is the most frequent pituitary tumor. It usually
develops in the lateral portions of the anterior hypophysis, but, with its slow growth, it
can occupy the whole sella turcica, with mass effect on the posterior and anterior
pituitary. The sex ratio for microprolactinomas proves a feminine dominance (20:1),
which is not present in macroprolactinomas. The most frequent age of diagnostic is
between 20 and 40 years of age.
The histopathologic examination describes cromophobe cells with secretory
granules in electronic microscopy (100-400nm, and rarely 400-800nm). These cells
stain positive for PRL in immunohistochemistry. There are also tumors with
combined secretion of PRL and ACTH, GH or TSH.


Clinical findings
In women the main signs and symptoms are: oligomenorrhea, bradimenorrhea, hypomenorrhea, primary or secondary amenorrhea, galactorrhea and
infertility. Especially at the debut we can also find metrorrhagia dysfunctional
uterine bleeding due to luteal insufficiency. Other signs are the decreased libido,
hot flashes, atrophic vaginitis. If left untreated, the hypogonadism (due to the
inhibition of the pulsatile GnRH secretion) can lead to osteopenia and osteoporosis.
In men, sexual dysfunction manifests itself by the decrease or disappearance
of the libido, erectile dysfunction (impotence, premature ejaculation, loss of the
erections). Its cause is unclear, because testosterone replacement may not reverse
it if hyperprolactinemia is not corrected. Male infertility accompanied by reduction in
sperm count is a less common initial complaint.
Both in men and women the pituitary tumor syndrome can be associated or it
can precede the endocrine symptoms (for reference see also the pituitary tumors).
Laboratory and paraclinical evaluation
The serum PRL levels are positively correlated with the size of the tumor and
the clinical findings. Values over 100 ng/ml suggest a microadenoma, while those
over 200 ng/ml are suggestive for a macroadenoma. The PRL evaluation can be
carried out independently to the moment of the day. Sleep, intense physical activity
or a hyperproteic food intake can all determine a slight elevation of the PRL level.
Levels between 20 and 40 ng/ml are usually considered functional hyperprolactinemias; those between 40-100ng/ml appear in case of hypothalamic-pituitary
dysfunction. An elevated level needs to be confirmed by a second evaluation in order
to sustain the diagnostic of hyperprolactinemia. False positive or negative results are
possible (for example elevated values due to big PRL glycosylated fractions,
biologically inactive).
The evaluation of the other pituitary hormones is recommended: IGF-1, for
the exclusion of a combined secreting adenoma, but also TSH and fT4, plasmatic
cortisol for the exclusion of a pituitary failure.The pituitary gonadotropes are usually
within normal ranges because the hypogonadism is caused by the modification of
the GnRH regulation, but the plasmatic estradiol and testosterone are decreased.
The imaging evaluation and the neurologic and ophthalmologic consults are
necessary for the final diagnosis and the evaluation of the complications.
Differential diagnosis
The PRL secreting adenoma must be first of all differentiated from pituitary
hyperplasia and non-tumoral syndromes as well as from the para- and suprasellar
tumors for reference see also the pituitary tumors.
Hyperprolactinemia can also be caused by:
1. Physiologic factors, systemic and metabolic diseases (table 1.2.),
endocrine causes (hypothyroidism, hyperestrogenemia, Addisons disease
or polycystic ovary syndrome).
2. Pharmacological factors the list of medications causing hyperprolactinemia includes anesthetics, neuroleptics (prometazine, haloperidol, etc),
antidepressants (amitriptyline), antiepileptic (phenitoine), histamine
H2 antagonist (cymetidine), antihypertensive, dopamine receptor blockers
(metoclopramide), dopamine synthesis inhibitors, estrogens, opioids, TRH.

3. Hypothalamic or pituitary stalk syndrome: trauma, surgery affecting the

pituitary stalk; irradiation of the region, infiltrative disorders.
4. Unknown causes idiopathic.
Evolution, complications, prognosis
The great majority of microprolactinomas do not progress and under adequate
dopaminergic treatment 90% of them reduce their size or even disappear.
The lack of treatment for the hypogonadism can lead to osteoporosis and its
complications. The macroprolactinomas can extend laterally, inferior or superior,
causing complications like neurologic, ophthalmologic syndromes, CSF rhinorrhea,
hydrocephalus, diabetes insipidus.
The first line of treatment for the hyperprolactinemia caused by PRL secreting
adenoma is the dopamine agonists. They have the effect of reducing the PRL level
regardless of its cause and they also reduce the secretion and size of the tumor.
There are various preparations among which:
Bromocriptine semisynthethic ergot derivate; the doses are 2.5 mg three
times a day (t.i.d.), with slow titration of the dose the initial dose mustnt be
higher than 1.25 mg, in the evening.
Cabergoline (Dostinex) has a longer half-life and it can be administered once
every 3-4 days or weekly. The usual dose is 0.5-1 mg twice a week. It is
better tolerated than bromocriptine.
Pergolide (Mesilate) it is 100 times more active than bromocriptine; the
usual dose is 50 g/day.
Quinagolide a nonergot dopamine agonist administered once a day in case
of intolerance or resistance to bromocriptine.
The most frequent side effects of dopamine agonists are: nausea, postural
hypotension and somnolence. Other rare side effects are depression, psychosis,
nasal congestion, Raynaud phenomenon, constipation, alcohol intolerance,
arrhythmias, valvular disease (at high doses of cabergoline and pergolide), liver
Bomocriptine was the first effective medical therapy for pituitary adenomas;
however, cabergoline is more potent, much longer acting, and better tolerated.
Cabergoline has, therefore, become the dopamine agonist of choice in the therapy of
For the microprolactinomas the treatment with dopamine agonist must be
administered 2-3 years, in doses that assure a PRL level within normal range. For
the macroprolactinomas the therapy is usually longer. Current studies suggest that
30% to 40% of patients with micro- and macroadenomas will remain in long-term
remission after withdrawal of cabergoline therapy of 2 to 3 years duration provided
that they have normalization of PRL levels and tumor shrinkage.
In women with macroprolactinomas, replacement estrogen therapy, if
necessary, should be initiated only after PRL hypersecretion has been controlled
by dopamine agonist therapy since estrogen stimulates lactotroph hyperplasia and
may increase tumor size.
Transsphenoidal surgery for the excision of the tumor is indicated only in case
of resistance to the medications mentioned above or in case of big macroprolactinomas (> 3cm) when the patient desires a pregnancy.

The radiation therapy is only indicated after surgery for recurrence preventions, due to its lack of supplemental benefice over the medication.
In case of pregnancy the cessation of the treatment is recommended along
with a periodic check-up of the visual field. Macroprolactinomas have a 20% risk of
growing in this period, in which case it is recommended to restart medical treatment.
Acromegaly and gigantism
Etiology and pathogenesis
These diseases are caused by the exaggerate secretion of GH and have a
prevalence of 40-70/1 million people, with even sex distribution and a maximal
incidence in the 4th decade
The disease can be caused by:
1. GH excess
GH secreting pituitary adenoma isolated, combined GH and PRL
secreting, or plurihormonal
Genetic syndromes McCune Albright, MEN 1, familial
acromegaly, Carney syndrome
Extrapituitary GH secretion lymphomas or pancreatic endocrine
2. GHRH excess always accompanied by a hyperplasia of the somatotroph
pituitary cells
Hamartomas or other hypothalamic tumors
Peripheral tumors (ectopic secretion) small cell lung carcinoma,
carcinoid bronchial tumors, pheochromocytoma, etc.
The GH secreting adenoma is the most frequent cause of acromegaly, the
great majority of them being macroadenomas at the time of diagnosis.
Clinical findings
The clinical findings are different depending of the age of onset. Before
puberty, the growth plates are opened and a linear growth can be observed with
consequent gigantism. Once the growth plates close, the acromegaly develops with
extremity and visceral hypertrophy. The symptoms usually develop slowly, with a 5
to 10 years delay of the diagnosis. At diagnosis, most patients have classic
manifestations, and acral and soft tissue changes are always present.
The main signs and symptoms are the following:
Signs determined by the GH excess:
1. Hypertrophy of the hand, feet, tongue and vocal chords. The hands and
feet are large, thickened, and bulky. Theres a frequent change in shoe
size, gloves, rings; the voice changes its tonality.
2. Thickness of the skin, with increased oiliness and sweating, acne,
acanthosis nigricans, cutis verticis gyrata.
3. A gradually change of the physiognomy through the appearance of frontal
bossing (frontal hyperostosis), prominence of the supraorbital ridges,
zygomatic hypertrophy, a massive nasal pyramid, downward and forward
growth of the mandible, which leads to prognathism and widely spaced
teeth (dental diastema), lip and ear lobe hypertrophy.
4. Musculo-skeletal signs paresthesia of the limbs, arthralgia, osteoarthritis,
carpal tunnel syndrome, proximal myopathy, jaw arthritis.


5. Respiratory and pulmonary signs narcolepsy, sleep apnea syndrome

(both peripheral and central).
6. Visceromegaly and increased risk for colorectal polyps with malign
7. Cardiovascular signs left ventricle hypertrophy, arterial hypertension,
cardiac failure, cardiomyopathy.
8. Systemic manifestations: hyperhidrosis, heat intolerance, lethargy, fatigue,
and increased sleep requirement.
9. Metabolic and endocrine signs
o Diabetes mellitus or impaired glucose tolerance, hyperinsulinemia with
insulin resistance,
o Decreased renin and increased aldosterone,
o Thyroid hypertrophy,
o Hypercalciuria,
o Hypertriglyceridemia,
o Macrogenitosomia, but decreased libido and impotence in men,
menstrual disturbances, galactorrhea and hirsutism in women,
o Hyperparathyroidism and pancreatic tumors in MEN 1.
Signs caused by the tumoral mass for reference see the pituitary tumor
Signs of hormonal insufficiency.

Laboratory and paraclinical investigations

The best screening test for acromegaly is the IGF-1 level. Patients with
acromegaly have higher levels than normal subjects of the same age and sex. Unlike
the GH level, the IGF-1 values do not variate with food intake or sleep and reflect the
GH secretion for the past few days or weeks.
In case of IGF-1 equivocal value, but also for confirmation of the diagnosis it
is imperative to perform a glucose tolerance test. In normal subjects, after ingestion
of 75 g glucose administered orally the GH level falls beneath 1ng/ml. This test has
also the advantage of unfolding carbohydrate metabolism disturbances which are
frequent in case of acromegaly.
Basal GH values are frequently between 2-10 ng/ml both in normal subjects
and patients with acromegaly. Therefore this test hasnt diagnostic value unless the
levels are very high (over 30 ng/ml).
Other dynamic tests seldomly used are:
TRH test 500 g i.v. with consequent GH determination after 20-30
minutes an increase of at least 50% in the GH level is seen only in
patients with acromegaly.
Dopamine agonist test in patients with acromegaly this medication has
an opposite effect compared with normal subjects it inhibits the GH
Other hormonal evaluations are also necessary: PRL (for the diagnosis of a
combined secreting adenoma), gonadotropes, estradiol/testosterone, thyroid and
adrenal function in case of eventual hypopituitarism. Confirmation of the diagnosis
implies imaging evaluation and the neurologic and ophthalmologic exams are
necessary in order to diagnose the complications.


Differential diagnosis
The pituitary tumor must be differentiated from other intra- and parasellar
masses. The elevated basal GH level can be found in physiologic states like puberty,
pregnancy, intense physical activity, but also in some pathological states: liver or
renal failure, malnutrition.
The limb hypertrophy (especially of the hands) can be found in people doing
manual labor, obesity, primary amiloidosis, myxedema, hypertrophic pulmonary
osteoarthropathy (Pierre Marie Bamberger syndrome which appears most often in
case of lung tumors), pachydermoperiostosis (the hereditary form of the previous
finger clubbing) or in acromegaloidism, in which the physical features suggesting GH
excess appear with familial inheritance, but theres no tumor.
Evolution, complications, prognosis
Theres a slow evolution of the disease, but the complications are frequent:
neurologic, cardiovascular, metabolic and pulmonary. The risk for neoplasia is high,
especially in the colon. The mortality rate is increased; after age 45, the death rate
in acromegaly from cardiovascular and cerebrovascular atherosclerosis, respiratory
diseases, and colon cancer is two to four times that of the normal population.
The main objectives of the therapy should be: reduction or total excision of the
tumor, lowering the GH and IGF-1 secretion, prevention or correction of the
complication with preservation of the anterior and posterior pituitary function.
The first line of treatment is considered surgical resection of the tumor, with a
transsphenoidal approach if possible. The rate of recurrence is low for the patients
who have IGF-1 levels and dynamic test results similar with normal subjects.
If after surgery there are signs of GH excess, the medical treatment should be
started. It includes:
Somatostatin analogues with prolonged time of action (depot
preparations). They have the advantage of lowering the GH secretion and
sometimes reducing the size of the tumor (in 20-30% of the cases).
Frequent side effects include gastro-intestinal symptoms and the
development of gallstones. They can be administered in association with
o Sandostatin-LAR (octreotide) is a molecule containing the first 8
aminoacides of the natural somatostatin, built in microspheres with
prolonged release; it is administered i.m. 20-40 mg each 4 weeks.
o Lanreotide is a cyclic analogue of the octapeptide, administered
every 7-14 days, i.m. 30mg. There is also a subcutaneous
administration formula (Somatuline Gel), administered every 4
weeks in dose of 60-120 mg.
GH receptor antagonists synthetic analogs of GH which prevent it from
binding with its receptors. They have a lowering effect on the IGF-1 level,
but do not influence the GH level and can determine a slight increase in
tumor size. Side effects elevation of the liver enzymes and lipodystrophy
and pain at the injection site.
o Pegvisomant is administered in daily s.c. injections, in dose of 1030 mg/day.
Dopamine agonists

o Bromocriptine (20 mg) and cabergoline (0.5 mg/day) can reduce the
GH secretion in adenoma with combined secretion, but the doses
are higher than those used in prolactinomas.
Radiation therapy is used as an adjuvant method in case the other options failed.
Conventional radiotherapy 40-50 Gy administered in 5 weeks has the
disadvantage of hypopituitarism.
Proton beam therapy.
Gamma knife surgery.
Cushings disease
Etiology and pathogenesis
Cushings disease is defined as ACTH excess due to a pituitary adenoma
which will determine bilateral adrenal hyperplasia and non-suppressible cortisol
secretion. Most frequently its a basophile or cromophobe microadenoma. Electronic
microscopy shows secretory granules of 200-700nm in the tumoral cells. The
adrenal glands are big 12-24g (normal range 8-10g).
Cushings disease is more frequent in women with a sex ratio of 8:1 in favor of
them. In contrast, the ectopic ACTH syndrome occurs more commonly in men
(male:female ratio of 3:1). The usual age range is 20 to 40 years, but Cushing
disease has been reported in infants and in patients over 70.
The term Cushing syndrome is reserved for other causes of hypercorticism.
Cushings syndrome etiology:

ACTH dependent
ACTH secreting pituitary adenoma
ACTH secreting tumors ectopic secretion causes 15-20% of the Cushing
Hypothalamic CRH excess Itenko Cushing disease
Ectopic paraneoplastic CRH secretion, especially in carcinoid tumors.


ACTH independent
Benign adrenal tumors (adenomas) causing 10% of the Cushing syndromes
Adrenal carcinomas rare
Micronodular adrenal hyperplasia
Macronodular adrenal hyperplasia
Ectopic cortisol secretion in ovarian or testicular tumors extremely rare.


Pseudo-Cushing in chronic alcohol ingestion, depressive psychosis.

In medical practice the most frequent cause of Cushing syndrome is the
administration of ACTH or glucocorticoids preparations; usually the patient doesnt
have endocrine disturbances (Iatrogenic Cushing syndrome).
Clinical findings
The signs and symptoms of Cushings disease include both the pituitary tumor
syndrome (rarely seen due to the small tumor size) and the symptoms caused by the
excess cortisol and androgens. The last ones include:

Weight increase, with central obesity, with special distribution on the trunk
and face (moon-like facies), abdominal, interscapular (buffalos neck)
Thin skin, with capillary fragility, purple striae (thighs, abdomen, axillae),
bruises, skin ulcerations, acne, facial hyperemia, fungal skin infections,
slow healing of skin lesions
Inferior limb edema
Hypotrophy and hypotonia of the proximal muscular groups
Arterial hypertension
Impaired glucose tolerance or diabetes mellitus
Osteopenia or osteoporosis with vertebral or fragility fractures, avascular
necrosis of the femoral head
Hyperpigmentation and hypokalemia are seldomly seen (<10% of patients)
or never in Cushings disease. They are characteristic for the ectopic
ACTH secretion.
Bipolar psychosis
Secondary amenorrhea, hirsutism, erectile dysfunctions
Leucocytosis, lymphopenia, eosinopenia, a fall of the immunity, frequent
Growth arrest in children.

Differential diagnosis
First of all it must be differentiated from the reactive hypercorticism seen in
obesity, pregnancy or professional athletes. Cushing syndrome must be also
differentiated from the primary glucocorticoid resistance.
Evolution, complications, prognosis
Without treatment the evolution is with aggravation and death. The most
frequent complications are cardiovascular due to arterial hypertension, embolic
strokes, infections, fractures especially in the vertebrae and wide bones, steroid
diabetes complications.
If bilateral adrenalectomy is performed Nelson syndrome can occur growth
of the pituitary tumor with neurologic and ophthalmologic syndrome caused by the
supra- and parasellar extension; clinical findings include intense hyperpigmentation,
adrenal failure; laboratory findings include extremely high ACTH levels (due to lack
of negative feedback from glucocorticoids). This syndrome can be prevented with
pituitary radiation and adequate glucocorticoid substitution. Its a rare complication
nowadays considering the diagnostic and therapeutic means available.
Surgery through transsphenoidal approach is the treatment of choice for
Cushings disease. The recurrence rate is higher in case of macroadenomas. If
surgery is not successful in removing the ACTH source, reintervention, conventional
radiotherapy and stereotactic radiation are the next options. The last two can cause
pituitary failure in time.
Medical treatment is indicated just as adjuvant therapy or in case of
inoperable tumors. It acts through inhibition of various steps of steroidogenesis.
Their use has replaced the bilateral adrenalectomy employed before in case the
surgery didnt achieve a satisfying lowering of cortisol secretion.
The medication available:

Ketoconazole 600-1200mg/day, antifungal imidazol derivative, with

liver toxicity
Metyrapone 2-4g/day, inhibits 11 hydroxylase
O,p-DDD Mitotane 3-6g/day, has cytotoxic effects results in
adrenal atrophy predominantly of the zonae fasciculata and reticularis.
Aminoglutetimide 250mg t.i.d., less toxic
Cyproheptadine 24mg/day for the hypothalamic form
Etomidate i.v. route, 0.3mg/kg/hr.
TSH secreting pituitary adenoma

It represents one of the most rare pituitary masses (under 1%), being
responsible for less than 1% of the total causes of hyperthyroidism. Nevertheless,
the TSH secreting adenoma must be considered in the differential diagnosis of
hyperthyroidism with diffuse goiter, in absence of extrathyroid signs of Graves
disease. Almost 25% of TSH secreting tumors have a combined secretion
(especially GH and PRL, rarely gonadotropes).
Besides the thyreotoxicosis (fore reference see also Graves disease), the
pituitary tumor syndrome is often seen, with visual field defects. Menstrual
disturbances and galactorrhea can occur due to the secretion of PRL or to the
pituitary stalk syndrome.
The characteristic biochemical finding is the association of elevated thyroid
hormone levels (both the free fraction and total level) with improper high levels of
TSH (it can reach 500 mUI/ml). In 85% of patients the subunit of the glycoproteic
hormones is also elevated. The imaging evaluation (CT or preferably pituitary MRI) is
mandatory and usually shows a macroadenoma.
The differential diagnosis implies primarily the pituitary form of the thyroid
hormone resistance syndrome in which case the TSH is elevated and there are
clinical signs of hyperthyroidism, but also with the other forms of thyreotoxicosis.
The first line of treatment is surgery associated in case of inadequate
response with medical treatment: dopamine agonists or octreotide in doses similar
with those used in acromegaly. Radio-iodine therapy or thyrostatic drugs is not
recommended because the thyroid hormone inhibition can lead to increased
secretion of TSH and tumor size.
Gonadotropin-Secreting Pituitary Adenomas
Although many pituitary adenomas synthesise gonadotropins (especially
FSH) and their subunits, only a minority of these patients have elevated serum levels
of FSH or LH. The majority of these tumors produce FSH and the alpha subunit.
Gonadotropin-secreting pituitary adenomas are usually large chromophobe
adenomas presenting with visual impairment. Most patients have hypogonadism and
many have panhypopituitarism. Hormonal evaluation reveals elevated FSH in some
patients accompanied by normal LH values. Basal levels of the alpha subunit may
also be elevated.
The presence of elevation of both FSH and LH should suggest primary
hypogonadism. TRH stimulation leads to an increase in FSH secretion or in LH- in
some patients.

Therapy for gonadotropin-secreting adenomas is surgical removal. Because

of their large size, adequate control of the tumor is difficult to achieve, and
radiotherapy is usually required.
Dopamine agonists, octreotide, GnRH superagonists and antagonists can be used.
Alpha Subunit-Secreting Pituitary Adenomas
Excessive quantities of the alpha subunit of the glycoprotein pituitary
hormones have been observed in association with the hypersecretion of many
anterior pituitary hormones (TSH, GH, PRL, LH, FSH). However, pure alpha subunit
hypersecretion has been identified in several patients with large invasive
chromophobe adenomas and partial panhypopituitarism. Thus, the determination of
the alpha subunit may be a useful marker in patients with presumed "nonfunctioning"
pituitary adenomas.
Nonfunctional Pituitary Adenomas
"Nonfunctional" chromophobe adenomas currently account for only about
10% of all pituitary adenomas. These tumors are usually large when the diagnosis is
established; headache and visual field defects are the usual presenting symptoms.
However, endocrine manifestations are usually present for months to years before
the diagnosis is made, with gonadotropin deficiency being the most common initial
symptom. Hypothyroidism and hypoadrenalism are also common, but the symptoms
are subtle and may be missed.
Because these tumors are generally large, both surgery and radiation therapy
are usually required to prevent tumor progression or recurrence. In the absence of
an endocrine index of tumor hypersecretion such as PRL excess, serial scans at
yearly intervals are required to assess the response to therapy and to detect
possible recurrence.
The small pituitary adenomas, discovered incidentally, without pituitary failure
can be monitored by imaging techniques annually, without the therapeutic methods
described above.
Pituitary failure (PF) - Hypopituitarism
Etiology and pathogenesis
The absence or the decrease in synthesis (due to pituitary destruction) and/or
the secretion (secondary to hypothalamic hormone deficit) of one or more pituitary
hormones determines pituitary failure. The causes of hypopituitarism are multiple:
1. Hereditary they determine isolated or combined hormonal deficits. Mutations
in the genes encoding important ontogenetic (for example HESX1, LHX3,
LHX4) or cell differentiation (Prop-1, Pit 1) transcription factors usually cause
combined deficits of variable severity. The most frequent mutation in
plurihormonal hypopituitarism is the Prop-1 gene mutation. It presents at birth
with GH and PRL deficit and later also with TSH, LH/FSH and sometimes
ACTH. In case of Pit 1 (POU1F1) gene mutations theres only a GH, TSH and
PRL deficit. A useful example for isolated pituitary hormonal deficit is the
hereditary form of GH deficit table 4.

Table 4. Hereditary GH deficits

Type Mechanism


Mutation type





Micro- deletions,
substitutions, nonsense mutations




Substitutions, splicing

-no response to treatment,
development of GH antibody
-Dysmorphic features: frontal
bossing, midfacial hypoplasia,
2nd dentition delay
-GH detectable at stimulation
-No GH antibody development




Splicing defects,
missense mutations


Recessive X

-at least an affected parent

-normal response to GH
-there can be also a TSH and
ACTH deficit
-association with

2. Anomalies in pituitary development pituitary hypoplasia or aplasia. Pituitary

hypoplasia can be associated with midline defects (corpus callosum
hypoplasia, septum pellucid anomalies) and optical nerve hypoplasia in case
of septo-optic dysplasia.
3. Tumoral causes pituitary or hypothalamic space occupying lesions which
determine hypopituitarism through the destruction of the gland:
Pituitary macroadenomas
Pituitary metastases
Parasellar dermoid cysts
Craniopharyngioma, hypothalamic hamartomas
Germinomas, gliomas, meningiomas
Lymphoma, leukemia.
4. Pituitary infarction
It can be secondary to vascular insufficiency occurring during coronary
artery bypass surgery in the elderly or diabetic people.
Sheehan syndrome, more frequent in the past, appears in the post-partum
period. It develops in the context of a massive bleeding during labor and
can be severe, recognized immediately post-partum with lethargy,
anorexia, important weight loss and lack of lactation. There are also mild
forms, sometimes recognized years after the trigger event. Diabetes
insipidus can be associated.
5. Pituitary apoplexy spontaneous infarction or hemorrhage in a pituitary tumor
usually an adenoma with impressive clinical findings: intense headache,
meningism, visual disturbances and signs of acute pituitary failure which can
lead to death if left untreated.
6. Infiltrative lesions: hemochromatosis, histiocytosis, sarcoidosis.
7. Autoimmune diseases autoimmune hypophysitis can be associated with
other endocrine disturbances of the same origin.

8. Post-traumatic it is associated with DI and other hypothalamic dysfunctions.

9. Iatrogenic after surgery or radiation therapy (in this case the pituitary failure
can become manifest many years after).
10. Infectious rare nowadays, frequent in the past after meningitis, tuberculosis,
syphilis, fungal infections.
11. Empty sella syndrome appears following a defect of the diaphragma sellae
which allows the herniation of a diverticulum, filled with CSF, in the sella
turcica. It can lead to pituitary failure.
Clinical findings
Adult pituitary failure:
Usually the patient is slightly overweight, with thin, smooth skin and multiple
facial wrinkles. Pubic and axillar hair is reduced or absent and a hypotrophy of
external genitalia can develop in time.
PF have an acute and also a chronic, insidious form; it can be severe or mild; it
can affect the secretion of one or more pituitary hormones.
The ACTH deficit manifests itself through the subsequent cortisol deficit
(central adrenal failure). The acute deficit can determine vascular shock and
The gonadotrope deficit is associated with gonadal insufficiency and infertility.
The GH deficit causes asthenia, muscular mass loss and increased adipose
tissue, especially central.
The TSH deficit is associated with clinical signs of hypothyroidism.
The PRL deficit doesnt cause any clinical signs besides lack of lactation postpartum.

Pituitary failure in children

The ACTH and TSH deficit have the same clinical signs as for the adult.
The isolated childhood GH deficit manifests with short stature (described after
2 years of age, at birth the stature is usually normal) with more than 3 SD
deficit and its called pituitary dwarfism. The final height without treatment
reaches 130-140cm, with a growth velocity reduced to 4-5 cm/year. Clinical
o Thin, pale, dry skin,
o Overweight,
o Lack of muscular mass, hypotonia,
o Acromicria,
o Infanto-senescent facies childish with wrinkles, orthodontic
o High pitched voice,
o Microphalus can be seen in boys (<2 cm at birth) especially if there is
also a gonadotrope deficiency;delayed puberty is described in both sexes,
o IQ is not affected, but the behavior is childish with inferiority complexes.

Laboratory and paraclinical findings

Blood analysis can reveal anemia (caused by the combined deficit of androgen,
GH and thyroid hormones), hypoglycemia, low sodium (without hyperkalemia), high
LDL cholesterol. Theres also a decrease in bone mineral density. The differential
diagnosis of neo-natal hypoglycemia must take into account the congenital pituitary
failure as well!

In the case of a suspected pituitary failure each hormone must be evaluated,

because the signs can be absent.
1. The ACTH deficit is certain if the 8 A.M. plasma cortisol is below 3 g/dl (83
nmol/l), normal range 5-25g/dl (138-690nmol/l), in 2 different blood samples
and the ACTH determined at the same time is normal or low (normal range 852 pg/ml). An 8 A.M. plasma cortisol 18 g/dl (497nmol/l) indicates a
sufficient ACTH secretion. Values in the range 3-18 g/dl need to be
investigated by:
Insulin tolerance test 0.05-0.15 U/kg insulin is administered i.v. and
plasma cortisol is measured at -30, 0, 30, 60, 90 minutes. In normal
subjects, if the glucose level reaches 50mg/dl, the cortisol should rise to
>18 g/dl or with 7 g above the basal level.
Metyrapone test 750 mg every 4 hours, 24 hours. In normal persons the
8 A.M. plasma cortisol determined the next day should be <7 g/dl
(172nmol/l) and 11-deoxycortisol 10 g/dl (289nmol/l).
ACTH (Cortrosyn) stimulation test 250 g i.v. or i.m. In normal subjects
the plasma cortisol 60 minutes after rises >18 g/dl.
2. The TSH sufficient secretion is evidenced through the fT4 level; many patients
with central hypothyroidism have normal or slightly reduced TSH levels. A
normal TSH value does not exclude central hypothyroidism in patients with
hypothalamic-pituitary suspected disease. The TRH test is negative in the
pituitary form and positive, with a late response in the hypothalamic form.
3. The gonadotroph deficit needs a different approach depending on the sex and
In men testosterone level in the morning (8-10 A.M.) low levels in 2
different samples with normal or reduced LH indicates pituitary failure.
In women with normal menstrual cycles theres no need for further
investigations, proving a normal hypothalamic-pituitary function.
In case of amenorrhea or bradymenorrhea, estradiol and LH, FSH
levels can indicate pituitary failure if E2 is low and FSH and LH are not
4. The GH deficit is investigated through:
IGF-1 and IGFBP3 levels are low in pituitary failure. The levels must be
adjusted for age, sex and pubertal status. The lack of standardization of
these values must be taken into account and also their low values in case
of malnutrition or liver failure.
Stimulation tests although theres much debate about the nonphysiological stimulation, they remain the sole method to prove the GH
deficit both in adults and children.
o Insulin tolerance test 0.05-0.15 U/kg insulin is administered i.v. and
glucose and GH level are determined -30, 0, 30, 60, 90, 120 minutes
after. A subnormal response for the adult is considered a value below
5.1 ng/ml and in children < 10 ng/ml.
o Arginine test 0.5 g/kg, i.v. in 30 min it can be done in combination
with GHRH administration at the end, in dose of 1-5 g/kg, in order to
increase the sensibility of the test. For children the same values as for
the insulin test are used; in adults the values must be above 4.1ng/ml.
o Other stimulation tests clonidine 0.1-0.15 mg/m2 orally, glucagon 0.03
mg/kg i.m or s.c. or L-Dopa 0.125-0.5 g.

In case of GH deficit theres also a low level of serum and urinary

hydroxyproline, alkaline phosphatase, and phosphorus.
For diagnosis confirmation the imaging evaluation is mandatory (CT or MRI).

Special features in child pituitary failure

In children the suspicion of pituitary failure imposes the evaluation of pubertal
status and anthropometric measurements:
Weight, height, BMI;
Sitting height;
Inferior segment length the distance from the pubic symphysis to the
Arm span;
Cranial circumference;
Construction of the growth curve.
In case of a child with a GH deficit, the calculation of the bone age is often
used through hand X-ray, using different standards (for example the Tanner
Whitehouse standard, also called TW20 because it uses the evaluation of 20
ossification nuclei). In pituitary dwarfism (partial or complete GH deficit) the bone age
is always delayed from the chronologic age, corresponding to the age for height. If
theres also a concurrent hypothyroidism, the bone age is delayed from the age for
height also.
Differential diagnosis
PF must be differentiated from primary endocrine insufficiencies (thyroid,
adrenal or gonadal) but also from the isolated pituitary syndrome (in which case DI
and high PRL values are described). Another differential diagnosis is with the
feeding behavior disturbances in anorexia nervosa.
Pituitary failure in children pituitary dwarfism must have a multidisciplinary
approach for a correct evaluation of short stature. Short stature can be determined
Endocrine diseases:
o Functional GH deficit psychosocial dwarfism in children with maternal
deprivation, or from families in which the child is either ignored or severely
o Primary IGF-1 deficit These disorders reflect GH receptor or
postreceptor defects that are inherited in autosomal recessive fashion.
Different mutations or dysfunctions of the GH receptor; the classic
form is called Laron dwarfism GH resistance.
IGF-1 gene deletions or defects in transport or metabolism of IGF 1
like pygmies.
IGF-1 resistance mutations in its receptor (IGF-1 R).
o Hypothyroidism.
o Glucocorticoid excess exogenous or endogenous.
o Diabetes mellitus with poor metabolic control (Mauriac syndrome).
o Untreated diabetes insipidus.
o Vitamin D resistant hypophosphatemic rickets.
o Untreated congenital virilizing adrenal hyperplasia.
o Precocious puberty.

Malnutrition anorexia nervosa, iron, Zn deficit, anorexia following

chemotherapy, amphetamine use.
Skeletal dysplasia osteogenesis imperfecta, osteochondrodysplasia,
Chronic diseases and thesaurismosis mucopolysacharidosis, cardiac,
pulmonary, gastro-intestinal, liver, immune, hematologic diseases, juvenile
rheumatoid arthritis, chronic inflammation.
Genetic syndromes with short stature Turner, Noonan, Silver Russel, Prader
Willi, Bardet Biedl, Down, etc.
Constitutional or familial short stature.
Idiopathic short stature, constitutional delay in growth (delayed puberty).
SGA (small for gestational age) unrecovered by 4 years of age.

Evolution, complications, prognosis

The evolution depends on the severity of PF and the rapidity of the onset. The
acute PF can lead to pituitary coma, which is governed by the symptoms of adrenal
failure marked hypotension with shock to which the signs of chronic pituitary
insufficiency are added thin, dry skin, vitiligo, hypothermia, lack of pubic and axillar
hair, hypotrophy of external genitalia.
In case of chronic PF, the evolution is insidious; the first hormonal line being
affected is GH axis followed by the FSH/LH, TSH and ACTH considered to be the
most resistant. In these forms, due to precipitating factors (infections, surgery,
trauma, pituitary apoplexy, and tumor infarction) pituitary coma can occur. The
complications are related to the PF etiology, but also to the low bone mineral density
caused by GH and gonadotroph deficit.
The acute forms for which the mortality is high need urgent cortisol
administration hemisuccinat hydrocortisone 100 mg bolus i.v. then every 4-6 hours.
Dextrose 50% or glucose 5% perfusion may be added, depending on the glucose
level. Following these procedures, L-Thyroxin 100 g/day is added i.v. or through the
gastric tube.
Chronic PF is treated with:
Hydrocortisone 10-20 mg in the morning, 5-10 mg in the evening or Cortisone
acetate 25 mg in the morning and 12.5 mg in the evening or Prednisone 5 mg in
the morning and 2.5 mg in the evening, all administered orally.
L-Thyroxin 0.075-0.15 mg/day, orally.
In women with gonadotroph deficit:
o Ethinilestradiol 0.02-0.05 mg/day, 21 days
o Conjugated estrogens 0.625 mg/day, 21 days
o Estradiol patch 4-8 mg twice a week
o If the uterus is intact a progestative is added progesterone 5-10mg b.i.d
the last 7-10 days of estrogen administration.
o If the patient wishes a pregnancy menopausal gonadotroph or recombined
FSH are used in adjusted doses of 75-150 IU, 10-15 days, i.m. or S.C. and
hCG 10 000 IU single dose, i.m. for induction of ovulation. Theres also the
option for GnRH pulsatile administration.
In men
o Testosterone enanthate 200 mg i.m. once every 2-3 weeks

o Testosterone gel 3-6 g/day, transdermal

o For fertility hCG 2000 IU twice a week, i.m., alone or in association with
recombined FSH 75 IU twice a week s.c. or i.m. or GnRH administered in a
pulsatile manner. The doses are adjusted depending on the response.
The GH deficit is treated with recombined GH preparations Somatropinum
(rhGH), s.c., 0.025-0.035 mg/kg/day in children and 0.2-1 mg/day in adults.
Treatment in children is carried out for a long period, until the target height is
achieved or the growth velocity is reduced. Possible side effects are: glucose
intolerance or diabetes mellitus, slipped capital femoral epiphysis, local
reactions, and benign intracranial hypertension. A TSH increase or
hypothyroidism can occur. Contraindications: active malign tumors. The risk of
leukemia or other types of malign tumors under treatment isnt higher than for
general population.

NB!! T4 should not be administered until adrenal function, including ACTH reserve,
has been evaluated and either found to be normal or treated. In a patient with
coexisting hypothyroidism and hypoadrenalism, treatment of the hypothyroidism
alone may increase the clearance of the little cortisol that is produced, thereby
increasing the severity of the cortisol deficiency. Glucocorticoid substitution can
reveal a DI through rising the arterial pressure and renal flow.
Empty sella syndrome
Empty sella syndrome occurs when the subarachnoid space extends into the
sella turcica, partially filling it with cerebrospinal fluid. This process causes
remodeling and enlargement of the sella turcica and flattening of the pituitary gland.
Primary empty sella syndrome results from congenital incompetence of the
diaphragma sellae. It is the most frequent cause of enlarged sella turcica.
The secondary form appears after surgery, radiation therapy, pituitary
infarction or hemorrhage.
From the clinical point of view, the symptoms can be absent, or it can
associate signs of PF, high PRL, headache, visual disturbances or CSF rhinorrhea.
Its more frequent in middle-aged obese women, with hypertension and pseudotumor
cerebri. For the confirmation of the diagnosis imaging exploration is mandatory (CT
or MRI) which can exclude a tumor.
Usually it requires only symptomatic treatment. Substitution therapy in case of
PF or dopamine agonists in case of high PRL can be necessary. Surgery is only
indicated in case of bilateral temporal hemianopia.



Anatom y, histology and embryology
The thyroid gland is composed of two lobes, located on the antero-lateral
tracheal wall. The two lobes are connected by an isthmus from which, in 30 % of the
cases, a third lobe emerges, called the pyramidal lobe, a remnant of the
thyreoglossal duct. Each lobe has approximately 4 cm in length and 2 cm in width.
The thyroids volume is correlated with sex, age, weight and iodine intake. The
thyroid has 15-30 grams, being one of the biggest endocrine organs and having one
of the richest vascular beds:
The superior thyroid arteries branches of the external carotid artery,
The inferior thyroid arteries branches of the subclavian artery,
The ima thyroid artery an inconstant branch directly from the aorta.
In diffuse toxic goiter resulting from Graves disease, blood flow may exceed 1
L/minute and may be associated with an audible bruit or even a palpable thrill.
The venous drainage is through the thyroid veins in the external jugular vein.
The lymph is drained predominantly in the internal jugular lymph nodes.
The thyroid gland has clinically important anatomical relationships with the
recurrent laryngeal nerves. The thyroid is also draped around the trachea and the
posterior margins of its lobes abut the esophagus. All of these structures can be
compressed by gland enlargement, invaded by thyroid malignancies, or injured in the
course of thyroid surgery.
The morphological unit of the thyroid is the thyroid follicle, which is spherical
and has variable sizes. The follicle wall is composed of one layer of epithelial cells,
called thyreocytes, usually cuboid in shape. In case the thyroid becomes inactive,
the epithelium flattens and chronic TSH stimulation (in iodine deficit for example)
determines an increase in the cells height.
The follicles lumen is filled with colloid, a gelatinous substance which
contains mainly proteins, thyroglobulin primary, but also other iodide-proteins and
albumin.The space between the follicles contains fibroblasts, endothelial cells and
some clear cells, single or in groups, derived from the neural crest and called C cells
or parafollicular cells. They secrete calcitonin in response to an increase in serum
calcium. Their main hypocalcemic function takes place through decrease of bone
resorption. Theyre abundant in childhood, but represent only 1% of thyroid cells in
the adult. The medullary thyroid carcinoma derives from these cells.
The thyroid gland originates in the embryo as a mesodermal invagination in
the pharyngeal floor at the foramen cecum, from which it descends anterior to the
trachea, starting at the base of the tongue. The thyroid follicles contain colloid and
the thyroid is capable of absorbing and binding iodide by the 12th gestational week.
The number of follicles increases until the embryo is 16 cm long, after which their
number is constant but they increase in size. The number of follicles can increase in
adults, in case of intense stimulation.
The parathyroid glands derive from the endodermal crest, those superior from
the fourth branchial pouch and the inferior ones from the third branchial pouch.
The common embryologic origin of these glands has 3 clinical implications:

1. The thyreoglossal cysts caused by the incomplete resorption of the duct.

These masses are present in the midline and will move upwards with
protrusion of the tongue.
2. Theres the possibility of thyroid or parathyroid tissue to be present at the
base of the tongue or in the thoracic cavity.
3. Surgical resection of the thyroid can excise also the parathyroid glands with
consequent hypoparathyroidism.
Thyroid hormone synthesis and secretion
There are two active forms of thyroid hormones: thyroxin (T4) and 3,5,3
triiodothyronine (T3). The thyroid gland must provide a sufficient quantity of hormone
to the peripheral tissues. The hormonal synthesis implies:
1. The intake or active transport of the inorganic iodide in the follicular cells
through a transport mechanism with energy expenditure (trapping). This
mechanism is dependent on the ATP-ase which allows iodide caption from
capillary blood in change for Na+ (the natrium iodide symporter, NIS). The
mechanism allows the human thyroid gland to maintain a concentration of free
iodide 30 to 40 times higher than that in plasma and is stimulated by TSH or
TSH receptor antibody. Other ions like perchlorate ion (ClO4) or bromide and
pertechnetate (TcO4) can compete with the iodide for NIS. The iodide per se
has an auto regulation effect on thyroid function.
2. Once the iodide enters in the thyreocyte it is rapidly transported to the apical
extremity of the cell where it is oxidized by hydrogen peroxide (oxidation).
The reaction is mediated by the hem-containing protein thyroid peroxidase
(TPO). An active process of transportation of the activated iodide takes places
at the apical membrane through pendrin a membrane transport glycoprotein.
3. After the iodide is integrated in the vesicles located at the apical membrane of
the cell it bonds covalently with the tyrosine residues of thyroglobulin. This
process is called organification. Thyroglobulin (TG) is synthesized and
glycated in the follicular cells, in the endoplasmic reticulum. It is a homodimer
of 660 kd and 134 tyrosine residues of which only 25-30 are iodinated.
Antithyroid drugs (methimazole or propylthiouracil - PTU) inhibit the
organification process.
4. The coupling represents the fusion of iodotyrosyl residues from the thyroglobulin. It is also mediated by TPO and culminates with the thyroxin
synthesis from the fusion of 2 DIT (diiodotyrosine) molecules and T3 synthesis from the fusion of monoiodotyrosine with a molecule of diiodotyrosine
(MIT+DIT). One molecule of thyroglobulin usually contains 6 MIT, 4 DIT, 2 T4
and 0.2 T3.
The thyroid gland is the only endocrine gland which has an important hormonal
reserve, sufficient for maintaining the euthyroid state for 50 days; the thyroid
hormonal turnover rate is low (~1%).
The thyroid hormone secretion implies the resorption of the colloid in the follicular
cells through pinocytosis. Coupling of these drops with the lysosomes will determine
the formation of fagolysosomes. Inside these, the proteolysis of thyroglobulin will
release T4, T3 and iodotyrosines. At this level, 10-20% of T4 is deiodinated with T3
formation. The thyroid hormones are released in the perifollicular capillaries and the

iodide from MIT and DIT will be recycled (through the iodotyrosine dehalogenase)
and is retrieved for hormone synthesis.
The release of T4 is inhibited primarily by iodide. This mechanism is responsible
for the rapid improvement of thyroid function in case of hyperthyroidism after iodide
administration. Lithium has a similar effect, but the mechanism is unknown so far.
T3 is 10 times more active than T4. Approximately 20% of the T3 comes from
thyroid secretion; the rest of 80% is formed by the extrathyroid deiodination of T4, a
reaction mediated by the 5-deiodinase. This enzyme has two forms:
Type I predominant in the liver, kidney, thyroid, skeletal and heart
muscle, and other tissues. It is sensitive to PTU.
Type II it is found in brain and pituitary where it maintains a constant
level of intracellular T3 in the central nervous system. It is not inhibited by
The corticosteroids and beta-blockers have an inhibitory effect on type I 5deiodinase. The enzyme contains selenocysteine, therefore, lack of selenium causes
functional disturbances. The reverse T3 (rT3) is biologically inactive and comes from
the peripheral conversion of T4 mediated by the 5-deiodinase, an enzyme which is
ubiquitary but predominates in brain, placenta and fetal tissues.
Thyroid hormone metabolism
The T4 production rate is 80-100 g/day; the whole quantity is produced in the
thyroid. The rate of T4 degradation is 10% per day. Approximately 80% is
deiodinated with T3 and rT3 formation in proportional quantities, the rest of 20%
being glucurono- or sulphoconjugated, deaminated or decarboxylated with formation
of the tetraiodothyroacetic acid (TETRAC).
The T3 production rate is 30-40 g/day. The degradation of T3 is mainly by
deiodination in a more rapid pace then T4 approximately 75%/day.
The thyroid hormone transport
Both T4 and T3 circulate bonded with different proteins, for example, thyroxinbinding-globulin (TBG), transthyretin (TTR), albumin or lipoproteins. This large
circulating thyroid hormone pool with a stable 7-day plasma half-life ensures the
homogeneous distribution of thyroid hormones in target tissues.
The free fraction of T4 represents only 0.04 % of total T4 (TT4), meaning 2
ng/dl (20 pmol/l); the free T3 fraction represents 0.4 % of total T3 (TT3), meaning 0.4
ng/dl (6 pmol/l). The laboratory assays for total T4 and T3 measure both the free and
bonded fractions of the hormones. Therefore, factors affecting the concentrations of
the binding proteins can influence the TT4 and TT3 values, although the free
fractions are not modified and the patient is euthyroid.
Causes of TBG elevation:
Hereditary form, with a dominant X-linked inheritance.
A raise in the estrogen level in pregnant women, those using oral
contraceptives, estrogen secreting tumors, etc.
Drugs or medications: 5-fluorouracil, clofibrate, heroin, methadone.
Acute intermittent porphyria.

Causes of TBG decrease (and therefore TT4 and TT3 decrease):

Hereditary deficit, with recessive X-linked inheritance.
Administration of high doses of androgen or their serum increase.
Cushing syndrome or glucocorticoid administration.
Nephrotic syndrome.
Drugs: niacin, danazole.
Control of the thyroid hormone production
It is realized through:
TSH regulation of T4 and T3 secretion. TSH secretion is inhibited
through a feed-back mechanism by the thyroid hormones. It is
stimulated by TRH. This mechanism provides a sensible protection
over slight changes in thyroid hormone levels.
Factors influencing peripheral conversion of T4 to T3: nutritional,
hormonal or other pathological factors (non-thyroid). This mechanism is
responsible for the rapid change in thyroid hormone bioavailability as a
response to non-thyroid diseases.
TSH stimulates all the steps of thyroid hormone synthesis and secretion, the
intermediary metabolism, gene expression and it determines thyroid hyperplasia and
hypertrophy. Its action on the thyroid initiates after binding to a membrane receptor,
stimulation of the adenylate cyclase and a consecutive rise in the cyclic AMP. Table
5 describes the endogenous and exogenous factors which can influence the TSH
secretion. Other substances with a stimulatory effect on the thyroid are IGF-1, EGF
(epidermal growth factor); for both these substances there are receptors in the
follicular cells and participate in the goiter formation.
Table 5 The stimulatory and inhibiting factors of the TSH secretion
Alpha adrenergic agonists

Dopamine and dopamine agonists
Somatostatin and its analogs (octreotide)
Glucocorticoids in high doses
1 Interleukin, interleukin 6
Tumor necrosis factor- (TNF)

The extrathyroid T3 production is regulated by all the factors that influence the
iodothyronine deiodinases (table 6): the types I and II (5 deiodinases which mediate
the formation of T3 from T4) and type III (5 deiodinase responsible for the T4
inactivation via rT3 formation).


Table 6. Iodothyronine Deiodinase Types and Characteristics

Fetal life
Tissue distribution

Type I

Liver, kidney, skeletal

muscle, thyroid

Type II


Type III

Brain, placenta, fetal


Thyroid autoregulation
It refers to thyroids capacity to modify its function in order to adapt to changes
in the diet iodine availability, independently from TSH. The main adjustment to the
reduced iodine concentration in the diet is the preferential T3 over T4 synthesis in
the thyroid.
On the other hand, an excessive quantity of iodine administered to a euthyroid
person leads to an initial reduction in the synthesis and secretion of thyroid
hormones, but also of the iodide transport, cAMP generation or hydrogen peroxide
formation. This inhibitory effect is called Wolff Chaikoff effect. After 2-4 weeks theres
an escape phenomenon described, the normal thyroid resumes the hormone
production. The Wolff-Chaikoff effect is used in medical practice for rapid reduction
of thyroid function with therapeutic doses of iodide. Iodide administration 10-14 days
before surgery has also an important reduction effect on thyroid vascularization.
A great susceptibility to the Wolff-Chaikoff effect appears in case of:
Autoimmune disorders Hashimotos thyroiditis,
During fetal life due to inadequate iodide organification,
Radioactive iodine administration in Basedows disease or external thyroid
In these situations a goiter and severe hypothyroidism may develop after
excessive iodine administration for a long period because the thyroid may be
incapable of escaping from iodide-induced inhibition of its function.
Useful to note that iodine excess may also have the effect of exacerbating
hyperthyroidism especially in patients with multinodular toxic goiter, latent Basedows
disease or even in people without any apparent thyroid malfunction.
The Thyroid Hormone Receptors and Mechanisms of Action
Thyroid hormones (TH), that are unbound in plasma, are transported
intracellularly, by either specific carriers including monocarboxylate transporter 8
(MCT8), MCT10, and organic anion transporting polypeptide (OATP1C1).
TH act via 2 mechanisms:
1. Genomic action T3 binding to specific nuclear receptors and
regulation of other genes activity.
2. Non-genomic action T3, T4 interaction with certain enzymes
(Calcium dependent ATP-ase, adenylate cyclase), mitochondrial
proteins or enabling glucose and some aminoacids transport.

T3 interacts with specific nuclear receptors (thyroid hormone receptor TR)

which bind to DNA. The TRs can function as heterodimers with retinoid X receptors.
These receptors have the following features:
They bind T3 with a 15 fold higher affinity than T4; therefore T4 is
considered a prohormone with reduced biological activity.
Practically, in vivo only T3 binds to TR.
There are 2 types of TR each with multiple variants that result after
alternative splicing of mARN:
o Alpha 1, 2.
o Beta 1, 2.
The concentration of these receptors in tissue varies among cell type and is
correlated with their stage of development. For example, the brain contains
predominantly TR, the liver mostly TR, and cardiac muscle contains both. Point
mutations in TR gene have been shown to be responsible for the syndrome of
generalized resistance to thyroid hormone.
Physiologic effects of the thyroid hormones
T3s regulation of the gene expression takes place after a period of latency of
hours or days and it determines multiple vital effects like tissue growth, brain
maturation, increase of metabolism or oxygen consumption (by stimulating the Na/K
ATP-ase in almost every tissue).
Thyroid hormones increase the number of adrenergic receptors in heart and
skeletal muscle, adipose tissue, and lymphocytes. They may also amplify
catecholamine action at a postreceptor site. Many of the clinical manifestations of
thyrotoxicosis appear to reflect increased sensitivity to catecholamines. Furthermore,
therapy with -adrenergic blocking agents is often helpful in controlling these
sympathomimetic manifestations of thyroid hormone excess.
Thyroid hormones also have specific effects on various systems:
1. Cardio-vascular TH increase the diastolic relaxation time and they
intensify the myocardial systolic function, having therefore a positive effect
on the expression of beta adrenergic receptors. The rate of sinus node
depolarization and repolarization is also increased, a fact which explains
the inotropic and chronotropic positive effect of TH.
2. Pulmonary TH maintain the ventilatory responses to hypoxia and
hypercapnia in the brain stem respiratory center; therefore hypoventilation
can occur in myxedema.
3. Digestive TH increase bowel motility, so they can increase the bowel
movements during hyperthyroidism and cause constipation in case of
4. Osteoarticular system TH cause the increase in bone turnover, bone
resorption and bone formation in a smaller percent. Hypercalciuria and
rarely hypercalcemia can occur in hyperthyroidism, but also there can be a
significant loss of bone mineral mass.
5. Neurologic and muscular systems TH are essential for normal CNS
development and function; thyroid insufficiency during fetal life is
associated with severe, irreversible mental retardation. In the adult, TH in
excess affects muscular mass, even proximal myopathy, exaggerated

reflexes, tremor, hyperactivity, anxiety. Slow reflexes, depression, somnolence are often signs of myxedema.
6. Glucose and lipid metabolism TH determine an increase in glycogenolysis and liver neoglucogenesis, favoring also glucose absorption
from the bowel. Diabetic patients with hyperthyroidism can have a
worsening of their glycemic control. Cholesterol synthesis and metabolism
are positively influenced by TH, especially by increasing the number of
LDL receptors in the liver and its clearance. A rise in the LDL fraction and
of total cholesterol as well can be found in case of hypothyroidism.
7. Endocrine system TH affect hormone production, receptor sensitivity and
the metabolic clearance of some hormones. In case of hypothyroidism
during childhood the growth is profoundly affected as a consequence of a
decrease in GH release. Both delayed and precocious puberty are
described in case of myxedema. The former appears because of GnRH
and gonadotroph affected release; the latter is caused by the increased
effect of TSH on the LH and FSH receptors. In adulthood myxedema can
cause hyperprolactinemia and consecutively dysfunctional uterine
bleeding, amenorrhea, anovulation and infertility. The responsiveness of
the hypothalamic-pituitary-adrenal axis to stress is blunted in hypothyroid
patients. Hyperthyroidism can be associated with gynecomastia, as a
consequence of increased androgen aromatization and SHBG levels. All
the endocrine malfunctions are reversible through adequate treatment and
reestablishing the euthyroid state.
Thyroid morphologic and functional evaluation
In vitro evaluation
Basal determinations
1. TSH measurement is the most frequently used test for evaluating thyroid
function. Immunometric (IMA) or radioimmunometric (RIA) assays can be used.
The great majority of laboratories now use methods with a range limit below 0.02
mUI/l (UI/ml). Normal TSH values: 0.5 - 4.5 mUI/l.
2. TH can be measured as total quantity, including that bonded with proteins (TT4
and TT3) and also as free form (fT4 and fT3), the latter with a broader utilization.
Normal fT4 values: 9-30 pmol/l (0.7-2.5 ng/dl) and fT3: 3-8 pmol/l (0.2-0.5ng/dl).
There is an inverse logarithmic relationship between TSH and peripheral thyroid
hormone values. An elevated () TSH associated with a decreased () fT4 and
fT3 means primary hypothyroidism, while a TSH below 0.1 mUI/l associated with
elevated fT4 and fT3 is found in case of hyperthyroidism. There are situations in
which the TSH value is not correlated with the thyroid hormone values, among
which the following:
Central hypothyroidism (pituitary or hypothalamic) with normal or slightly
decreased TSH and low fT4 and fT3.
Subclinical hypothyroidism with TSH and normal fT4 and fT3.
Subclinical hyperthyroidism with TSH and normal fT4 and fT3.
Elevated TSH with elevated fT4 and fT3 TSH secreting pituitary
adenoma or thyroid hormone resistance.
During systemic illness normal or fT4 with TSH in the acute phase
and in the recovery phase.

Dopamine or glucocorticoid administration TSH , normal fT4 and fT3.

3. Thyroglobulin measurement is used in the following situations:
Monitorization of the remnant or recurring thyroid tissue after thyroidectomy for thyroid cancer.
Differential diagnosis of hyperthyroidism induced by exogenous thyroid
hormone administration with thyroid causes of hyperthyroidism. In the
former case the TG is decreased, while in the latter its normal or even
Establishment of the etiology of congenital myxedema thyroid agenesis
is associated with non-measurable TG levels.
4. The thyroid antigens against which specific antibodies can be formed, with
implications in autoimmune thyroid disorders diagnostic are the following:
Thyroglobulin anti TG antibodies,
TSH receptor TRAb stimulating, inhibitory or neutral antibodies,
Thyroid peroxidase anti TPO antibodies, formerly known as antimicrosomal antibodies.
Dynamic testing
1. TRH test consists of administration of 200 g TRH i.v. and TSH measurement
before administration and after that at 30 and 60 minutes. The lack of TSH
elevation above 7 mUI/l indicates a central pituitary cause of hypothyroidism
(secondary hypothyroidism) or external administration of thyroid hormones. An
exaggerated but late response is described in tertiary (hypothalamic) hypothyroidism. The test is seldom used nowadays giving the existence of
ultrasensitive TSH and TH assays.
2. The TSH test allows the differential diagnosis between primary and secondary
hypothyroidism, but, it can also be used to highlight the thyroid scintiscan
inhibited in case of thyroid autonomy.
Functional in vivo exploration
Radioiodine uptake allows differential diagnosis in case of thyrotoxicosis,
especially used in combination with external scintiscanning. The ideal isotope is I123,
with a half-life of 13 hours; in case of its absence I131 can also be used (it has a halflife of ~ 8 days). After oral administration of iodine its radioactivity at thyroid level is
measured with a scintillator after 2 or 6 hours and 24 hours, respectively 48 hours if
I131 is being used.
Iodine uptake values vary depending on the recent diet iodide intake. Normal
ranges in countries with sufficient iodide intake are 5-15% at 6 hours and 8-30%
after 24 hours (for I123) and 20 5% at 2 hours, 40 5% at 24 hours and 10-15% less
from the precedent value at 48 hours if I131 is being used. In case of hyperthyroidism
the 24 hour values reach 60-90% and, in the forms with increased iodide turn-over or
hormonal synthesis anomalies and deficient iodide intake, the value after 6 hours is
greater than the one after 24 hours.
Causes of reduced radioiodine uptake and thyrotoxicosis are:
Subacute or post-partum thyroiditis local inflammation causes increased
release of preformed thyroid hormones.
Exogenous intake of thyroid hormones.

Use of contrast substances or drugs with high iodide concentration

(amiodarone for example).
If the functioning tissue is localized in a different place (tongue, mediastinum,
struma ovary, functioning thyroid metastases), the RIU at cervical level will also be
Thyroid scintigraphy is performed 8-24 hours after oral administration of 50
Ci I131 or 200-300 Ci of I123. Tcm99 can also be used; it is captured by the NIS but
its not organified or retained at thyroid level. Its i.v. administration is followed by
obtaining a thyroid scan image after 30-60 minutes, using a gamma chamber or a
linear scanner. Thyroid scintiscanning provides information about the size and shape
of the thyroid gland. It is useful especially for highlighting the autonomous areas
inside the thyroid and for the differential diagnosis of thyrotoxicosis. It can be used
also in suspicion of retrosternal goiter or ectopic thyroid tissue.
The aspect of a nodule in scintiscanning can be one of the following:
Isofunctional nodule: normal uptake (normal functioning) or warm, the
nodules uptake is the same with the one in the rest of the thyroid gland.
Hyperfunctional or hot nodule: high uptake, the nodules uptake is higher
than that of the rest of the thyroid. These nodules are the proof of thyroid
autonomy which determines the suppression of surrounding thyroid tissue
and is associated with a decrease in the TSH values. The great majority of
these nodules are benign.
Non- or hypofunctional, cold nodule, the iodide uptake is absent or reduced
compared with the rest of the thyroid.
The WERNER test T3 suppression can be used for evaluating the
functional tissues autonomy. In healthy persons, administration of 75-100g T3, for
5 days causes a 50% fall of iodide uptake at 24 hours, compared with the basal
uptake. In case of autonomy this fall is not present. Furthermore in the compensated
phase of the thyroid toxic adenoma (hot nodule at scintiscanning), these high T3
doses will suppress the TSH value and consecutively, the iodide uptake in the
unaffected surrounding thyroid tissue will disappear, the autonomic nodule not being
affected by the TSH suppression.
Due to the fact that the great majority of thyroid nodules are cold or
hypofunctioning, thyroid scintiscaning has a reduced diagnostic value in thyroid
cancer. On the other hand, the whole body scan has proved to be useful in the
follow-up of the patients with total thyroidectomy for certain types of cancer, for
evaluating the possible peripheral metastases.
High resolution thyroid ultrasonography represents the method of choice for
establishing thyroid size (normal thyroid volume is 15-18 ml in male and 12-15 ml in
women), identifying nodular lesions, evaluating the solid or cystic nature of a nodule,
monitoring their size and detection of latero-cervical lymphadenopathy. It can be
used for guiding the thyroid biopsy.
There are some sonographic features suggestive for a malignant nodular
The hypoechoic aspect of the nodule,
Irregular margins,
Incomplete or irregular halo (halo is the hypoechogenic thin rim which
surrounds a nodule, representing usually the capsule or perinodular
Intra-nodular vascularity,

Dimensional growth on successive examinations,

Intranodular microcalcifications.
For the latero-cervical lymphadenopathies, the suspect ultrasonographic
features include hypervascularity, cystic degeneration, microcalcifications.
The anterior cervical regions ultrasonography often finds small thyroid
nodules, less than 1cm, non-palpable with a clinical value not fully understood yet.
This small nodules are called incidentalomas. Usually, these lesions need periodic
monitorization because recent studies show a similar cancer prevalence in both
palpable nodules and in incidentalomas if the suspect ultrasonographic features are
Magnetic resonance imaging and computed tomography are used for
evaluating the retrosternal or posterior extension of massive goiters or in order to
identify distant metastases in case of thyroid cancer.
Fine needle aspiration biopsy (FNAB) is the method of choice for
differentiating benign and malignant nodules. It can be done ambulatory, without
local anesthesia, with a 27 or 25G needle through which a small quantity of nodule
material is aspirated for the cytological exam. Cystic lesions can be drained almost
entirely, but recurrences are described in more than 50% of cases.
The FNAB results can be categorized as follows:
Benign represents ~ 70% of results
Malignant 1-5%
Suspect, follicular lesion 11-13%
Inadequate, nondiagnostic 11-13%.
The sensibility and specificity of this method exceeds 90%.
Hyperthyroidism and thyrotoxicosis
The term thyrotoxicosis refers to the clinical syndrome caused by tissue
exposure to an elevated level of TH, a state which is associated with acceleration of
all metabolic pathways. The most frequent cause is the increased production of TH
in the thyroid or hyperthyroidism. Thyrotoxicosis is not synonymous with
hyperthyroidism, which is the result of excessive thyroid function.
Hyperthyroidism etiology:
Basedow Graves disease,
Toxic thyroid adenoma,
Toxic multinodular goiter,
hCG induced hyperthyroidism (the human chorionic gonadotropin has
intrinsic TSH action):
o transient gestational hyperthyroidism,
o trophoblastic tumors hydatiform mole,
Iodine induced hyperthyroidism Jod Basedow,
Struma ovary (ovarian teratoma with hyperfunctioning thyroid tissue
treatable by tumor excision),
Hyperfunctioning metastatic follicular carcinoma,
TSH secreting pituitary adenoma,
Thyroid hormone resistance partial form with a pituitary

Inherited nonimmune hyperthyroidism associated with TSH receptor

gene or G protein gene activating mutations.
Other causes of thyrotoxicosis:
o Autoimmune: lymphocytic, post-partum, painless,
o Subacute: postviral,
o Drug induced: amiodarone, interferon, interleukin 2, lithium, etc.
o Acute bacterial.
Exogenous TH excess:
o Iatrogenic overreplacement of TH,
o Factitious thyrotoxicosis (utilization of TH preparation without any
medical recommendation),
o Ingestion of food products with excessive animal TH hamburger

Basedow Graves disease (BGD)

It is considered an autoimmune disease, being the most frequent cause of
thyrotoxicosis, with a 5 fold higher prevalence in women. The peak incidence is from
the second to fourth decade of life, but it can appear at any age. It manifests itself
through one or more of the following clinical aspects:
Dermopathy pretibial myxedema.
Etiology and pathogenesis
In Basedows disease there is a defect in suppressor T lymphocytes that
allows helper T lymphocytes to stimulate B lymphocytes to synthesize thyroid autoantibodies.
The TSH receptor antibodies (TRAb or TSI) play a key role in the immune
pathogenesis of this disease. They are secreted by the B lymphocytes and can have
a stimulatory effect, increasing TH synthesis and secretion, but also encouraging
cellular proliferation and iodide uptake. There are also inhibitory or neutral TSH
receptor antibodies, some patients having both the stimulatory and the blocking
antibodies in their serum, their clinical state depending on the ratio between the two
types of antibodies.
A genetic predisposition is a unanimously accepted factor in Graves disease.
The disease is often found in multiple family members, but the inheritance is
multifactorial and a combination of environmental and genetic factors, including
polymorphisms in HLA-DR or genes like TSH-R contribute to Graves' disease
The main decompensating factors in Graves disease are the following:
pregnancy, particularly the postpartum period;
psychological stress,
iodide excess, particularly in geographic areas of iodide deficiency, where
the lack of iodide may hold latent Graves disease in check;
interferon alpha, perhaps by modifying the immune response;
certain viral or bacterial infections for example Yersinia enterocolytica.

Clinical findings
The main symptoms of Graves disease are: hyperactivity, irritability,
dysphoria, hyperhidrosis, termophobia, palpitations, weakness, and fatigue, weight
loss with preserved appetite and polyphagia, dyspnea, increased bowel movements.
In young people clinical findings are dominated by nervousness, hyperkinetic
cardiac syndrome, fatigue, hyperkinesia, weight loss and diarrhea. In children the
linear growth and bone maturation are accelerated, while in people over 60 years of
age the cardio-vascular and muscular (frequent myopathy) signs are frequently
described (the clinical findings in elderly are mostly atypical).
The physical examination can highlight different changes in almost all
1. Skin, hair, nails:
Warm, sweat, soft, moist skin, with friable hair,
Onycholysis, thin and smooth nails,
Diffuse or localized alopecia,
Dermopathy marked thickening of the skin is noted, usually over the
pretibial area (pretibial myxedema) with a livid color and orange peel
Hyperpigmentation especially of the eyelids (Jellinek sign) caused by
cortisols accelerated metabolism and secondary rise of ACTH.
2. Cardio-vascular system:
Increased heart rate, sinus tachycardia (at rest, during sleep, and
exaggerated during exercise),
Increased cardiac output and wide pulse pressure, these will determine
systolic hypertension,
Celer et altus pulse, with augmented cardiac sounds,
Decreased peripheral resistance due to the vasodilation,
Cardiac failure with normal or increased cardiac output in case of severe
Atrial fibrillation or flutter and extrasystolic arrhythmia,
Exertional dyspnea, which is due more to respiratory and skeletal muscle
weakness than cardiac dysfunction.
3. Respiratory system:
Dyspnea through elevation of O2 consumption and hypercapnia,
Respiratory muscle weakness,
Exacerbation of a preexisting asthma.
4. Digestive system:
Weight loss due to increased metabolic rate (hypermetabolism),
Malabsorption, increased bowel motility, hyperdefecation, sometimes,
Hyperphagia, in the elderly anorexia,
Celiac disease is more frequent in patients with Graves disease,
Abnormalities in liver function tests, particularly high serum alkaline
phosphatase concentrations, and rarely cholestasis.
5. Urinary and reproductive system:
Polyuria, nycturia, nocturnal enuresis in children,
In women olygomenorrhea, anovulation and infertility,





In male decreased libido, gynecomastia and erectile dysfunction caused

by extragonadal increased conversion of testosterone to estradiol.
Osteoarticular system:
Scapulo-humeral periarthritis,
Osteoporosis and increased fracture risk ,
Acropachy with clubbing and subperisoteal new bone formation at the
phalangeal and metacarpal level.
Neurologic and muscular systems:
Behavioral and personality changes: irritability, anxiety, nervousness,
insomnia, termophobia, impaired concentration, sometimes psychosis,
Brisk tendinal reflexes (hyperreflexia),
Smooth upper limb tremor, with high frequency and reduced amplitude,
Graves disease can be associated with myasthenia gravis,
Periodic thyreotoxic paralysis, a form of hypokalemic periodic paralysis
particularly common in Asian males with thyrotoxicosis,
Proximal myopathy.
Endocrine system increased ACTH secretion, inhibition of parathyroid
hormone secretion, impaired glucose tolerance in untreated patients.The
thyroid is usually diffusely enlarged to two to three times its normal size,
mobile, non-tender. The consistency varies from soft to firm and rubbery.
There may be a thrill or bruit due to the increased vascularity of the gland and
the hyperdynamic circulation.
Ocular signs
Due to increased adrenergic tone stimulating the levator palpebral
muscles (increased sympathicotonia): eyelid lag (Graefe sign), eyelid
retraction (Dalrympl sign), stare, and rare blinking (Stellwag sign), and
Geoffroy sign (lack of forehead wrinkling at upper gaze). It is important to
differentiate these signs, which may occur in any form of thyrotoxicosis,
from those of infiltrative autoimmune orbitopathy, which are associated
with Graves disease!

Graves' ophthalmopathy (orbitopathy)

It appears in 20-40% of patients with BGD, before, simultaneously or after the
onset of thyrotoxicosis. It can be uni- or bilateral.
The pathogenesis of ophthalmopathy may involve cytotoxic T lymphocytes
and antibodies sensitized to a common antigen such as the TSH receptor that is
found in orbital fibroblasts, orbital muscle, and thyroid tissue.
Cytokines (tumor necrosis factor alpha and interferon gamma) from these
sensitized lymphocytes may cause activation and proliferation of orbital fibroblasts
and preadipocytes, resulting in increased volume of both the extraocular muscles
and retroorbital connective and adipose tissue. The inflammation and the
accumulation of hydrophilic glycosaminoglycans (GAG), especially hyaluronic acid,
causes a change in osmotic pressure, which in turn leads to a fluid accumulation and
an increase in pressure within the orbit. These changes displace the eyeball forward
and can also interfere with the function of the extraocular muscles and the venous
drainage of the orbits.
Risk factors for the development of GO exist in patients with BGD:
o Genetic predisposition some HLA alleles associated with a higher
risk to GO;

o Female gender;
o Smoking;
o The type of treatment used for BGD: radioactive iodine therapy may
increase the risk and the severity of GO;
o The titer of TRAb.
The clinical manifestations may be absent or they can be represented by the
sensation of grittiness, eye discomfort, excessive tearing, pain, double vision or even
sight loss.
Physical examination reveals conjunctival modifications such as erythema or
chemosis, and periorbital edema. In severe cases, proptosis may cause corneal
exposure and damage, especially if the lids fail to close during sleep. The
impossibility to obtain and maintain convergence (convergence asynergism) is a sign
of extrinsic ocular muscle involvement which typically is due to fibrosis and failure of
muscle relaxation, limiting the function of the antagonist muscle. The inferior rectus
is the most commonly involved muscle in the infiltrative process. By failing to relax
normally, upward gaze limitation is the most common physical finding in patients with
eye muscle involvement. The next most commonly involved muscle is the medial
rectus, impairing lateral gaze.
Exophthalmos or ocular protrusion is measured objectively with the Hertel
exophthalmometer. The normal upper limit is 19-20 mm in white and 22 mm in black
NOSPECS classification, an acronym with the following meaning, was
introduced to evaluate objectively GO:
o Class 0 No symptoms or signs the lack of clinical signs and
o Class I Only signs, no symptoms eyelid retraction or other signs of
o Class II Soft tissue involvement: periorbital edema, congestion or
redness of the conjunctiva, and edema of the conjunctiva (chemosis);
o Class III Proptosis: exophthalmos, as measured with the Hertel
o Class IV Extraocular muscle involvement the involvement of
extrinsic ocular muscles (the inferior rectus and the medial rectus are
the muscles most commonly involved in the infiltrative process);
o Class V Corneal involvement corneal lesions or ulcerations due to
o Class VI Sight loss as a consequence of optic nerve injury.
Laboratory tests and paraclinical investigations
Hormonal assessment: TSH is usually below 0.05 mIU/L, fT4 and fT3 are
increased. In the initial phase of the disease TSH is decreased, fT4 may be normal,
but fT3 is increased. The TRAb titer is elevated in the majority of patients, 70-80% of
persons with BGD present an increase of the anti TPO antibodies as well, and 2040% also have high levels of anti TG antibodies.
Other biochemical examinations can show: high glucose level, increased
alkaline phosphatase, normochromic normocytic anemia, prothrombotic state, low
total and HDL-cholesterol levels.
Scintigraphy and radioactive iodine uptake (RAIU) show increased thyroid
volume, with a diffuse aspect, elevated RAIU values at 6 and 24 hours. Thyroid

ultrasound shows hypoechoic thyroid with pseudonodular areas and hypervascularisation.

Retrobulbar CT and MRI demonstrate the infiltration of extrinsic ocular
muscles and retrobulbar edema. The ophthalmic examination is also required (visual
acuity, fundoscopic eye examination, intraocular pressure).
Differential diagnosis
Gravess disease must be differentiated from neurovegetative dystonia,
neurasthenia, panic attacks or mania.
BGD needs to be differentiated from other forms of thyrotoxicosis with or
without hyperthyroidism (see the classification of hyperthyroidism).
BGD variants associated with severe weight loss have to be differentiated
from malabsorption syndromes, tuberculosis, gastritis, gastroduodenal ulcer,
paraneoplastic consumptive syndromes, anorexia nervosa, diabetes mellitus and
Bilateral GO is differentiated from similar ophthalmic conditions in Cushings
disease, acromegaly, Hashitoxicosis, pheochromocytoma, severe obesity, orbital
myositis, infections, granulomatous diseases (histiocytosis, sarcoidosis), amyloidosis, myasthenia gravis, mediastinal irradiation, orbital tumors. In unilateral forms
retroorbital tumors, metastases, cysts and aneurysms must be excluded.
Evolution, complications and prognosis
BGD is a chronic disease evolving with periods of activity alternating with
phases of remission, the cause of exacerbations and recurrences not being known
Chronic complications in long-term hyperthyroidism are: cachexia, osteoporosis, cardiomyopathy, cardiac failure, cardiac arrhythmias (atrial fibrillation) with embolic risk in the absence of anticoagulant treatment (cardiothyreosis). Thyroid storm
represents an acute complication with a high risk of lethality.
In BGD the treatment is focused on both rapid improvement of symptomatology by general measurements and administration of beta-blockers, and inhibition of
thyroid hormone synthesis with one of the following measures:
1. Conservative treatment with antithyroid agents (ATS thionamides);
2. Radioactive iodine therapy with 131I (RIT);
3. Surgery.
The principal advantages and disadvantages of every treatment option are
showed in table 7.
The administration of beta blockers reduces symptomatology induced by the
increased beta-adrenergic tonus: tachycardia, palpitations, anxiety, termophobia or
tremor. Atenolol 25-50 mg/day once a day or Propranolol 20-40 mg 2-4 times/day
can be administered (the latter also inhibits conversion of T4 into T3). Other general
measurements consist of avoiding excessive exercise, psychic stress and exposure
to high temperature, as well as adequate rest, vitamins and high protein diet are
recommended. Sedatives, tranquilizers and anxiolytic agents can be used.


Table 7. The principal advantages and disadvantages of different

therapeutic options in hyperthyroidism


for 1-2 years)

-Chance of
permanent remission
-Avoiding permanent
- Low cost




-Minor adverse events: skin eruptions, erythema,

arthralgias, fever, gastrointestinal symptoms,
vasculitis, cholestasis (methimazole),
-Major adverse reaction: (low) risk of leukopenia,
agranulocytosis (accompanied by fever and sore
throat), thrombocytopenia, anemia, hepatitis and
liver failure (PTU),
-Risk of fetal goiter and hypothyroidism in case
of administration in pregnancy,
- Frequent controls at specialist.
Permanent remission -Permanent hypothyroidism,
of hyperthyroidism
-Patients need to avoid close, prolonged contact
with children and pregnant women for several
-Radiation thyroiditis rare.
Rapid and permanent -Permanent hypothyroidism,
cure of
-Risk of iatrogenic hypoparathyroidism and injury
of recurrent nerves,
-High cost.

The antithyroid agents are:

Thiouracil derivatives: Propylthiouracil (PTU) 50 mg/tb or Methylthiouracil
(MTU) 50 mg/tb. The initially dose is 300-400 mg/day (attack dose for few
weeks); that can be reduced to the usual daily maintenance doses of 50-150
Imidazole derivatives: Carbimazole (it needs activation into methimazole in
the liver), Methimazole or Thiamazole. The attack dose (30-60 mg/day, every
8 hours for 2-6 weeks), can be gradually reduced (titration regimen) to 5-15
The mechanism of action is mainly related to the inhibition of iodide
organification, but PTU has also an inhibitory effect on conversion T4 to T3. Both
have immunosuppressive effect. Methimazole is more efficient, has a longer time of
action and reduced side effects. PTU is recommended to pregnant and nursing women due to lesser permeability for placental barrier; its effect sets on more rapidly.
Treatment monitoring is performed by fT4 measurement (TSH may remain
suppressed for a few months), initial at 2-3 weeks and then at 2-3 months. A
complete blood count is recommended before antithyroid drug therapy is started. If
the absolute neutrophil count falls to less than 1500 cells/L, the drug should be
withdrawn and glucocorticoids, lithium carbonate, folic acid or Neupogen
(granulocyte colony stimulatory factor) are given. Treatment with ATS is indicated 12 years in order to reduce the risk of recurrence, with the addition of thyroid
hormones sometimes being necessary, especially LT4 in doses which can maintain
an euthyroid state.

Other conservative therapeutic measures:


Iodine in high doses, such as Lugols solution (a saturated solution of

potassium iodide) in 3x1 drops per day (with gradually increasing doses), in
forms with moderate severity and only associated with ATS.
The administration of iodine containing contrast media, iopanoic acid or
sodium ipodat in 1g per day is used especially in thyroid storm due to their
rapid effect, or as a preoperative preparation.
Lithium as lithium carbonate (600-1000 mg/day) inhibits the secretion of
thyroid hormones, but is rarely used due to its high toxicity.
Potassium perchlorate 800-1000 mg/day, blocks NIS, can be used for a short
period of time due to frequent adverse events (nephrotic syndrome, aplastic
Radioactive iodine (radioiodine) therapy (RIT) causes progressive destruction
of the thyroid tissue. 131I is administered taking into account the thyroid volume and
the uptake of iodine (dosimetry). In some centers fixed iodine doses of 5, 10 or 15
mCi are preferred.
Long-term follow-up studies have shown that therapy does not cause
infertility, birth defects, or cancer later in life.
The possible adverse effects are:
Permanent hypothyroidism usually occurs in the first 6 to 12 months after
radioiodine therapy in about 80% of patients;
Radiation thyroiditis;
Possible activation of ophthalmopathy.
Severe Gravess eye disease is a relative contraindication to radioiodine
therapy. Pregnancy and nursing are absolute contraindications for RIT and the
avoidance of conception for at least 4-6 months post-RIT is recommended.
RIT is not recommended if there is:
a suspicion of malignancy,
compressive phenomena,
previous contamination with iodine containing preparations.
The elective surgical ablation of BGG is total or near-total thyroidectomy.
Surgery is recommended in large goiters with obstructive phenomena, in case of
allergy or contraindications to ATS or RIT, in noncompliant patients or if thyroid
malignancy is suspected. Attaining euthyroid state before surgery is mandatory to
prevent thyroid storm. In addition, starting 2 weeks before the day of surgery, the
patient may be given saturated solution of potassium iodide, five drops twice daily.
Thyroidectomy can be performed to pregnant women with severe Graves disease
who are allergic or develop reactions to antithyroid drugs.
Ophthalmopathy requires no active treatment when it is mild or moderate,
because there is usually spontaneous improvement. General measures include
meticulous control of thyroid hormone levels and cessation of smoking. Prompt
treatment of hyperthyroidism but avoiding long-term hypothyroidism (by association
of LT4 and antithyroid drugs) are also important. Taking into account that RIT can
aggravate GO, glucocorticoids can be administered for prevention few days before
and 2-3 months after 131I administration.
Eye discomfort can be relieved with artificial tears (e.g., 1% methylcellulose),
ocular solution 5% guanethidine and the use of dark glasses with side frames.
Periorbital edema may respond to a more upright sleeping position or a diuretic.
The development and progression of proptosis with the appearance of
infiltrative manifestations requires high-dose glucocorticoid administration:


Prednisone in initial dose of 1-2 mg/kg/day with gradually decreasing

doses in relation to response. The treatment can last for 6 months and
Cyclosporine 3mg/kg/day may be associated.
Pulsetherapy with intravenous Methylprednisolone administration (0.5-1.0
g/week for 6 weeks or 500 mg/day for 3 consecutive days in repeated
cures) followed by an oral regimen.
If corticosteroid therapy is not effective or if there is recurrence after the drug
is tapered, external x-ray therapy to the retrobulbar area may be helpful. The dose is
usually 2 Gy in 10 fractions (it is not recommended in optic neuropathy or diabetic
In very severe cases when vision is threatened, orbital decompression can be
achieved by removing bone from any wall of the orbit, thereby allowing displacement
of fat and swollen extraocular muscles.

Toxic adenoma (Plummers disease)

It is also called hyperfunctioning solitary nodule. The basic pathogenesis in
many cases is one of several somatic point mutations in the TSH-receptor gene that
lead to constitutive activation of the TSHR in the absence of TSH. A small number of
autonomous adenomas have mutations in G-protein genes.
The typical patient is an individual (female patient in the third or fourth decade
of life) who has noted recent growth of a long-standing thyroid nodule. These
nodules grow gradually over the years, those smaller than 3 cm rarely being hyperfunctioning. Hemorrhage, necrosis and macrocalcifications may appear inside the
Symptoms of weight loss, weakness, and shortness of breath, palpitations,
tachycardia, and heat intolerance are noted. Infiltrative ophthalmopathy is never
Laboratory findings show a low TSH associated with normal thyroid hormone
levels in the first phase, then fT4 and fT3 increase parallel with nodule growth (only
fT3 elevation may occur T3 thyrotoxicosis - with fT4 being normal). A radionuclide
scan reveals a hot nodule, with diminished or absent function of the contralateral
lobe. Thyroid ultrasound shows a solid or mixed nodule, which frequently is
hypoechoic, rarely isoechoic or hyperechoic and sometimes with central cystic
degeneration. Toxic adenomas are usually benign follicular adenomas and almost
never malignant.
Differential diagnosis includes endemic or sporadic multinodular goiters, BGD,
focal thyroiditis, acute thyroiditis, hemorrhagic cyst, thyroid cancer, partial (lobar)
thyroid agenesis or other extrathyroidal masses: lipoma, thyreoglossal cyst,
parathyroid adenomas, teratomas etc.
Definitive treatment is represented by RIT (administration of 20-30 mCi is
necessary to destroy autonomous tissue) or surgery (lobectomy with isthmectomy) if
the nodule is very large and causing obstructive symptoms. The first option is
attractive because the contralateral lobe can be spared the destructive effects of the
radiation due to TSH suppression. If antithyroid drugs are used to pretreat the
patient, it is important that the serum TSH remains low, so that the contralateral lobe
will not be stimulated to take up the radioiodine.
A controversial therapeutic method is intranodular percutaneous ethanol
injection with the advantage to prevent hypothyroidism, but with transient local
adverse events, such as intense pain and even dysphonia.

Antithyroid drugs may be used to normalize thyroid function prior to

radioiodine or surgery but are not a good long-term solution, because, unlike the
situation with Graves disease, long-term remissions do not occur.
Multinodular toxic goiter
It represents a form of thyrotoxicosis appearing in patients with long standing
multinodular goiter living in iodine deficient areas. The etiopathogenesis is complex,
the intrathyroidal lesion being structurally and functionally heterogenetic. The
functioning autonomy develops gradually. The somatic mutations demonstrated in
toxic adenomas have been demonstrated in some cases of toxic multinodular goiter.
This disorder usually occurs in older patients. The patient presents with
tachycardia, heart failure, or arrhythmia and sometimes the muscular weakness is
the prevailing symptom. Physical examination reveals a multinodular firm goiter that
may be small or quite large and may even have substernal extension. Obstructive
phenomena are described more frequently than in BGD.
Laboratory studies reveal a suppressed TSH and elevation in serum T3
levels, with less striking elevation of serum T4. Thyroid ultrasound is useful in
differentiating from thyroid adenoma or carcinomas, situations which require fine
needle aspiration biopsy. Radioiodine scan reveals multiple functioning nodules in
the gland or occasionally an irregular, patchy distribution of radioactive iodine
Hyperthyroidism in patients with long-standing multinodular goiters can be
precipitated by the administration of pharmacologic doses of iodine-containing drugs.
The therapy of choice, in the absence of obstructive manifestations is RIT,
which can reduce the dimension of the nodules. If surgery is recommended,
preoperative preparation is performed with ATS, but iodine is not indicated in order
to reduce vascularization. Substitution of LT4 is initiated after surgical treatment in
order to correct hypothyroidism and prevent recurrence.
Iodine-induced hyperthyroidism
Supplemental iodine administration to persons with endemic goiter or autoimmune thyroid pathology can result in hyperthyroidism; this effect is termed JodBasedow and occurs in only a small fraction of individuals at risk.
There are two possibilities according to age and preexisting pathology:
In young persons with diffuse goiter and usually positive TRAb;
In older individuals with multinodular goiter with areas of autonomous
functions and negative TRAb;
The administration of preparations with high content of iodine such as
expectorants, disinfectant and antiseptic agents, contrast media agents, amiodarone,
must be done carefully, taking also into account the presence of thyroid pathology,
especially in older people.
In subjects with high risk (multinodular goiter or history of hyperthyroidism,
autoimmune pathology) a prophylactic treatment with potassium perchlorate (0.5
g/day before and 1-2 weeks after iodine administration) associated with 20-40
mg/day methimazole (1-2 days before and then 1-2 weeks after) is recommended if
drugs with high iodine content are administered.
Amiodarone is a very efficient antiarrhythmic agent in certain severe cardiac
arrhythmias, and with complex actions on thyroid gland. About 80% of patients
taking this drug remain euthyroid. Its half-time is 50-60 days, amiodarone being
accumulated in adipose tissue, liver, muscle so high iodine levels persist for >6

months after discontinuation of the drug. Amiodarone inhibits deiodinase activity, and
its metabolites function as weak antagonists of thyroid hormone action.
Amiodarone may induce hypothyroidism (the most frequent complication in
iodine-sufficient areas). Amiodarone treatment causes thyrotoxicosis in 10% of
patients living in areas of low iodine intake and in 2% of patients in regions of high
iodine intake. There are two types of amiodarone-induced thyrotoxicosis (AIT),
although some patients have features of both.
Type 1 AIT is associated with an underlying thyroid abnormality (preclinical
Graves' disease or nodular goiter). Thyroid hormone synthesis becomes
excessive as a result of increased iodine exposure (Jod-Basedow
Type 2 AIT occurs in individuals with no intrinsic thyroid abnormalities and
is the result of drug-induced destructive thyroiditis.
The distinction between the two types can be sometimes made by Color-Flow
Doppler ultrasound: in type I the vascularization is increased and thyroid volume is
enlarged and in type II vascularization is absent or reduced and the thyroid volume is
normal or reduced. Thyroid scintiscans are difficult to interpret in this setting because
the high endogenous iodine levels diminish tracer uptake. However, the presence of
normal or rarely increased uptake favors type 1 AIT.
The treatment consists of the following recommendations:
The drug should be stopped, if possible, although this is often
impractical because of the underlying cardiac disorder.
In type I AIT: 20-60 mg/day methimazole until thyroid function is
normalized, which may be associated with potassium perchlorate
2x500 mg/day for 1-2 weeks.
In type II AIT: 20-40mg/day prednisone for 4-6 weeks.
In some situations the distinction between type I and II is not possible
by clinical manifestations and paraclinical findings, so in these cases
combined therapy with ATS and glucocorticoids is preferred.
In patients who are nonresponsive to pharmacologic therapy total
thyroidectomy may be needed.
Transient (accompanying) thyrotoxicosis
In these forms thyroid parenchyma is destroyed and there is a release of Tg
and thyroid hormones, leading to a transient thyrotoxicosis, followed by the recovery
of thyroid function or the development of transient or permanent hypothyroidism.
RAIU is always reduced. The principal forms are:
1. autoimmune (Hashimotos) thyroiditis has received the name of
Hashitoxicosis in the phase of thyrotoxicosis;
2. silent (painless) thyroiditis is considered also a form of autoimmune
3. postpartum thyroiditis;
4. subacute (postviral or de Quervains) thyroiditis appears at 2-3 weeks
after a viral infection, it is associated with local pain in the thyroid bed
and increased erythrocyte sedimentation rate (ESR). The course of
thyroid function in subacute thyroiditis: after the initial phase of
thyrotoxicosis appeared due to the release of thyroglobulin in the
bloodstream, a short phase of euthyroid state develops, followed by a
transient TSH-elevation and then complete recovery of thyroid function.


bacterial or fungal thyroiditis;

thyroid inflammation induced by drugs such as lithium, amiodarone,
interleukin 2, interferon , Granulocyte-macrophage colony-stimulating
factor (GM-CSF), Sunitinib (Sutent) used for gastrointestinal, renal
tumors, Imatinib (Gleevec) used in chronic granulocytic leukemia.

Thyroid storm
Thyroid storm is the most severe acute complication of hyperthyroidism. It
may occur in patients with neglected chronic hyperthyroidism but is most frequently
triggered by an acute event like:
Thyroid or non-thyroid surgery;
Administration of high dose iodine or RIT;
Sudden suspension of ATS;
Other severe diseases: myocardial infarction, uncontrolled diabetes
The clinical manifestations are an exaggeration of the typical thyrotoxicosis
picture: tachycardia with heart rate over 140/min or atrial fibrillation; occasionally
heart failure occurs. Fever ranges from 38C to 41C and is associated with flushing
and sweating. Significant agitation, anxiety, delirium or even coma may develop.
Gastrointestinal symptoms include nausea, vomiting, diarrhea, and jaundice. A fatal
outcome is associated with heart failure and shock.
The treatment of thyroid storm besides the prompt intervention on the trigger
cause consists of:
ATS like methimazole; MTU is the antithyroid drug of choice in thyroid
storm: PTU 250 mg every 6 hours p.o. The drugs can be given by rectal
suppository or enema if the patient is unable to take medication by mouth.
Iodide can be administered one hour after the first dose of ATS, as Lugols
solution 4-6 x10 drops/day or iopanoic acid 0.5-1 g/day.
Hydrocortisone hemisuccinate 100 mg i.v., every 6 hour, Dexamethasone
8 mg/day p.o., in a unique dose or 2 mg i.v., every 6 hour. The beneficial
effects of glucocorticoids are attributed to reduce thyroid hormone
secretion and inhibition of peripheral conversion of T4 into T3. These
agents have antithermic action as well.
Intravenous administration of propranolol in dose of 1-2 mg at 10 minutes
maximal dose 10 mg;
In the presence of severe heart failure or asthma and arrhythmia, where
beta blockers may be contraindicated cautious intravenous
administration of verapamil in a dose of 5 to 10 mg is recommended;
Lithium carbonate 600 mg/day;
Proper fluid, electrolyte, and nutritional support are important (parenteral
administration of normal saline solution or 5% glucose solution);
Vigorous treatment of hyperpyrexia, antibiotherapy in case of infections;
Sedatives: phenobarbital (may be useful because it accelerates the
peripheral metabolism and inactivation of T4 and T3) or diazepam;
Oxygen, digoxin or dobutamine (2.5-10 g/kg/min) in heart failure;
The prophylaxis of thrombotic events with heparin and fraxiparine in atrial

Aspirin is contraindicated because of its tendency to bind to TBG and

displace T4 with more T4 available in the free state;
Plasmapheresis, peritoneal dialysis or even surgery (total thyroidectomy) if
clinical status does not improve.
Hypothyroidism and thyroidites

Hypothyroidism is a clinical syndrome resulting from a deficiency of thyroid
hormones, which in turn results in a generalized slowing down of metabolic
processes. This can be primary (in 99% of cases), appeared due to loss or
permanent distruction of thyroid tissue, or central (secondary and tertiary) due to
insufficent stimulation of thyroid gland as a consequence of pituitary, hypothalamic
diseases or TSH defect.
Classification of hypothyroidism:
1. Primary hypothyroidism:
Hashimotos autoimmune thyroiditis (HAT).
Iodine deficiency (endemic goiter), use of goitrogenic
Drugs: iodine excess (including iodine-containing contrast media
and amiodarone), lithium, antithyroid drugs, thyrozin-kinase
inhibitors (sunitinib) or cytokines (interferon , interleukin 2)
Thyroid infiltration (amyloidosis, hemochromatosis, sarcoidosis,
scleroderma, Riedels thyroiditis).
Iatrogenic: 131I treatment, subtotal or total thyroidectomy,
external irradiation of neck for lymphoma or cancer
Consumptive: rapid degradation of thyroid hormones in large
hemangiomas caused by high expression of 5-deiodinase (DIII)
Transient (in adulthood):
o Subacute thyroiditis,
o Silent thyroiditis,
o Postpartum thyroiditis.
i. Thyroid agenesis, dysplasia or ectopy (85% of congenital
ii. Disturbances in thyroid hormone synthesis and secretion:
Iodide transport or utilization defect (mutations in
Organification disorder (TPO deficiency or dysfunction), a variant: Pendreds syndrome characterised by deafness, goiter and congenital
Defect in TG synthesis or processing.
iii. Transient
Severe deficiency or excess of iodine,
Transfer of blocking antibodies from the mother,
ATS administration to the mother.

2. Central:
i. Secondary ( pituitary origin),
ii. Tertiary (hypothalamic),
iii. Dopamine administration,
iv. Bexarotene (retinoid X receptor agonist)
Severe illness.
i. TSH deficiency or structural abnormality,
ii. Plurihormonal pituitary insufficiency,
iii. TSH receptor defect.
3. Resistance to thyroid hormones:
Thyroid hormone deficiency is manifested in every tissue by accumulation of
glycosaminoglycans, especially hyaluronic acid due to their decreased metabolism.
This accumulation of hydrophilic substances in interstitial tissues increases capillar
permeability to albumine and account for the interstitial nonpitting edema (especially
in skin, myocardium and striated muscle).
Clinical manifestations
These manifestations are largely independent of the underlying disorder but
are a function of the degree of hormone deficiency, time of onset (acute or chronic,
slowly progressive) and the age of clinical onset. The term myxedema (sometimes
still used as a synonym for hypothyroidism) refers to the appearance of the skin and
subcutaneous tissues in the patient who is in a severely hypothyroid state.
Clinical manifestations in children
The term of endemic cretinism have been introduced for children born in
iodine deficiency areas with severe mental retardation, dwarfism and neurological
anomalies. In iodine-sufficent areas the major causes of congenital myxedema are
thyroid agenesia or ectopy, defects in hormonogenesis, excessive iodine or ATS
administration to the mother.
The incidence of congenital hypothyroidism varies between 1:1000 to 1:4000
in newborns, the transient forms being more frequent.
NB: More than 90% of newborns with congenital hypothyroidism do not
present at birth clinical signs or have just minor signs; thats why the introduction of
neonatal screening for precocious detection is justified.. Newborn baby with
congenital hypothyroidism frequently has a gestational age over 42 weeks. During
the first few months of life, symptoms and signs of hypothyroidism include:
respiratory difficulty;
feeding problems, failure to thrive, constipation,
hoarse cry,
In succeeding months, especially in severe cases, protuberance of the
abdomen, umbilical hernia, dry skin, delayed eruption of the deciduous teeth become
evident. The characteristic appearance includes a broad, flat nose; periorbital
puffiness; large protruding tongue. Important delay of bone maturation (at birth,

absence of the proximal tibial epiphysis and distal femoral epiphysis) and large
fontanelles are described. Palpable goiter appeares after a few months in case of
Thyroid hormone deficiency in fetal life or at birth affects neurologic
development including hypoplasia of cortical neurons, retarded myelinisation and
reduced vascularity. The uncorrected hypothyroidism immediately postnatal (first 4
months) determines irreversible CNS lesions, clinically manifested by retardation in
neuromotor development. The parameters of normal development are severely
delayed: the child can not hold his head at 3 months of age, can not sit around 6months and can not walk at 1-year of age.
In children and adolescents the main clinical sign of hypothyroidism is linear
growth impairment and dwarfism, as a consequence of reduced protein synthesis,
especially due to decreased GH and IGF-1 secretion. Disproportionated dwarfism
(short neck and limbs, epiphyseal dysgenesis delay in appearance of ossification
nuclei) and dental defects appear constantly in untreated children. Reduced school
performance, cognitive disturbances are frequently described. Deafness and mutism
or balbism may be present. The typical signs and symptoms of hypothyroidism seen
in adults may be present.
Delayed sexual maturation or premature puberty may develop.
Clinical presentation in adults
In adulthood hypothyroidism is well tolerated, mainly if it develops gradually.
The major signs and symptoms are described in table 8.
Table 8. Signs and symptoms of hypothyroidism
Tiredness, weakness
Dry skin
Sensation of cold
Hair loss
Difficulty concentrating and impaired memory
Weight gain with poor appetite
Hoarse voice
Menorrhagia (later oligomenorrhea or amenorrhea)
Impaired hearing

Dry, coarse skin; cold extremities
Puffy face, hands, and feet (myxedema)
Diffuse alopecia
Loss of eyebrows
Peripheral edema
Delayed tendon reflex relaxation
Carpal tunnel syndrome
Serous cavity effusions

Skin. The skin is cool and pale in patients with hypothyroidism because of
decreased blood flow. Sweating is decreased because of decreases in calorigenesis
and acinar gland secretion. Nonpitting edema (myxedema) occurs in severe
hypothyroidism and may be generalized. Reduced conversion of carotene to vitamin
A and increased blood levels of carotene may give the skin a yellow tint. In central
hypothyroidism skin infiltration is less expressed.
Cardiovascular signs. Hypothyroidism is manifested by impaired ventricular
contraction, bradycardia, and increased peripheral resistance, resulting in diminished
cardiac output. Increased peripheral resistance may be accompanied by
hypertension, particularly diastolic.
Cardiac enlargement may occur, due to:

interstitial edema,
left ventricular dilation,
nonhemodynamically significant pericardial effusion.
The electrocardiogram (ECG) may reveal low voltage of QRS complexes and
P and T waves. Coronary artery disease is more common in patients with
hypothyroidism, likely related to increased levels of total cholesterol, LDL cholesterol,
and possibly other nontraditional atherogenic factors such as lipoprotein A and
homocysteine. In patients with angina pectoris, hypothyroidism may protect the heart
from ischemic stress, and replacement therapy may aggravate the angina by
increasing myocardial oxygen consumption.
Respiratory system Fatigue, shortness of breath on exertion, rhinitis,
bronchial infections and decreased exercise capacity may result. Sleep apnea
occurs in some patients with hypothyroidism, mostly as a result of macroglossia.
Gastrointestinal disorders Decreased gut motility results in constipation
(may determine even marked ileus). Other gastrointestinal problems that can occur
in hypothyroidism are:
Decreased taste sensation;
Galbladder hypotonia;
Gastric atrophy due to the presence of antiparietal cell antibodies;
A modest weight gain due to decreased metabolic rate and accumulation of fluid (nonpitting edema) is a frequent finding. However,
marked obesity is not characteristic of hypothyroidism!!
AnemiaThere are at least four mechanisms that may contribute to anemia
in patients with hypothyroidism:
(1) impaired hemoglobin synthesis as a result of thyroxine deficiency;
(2) iron deficiency from increased iron loss with menorrhagia;
(3) folate deficiency from impaired intestinal absorption of folic acid;
(4)pernicious anemia, with vitamin B12-deficient megaloblastic anemia.
Pernicious anemia is often part of a cluster of autoimmune diseases, including
hypothyroidism due to Hashimoto or autoimmune thyroiditis associated with thyroid
autoantibodies, pernicious anemia associated with parietal cell autoantibodies,
diabetes mellitus associated with islet cell autoantibodies, and adrenal insufficiency
associated with adrenal autoantibodies (Schmidt syndrome; the polyglandular failure
Renal function is impaired; renal blood flow, glomerular filtration rate, tubular
reabsortion and secretion are all reduced; there is also an impaired ability to excrete
a water load. This predisposes the hypothyroid patient to hyponatremia from water
intoxication, if excessive free water is administered.
Reproductive abnormalities Women with hypothyroidism may have either
oligo- or amenorrhea or hypermenorrhea-menorrhagia. These menstrual changes
result in decreased fertility. If pregnancy does occur, there is an increased likelihood
for early abortion. Hyperprolactinemia with amenorrhea or galactorrhea may occur.
Decreased libido, erectile dysfunction, and delayed ejaculation are found in
some of the hypothyroid men, but are reversible under treatment with thyroid
Central and peripheral nervous system are equally affected in hipothyroidism.
All intellectual functions are slowed, with loss of initiative, lethargy, somnolence.
Decreased intellectual performances and even dementia may appear. Other

manifestations includ headache, carpal tunnel syndrome, polyneuropathy, syncope

(due to brain hypoxia) and even stupor and coma.
Neuromuscular system Many patients complain of symptoms referable to
the neuromuscular system, including severe muscle cramps, paresthesias, and
muscle weakness.
Psychiatric disorders of paranoid and depressive type are more frequent, but
agitation is sometimes described (myxedema madness).
The term "Hashimoto's Encephalopathy" has been used to describe the
association of encephalopathy with autoimmune thyroiditis. A somewhat controversial disorder, Hashimoto's encephalopathy is believed to be an immune-mediated
disorder, rather than representing the direct effect of an altered thyroid state on the
central nervous system.
In untreated primary hypothyroidism, the pituitary and adrenal function can be
affected secondary and adrenal insufficiency can be precipitated by the rapid thyroid
hormone substitution. The plasma renin activity is low.
Paraclinical investigations and laboratory
In the condition of low fT4 and T3 level, the measurement of TSH
differentiates primary hypothyroidism (high TSH over 10 mU/L) from secondary form
(normal or low TSH) in most of cases (excepting hypothyroidism after treatment of
hyperthyroidism when TSH may remain suppressed weeks or even months). Anti
TPO and anti TG antibodies are frequently usefull; in case of high titer the diagnosis
of Hashimotos thyroiditis is assured, and if they are negative, a transient form of
post-thyroiditis hypothyroidism or thyroid infiltration are suspected.
Congenital hypothyroidism requires first of all neonatal screening (TSH or T4
from a dry blood spot on filter paper, on the 3-5 days of life). The determination of
thyroglobuline (undeterminable in thyroid agenesis), ultrasound, RAIU with TSG
(with 99Tc) are also necessary. Bone age determination, growth chart and
morphogram complete the investigations in congenital forms or in case of childhood
onset. Psychomotor tests or IQ evaluations are effectuated to supervise neuropsychic development.
Biochemical explorations show hyponatremia, hypoglycaemia (through adrenal insufficiency), anemia, modifications of blood lipids (elevated serum cholesterol
levels, especially LDL). Hyperuricemia and positive calcium balance may appear.
RAIU is rarely necessary in the diagnosis of hypothyroidism in adults.
Ultrasound is important because can offer dates about the thyroid volume (atrophy,
goiter), the coexistence and course of nodules.
In primary hypothyroidism cerebral MRI may demonstrate an increase in
pituitary gland volume by the hypertrophy and hyperplasia of thyrotroph cells
(reversible with substitutive treatment).

Differential diagnosis
In children, differential diagnosis of congenital hypothyroidism has to be made
with other dwarfisms associated with mental retardation: Down syndrome,
mucopolysaccharidoses (Hurler, Hunter syndrome), but also with pituitary dwarfism,
Turner syndrome, pseudohypoparathyroidism.

In adulthood, hypothyroidism must be differentiated from nephrotic syndrome

or renal insufficiency, where edema is constantly present. Cardiac failure,
depression, ichthyosis, acromegaly at onset, gout or hyperuricemia and dyslipidemias are other diseases which must be differentiated from hypothyroidism. The
false low fT4 may appear after administration of phenitoin, glucocorticoids,
salicylates or carbamazepine. In severe illness the modification of thyroid hormone
and TSH secondary to the underlying diseases should be taken into account.
The best differentiation method to separate secondary (pituitary) hypothyroidism from tertiary (hypothalamic) form is MRI, focused on sellar and suprasellar
regions. If central form is suspected, adrenal and gonadal function, and in children
GH-secretion must be investigated paralelly.
Course, complications and prognosis
Untreated hypothyroidism determines a progressive, gradually deterioration of
all metabolisms, with possible appearance of myxedema coma and exitus. Longterm prognosis is excelent if treatment is adequate. The risk of overdosage does
exist: palpitation, cardiac arhythmias (atrial fibrillation, supraventricular tachycardias)
or reduced bone density may occure.
Treatment of patients with severe hypothyroidism and coronary artery
disease, may be very difficult, because levothyroxine replacement can be associated
with exacerbation of angina, heart failure, or myocardial infarction. Coronary angioplasty, or coronary artery bypass surgery are sometimes necessary before thyroxine
replacement therapy.
The treatment of both adulthood and childhood hypothyroidism consists of
substitution therapy with thyroid hormones. The drug of choice is levothyroxine
(LT4), administered once a day before breakfast, the absorption being about 80%.
Plasma half-time is 7 days. LT4 is a prohormone with a very reduced intrinsic
activity, is deiodinated into T3 in peripheral tissues, which constitutes an advantage,
because the own physiologic control mechanisms on active hormone production are
used. The dose of T4 varies according to the patient's age and body weight (tabel 9).
Table 9. Replacement Doses of Levothyroxine.
0-6 months
7-11 months
1-5 years
6-10 years
11-18 years

Dose (g/kg/day)

Although dessicated animal thyroid preparations are available, they are not
recommended because the ratio of T3 to T4 is nonphysiologic. The use of
levothyroxine combined with liothyronine (triiodothyronine, T3) has been investigated, but benefit has not been confirmed. There is no place for liothyronine alone as
long-term replacement, because the short half-life necessitates (three or four daily
doses) and is associated with fluctuating T3 levels.

In children and in the majority of adult patients the treatment is started with
the total estimated dose; the final dose is adjusted based on serum TSH level after
4-6 weeks. The goal is to normalize the serum TSH. In older patients or patients with
underlying heart disease, it is best to start with a low dose of T4 (eg, 0.025 mg daily)
and increase the dose at 4- to 6-week intervals based on serum TSH
The contraindications of the medication are: acute myocardial infarction,
untreated cardiovascular conditions, hyperthyroidism.
In children treatment monitoring is performed at 2-4 weeks at the beginning,
then at 3-6 months. At 2-years of age the medication could be withdrawn for 6 weeks
and determination made for fT4 and TSH in order to evaluate thyroid function and
diagnosis (transient forms with normalised hormone levels do not need further
In adults once full replacement is achieved and TSH levels are stable, followup measurement of TSH is recommended at 6 months and than at annual intervals.
The restabilization of euthyroid state may increase T4 clearance and consequently
dose adjustement is needed. In some situations thyroxin requirement is increased:
Gastrointestinal disorders associated with malabsorption;
Treatment with different drugs or substances which decrease T4
o Cholestyramine,
o Sucralfate,
o Aluminium hydroxide,
o Calcium supplements,
o Iron compounds
Treatment with substances which increase T4 metabolism :
o Carbamazepine,
o Estrogens,
o Phenytoin.
Inhibition of deiodinase synthesis in:
o Selenium deficiency,
o Cirrhosis;
Administration of soy products.
LT4 requirement decreases with age or androgen administration in women.
In subclinical form (TSH above 4.5 mU/L and normal fT4 and fT3) some
controversy exist regarding the opportunity of substitutive treatment, although it is
indicated in one of the following situations:
The presence of some symptoms of reduced or moderate intensity
(depression, constipation etc.);
Pregancy or infertility;
Dyslipidemia (usually hypercholesterolemia);
Very high titer of anti TPO antibodies and goiter.
Myxedema coma
The most redutabil complication of hypothyroidism is myxedema coma with a
high mortality rate ( 50%). Predisposing factors for coma are:
Cold exposure;
Infections, pneumonia;

Myocardiac infarction, gastrointestinal hemorrhage;
Some drug, such as sedativs and opioids, anesthetics.
Hypoventilation, leading to hypoxia and hypercapnia, plays a major role in
pathogenesis; hypoglycemia and dilutional hyponatremia also contribute to the
development of myxedema coma.
Clinically it appears with the signs of myxedema with insidious course to
extreme asthenia, lethargia and coma. Bradycardia, and marked hypothermia with
body temperature as low as 24C (75F) are unmissing clinical sings.
Very elevated TSH in primary form and usualy very high titer of anti TPO ab;
Lactescent serum with very high serum cholesterol;
Increased cerebrospinal fluid protein
Hypoglycemia, hypo- or hypercalcemia, hyponatremia, LDH, CPK.
The state of counsciousness is significantly affected, with obnubilation or
rarely agitation. Epileptic seizures or only EEG modifications appear.
The treatment of myxedema coma is an emergency and must be treated in an
intensive care unit; the patient needs periodical monitoring of blood gases and
mechanic ventilation.
In myxedema coma thyroid hormone must be administered intravenously (the
digestive absorption is profound alterated), T4 in high initial doses of 300-400 g,
then 100 g/day. If this treatment is not followed by evident clinical improvement, 5
g intravenous T3 is administered, every 6 hours.
External warming is indicated only if the temperature is <30C, as it can result
in cardiovascular collapse.
Any precipitating factors should be treated, including the early use of broadspectrum antibiotics, pending the exclusion of infection.
Maximal precaution at liquid administration must be taken due to risk of
hyponatremia. Primary or pituitary adrenal insufficiency may be associated, so
hydrocortisone hemisuccinate in 100 mg doses i.v. is administered, followed by 50
mg intravenously every 6 hours.
Chronic thyroiditis (Hashimoto thyroiditis, lymphocytic thyroiditis, CTH)
It is the most frequent cause of hypothyroidism in iodine-sufficient areas, it
affects about 3% of adult population, predominantly the female gender, but it
manifests also in children and adolescents.
Idiopatic myxedema is considered the final stage of CTH, when atrophic
thyroiditis develops by complete destruction of follicular parenchyma.
Etiopathogenesis of CTH
CTH is considered a multifactorial disease, appeared as a consequence of
interactions between genetic factors responsible for the susceptibility to this disease
and environmental factors. The frequent association with BGD inside families and
even transition of BGD in CTH and viceversa in some patients suggests a close
physiopathological interrelation. Anyway, it may be considered that the spectrum of
thyroid autoimmune diseases has two extremes represented by idiopathic
myxedema and BGD and multiple intermediate variants.

Histologically the thyroid contains a massive lymphocytic (both LT and LB)

and plasmocytic infiltration which destroy the normal follicular architecture. Follicular
cells are enlarged and contain eosinophilic cytoplasm (Hrthle cells); fibrosis is
generally present. Intrathyroidal B lymphocytes are activated and have the capacity
to secrete antibodies against certain specific antigenes. These antibodies are formed
against TG, TPO and TSH-R. The majority of patients with CTH anti TG antibodies
have high titer in incipient phase, then these disappear; in contrary, anti TPO
antibodies are present from the onset of the disease and persist many years. They
can have a direct cytotoxic effect on thyrocytes, but their importance is reduced in
comparasion with cytotoxicity induced by LT. In CTH, Th1CD4+ helper LT
dominates, inducing apoptotic destruction of thyrocytes by secretion of interleukine-2
(IL-2), interferon gamma and TNF- (tumor necrosis factor-beta).
Possible trigger factors of CTH are:
Certain viral infections there is suggestive evidence that the hepatitis C
virus may enter thyroid cells and precipitate thyroid disease in susceptible
Iodine and iodine-containing drugs (e.g., amiodarone);
Exposure to radiation.
Clinical presentation
The course of this disease is invariable to gradually loss of thyroid function.
Occasionally, CTH may begin with thyrotoxicosis by destruction or by the action of
stimulatory antibodies against TSH receptors.
The signs of hypothyroidism may develop over several years in patients who
are initially euthyroid. Clinical manifestations of juvenile form (with onset in childhood
or in adolescence) consist of impaired bone growth and maturation, decrease of
school performance, infiltrative modifications.
Goiter is present from the beginning, is usually moderate in size, mobile and
firm in consistency. The surface is either smooth or bumpy, but well-defined nodules
are not usually present. Both lobes are enlarged, but the gland may be asymmetric.
Older patients may present severe hypothyroidism and correlated with a
small, firm atrophic thyroid gland (called idiopathic myxedema, although the
autoimmune etiology is evident).
Laboratory and paraclinical investigations
Initial phases are manifested as subclinical hypothyroidism when only TSH is
increased, fT4 and fT3 are normal, but progressively overt hypothyroidism develops
and remains permanent in most patients. Positive diagnosis is given by the
increased titer of thyroid antibodies.
RAIU may be high, normal, or low and scintigraphy is not necessary but it can
evidentiate a heterogenous aspect. Thyroid utrasound shows frequently an
hypoechoic aspect.
Sometimes part of a gland with autoimmune thyroiditis may look and feel like
a firm thyroid nodule, and ultrasonography or even aspiration biopsy should be performed to resolve the issue.


Clinical forms
The following entities are considered variants of CTH:
Silent (painless) thyroiditis is more frequent in women. The major clinical
manifestation is thyrotoxicosis, that last from two to eight weeks before subsiding.
This phase may be followed by recovery or by hypothyroidism (usually clinically
mild or even asymptomatic) for two to eight weeks. The thyroid is diffusely
enlarged. The erytrocyte sedimentation rate (ESR) is sometimes moderately
elevated. RAIU shows low uptake and TSG could not be performed. Eventually,
however, up to 50 percent of patients develop chronic autoimmune thyroiditis with
permanent hypothyroidism, goiter, or both.
Postpartum thyroiditis is similar clinically and pathogenetically to painless
thyroiditis except that, by definition, it occurs in women within one year after
parturition (or after spontaneous or induced abortion). The onset of thyrotoxicosis
is usually in 3-4 months postpartum. It needs to be differentiated from Graves'
hyperthyroidism, which can also begin during the postpartum period, either as
recurrent or new-onset hyperthyroidism. The risk of recurrence of postpartum
thyroiditis at the following pregancies is higher. Selenium administration (200
mcg/day) to pregnant women with positive anti TPO ab can reduce the risk of
postpartum thyroiditis.
Riedels thyroiditis is a very rare form of CTH with extensive sclerosing fibrosis
which invades not only the thyroid but also the surrounding tissue. Riedels
thyroiditis clinically appears as a goiter of stony hard consistency, fixed, and often
not clearly separable from the adjacent tissues. It is probably a primary fibrosing
disorder, and has been reported in patients who also had mediastinal and
retroperitoneal fibrosis. Most patients are euthyroid, but a few are hypothyroid.
Glucocorticoids have been used for treatment, with sporadic improvement. The
use of tamoxifen has also been successful in some patients. Surgery may be
indicated to relieve tracheal or esophageal compression and occasionally to
exclude carcinoma.

Differential diagnosis
It has to be made with non-differentiated or differentiated forms of thyroid
carcinoma, subacute, or acute thyroiditis and non-toxic goiter.
The indications of treatment are goiter and hypothyroidism. Subclinical forms
require 25-50 g/day LT4 and overt hypothyroidism 100-150 g/day LT4. If only a
high antithyroid antibody titer does exist treatment is not necessary.
The administration of iodine containing preparation must be avoided.
In thyrotoxic phases of postpartum or silent thyroidites beta-adrenergic
blocker administration is enough (Propranolol 40-80 mg/day or Atenolol 25-50
Chronic thyroiditis may be a component of a multisystemic autoimmune
disease, therefore patient must be monitoring for other conditions such as pernicious
anemia, adrenal insufficiency, type I diabetes mellitus or lymphocytic hypophysitis
(especially in postpartum form) and their adequate treatment are required.


Subacute thyroiditis ( SAT)

It is an acute inflammation of thyroid parenchyma, also termed de Quervain's
thyroiditis, granulomatous thyroiditis, or viral thyroiditis. Subacute thyroiditis is
presumed to be caused by a viral infection or a postviral inflammatory process. The
majority of patients have a history of an upper respiratory infection prior to the onset
of thyroiditis (typically two to eight weeks before). Many viruses have been
implicated, including mumps, coxsackie, influenza, adenoviruses, and echoviruses,
but attempts to identify the virus in an individual patient are often unsuccessful and
do not influence management. It appears more frequently in women with HLA B35
Histopathologically the thyroid is enlarged with moderate inflammatory
reaction, thyroid capsule being also involved. Widespread infiltration with neutrophils,
lymphocytes, histiocytes and giant cells, disruption and necrosis of thyroid follicles
are described.
The onset may be sudden or gradual with fever, fatigue, malaise, anorexia,
and myalgia. In many patients neck pain is the dominant symptom. The pain may be
limited to the region of the thyroid (spontaneously and to palpation) or radiate to the
upper neck, jaw, throat, upper chest, or ears.
Clinical signs of thyrotoxicosis (by follicular destruction and release of thyroid
hormones) develop with palpitation, nervousness etc.
The thyroid gland is typically slightly or moderately (diffusely or asymmetrically) enlarged and tender. In some cases, the pain is so severe that the patient
cannot tolerate palpation of the neck. Ophthalmopathy is absent but tachycardia,
tremor, ehanced tendon reflexes may occur.
Laboratory shows:
The erythrocyte sedimentation rate is usually greater than 50 mm/hour
and may exceed 100 mm/hour. C-reactive protein, fibrinogene may
also be elevated.
TSH, fT4 and fT3 (acompanying thyrotoxicosis) in the initial phase,
followed by the second short period of euthyroid state. The third phase
corresponds to transient hypothyroidism and in the last recovery
phase, euthyroid state is restored.
A low RAIU (usually less than 1 to 3 percent) confirms the diagnosis;
On ultrasonography the thyroid appears to be normal or enlarged, but
is diffusely or focally hypoechogenic.
FNA biopsy usually is not necessary (could be very painfull), but it can
in identify the infiltration of thyroid with giant cells.
Positive diagnosis is performed on the basis of symptomatology, low RAIU
and the presence of inflammatory markers.
Differential diagnosis must consider other forms of thyroiditis (acute, HTC),
thyroid cysts, intracystic hemorrhage, BGD and thyroid cancers.
Subacute thyroiditis usually resolves completely and spontaneously over
weeks or months. Occasionally, the disease may begin to resolve and then suddenly
become worse, sometimes involving first just one lobe of the thyroid gland and then
the other (migrating or creeping thyroiditis).
The treatment consists of the administration of nonsteroidal antiinflammatory
drug (Phenylbutasone, Paduden, Ibuprofen, Indometacin) for 2-3 weeks in mild formes. If there is no improvement in two or three days, the nonsteroidal antiinfla82

mmatory drug should be discontinued and prednisone (40 mg daily) introduced.

These anti-inflammatory agents should be used for only a short period of time until
the pain resolves and then should be gradually discontinued. The usual course is
two to eight weeks.
Acompanying thyrotoxicosis is treated with betablockers and sedatives.
Transient hypothyroidism does not need any therapy, but if symptoms appear LT4 is
administered for 3-6 months and then suspended; the patient is evaluated again at
4-6 weeks after interruption. In about 10% of patients, permanent hypothyroidism
results, and long-term T4 therapy is necessary
Other forms of thyroiditis

Acute infectious, bacillary or fungal thyroiditis, with the formation of thyroid

abscesses arise usually in immunocompromised hosts, by hematogenic
dissemination. The most frequent involved germens in this case are Aspergillus,
Mycobacteria or Pneumocystis, but can be common pyogene germens
(streptococcus, staphylococcus) or Koch bacillus as well. All local signs of
inflammation are present: tumor, rubor, calor, dolor, functio lesa. Needle
aspiration confirms the diagnosis and identifies the organism. ESR, C reactive
protein, fibrinogen have high values, leukocytosis with neutrophilia develop.
Treatment includes antibiotic or antifungal therapy and occasionally incision and
Irradiation thyroiditis is caused by external radiation of the cervical region or at 510 days after RIT with 131I (for hyperthyroidism). Histologically tissular necrosis,
edema, local inflammatory infiltration or haemorrhage and thrombosis can be
present. Clinically local pain and the exacerbation of hyperthyroidism may
appear. Healing appear spontaneously but it may need NSAID or glucocorticoid
Palpation thyroiditis ensues a vigorous palpation of the thyroid during
examination, surgery, aspiration biopsy or posttraumatic (caused for example by
the seat belt in road accidents). It manifests clinically with neck pain, tenderness
and mild clinical signs of transient thyrotoxicosis.
Endemic goiter and other iodine deficit disorders

The diseases in this group refer to the pathology determined by the

geoclimacteric iodine deficit (IDD Iodine deficiency disorders).There are broad
geographic areas where the population's daily intake of iodine is below the
recommended dietary allowance, and the population is affected by IDD. These areas
frequently are mountainous because the soils with lowest iodine content are those
that were covered longest by quaternary glaciers. When these glaciers melted, most
of the iodine leached out of the ground beneath. All plants and cereals from these
regions will not contain enough iodine.
The most important effects of the iodine deficiency are:
Endemic goiter,
Mental retardation and cretinism,
Increased neonatal and infant mortality.

Endemic goiter
A geographic area is arbitrarily defined as an endemic goiter area if more than
5% of the children aged 6 to 12 years have a goiter. The disease may be seen
throughout the Andes of central South America, in the Himalayas, in the European
Alps where iodide prophylaxis has not yet reached the entire population, in the
Middle Eastern countries, Indonesia, in many foci in the People's Republic of China.
With the widespread use of iodized salt and the introduction of iodides into
fertilizers, animal feeds and food preservatives, iodide deficiency in developed
countries has become relatively rare. However, there are large areas where iodine
intake is still markedly deficient.
It is estimated that 50 percent of the world population still live in countries with
significant iodine deficiency and may risk its consequences.
Iodine nutrition at the community level is best assessed by:
measurements of urinary iodine,
thyroid size,
serum TSH and thyroglobulin.
The urinary iodine concentration indicates current iodine nutrition, while
thyroid size and the serum thyroglobulin concentration reflect iodine nutrition over a
period of months or years.
A system for classifying iodine deficiency and sufficiency has been developed
based upon the median urinary iodine concentration in a population (table 10)
Table 10. Urinary iodine concentration
Median urinary
iodine concentration (mcg/L)

Iodine nutrition
Severe deficiency
Moderate deficiency
Mild deficiency
More than adequate
Possible excess

Measurements of urinary iodine concentration in randomly collected urine

samples have proven to be as useful as measurements of urinary creatinine and
iodine and calculation of the iodine/creatinine ratio.
Etiopathogenesis of the endemic goiter
The main cause of the endemic goiter remains an exogenous iodine intake of
less than 150 g/day, in an adult. Iodine deficiency is not the sole cause of endemic
goiter. Indeed, the disease has been found in regions where there is no iodine
deficiency. Conversely, some other regions with extremely severe iodine deficiency
are free of endemic goiter .
These data strongly suggest that goitrogenic factors in the diet or
environment, in the presence of a suboptimal iodine supply or if their administration
is durable, can play a critical role in the etiology of the disease.
Goitrogens can be divided into agents acting directly on the thyroid gland and
those causing goiter by indirect action.

Substances with a direct goitrogen effect are acting by:

inhibiting transport of iodide into the thyroid: thiocyanate and
acting on the organification of iodide and/or the coupling reaction:
phenolic compounds, disulfides, goitrin, thiocyanate in higher doses,
interfering with TG proteolysis and thyroid hormone release: lithium
Indirect goitrogens increase the rate of thyroid hormone metabolism:
Polychlorinated (PCB), polybrominated (PBB) biphenyls, dinitrophenol
Natural goitrogens were first found in vegetables of the genus Brassica (of the
Cruciferae family) that cause goiter in animals. Their antithyroid action is related to
the presence of thioglucosides, which, after digestion, release thiocyanate and
A particular thioglucoside, goitrin is present in certain Cruciferae growing as
weeds. Goitrin has potent thionamide-like properties. It can probably reach humans
by ingestion of milk.
Another important group of naturally occurring goitrogens is the cyanoglucosides, which have been found in several staples (cassava, maize, bamboo
shoots, sweet potatoes, lima beans). After ingestion, they release cyanide, which is
detoxified by conversion to thiocyanate.
Selenium deficiency may have profound effects on thyroid hormone
metabolism and possibly also on the thyroid gland itself because of:
impaired function of type I deiodinase (a selenoprotein),
reduction of the selenium containing enzyme glutathione peroxidase,
posibly promoting apoptosis.
In the appearance of the goiter can also participate the urinary or fecal losses
of thyroid hormones and iodine (nephrotic syndrome, enterocolithis), periods of time
when there is an increased iodine need (pregnancy, nursing, puberty), an increase of
the blood proteins (hyperestrogenism, pregnancy, birth-control pills). Deficiencies of
iron and vitamin A may also have a goitrogenic effect in areas of iodine deficiency.
Endemic goiter is a disease of adaptation that develops in response to dietary
iodine deficiency. When iodine intake is abnormally low, adequate secretion of
thyroid hormones may still be achieved by marked modifications of thyroid activity.
These adaptations include stimulation of the iodide trapping mechanism as well as
preferential synthesis and secretion of T3. These responses are triggered and
maintained by increased secretion of TSH. The morphologic consequence of
prolonged TSH stimulation is the development of goiter, making it appear to be the
mechanism of adaptation to iodine deficiency. However, large goiters may no longer
be considered adaptive in view of their decreased ability to synthesize thyroid
High serum TSH levels have been reported often, but not systematically, in
humans with chronic iodine deficiency. Differences in the duration of high TSH levels
and in thyroid responsiveness to TSH, as well as other factors (e.g., growth
hormone, epidermal growth and fibroblast factors, insulin, cyclic GMP, or other
intrathyroidal mechanisms) may determine whether goiter develops.
The changes evolve through stages. In the first phase the characteristic
hyperplastic picture includes abundant parenchyma, high follicular epithelium and
rare colloid (hyperplastic goiter). On the contrary, in large goiters, the major part of
the gland is occupied by extremely distended vesicles filled with colloid with a

flattened epithelium (coloid goiter). Markedly distended follicles may fuse to form
colloid cysts, which are characteristic of nontoxic goiters.
A later stage is the formation of small nodules of different size and
consistency throughout the entire thyroid gland. The formation of nodules in nontoxic
goiters (adenomatous goiter) can only be explained by a constitutive heterogeneity
of the growth responses of individual thyroid follicular cells. There is an increase in
the total mass of follicular cells with autonomous iodine metabolism during goiter
growth. In large, old goiter areas of hemorrhagic necrosis, fibrosis, and even
calcification can be found. Repeated episodes of hyperplasia are followed by
involution and atrophy, the result being a gland containing a mixed bag of nodules,
zones of hyperplasia and involuting, degenerative, and repair elements.
Clinical manifestations
Anamnesis has to mention the place where the patient was born and raised,
eventually a goitrogens /drugs intake, the moment when goiter started to develop
and its growth pattern.
In most cases, a small goiter in a young person doesnt cause any symptoms
but only an esthetic discomfort. The changes in breathing, swallowing or speaking,
or even minor discomfort are present only in larger goiters.
The clinical general exam (inspection, palpation) has to focus on the position
and size of the goiter, the presence of nodules, their consistency and thyroid
consistency as a whole, mobility, sensibility, presence/absence of laterocervical
lymph nodes and compresive phenomena.
By palpation, a thyroid is considered goitrous when each lateral lobe has a
volume greater than the terminal phalanx of the thumbs of the subject being
The following simplified classification of goiter by palpation has been
proposed by WHO:
Grade 0: No palpable or visible goiter.
Grade 1: A goiter that is palpable but not visible when the neck is in the normal
position (i.e., the thyroid is not visibly enlarged). Nodules in a thyroid that is
otherwise not enlarged
fall into this category.
Grade 2: A swelling in the neck that is clearly visible when the neck is in a normal
position and is consistent with an enlarged thyroid when the neck is palpated.
The consistency of a goiter or of the nodules can be: soft, elastic or firm.
Hypertrophy can affect the entire thyroid or it can involve a lobe (lobar goiter). From
the point of view of its localization, it can be situated cervically (most frequently), at
the base of the tongue, intrathoracic (the inferior pole cannot be identified by
palpation), in the mediastin (retrosternally, usually without any conection with the
cervical thyroid). The mobility of the goiter with swallowing is usually maintained, and
the locoregional lymph nodes (laterocervical, submandibular, sub and
supraclavicular) are absent.
Laboratory and imagistic work-up
In most of the cases the patient has a normal thyroid function, with normal
fT3, fT4, TSH or TSH is slighly elevated and fT4 decreased; antibodies: anti TPO,
anti-TG and anti TSHR are negative. Urinary iodine excretion is diminished.
RAIU (radioiodine uptake) has high values (the thyroid is hungry for iodine)
and the scintigraphy of the thyroid reveals the marked heterogeneity of the goiters

and often cold or hot nodules. Thyroid ultrasound represents the most sensitive
method to evaluate thyroid volume, to identify and keep under surveillance possibly
existent nodules. Sometimes it is necessary to use other imagistic techniques:
thoracic X ray, MRI (for the mediastinal region, for example).
Differential diagnosis
The differential diagnosis with sporadic goiters (these appear in regions where
iodine is sufficient and have autoimmune mechanisms, or they are due to goitrogens,
drugs or even iodine excess) is established mainly by epidemiologic criteria.
Differential diagnosis of the endemic goiter is also made with benign tumors
(especially toxic adenoma) or malignant tumors, but also with other tumors from the
cervical region (thyrogloso-ductal cysts, parathyroid adenoma, lipoma, dermoid cysts
etc). If the pain is present, acute or subacute thyroiditis has to be also considered.
The thyroid in chronic thyroiditis has a firmer consistency and the antibodies are
Evolution and complications
Large goiters, which may displace or compress the trachea, esophagus, and
the neck vessels, can be associated with symptoms and signs including inspiratory
stridor, dysphagia, and a choking sensation. Compression of the recurrent laryngeal
nerve, resulting in hoarseness, suggests carcinoma rather than nontoxic goiter, but
vocal cord paralysis can occasionally result from benign nodular goiters.
The extension of the goiter towards the anterior mediastin can determine the
partial occlusion of the thoracic aperture, with consecutive obstruction of the venous
circulation. When the patient is asked to raise his arms above his head, this
maneuver narrows even more the thoracic inlet and it will be followed in a few
minutes by the external jugular venous obstruction and the appearance of the facial
congestion (Pemberton sign).
Another complication that can appear during this stage is the thyroid
inflammation called strumitis.
The nodules in an endemic goiter can be transformed as follows:
Toxic (autonomous) transformation of one of the nodules- appears
mostly because of a high iodine intake (drugs that contain a large
amount of iodine, contrast substances or excessive supplimentation of
iodine in food and water)
Cystic transformation can usually happen, and it leads to:
o Colloid cysts, formed by the coalescence of the macrofollicules,
o Hemorrhagic cysts (thyroid hematocell). One of the nodules
increases dramatically in volume, it is accompanied by acute pain.
Malignant transformation (rarely, especially a follicular carcinoma).
Nontoxic goiters, endemic or sporadic, usually grow slowly over decades, and
can never cause any problems. The current management for many cases consists
simply of observation, without any specific therapy.
The main indications for treatment of patients with nontoxic goiter are:
compression effects,
progressive growth of the entire goiter or of individual nodules,

sometimes, neck discomfort or cosmetic concerns.

The main therapeutic options are
administration of T4 and/or low-dose iodine treatment
administration of radioiodine.
Recommended iodine dose for treating endemic goiter, as in KI, is between
100 and 300 mcg/day, and this is only indicated in recent, diffuse, small goiters with
only a few symptoms, appearing in young persons. However, when the goiter is
multinodular, iodine supplementation is not advisable because it is rarely effective
and it may induce thyrotoxicosis.
Thyroid hormones are administered to suppress TSH, with doses between 0.1 and
0.2 mg/day (especially in elderly people, the starting dose is 12,5- 25 g/zi).
Suppression of serum TSH concentrations between 0.1 and 0.5 mU/L may be
adequate. This treatment is indicated in recent goiters, especially with hypothyroidism, when the response is optimal, with a significantly decrease of the thyroid
volume (with 30 to 40% reduction), but has to be continued for aproximately 1 year.
There are mixed regimen that can be used: T4 + iodine (75-150 g/day
levothyroxine and 100-200 g/day KI, like in Jodthyrox= 100 g levothyroxine and
100 g KI). Long-term T4 suppresive therapy may have adverse skeletal and cardiac
Surgery is indicated only if compresive phenomena are present or if theres
any suspicion of neoplasia (clinical or with FNA). Surgical treatment leads to rapid
decompression of vital structures and provides tissue for pathologic examination.
Usually bilateral subtotal thyroidectomy is performed, with removal of all grossly
abnormal tissue. Some surgeons advise more extensive resection (near-total or
even total thyroidectomy) in order to minimize the risk for recurrent goiter. The
prophylaxis of reccurence post-thyroidectomy is made by the administration of
levothyroxine in substitutive doses
Endemic goiter can also be treated with radioactive iodine in order to reduce
the volume of the goiter, especially in older people, in whom surgery or T4 treatment
is not advisable because of the associated heart disease. The efficacy of thyroid
volume reduction by radioiodine can be increased when pretreatment with
recombinant human TSH is given.
Endemic cretinism (EC) and other forms of IDD
Endemic cretinism is a developmental disorder that occurs in regions of
severe endemic goiter. The term was introduced before the description of the
congenital hypothyroidism and because of that there is a confusion between these
two term. The clinical pictures, even if there are common features, are not the same.
There are 3 forms:
Neurologic form, manifested by:
Deaf or deaf-mutism;
Neurological disorders: spasticity, motor dysfunction, coordination
severe mental retardation;
goiter in most of the cases, but not hypothyroidism.

Myxedematous form is characterized by:

Less severe degree of mental retardation than the neurological cretin;
Growth retardation;
Facial dysmorfism with macrocephaly;
Skeletal abnormalities (epifizis dysgenesis), dentition problems;
Myxedema with largely increased TSH, decreased fT4;
thyroid atrophy.
Mixed form.
The incomplete development of the cochlea, cerebral neocortex and corpus
striatum (mainly putamen and globus pallidus), because of the iodine deficit between
12 and 30 weeks of gestation are responsible for the neurological manifestations.
For myxedema forms with thyroid atrophy, iodine deficit manifests itself later
during pregnancy and after birth. There are also other factors that can contribute to
these manifestations: selenium deficiency or thiocyanate overload by the excessive
and constant use of cassava.
Iodine deficiency during pregnancy can determine mental retardation as its
unique manifestation or neurological discrete abnormalities. Infantile and neonatal
mortality is increased in endemic regions.

Prophylaxis and treatment

For endemic cretinism, T4 treatment are indicated only if there is
hypothyroidism or a large goiter. In order to prevent IDD, the World Health
Organization's recommendations for daily intake of iodine is:
o infants 5 years, 90 mcg/day;
o children aged 6 to 12 years, 120 mcg/day,
o adults, 150 mcg/day,
o pregnant and lactating women, 250 mcg/day.
Mild iodine deficiency is defined as an intake of 50 to 99 mcg/day, moderate
deficiency as an intake of 20 to 49 mcg/day, and severe deficiency as <20 mcg/day.
Iodine fortification and supplementation can be done by:
iodized salt, considered the most appropriate measure for iodine fortification:
20-50 mg of iodine/kg NaCl, as potassium iodide or iodate. Salt that is used
in animal feed and food industry needs also to be iodized,
iodized oil (orally or injectable),
potassium iodide tablets during periods with an increased need, in weekly
administration (1mg tablets: tb/week until 6 years, 1tb/week between 7
and 14 years, 2tb/week in pregnant and lacting mothers) or daily use of 100200 mcg tablets
iodized water (drinking water and irrigation).
Regular monitoring of iodine nutrition is essential for sustaining iodine
sufficiency. This is best performed by dosing the urinary iodine, TSH values and
thyroid volume in a large number of people from different regions. Some countries
that achieved iodine sufficiency are now in danger of backsliding because of
inadequate monitoring and lack of effective governmental infrastructure and


Thyroid neoplasia
Thyroid nodules are extremely common - the prevalence of palpable thyroid
nodules has been estimated to be about 4% of the adult population. Because of the
massive use of high-performance ultrasonography in clinical practice, it is estimated
that about 60% of healthy individuals can be diagnosed with thyroid nodules, the
vast majority of them being palpatory undetectable. These nonpalpable nodules,
called incidentalomas, have the same risk of malignancy as palpable nodules.
Table 11. Etiology of Benign Thyroid Nodules
Benign tumors
Multinodular goiter
Focal Hashimoto thyroiditis
Cyst: colloid, simple, hemorrhagic
Follicular adenoma: macro/microfollicular (cellular)
Hrthle cell adenoma (oxyfile): macro/microfollicular

The majority of thyroid nodules are benign (table 11), only about 5% to 10% of
nodules coming to medical attention are carcinomas. Thyroid cancer is considered a
rare disease, it represents 1% of the malign tumors, with an estimated annual
incidence of approximately 8.7 per 100,000 population. It appears 2-3 times more
frequently in women. Thyroid neoplasms can arise in each of the cell types that
populate the gland, including thyroid follicular cells, calcitonin-producing C cells,
lymphocytes, and stromal and vascular elements, as well as metastases from other
sites( tabel 12).
Table 12. The most frequent types of malignant thyroid nodules and their
Approximate Prevalence, %
Follicular epithelial cell
Well-differentiated carcinomas
Papillary carcinomas
Pure papillary
Follicular variant
Diffuse sclerosing variant
Tall cell, columnar cell variants
Follicular carcinomas
Minimally invasive
Widely invasive
Hrthle cell carcinoma (oncocytic)
Insular carcinoma
Undifferentiated (anaplastic) carcinomas



C cell (calcitonin-producing)
Medullary thyroid cancer

Other malignancies



Thyroid tumors etiopathology

Early studies of the pathogenesis of thyroid cancer focused on the role of
external radiation, which predisposes to chromosomal breaks. External radiation of
the mediastinum, face, head, and neck region was administered in the past to treat
an array of conditions, including acne and enlargement of the thymus, tonsils, and
adenoids. Radiation exposure increases the risk of benign and malignant thyroid
nodules, is associated with multicentric cancers, and shifts the incidence of thyroid
cancer to an earlier age group. Radiation from nuclear fallout also increases the risk
of thyroid cancer at 6 to 25 years after the event. The Cernobl accident resulted in
an increased number of papillary carcinoma (10-30 times more than before 1986) in
the contaminated regions (especially Belarus). Children seem more predisposed to
the effects of radiation than adults. Of note, many studies failed to show an increase
in cancer incidence among persons given 131I either for diagnosis or for therapy .
Autoimmune thyroiditis is a risk factor for thyroid lymphoma, and the thyroiditis
type of lesions frequently found in papillary carcinoma could represent reactive and
not inductive changes. Numerous studies found genetic anomalies in thyroid benign
and malignant tumors (as seen in table 13). An understanding of the mutations of the
proto-oncogenes and tumor suppressor genes that occur in these tumors should
eventually explain the diverse clinical characteristics of thyroid tumors and also direct
Table 13. Genetic modifications in thyroid tumors





involved genes
TSH receptor


Genetic anomalies/ outcome prediction

Gs-alpha subunit


Point mutation



Point mutations


1q 23



Activating mutations/increased reccurence



2q13, 3p25

Translocation/frequent vascular invasion,

appears in young



Activating point mutation/ distant




Point mutations, deletions, insertions


Activating mutations



Point mutations

Activating point mutation

Rearrangements (inversions, translocations/

positive outcome prediction


Clinical manifestations, paraclinical and laboratory work-up

In order to differentiate malignant from benign nodules, it is imperatory to have
a good anamnesis and physical exam, and also a thyroid ultrasonography,
scintigraphy (sometimes) and fine needle aspiration- considered as the gold
standard in the identification of malignant thyroid nodules.
The main physical and anamnestic risk factors useful in distinguishing benign
from malignant thyroid lesions:
Age: under 20 or over 60,
Sex: male gender,
History of head or neck irradiation during childhood or adolescence,
Accidental or therapeutical total irradiation (for medular transplant, for
example) ,
Positive family history of thyroid carcinoma or multiple endocrine neoplasia
(MEN syndromes)
A large nodule size (>4 cm), with irregular shape and firm consistency, imobile
(fixation to adjacent structures),
Rapid growth of the nodule or an increase of its volume under treatment with
thyroid hormones
Hoarseness (vocal cord paralysis), dysphagia, or obstruction,
Suspected regional lymph node involvement.
Elastography is a promising new technique that assesses hardness as an
indicator of malignancy in thyroid nodules and has high specificity and sensitivity
independent of nodule size.
The cytological results of the fine needle biopsy, as well as the ultrasound
findings in favor of malignant thyroid nodules are presented in extenso in the chapter
In vivo exploration. Scintigraphic malignant nodules are cold, they do not trap and
organify iodine. The hot nodules are almost always benign. Scintigraphy is no longer
considered a sensitive method to differentiate benign from malignant nodules, her
place in the thyroid nodules work-up has been taken by FNA.
MRI and CT imaging can define the extension of the thyroid tumor to the
mediastinum and its relationships to surrounding structures and search for bone or
lung metastases but are less sensitive than neck ultrasonography for the detection of
lymph node metastases.
Thyroid nodules discovered incidentally on Positron emission tomography
(PET) scans require ultrasound-guided FNA biopsy because they have a high rate of
A clinical algorithm to investigate a patient who has thyroid nodules is
presented in figure 4.


Figure 4. Decision matrix for work-up of a thyroid noduleadapted after Gardner DG, Shobank, Greenspans Basic and Clinical
Endocrinolog, 9-th edition

Papillary carcinoma (PC)

The most frequent clinical presentation is as a firm, solitary nodule, cold at
scintigraphy, solid in ultrasound examination. Sometimes, there is internal
calcifications or hemorrhage, necrosis and even cyst formation in the malignant
nodule. It can also appear in a multinodular goiter as a dominant nodule with a totally
different structure when compared with the rest of the nodules or the whole gland.
Occasionally, especially in children, enlarged cervical lymph nodes are the first sign
of the disease. Papillary carcinoma is highly differentiated and radiosensitive.
PC associates, in a variable proportion, papillae and follicles, but the follicular
compartment can predominate. Tumoral papillae are ramificated structures with a
central fibrovascular core and a single lining of cuboidal or columnar cells. The cells
present characteristic nuclear changes (big, pale, with clear intranuclear inclusions)
and other inconstant signs: invasive proliferative growing, laminated calcified
spheres and fibrous stroma. They grow very slowly and they invade the local tissues
and the lymph nodes. In some older patients, a long-standing, slowly growing
papillary carcinoma begins to grow rapidly and invade the trachea and the muscular
local tissue, disseminating to the lungs, bones, CNS.
The tumoral cells can produce thyroglobulin, which can be used as a marker
for recurrence or metastasis


Follicular carcinoma (FC)

The age at which develops is around 50, with a sex distribution of 1.5 : 1 for
female gender. The frequency of the follicular carcinoma is constantly diminishing: it
represents 5-10% of the thyroid carcinomas. This decrease is due to the iodine
prophylaxis - the regions with iodine deficit are those where the follicular carcinoma
appears more frequently.
The clinical presentation is similar to the PC. Follicular carcinoma can be
distinguished from benign follicular adenoma only microscopically by the presence of
the capsule and/or vascular invasion within the tumor capsule.
The tumoral cells have a morphology similar to the normal ones, except the
FC variants (oncocitar carcinoma, carcinoma with oxyfil cells or with clear cells), and
the nuclei are big, rounded and have nucleoli inside. The tumoral spread is
centrifugal, with the limited rupture of the nodule capsule, then by step-by-step
These tumors often retain the ability to concentrate radioactive iodine, form
thyroglobulin, and, rarely, synthesize T3 and T4 which is the reason why the
hyperfunctional secondary tumors are always from a FC. Even if the FC is more
aggressive than the PC, it responds well to radioiodine therapy. The dissemination of
the FC is done primarily through blood, with secondary tumors in the bone, lungs,
Medullary carcinoma (MC)
MC originates in C cells (parafollicular cells) derived from the neural ridges
and migrated into the ultimobranchial body, which serves as a vector to incorporate
into the thyroid lobes. They will not capture radioactive iodine. They can secrete
ACTH, VIP, prostaglandins, serotonin, carcinoembryonic antigen (CEA), but the
main secretory product of the C cells is calcitonin (CT). It is a hormone that produces
hypocalcemia by diminuating the bone resorbtion by the osteoclasts and the
regulation of the urinary calcium excretion. The seric calcitonin secretion is
stimulated by pentagastrin (PG), a substance that can be clinically used to stimulate
the calcitonin secretion.
MC represents approximately 4-5 % of the thyroid neoplasia, with an equal
male/female ratio. The age at which appears is variable: 50 years for the sporadic
form, earlier for the familial form. There are 2 clinical forms:
Sporadic MC approximately 75% - unilateral;
Familial MC approximately 25%, hereditary, with an autosomal dominant
transmission (activating mutations of the RET proto-oncogene). Familial MC
can be:
isolated, without associated endocrine disease,
associated with other endocrine disease, in a multiple endocrine
neoplasia, MEN 2 syndrome, type A or B:
MEN 2 A, consisting of: bilateral MC, bilateral pheochromocytoma (preceded by a medulosuprarenal hyperplasia), hyperparathyroidism (more frequent hyperplasia than adenoma).
There can be a pruritic skin lesion, named cutaneous lichen
MEN 2 B, very rare, consisting of: bilateral MC with an early
appearance (in 90% before 20 years of age) and rapid
progression, pheochromocytoma (in 50% of the cases),

dismorphism (marfanoid or skeleton anomalies), intestinal

ganglioneuromatosis simulating Hirschsprung disease, multiple
mucosal neuromas. There is no hyperparathyroidism. MEN type
2 B seems to be mostly sporadic (de novo mutations).
It is reccomended that MC diagnosis is made before surgery, because the
tumor needs first a large surgical intervention, which should be done by a specialized
team. There can be an associated pheochromocytoma, which involves major
anesthesia risks. This diagnosis is done by the citological examination of the thyroid
tissue or by dosing the seric calcitonin, before and after the administration of
pentagastrin. Some guidelines recommend routinely calcitonin measurement in
patients with thyroid nodules but there is a high false-positive rate.
The tumoral cells are poliedrical, fusiforms or rounded, their architecture is
variable, and the stroma, inequally disposed, contains pink-staining substance that
stains with Congo red, typical of amyloid.
If medullary thyroid cancer is diagnosed by cytology or at surgery, it is
essential that the patient be screened for one of the familial medullary thyroid
carcinoma syndromes by DNA analysis for mutations in the RET protooncogene. If a
mutation is found, family members should then be screened and genetic counseling
can be offered to those individuals who test positive for mutations.
Medullary thyroid carcinoma is typically more aggressive than papillary or
follicular carcinoma, extending locally to cervical lymph nodes and into surrounding
tissues. It can metastasize to lungs, liver and other viscera.
Anaplastic carcinoma (AC)
The tumor appears mostly in older patients and it predominates in females. It
is a big cervical mass locally compresive and producing dyspnea and difficulties in
swallowing. Sometimes it is a well-known thyroid nodule which hasnt changed
during the last years and suddenly starts to grow, rapidly increasing in volume. It is
sometimes accompanied by a cervical infiltration. The first sign of this type of cancer
can be the appearance of a lymphonodular or/and lung metastasis.
Hystopathologically the tumors are made partially or totally of undifferentiated
cells, fusiform, giant or/and poligonal cells that are always atypical and have
numerous mitosis.
AC has a reserved prognostic because these tumors are very resistant to all
currently available therapies and has a rapid local post-surgery reccurence. The
differential diagnosis is made by fine needle biopsy with Riedl thyroiditis and
lymphoma, as well as with other causes of thyroid nodules (solitary or multiple).
Thyroid lymphoma
The lymphoid tissue, which is absent in the normal thyroid gland, appears in
different diseases like nodular goiter, some epitelial tumors, but mostly during
chronic thyroiditis. Thyroid lymphoma can be primary, when theres always a chronic
active thyroiditis, or it appears within a generalised lymphoma. The treatment
consists in surgery, chemo- and radiotherapy.
Thyroid neoplasia treatment
The patients with well-differentiated thyroid carcinoma (PC and FC) may be
classified loosely into low-risk and high-risk groups. The low-risk group includes
patients under age 45 with primary lesions under 2 cm and no evidence of intra- or

extraglandular spread. All other patients should be considered high-risk .

I. The first step in treating these patients is surgery:
For the low-risk group - total thyroidectomy is generally recommended,
although lobectomy is probably adequate therapy for small (<1 cm) tumors.
For the high-risk group - total thyroidectomy andif there is preoperative
evidence of lymphatic spreadcentral compartment neck dissection are
indicated. In the absence of evidence of lymphatic spread, prophylactic
neck dissection may not be necessary, but can be considered for larger
tumors (>4 cm).
For those cases with an uncertain or suspect preoperative cytology, it might
be necessary to perform an intraoperatory histological exam.
A second surgical intervention for the removal of the whole thyroid gland is
needed for multifocal tumors or big tumors or less-differentiated histological types of
tumor, if a total thyroidectomy was not performed during the previous one.
II. For many low-risk patients and all high-risk patients, postoperative
radioiodine ablation of residual thyroid remnant is recommended to decrease the
likelihood of recurrent disease. To achieve maximal uptake of radioiodine into the
remnant, an elevated serum TSH level is required. This can be achieved by
withdrawing the patient from thyroxine therapy or using injections of recombinant
human TSH (rhTSH) given to patients in the euthyroid state. Regardless of how the
patient achieves an elevated serum TSH level, a low-iodine diet is prescribed for 1 to
2 weeks to enhance uptake of the radioisotope. Following either rhTSH stimulation
or thyroid hormone withdrawal, the serum thyroglobulin level is determined, and the
patient is scanned 24 to 72 hours after a low dose of radioiodine (ie, 1-4 mCi of 131I
or 1-2 mCi 123I). If there is evidence of residual radioactive iodine uptake in the neck
or elsewhere, or if there is a rise in serum thyroglobulin to detectable levels,
radioactive iodine (131I) is administered in a dose of 30 to 200 mCi, depending on the
size and invasiveness of the primary tumor. A whole body radioiodine scan (WBS) is
then repeated 4 to 7 days later (called a posttherapy scan) to be sure no additional
areas of radioiodine uptake are revealed.
III. All patients will need treatment with thyroid hormones, to prevent the
development of the symptoms and complications of hypothyroidism, as well as to
avoid the stimulating effect of TSH on the tumoral proliferation. For the first year,
patients are typically maintained on doses of LT4 that are adequate to suppress
serum TSH to levels that are less than 0.1 mU/L. LT4 in a dose of 2.2 g/kg/d
usually suppresses TSH to this level. The adverse cardiac and bone effects are
inevitable, but the efficacy of the suppressive doses in preventing recurrence justifies
its use.
Six to 12 months later, thyroid hormone therapy is withdrawn or rhTSH is
administered and a radioiodine scan and serum thyroglobulin are repeated to
document ablation of all functioning thyroid tissue. An undetectable serum
thyroglobulin level at a time when the serum TSH is elevated ( 30 mUI/L) is the
most sensitive evidence that all thyroid tissue has been eradicated and a repeat
whole body radioiodine scan may not be needed in low-risk patients.
Once it has been established that the patient is free of disease, the dose of
LT4 can be decreased to allow the serum TSH to rise into the low-normal range (0.32 mU/L).
For the next follow-up evaluations if the patient's TSH-stimulated serum
thyroglobulin is less than 1 ng/mL and the whole body radioiodine scan, if obtained,

is negative, the patient is likely free of disease. On the other hand, if the serum
thyroglobulin concentration rises above 2 ng/mL and/or if the radioiodine scan is
positive, the patient is likely to have either persistent thyroid remnant tissue or
residual thyroid cancer. Neck sonography, CT, or MRI should be considered in this
circumstance to look for evidence of residual thyroid cancer. If disease is localized
anatomically and proven to be thyroid cancer, additional surgery may be warranted.
If the stimulated thyroglobulin is greater than 20 ng/mL and other anatomic imaging
studies are negative, some experts recommend empiric radioiodine therapy because
of the high suspicion of residual disease that might then be visualized on the
posttreatment scan. The risk of leukemia and of solid cancers rises significantly with
a cumulative activity greater than 500 mCi of 131I.
Follow-up at intervals of 6 to 12 months should include careful examination of
the neck, sometimes including neck ultrasound, looking for recurrent masses. If an
abnormal lymph node is discovered, FNAB is indicated to confirm or rule out cancer.
The patient's serum TSH should be checked to be certain it is adequately
suppressed. The serum thyroglobulin should be periodically assessed to be certain it
is undetectable. A rise in serum thyroglobulin to detectable levels while TSH is
suppressed suggests tumor recurrence, and imaging studies such as neck
ultrasound, CT, and MRI are necessary. PET scanning may also be useful to localize
residual disease, especially in patients with very high serum thyroglobulin levels (>50
ng/mL) when conventional imaging studies have been unrevealing.
Thyroglobulin autoantibodies present in 20% of patients interfere with
accurate measurement of thyroglobulin in radioimmunometric assays causing falsely
low values. Patients with thyroglobulin autoantibodies must be followed with periodic
imaging studies, such as thyroid ultrasound or CT scan.
For patients with noniodine-avid metastatic disease that is progressive, recent
studies have shown that several kinaseinhibiting drugs, including
sorafenib and sunitinib, can be effective in halting further tumor growth for 1 to 2
years. The kinases involved include the vascular endothelial growth factor receptor
family (VEGF), RET, and BRAF. For patients with bone or brain metastases,
combined external radiation and 131I therapy may be effective.
Patients with MC needs only early and adequate initial thyroidectomy
associated with cervical node dissection followed by thyroid hormone substitution
therapy. They should be followed postoperatively with periodic measurement of
serum markers (eg, calcitonin and CEA) that indicate residual disease.
Chemotherapy with tyrosine kinase inhibitors, especially the experimental RET
inhibitor vandetanib (ZD 6474), has recently been shown to be highly effective in
preventing disease progression in many patients with medullary cancer.
Treatment for anaplastic carcinoma consists of surgery in order to debulk the
tumor and prevent tracheal compression. Standard treatment incorporates combined
radiotherapy and chemotherapy with doxorubicin, which is sometimes combined with
other agents
The prognostic of the thyroid carcinoma depends on its histology type, the
subjects age, sex (better outcomes for females), and the quality of the treatment.
The best 10 years survival is for PC (80-95%), followed by FC (50-70% if there is a
minimal or franc invasion of the tumoral capsula) and medullar carcinoma with lymph
node invasion (40-50%). The most unfavorable outcome is for the anaplastic
carcinoma, with a 10 years survival of only 3%.

Euthyroid sick syndrome

Any acute, severe illness can cause abnormalities of circulating TSH or
thyroid hormone levels in the absence of underlying thyroid disease, making these
measurements potentially misleading. The major cause of these hormonal changes
is the release of cytokines such as IL-6. Unless a thyroid disorder is strongly
suspected, the routine testing of thyroid function should be avoided in acutely ill
The most common hormone pattern in sick euthyroid syndrome (SES) is a
decrease in total and free T3 levels (low T3 syndrome) with normal levels of T4 and
TSH. T4 conversion to T3 is impaired, leading to increased reverse T3 (rT3). It is
generally assumed that this low T3 state is adaptive (may limit catabolism) and it can
be induced also in normal individuals by fasting.
Very sick patients may exhibit a dramatic fall in total T4 and T3 levels (low T4
syndrome). This state has a poor prognosis. Fluctuation in TSH levels (from <0.1 to
>20 mIU/L) also creates challenges in the interpretation of thyroid function in sick
patients. A rise in cortisol or administration of glucocorticoids may provide a partial
explanation for decreased TSH levels.
The diagnosis of SES is frequently presumptive, given the clinical context and
pattern of laboratory values; only resolution of the test results with clinical recovery
can clearly establish this disorder. Treatment of SES with thyroid hormone (T4
and/or T3) is controversial, but most authorities recommend monitoring the patient's
thyroid function tests during recovery, without administering thyroid hormone, unless
there is historic or clinical evidence suggestive of hypothyroidism.
Thyroid hormone and TSH resistance syndromes
Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by reduced responsiveness of target tissues to thyroid homones. In
approximately 85 percent of cases, RTH is due to mutations in the TH receptor beta
gene. RTH is subdivided based upon clinical findings into:
generalized RTH,
selective pituitary RTH,
isolated peripheral tissues resistance.
The clinical presentation in the generalized or peripheral forms is variable;
although most patients are clinically euthyroid, some present with:
short stature and delayed maturation,
attention deficits,
hyperactivity disorders,
learning disability,
resting tachycardia,
recurrent ear and throat infections.
Most of reported cases are familial. Inheritance is autosomal dominant.
Laboratory tests reveal elevated T4, fT4, T3, and normal or elevated TSH. The
differential diagnosis is made first with pituitary adenoma that produces TSH
(thyrotropinoma) and with defects in the thyroid hormones transport (for example
familial disalbuminemic hyperthyroxinemia, TBG excess etc). In most patients with

generalized form, the increased levels of T3 and T4 compensate in part for the
receptor defect, and treatment is not necessary. In some children, administration of
thyroid hormones may be necessary to correct defects in growth or mental
Selective pituitary RTH is less common and usually presents with symptoms
of mild hyperthyroidism, goiter, elevated serum T4 and T3, and normal or elevated
serum TSH. It is currently thought that this form is not a distinct syndrome, but
rather the result of the poor sensitivity and specificity of the signs and symptoms of
hyperthyroidism, and the fact that thyroid hormone resistance is not necessarily
complete and may vary from tissue to tissue. In fact, identical mutations in the TR
receptor have been found in patients with diferent clinical variants of thyroid hormone
Inactivating mutations in the TSH-receptor gene produce resistance to TSH
with uncompensated or compensated hypothyroidism. Affected individuals have
normal or hypoplastic thyroid glands, high serum TSH concentrations, and normal or
low serum T4 and T3 concentrations. Some patients may have normal growth and
development but persistently elevated serum TSH. Others may be severely
hypothyroid (cretinoid), with low fT4 levels, elevated TSH.
Individuals with partially compensated or uncompensated forms should be
treated with LT4, like any other hypothyroid patient. Because these individuals have
normal responsiveness to thyroid hormone, the goal is to normalize their serum TSH
Thyroid disorders in pregnancy
The most important physiological changes that affect the thyroid during
pregnancy are:
A doubling in blood TBG levels (thyroxine binding-globuline) because of
the stimulation produced by estrogens, but also as a result of a reduced
metabolism. The TBG rise will lead to TT4 and TT3 rises, but their free
fractions remain the same
A rise in seric hCG, which mildly stimulate the thyroid (TSH-like). hCG
reaches a maximum at 10-12 weeks of pregnancy. fT4 and fT3 can
slightly increase during this period, without exceeding the limits, and TSH
decreases correspondenly.
The fetus has developed its own thyroid by 10-12 weeks gestation, which can
concentrate iodine and synthesize iodothyronines, but the thyroid hormones
synthesis begins only by 18-20 weeks of pregnancy, after which the secretion of the
thyroid rises constantly.
Immediately after birth, the new-born TSH level rises to 50-80mUI/L and then
decreases to 10-15 mUI/L during the first 48 hours, and T3 and T4 rise to levels that
are superior to adults levels.
Iodine suplimentation during pregnancy has to be carefully done, so that the
intake doesnt exceed 300 mcg/day. An increased iodine intake during pregnancy
can manifest as goiter and hypothyroidism in the child, while iodine deficit is
responsible of endemic cretinism or mental retardation.


Hyperthyroidism during pregnancy, in foetus and the new-born

During pregnancy, any clinical form of hyperthyroidism can develop, but
Basedow-Graves disease represents the most frequent cause. It is unusual,
affecting approximately 0.2% of pregnancies. The clinical picture is typical of
hyperthyroidism: goiter, ophtalmopathia, but tachycardia, the skin aspects, weight
loss, dyspnea or thermofobia can hardly be differentiated from the unspecific
changes that appear during pregnancy. During the last weeks of pregnancy the
severity of the disease can be reduced, but there is a high risk of reccurence after
Diagnosing hyperthyroidism during pregnancy is difficult, and has to be made
by all clinical and laboratory means (TSH < 0.01mUI/L, high titer of TRAb).
Pregnancies with associated Basedow disease need special embrio-fetal monitoring
(heart frequency and growth rate). Poorly controlled hyperthyroidism can lead to:
Spontaneous abortions
Premature delivery;
Heart failure;
Low birth weight.
Graves disease must be diferentiated from hCG mediated hyperthyroidism.
There are a number of examples of hCG-mediated hyperthyroidism:
Gestational transient thyrotoxicosis sometimes with subclinical hyperthyroidism- it can last until the end of the first trimester, but it does not require
treatment. This is a transient phenomenon and is physiologic, not pathologic.
Hiperemesis gravidarum a syndrome that associates nausea and vomiting
with a weight loss of more than 5%. Estradiol and hCG levels are increased;
free T4 concentrations are only minimally elevated and serum T3
concentrations are frequently not elevated. It doesnt need specific antithyroid
drugs treatment.
Trophoblastic hyperthyroidism appears if a hydatiforme mole develops, a
benign condition, that may give rise to choriocarcinoma. Both are characterised by high levels of hCG or abnormal isoformes, some patients may have
also a diffuse goiter and clinical signs of hyperthyroidism.
Treatment of hyperthyroidism in preganacy should be as it follows:
Antithyroid agents: Propylthiouracil is the drug of choice for the first
trimester, and then it is recommended to switch to methimazole. Both
need to be used in minimal doses, capable of maintaning fT4 in the
superior normal range. This treatment requires monthly hormonal
Betablocking agents: Atenolol 50 mg -1 tb/day, may be given to
ameliorate the symptoms of moderate to severe hyperthyroidism, in
short term use because it is accompanied by a high risk of neonatal
growth restriction and spontaneous abortion.
The administration of radioiodine is strictly forbidden!
Surgery is advisable only for emergencies if antithyroid drugs cannot
be used, but only after the second trimester.
Fetal and neonatal hyperthyroidism appear in 2% of the children of the
mothers suffering from BGD, no matter what the hormonal millieu of the mother is.
Fetal heart rate is higher than 160 beats/minute and a goiter is also present. TRAb
that cross the placenta are responsible for this pathology. Antithyroid drugs need to

be administered to the mother. Fetal hyperthyroidism can lead to mental retardation.

In the new-born the clinical aspects are low birth-weight, tachycardia,
irritability, hepatosplenomegaly, goiter (sometimes compressive), heart failure,
psychomotor agitation.
If the mother is not treated with antithyroid drugs, these manifestations can
occur right after birth. The children of the mothers who are treated can be euthyroid
or hypothyroid at birth and they develop later, days or even weeks after, the
described symptoms (because the antithyroid drugs from their mother are being
gradually eliminating from the blood).
No matter how it starts, the disease is self-limited, after 3-12 weeks the TSHR antibodies dissapear from the childs blood. During this period of hyperthyroidism
the antithyroid drug methimazole (0.5 to 1.0 mg/kg per day), should be administered
every eight hours. Propylthiouracil is also effective, but has more frequent and
severe side effects, including a risk of hepatotoxicity and is not the first-line
treatment. Propranolol 1mg/kg/day tid, with frequent dosing of fT4 and fT3 and
slowly decreasing the doses. The severe forms can benefit from the administration of
glucocorticoids or iodine as Lugols solution after starting the antithyroid drugs
treatment. Late complications that are mentioned are craniosinosthosis, growth
retardation, behavior disorders, hyperactivity.
Very rarely, neonatal hyperthyroidism is persistent and it is due to activation
mutations of TSH receptor or to McCune Albright syndrome. In these cases, ablative
therapy is suitable (surgery or radioiodine).
Hypothyroidism and the pregnancy
Clinically manifest hypothyroidism is accompanied by anovulatory cycles and
reccurent spontaneous abortions. In continuing pregnancies, hypothyroidism has
been associated with an increased risk of several complications, including:
Preeclampsyia and hypertension
Postnatal hemorrhage;
Preterm delivery, including very preterm delivery (before 32 weeks)
Low birth weight
Perinatal mortality and morbidity;
Neuropsychological and cognitive impairment
The last one can appear in the foetus even if the mother has a mild subclinical
hypothyroidism! Women with treated hypothyroidism prior to their pregnancy should
increase the dose of levothyroxine by 25-50%. Several factors are responsible for
the increased T4 requirement during pregnancy. They include weight gain, high
serum TBG concentrations, placental deiodinase activity (which increases clearance
of T4), transfer of T4 to the fetus. The treatment is monitorized every 4-6 weeks, with
the purpose of normalizing TSH (it should be under 3 mUI/L) and fT4. Euthyroid
women with positive anti TPO antibodies can develop a subclinical hypothyroidism
during pregnancy and they have a high risk of spontaneous abortion




Anatom y, histology and embryology of the parathyroid glands

PTH is secreted from four glands located adjacent to the thyroid gland in the
neck. The two superior glands are usually found near the posterior aspect of the
thyroid capsule; the inferior glands are most often located near the inferior thyroid
margin. However, the exact location of the glands is variable, and 12% to 15% of
normal persons have a fifth parathyroid gland (cervical or mediastinal). The glands
weigh an average of 40 mg each. The small size, the possible ectopic location and
the variation in the number of the parathyroid glands make sometimes the diagnosis
of hyperparathyroidism very challenging.
The inferior parathyroid glands arise from the third branchial pouches and the
superior parathyroid glands from the fourth branchial pouches.
The parathyroid glands are composed of
epithelial cells there are two types, both contain PTH and it is not known
whether their secretory regulation differs fundamental:
o chief cell, the predominant cells, with clear cytoplasm;
o oxyphil cell, slightly larger, that has eosinophilic granular cytoplasm.
stromal fat.

Bios ynthesis and secretion of PTH

PTH is an 84-amino-acid peptide; its gene is located on chromosome 11. The
gene encodes a precursor called preproPTH with a 29-amino-acid extension added
at the amino terminus of the mature PTH peptide. This extension includes a 23amino-acid signal sequence (the pre sequence) and a 6-residue prohormone
sequence. In the lumen of the endoplasmic reticulum, the signal sequence from
preproPTH is cleaved and proPTH travels to the Golgi apparatus, where the pro
sequence is cleaved from PTH. As it leaves the Golgi apparatus, PTH is repackaged
into dense neuroendocrine-type secretory granules, where it is stored to await
The primary function of PTH is to maintain the extracellular fluid (ECF)
calcium concentration within a narrow normal range. PTH production is closely
regulated by the concentration of serum ionized calcium. ECF calcium controls PTH
secretion by interaction with a calcium-sensing receptor (CaSR), a G protein
coupled receptor for which Ca2+ ions act as the primary ligand. The receptor is
present in parathyroid glands and the calcitonin-secreting cells of the thyroid (C
cells), as well as in other sites such as brain and kidney. Heterozygous point
mutations associated with loss-of-function cause the syndrome of familial benign
hypocalciuric hypercalcemia (FHH), in which the blood calcium abnormality
resembles that observed in hyperparathyroidism but with hypocalciuria.
An increased extracellular [Ca2+], inhibits the secretion of PTH, after coupling
the CaSR, by increasing the enzyme phospholipase C and by inhibition of cyclic

adenosine-3',5'-monophosphate (cAMP) generation. The negative feedback relationship of PTH with serum [Ca2+] is steeply sigmoidal, with the steep portion of the
curve corresponding exactly to the normal range of serum calcium (Figure 5). The
setpoint is the calcium concentration at which there is half-maximal inhibition of
PTH secretion.
Besides calcium, there are several regulators of PTH secretion. Prolonged
depletion of magnesium will paralyze PTH secretion. Catecholamines, acting through
beta-adrenergic receptors, stimulate the secretion of PTH. This effect does not
appear to be clinically significant. Transcription of the PTH gene is also regulated by
vitamin D: high levels of 1, 25(OH)2 D inhibit PTH gene transcription. Vitamin D
analogs are used to treat secondary hyperparathyroidism in dialysis patients with
renal osteodystrophy.


Figure 5. The relationship between the serum-ionized calcium level and the
simultaneous serum concentration of intact PTH in normal humans.
The serum calcium concentration was altered by the infusion of calcium (closed
circles) or citrate (closed triangles). Parathyroid sensitivity to changes in serum
calcium is maximal within the normal range (the shaded area). Low concentrations of
PTH persist in the face of hypercalcemia.

Metabolism and assay of PTH

PTH secreted by the gland has a circulating half-life of 2 to 4 minutes. Intact
PTH(1-84) is predominantly cleared by the liver and kidney. There, PTH is cleaved to
produce an amino terminal fragment and a carboxyl terminal fragment. Amino
terminal fragments of PTH do not circulate to the same extent as carboxyl terminal
fragments. The latter are cleared from blood by renal filtration, and they accumulate
in chronic renal failure. Although the classic activities of PTH are encoded in the
amino terminal portion of the molecule, mid region and carboxyl terminal fragments
of the hormone may not be metabolically inert. Recent evidence suggests that they
may have their own receptors and biologic actions.

Current assays of intact PTH(1-84) employ two-site immunoradiometric assay

(IRMA) or immunochemiluminescent assay (ICMA) techniques, in which the normal
range for PTH is approximately 10 to 60 pg/mL (1-6 pmol/L).
Mechanism of action and biologic effects of PTH
There are two mammalian receptors for PTH:
the PTH-1 receptor, recognizes PTH and PTH related peptide (PTHrP), is
present in kidney and bone. Is a member of the G protein receptor
the PTH-2 receptor is activated by PTH only.
The central function of PTH is to regulate ionized [Ca2+] levels by concerted
effects on three principal target organs: bone, intestinal mucosa, and kidney.
The effect of PTH on intestinal calcium absorption is indirect, resulting
from increased renal production of the intestinally active vitamin D
metabolite 1,25(OH)2D (calcitriol)
In the kidney, PTH has direct effects on the tubular reabsorption of
calcium, phosphate, and bicarbonate. PTH markedly increases the
reabsorption of calcium, predominantly in the distal convoluted tubule
and inhibits the reabsorption of phosphate in the renal proximal tubule.
PTH has multiple actions on bone, some direct and some indirect. PTHmediated changes in bone calcium release can be seen within minutes.
The chronic effects of PTH are to increase the number of bone cells,
both osteoblasts and osteoclasts, and to increase the remodeling of
bone; these effects are apparent within hours after the hormone is given
and persist for hours after PTH is withdrawn. Continuous exposure to
elevated PTH (as in hyperparathyroidism or long-term infusions in animals) leads to increased osteoclast- mediated bone resorption.
However, the intermittent administration of PTH, elevating hormone
levels for 12 hours each day, leads to a net stimulation of bone
formation rather than bone breakdown. Osteoblasts (or stromal cell
precursors), which have PTH/PTHrP receptors, are crucial to this boneforming effect of PTH; osteoclasts, which mediate bone breakdown, lack
such receptors. PTH-mediated stimulation of osteoclasts is indirect,
acting in part, through cytokines released from osteoblasts to activate
Primary Hyperparathyroidism (PHPT)
Etiology and pathogenesis
PHPT results from the excessive secretion of PTH due to:
single parathyroid adenoma, in about 80% of cases,
primary hyperplasia of the parathyroid glands, in 10% to 15% of cases
parathyroid carcinoma, a rare cause of hyperparathyroidism, accounting
for 1% to 2% of cases. Parathyroid carcinoma is often recognizable
preoperatively because it presents with severe hypercalcemia or a
palpable neck mass.
Parathyroid tumors are most often encountered as sporadic, but they may
also be familial. Hereditary hyperparathyroidism can occur without other endocrine
abnormalities but is usually part of a multiple endocrine neoplasia syndrome in MEN

1 (hyperparathyroidism and tumors of the pituitary and pancreas, often associated

with gastric hypersecretion because of the loss of the functioning menin protein, a
tumor suppressor) or MEN 2 A (characterized by pheochromocytoma, medullary
carcinoma of the thyroid, hyperparathyroidism as a consequence of expression of
activating mutations of the RET gene). The hyperparathyroidism jaw tumor (HPT-JT)
syndrome occurs in families with parathyroid tumors (sometimes carcinomas) in
association with benign jaw tumors.
Hyperparathyroidism is a common and usually asymptomatic disorder. Its
incidence is approximately 45 per 100,000, and its prevalence is up to 4 per 1000 in
women over age 60. Primary hyperparathyroidism is approximately 2 to 3 times
more common in women than in men.
Primary hyperparathyroidism is characterized by abnormal regulation of PTH
secretion by calcium. PTH secretion in this condition is not completely autonomous
and can usually be partially inhibited by a further rise in serum calcium. The increase
in PTH secretion in primary hyperparathyroidism is in part due to an elevation in setpoint. The increase in the set-point, is the major determinant of the severity of the
hypercalcemia. The degrees of hypersecretion and nonsuppressibility are a function
of tumor mass. Both a functional change at the cellular level (a reduced number of
calcium receptors on the parathyroid cell) and increased numbers of cells probably
contribute to these changes in PTH secretion. Perhaps surprisingly, no mutations in
the gene encoding the CaSR have been found in parathyroid adenomas.
Parathyroid adenomas are caused by mutations in the DNA of parathyroid
cells; these mutations confer a proliferative or survival advantage for affected cells
compared with their normal neighbors. As a consequence of this advantage, the
descendants of one particular parathyroid cell, a clone of cells, undergo clonal
expansion to produce an adenoma. Multiple chromosomal regions are missing in the
parathyroid cells of individual parathyroid adenomas, probably reflecting the deletion
of tumor suppressor genes. One parathyroid proto-oncogene has been identified: the
cyclin D1 gene (CCND1, also called parathyroid adenomatous 1 or PRAD1).
As expected for a disease caused by mutations in DNA, parathyroid
adenomas occur more frequently in patients who underwent neck irradiation
decades earlier, with greater radiation exposure leading to higher risk.
Clinical features
Clinical presentation of primary hyperparathyroidism may include:
1. asymptomatic hypercalcemia with an elevated or high-normal intact PTH
2. classical signs and symptoms of hypercalcemia,
3. patients in the course of an evaluation for osteoporosis, fracture, low bone
density or nephrolithiasis,
4. symptomatic severe hypercalcemia (parathyroid crisis) or the severe bone
disease called osteitis fibrosa cystic.
The typical clinical presentation of PHPT has evolved considerably over the
past few decades. Nephrocalcinosis and the classic osteitis fibrosa cystica are rare
today. In fact, about 85% of patients presenting today have neither bone nor renal
manifestations of hyperparathyroidism and are regarded as asymptomatic or
minimally symptomatic.
Primary hyperparathyroidism, one of the most common etiologies for
hypercalcemia, has the mnemonic for recalling its signs and symptoms as stones,

bones, abdominal groans and psychic moans. A number of symptoms and signs
accompany hypercalcemia. They include:
Central nervous system effects such as:
memory loss, lethargy, depression,
psychosis, ataxia,
confusion, stupor, and coma.
Neuromuscular and skeletal effects such as:
proximal myopathy;
Cardiovascular effects such as:
bradycardia (and eventually asystole),
deposition of calcium in heart valves, coronary arteries, and myocardial
a shortened QT interval.
Renal effects such as:
renal stones, nephrocalcinosis,
polyuria, polydipsia, decreased glomerular filtration,
nephrogenic diabetes insipidus
hyperchloremic acidosis;
renal insufficiency.
Gastrointestinal effects such as:
nausea, vomiting,
pancreatitis, peptic ulcer,
epulis - benign lesion situated on the gingiva.
eye findings such as band keratopathy;
systemic metastatic calcification.
The clinical manifestations that are directly related to PHPT include:
Bone disease, reflects a generalized increase in osteoclastic bone
resorption, is characterized clinically by:
o bone pain,
o generalized demineralization of bone, decreased bone mineral density
(BMD), in particular at more cortical sites (forearm and hip) as
compared with trabecular bone (spine),
o the classic manifestation, osteitis fibrosa cystica with:
subperiosteal bone resorption often most evident in the phalanges of the
bone cysts, usually multiple,
brown tumors, consist of collections of osteoclasts intermixed with fibrous
pathologic fractures.
Nephrolithiasis, because of increased production of calcitriol,
Hypophosphatemia and hypomagnesemia,
Proximal renal tubular acidosis,

Hyperuricemia and gout,

Calcification of articular cartilage (chondrocalcinosis),
Laboratory and paraclinical findings
Hypercalcemia (calcium 11 mg/dl) is virtually universal in primary hyperparathyroidism, although the serum calcium sometimes fluctuates into the upper
normal range. In patients with subtle hyperparathyroidism, repeated serum calcium
measurements may be required to establish the pattern of intermittent hypercalcemia. Both total and ionized calcium are elevated.
Patients with mild hypercalcemia (calcium <12 mg/dl [3 mmol/L]) may be
asymptomatic. A serum calcium of 12 to 14 mg/dL (3 to 3.5 mmol/L) may be welltolerated chronically, while an acute rise to these concentrations may cause marked
symptoms, including polyuria, polydipsia, anorexia, nausea, muscle weakness etc.
The diagnosis of mild primary hyperparathyroidism may be obscured by
vitamin D deficiency (due to poor dietary intake of vitamin D or sunlight exposure)
and may not be recognized until vitamin D is repleted and hypercalcemia and/or
hypercalciuria develop.
Other laboratory findings:
- intact PTH level (by two-site intact PTH assay) an elevated or even uppernormal level of PTH is clearly inappropriate in a hypercalcemic patient.
- serum phosphorus level is low-normal or low (<2.5 mg/dL),
- measurement of urinary calcium excretion, is required for distinguishing PHPT
from familial hypocalciuric hypercalcemia. Approximately 40 % of patients with
PHPT are hypercalciuric (urinary calcium concentration >300 mg/24 hours). A
Ca/Cr clearance ratio, which is equivalent to the fractional excretion of
calcium, also may be helpful (ratio usually >0.02 in PHPT).
- mild hyperchloremic metabolic acidosis,
- vitamin D metabolites due to the significant prevalence of vitamin D
insufficiency in individuals with PHPT. The measurement of 25OHD is
recommended in all patients and supplementation of those with low levels
(defined as 20 ng/mL [50 nmol/L]) prior to making any management
- biochemical markers of bone turnover (collagen crosslinks, osteocalcin, bonespecific alkaline phosphatase) are typically high in those with severe disease.
They are only occasionally helpful in the management of hyperparathyroidism
and should not be routinely measured.
- determinations of BMD must be carried out at the spine, hip, and distal onethird forearm sites. The degree of bone loss is reflective of the severity of
- serum creatinine provides information about renal function
- renal imaging a plain abdominal radiograph for renal stone or abdominal
- bone radiography: salt-and-pepper radiographic appearance of the skull,
subperiosteal resorption, often most evident in the phalanges of the hands,
clavicles, ribs.
Localization studies in order to identify the source of excess of PTH one or
more of the following can be used: ultrasonography, technetium-99m107

methoxyisobutylisonitrile (99mTc-sestamibi or MIBI), sestamibi-single photon

emission computed tomography (SPECT or MIBI-SPECT), CT or MRI. They are
commonly used now, along with intraoperative PTH monitoring, to facilitate unilateral
exploration and minimally invasive surgery in those with probable single gland
Differential diagnosis of primary hyperparathyroidism
The diagnosis of primary hyperparathyroidism is usually made by finding a
frankly elevated PTH concentration or one that is within the normal range but
inappropriately elevated given the patient's hypercalcemia.
Differential diagnosis of primary hyperparathyroidism includes other forms of
hypercalcemia. Many disorders are associated with hypercalcemia but there are a
limited number of mechanisms: (1) increased bone resorption, (2) increased
gastrointestinal absorption of calcium, or (3) decreased renal excretion of calcium.
The causes of hypercalcemia are numerous:
1. Hypercalcemia of malignancy, in this situation hypercalcemia is determined by:
o tumor secretion of parathyroid hormone-related protein (PTHrP) - in
nonmetastatic solid tumors, adult T-cell leukemia-lymphoma;
o activation of extrarenal 1 alpha-hydroxylase and increased production of
1,25-dihydroxyvitamin D (calcitriol): in Hodgkin lymphoma and in other
forms of lymphoma;
o induction of local osteolysis by tumor cells is common with some solid
tumors that are metastatic to bone and with multiple myeloma;
o ectopic secretion of PTH has been described very rare.
2. Familial hypocalciuric hypercalcemia (FHH) is due to an inactivating mutation in
the calcium-sensing receptor in the parathyroid glands and the kidneys. A
family history of hypercalcemia, especially in young children, and the absence
of symptoms and signs of hypercalcemia are characteristic of this disorder.
3. Sarcoidosis and other chronic granulomatous disorders are associated with
increased production of calcitriol in macrophages.
4. Endocrine disorders:
o Hyperthyroidism causing increment of bone resorption,
o Acromegaly ,
o Pheochromocytoma,
o Adrenal insufficiency as a result of hemoconcentration.
5. Drug related
o Vitamin D intoxication from increased intestinal absorption of calcium
and direct effect of calcitriol to increase resorption of bone,
o Excessive Vitamin A probably caused by the action of retinoids to
stimulate bone resorption,
o Thiazide diuretics by reducing urinary calcium excretion,
o Lithium decreases parathyroid gland sensitivity to calcium, shifting the
calcium-PTH curve to the right,
o Teriparatide,
o Theophylline toxicity.
6. Immobilization
7. Milk alkali syndrome. The triad of hypercalcemia, metabolic alkalosis, and renal
failure can be the consequence of massive ingestion of calcium and absorbable

Primary hyperparathyroidism (PHPT) and malignancy are the most common

causes of hypercalcemia, accounting for more than 90 percent of cases. It is usually
not difficult to differentiate between them. Malignancy is often evident clinically by the
time it causes hypercalcemia, and patients with hypercalcemia of malignancy have
higher calcium concentrations. Measurement of intact PTH will usually distinguish
the two diseases. Intact PTH concentrations are generally undetectable or very low
in hypercalcemia of malignancy because of the PTHrP secretion.
Very important is to differentiate PHPT from the secondary hyperparathyroidism that occurs when the parathyroid gland appropriately responds to a
reduced level of extracellular calcium. PTH concentrations rise and calcium is
mobilized by increasing intestinal absorption and by increasing bone resorption.
Thus, it is characterized biochemically by elevated PTH and normal or low serum
calcium concentrations. Causes of secondary hyperparathyroidism include:
- Renal failure will determine impaired calcitriol production and
hyperphosphatemia, the last one independently increasing PTH secretion,
- Decreased calcium intake,
- Calcium malabsorption (in vitamin D deficiency, bariatric surgery, celiac
- Renal calcium loss (by using loop diuretics),
- Inhibition of bone resorption (bisphosphonates treatment).
In some patients with advanced renal failure, the progression from appropriate
parathyroid hyperplasia to autonomous overproduction of PTH can lead to
hypercalcemia, a disorder called tertiary hyperparathyroidism.
Evolution and prognostic
The majority of patients with asymptomatic PHPT do not have disease
progression, as evidenced by stable biochemical abnormalities and BMD for up to a
decade of observation. However, a proportion of individuals with asymptomatic
PHPT have evidence of disease progression (worsening hypercalcemia,
hypercalciuria, newly diagnosed nephrolithiasis or osteoporosis).
One of the rare, acute and dangerous complication is parathyroid crisis.
Parathyroid crisis is characterized by severe hypercalcemia, with the serum calcium
concentration usually above 15 mg/dL (3.8 mmol/L) and marked symptoms of
hypercalcemia, in particular, central nervous system dysfunction (agitation, lethargy,
confusion and coma) but also severe abdominal pain, nausea, vomiting, peptic ulcer,
and pancreatitis. The mechanism for the development of parathyroid crisis is not
known, but may be related to an intercurrent illness, volume depletion, or infarction
of a parathyroid adenoma. Cardiac arrhythmias may occur, particularly
bradyarrhythmias or heart block as well as lethal acute renal failure.
Surgical excision of the abnormal parathyroid tissue is the definitive therapy
for this disease. Two surgical approaches are generally practiced:
- the conventional parathyroidectomy procedure: neck exploration with
general anesthesia. In patients with hyperplasia, the preferred operation is a
31/2 gland parathyroidectomy, leaving a remnant sufficient to prevent


minimally invasive parathyroidectomy, an outpatient procedure with local

anesthesia. Preoperative SPECT are used to predict the location of an
abnormal gland and intraoperative sampling of PTH is mandatory.
Acute postoperative hypocalcemia is likely only if severe bone mineral deficits
are present (hungry bones syndrome) or if injury to all the normal parathyroid
glands occurs during surgery.
Medical surveillance without operation for patients with mild, asymptomatic
disease is still preferred by some physicians and patients, particularly when the
patients are more elderly. In asymptomatic patients surgery is indicated if any of the
following conditions are present:
- serum calcium concentration of 1.0 mg/dL (0.25 mmol/L) or more above the
upper limit of normal,
- sreatinine clearance that is reduced to <60 mL/min,
- bone density at the hip, lumbar spine, or distal radius that is more than 2.5
standard deviations below peak bone mass (T score <-2.5) and/or previous
fragility fracture,
- age less than 50 years.
A number of measures should be recommended to patients who do not
undergo surgery, including the following:
- Avoid prolonged bed rest or inactivity, encourage physical activity to
minimize bone resorption.
- Avoid high calcium diet (>1000 mg/day) but maintain a moderate calcium
intake. A low calcium diet could aggravate bone disease.
- Avoid thiazide diuretic and lithium carbonate therapy.
- Encourage adequate hydration (at least six to eight glasses of water per day)
to minimize the risk of nephrolithiasis.
- Maintain moderate vitamin D intake (400 to 600 IU daily).
Periodic monitoring should be performed for disease progression and
development of indications for surgery. Measurements of serum calcium and
creatinine annually and bone density (hip, spine, and forearm) every one to two
years is sufficient.
Certain medications can be beneficial in PHPT if surgery is not an option:
- Estrogen-progestin therapy in postmenopausal women because of its ability
to reduce bone resorption.
- Bisphosphonates are potent inhibitors of bone resorption for example
alendronate 70 mg/week.
- Raloxifene a selective estrogen receptor modulator can reduce mean serum
calcium concentration 60 mg/day.
- Calcimimetics activate the calcium-sensing receptor in the parathyroid gland,
thereby inhibiting PTH secretion. Cinacalcet, is available for the treatment of
secondary hyperparathyroidism associated with renal failure- 30 to 50 mg
twice daily.
Severe hypercalcemia (parathyroid crisis) in patients who are symptomatic or
have serum calcium levels greater than 14 mg/dL ordinarily should be treated
aggressively. The most important measures are:
- rehydration usually by infusing isotonic saline at a rate of 2 to 4 L/day,
sometimes, but only after rehydration, Furosemide, 20-40 mg IV, is added,
- administration of a bisphosphonate intravenously, rapidly inhibits bone
resorption and is currently the agent of choice in managing severe

hypercalcemia that is known or suspected to be driven mainly by osteoclastic bone resorption: Pamidronate, 60-90 mg IV over 2-4 hours or
Zolendronate, 4 mg IV over 15-30 min,
calcitonin, can be useful as a temporary measure early in therapy: 4-8 IU/kg
intravenous glucocorticoids, 100-200 mg hydrocortisone IV at 4-6 hours,
should be considered in patients with suspected vitamin Ddependent
hypercalcemia (lymphoma or granulomatous disease),
dialysis, may be indicated in some patients,
urgent parathyroidectomy, after initial medical stabilization.

Hypoparathyroidism (hPT)
Hypoparathyroidism can be hereditary or acquired.
Hereditary hPT is often manifest within the first decade but may appear later.
There are different forms:
- Isolated hereditary hypoparathyroidism - the inheritance may be autosomal
dominant, autosomal recessive, and X-linked. Examples: gain-of-function
mutations in CaSR gene in autosomal dominant hypocalcemic hypercalciuria
(ADHH) or mutations in PTH gene.
- Hypoparathyroidism associated with mitochondrial dysfunction and
myopathy because of mutations or deletions in mitochondrial genes.
- DiGeorge syndrome, or the velo-cardio-facial syndrome (defective development of both the thymus and the parathyroid glands) dimorphic facies,
cardiac defects, immune deficiency, and hypoparathyroidism.
- Polyglandular autoimmune type 1 deficiency a complex hereditary autoimmune syndrome involving failure of the parathyroid glands, the adrenals,
the ovaries and the immune system, in association with recurrent mucocutaneous candidiasis, alopecia.
Acquired hypoparathyroidism is usually the result of:
- inadvertent surgical removal of all the parathyroid glands; in some instances
when not all the tissue is removed a transient form exist: normal parathyroid
function may return due to hyperplasia or recovery of remaining tissue,
- radiation-induced damage of parathyroid glands subsequent to radioiodine
- glandular damage in patients with hemochromatosis or hemosiderosis,
Copper or Aluminium deposition,
- severe infections,
- autoimmune hypoparathyroidism (with autoantibodies to the CaSR)
sometimes still termed idiopathic hypoparathyroidism.
Severe magnesium depletion temporarily paralyzes the parathyroid glands,
preventing secretion of PTH (functional hypoparathyroidism). Magnesium depletion
also blunts the actions of PTH on target organs (kidney and bone) to counteract the
hypocalcemia. This is seen with magnesium losses due to gastrointestinal and renal
disorders and alcoholism.
Clinical features
Most of the symptoms and signs of hypocalcemia occur because of increased
neuromuscular excitability (tetany, paresthesias, seizures, organic brain syndrome)

or because of deposition of calcium in soft tissues (cataract, calcification of basal

Neuromuscular Manifestations Clinically, the hallmark of severe hypocalcemia
is tetany. Tetany is a state of spontaneous tonic muscular contraction. Overt tetany
is often preceded by tingling paresthesias in the fingers and around the mouth, but
the classic muscular component of tetany is carpo-pedal spasm. This begins with
adduction of the thumb, followed by flexion of the metacarpophalangeal joints,
extension of the interphalangeal joints, and flexion of the wrists to produce the main
d'accoucheur posture. These involuntary muscle contractions are painful. Although
the hands are most typically involved, tetany can involve other muscle groups,
including life-threatening spasm of laryngeal muscles. Tetany is not specific for
hypocalcemia. It also occurs with hypomagnesemia and metabolic alkalosis, and the
most common cause of tetany is respiratory alkalosis from hyperventilation.
Hypocalcemia predisposes to focal or generalized seizures. Twenty percent of
children with chronic hypocalcemia develop mental retardation. The basal ganglia
are often calcified in patients with long-standing hypoparathyroidism or pseudohypparathyroidism. This is usually asymptomatic but can produce a variety of movement
disorders. Other central nervous system effects of hypocalcemia include
pseudotumor cerebri, papilledema, and organic brain syndrome. Hypocalcemia can
cause psychological symptoms, particularly emotional instability, lassitude, anxiety
and depression. Less common are confusional states, hallucinations, and frank
psychosis. All are reversible with treatment.
Lesser degrees of neuromuscular excitability produce latent tetany, which can
be elicited by:
- Chvostek sign is elicited by tapping the facial nerve about 2 cm anterior to
the earlobe, just below the zygoma. The response is a contraction of facial
muscles ranging from twitching of the angle of the mouth to hemifacial
- Trousseau sign is elicited by inflating a blood pressure cuff to about 20 mm
Hg above systolic pressure for 3 minutes. A positive response is carpal
spasm. Trousseau sign is more specific than Chvostek
Ectodermal manifestations correlate with the severity and chronicity of
hypocalcemia and are reversible with restoration of normocalcemia:
the skin is dry, puffy and coarse,
- coarse, brittle, and sparse hair with patchy alopecia,
- brittle nails, with characteristic transverse grooves,
- dental abnormalities (when hypocalcemia is present during early
development): dental hypoplasia, failure of tooth eruption, defective enamel
and root formation, carious teeth,
- moniliasis, often refractory to antifungal therapy, occurs only in patients with
polyglandular autoimmune syndrome type 1. The nails, skin, and the
gastrointestinal tract are typically involved.
Ocular disease Subcapsular cataract is common in chronic hypocalcemia,
and its severity is correlated with the duration and level of hypocalcemia.
Cardiac effects
- delayed repolarization, with prolongation of the QT interval,
- ventricular dysrhythmias - very rare,
- refractory congestive heart failure particularly in patients with underlying
cardiac disease.

Laboratory and paraclinical evaluation

The diagnostic approach to hypocalcemia involves confirming, by repeat
measurement, the presence of hypocalcemia and distinguishing among the potential
The first step in the evaluation of a patient with hypocalcemia is measurement
of the serum albumin concentration. Calcium in serum is bound to proteins,
principally albumin. As a result, the total serum calcium concentration in patients with
low or high serum albumin levels may not accurately reflect the physiologically
important ionized (or free) calcium concentration. Each 1 g/dL reduction in the serum
albumin concentration will lower the total calcium concentration by approximately 0.8
mg/dL (0.2 mmol/L) without affecting the ionized calcium concentration.
If the diagnosis of hypocalcemia is in doubt serum ionized calcium should be
measured if a laboratory known to measure ionized calcium reliably is available.
Normal ionized calcium: 4.0 - 5.2 mg/dl (1.0 -1.3 mmol/L).
Serum intact PTH measurements provide critical information in patients with
hypocalcemia, but can be interpreted correctly only when serum calcium is
measured simultaneously. Other measurements that may be helpful for differential
diagnosis include:
- serum magnesium, creatinine, phosphate,
- the vitamin D metabolites calcidiol (25-hydroxyvitamin D) and calcitriol (1,25dihydroxyvitamin D, the active vitamin D hormone),
- alkaline phosphatase,
- amylase,
- urinary calcium, magnesium and phosphate excretion.
The presence of a low serum phosphate concentration in the context of
hypocalcemia means secondary hyperparathyroidism (abnormality in vitamin D
intake or metabolism, like phenytoin therapy or hepatobiliary disease), or low dietary
phosphate intake, which is uncommon. Chronic kidney disease is the only condition
in which hypocalcemia and secondary hyperparathyroidism are not associated with
low or low-normal serum phosphate (as a result of the inability of the diseased
kidney to respond to the high PTH).
Persistent hypocalcemia and hyperphosphatemia is, in the absence of kidney
disease or increased tissue breakdown, virtually diagnostic of either hypoparathyroidism or pseudohypoparathyroidism (PTH resistance). Serum PTH is reduced
or inappropriately normal in patients with hypoparathyroidism and elevated in
patients with pseudohypoparathyroidism.
Other tests that may be helpful:
- urinary calcium is low in hPT,
- Electromyography: in tetany repetitive motor neuron action potentials, usually
grouped as doublets are described,
- ECG: prolonged QT interval.
Differential diagnosis
The major factors that influence the serum calcium concentration are PTH,
vitamin D, the calcium ion itself and phosphate. Other causes of hypocalcemia
- Resistance to PTH action:

Pseudohypoparathyroidism (PhPT) a group of heterogeneous disorders

defined by target organ (kidney and bone) unresponsiveness to PTH. It is
characterized by hypocalcemia, hyperphosphatemia and elevated PTH
Renal insufficiency.
Medications that block osteoclastic bone resorption, like Plicamycin,
Calcitonin, Bisphosphonates
- Failure to produce 1,25(OH)2D normally
Vitamin D deficiency: inadequate nutrition or inadequate sunlight
exposure. Heavily pigmented and elderly individuals have less efficient
production of vitamin D for a given exposure to ultraviolet irradiation.
Serum levels of 25(OH)D are used to indicate vitamin D status. Although
there is no consensus on what level of 25(OH)D constitutes sufficiency,
30 ng/mL has become the preferred target.
Gastrointestinal malabsorption, celiac disease, cystic fibrosis.
Drugs that induce the inactivation of vitamin D such as phenytoin,
phenobarbital, carbamazepine, isoniazid, and rifampin.
Severe parenchymal or obstructive hepatic disease may have reduced
production of calcidiol (25OHD).
Hereditary vitamin D-dependent rickets, type 1 (renal 1 alpha-hydroxylase
- Resistance to 1,25(OH)2D action:
Hereditary vitamin D-dependent rickets, type 2 (defective VDR vitamin D
receptor)- many of these patients have alopecia.
Acute complexation or deposition of calcium
Acute hyperphosphatemia like in crush injury with muscular necrosis,
rapid tumor lysis, parenteral or excessive enteral phosphate
Acute pancreatitis causes hypocalcemia by sequestration of calcium by
saponification with fatty acids, which are produced in the retroperitoneum
by the action of pancreatic lipases.
Citrated blood transfusion causes acute hypocalcemia by complexation
of calcium as calcium citrate.
Rapid, excessive skeletal mineralization like in hungry bones syndrome or
osteoblastic metastasis.
Pseudohypoparathyroidism (PhPT) and pseudo-pseudohypoparathyroidism
Two distinct forms of PhPT are recognized. PhPT type IB is a disorder of
isolated resistance to PTH, which presents with the biochemical features of
hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism.
PhPT type IA has, in addition to these biochemical features, a characteristic
somatic phenotype known as Albright hereditary osteodystrophy (AHO). This
consists of:
- short stature,
- round face, short neck,
- obesity,
- brachydactyly (short digits), shortened metatarsals,
- subcutaneous ossifications,


- resistance to various other G-protein coupled hormones including TSH, LH,

Theses autosomal dominantly inherited conditions are caused by mutations of
GNAS1, a gene encoding the alpha subunit of the G protein, coupled to the PTH
receptor. All mutations result in a protein with defective function.
Interestingly, certain individuals in families with PhPT inherit the somatic
phenotype of AHO without any disorder of calcium metabolism; this state, is called
Evolutions and prognostic
Chronic hypocalcemia from hypoparathyroidism may be associated with
cataract formation, ectopic calcification (basal ganglia), and occasionally
parkinsonism and dementia. In some cases, extrapyramidal symptoms improve after
treatment with vitamin D and calcium.
In acute hypocalcemia with tetany, patients should receive intravenous
calcium as calcium chloride (270 mg calcium/10 mL) or calcium gluconate (90 mg
calcium/10 mL). Initially, intravenous calcium (1 to 2 g of calcium gluconate,
equivalent to 90 to 180 mg elemental calcium, in 50 mL of 5 % dextrose) can be
infused over 10 to 20 minutes. The calcium should not be given more rapidly,
because of the risk of serious cardiac dysfunction, including systolic arrest. This
should be followed by a slow infusion of calcium in patients with persistent
hypocalcemia. Patients typically require 0.5 to 1.5 mg/kg of elemental calcium per
hour. Oral calcium and a rapidly acting preparation of vitamin D should be started. If
the serum magnesium concentration is low, 2 g of magnesium sulfate should be
infused as a 10 % solution over 10 to 20 minutes or oral magnesium should be
The objective of chronic therapy is to keep the patient free of symptoms and
to maintain a serum [Ca2+] in the lower normal range to avoid marked
hypercalciuria. The patients can be treated initially with 1000 to 2000 mg of
elemental calcium given as calcium carbonate or calcium citrate daily, in divided
doses in combination with ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3).
In hPT, large dose of D2 or D3 is required: 25,000-100,000 International Units daily
(40 UI=1g). Disadvantages include the necessity for hepatic and renal metabolism
and slow onset and long duration of action. Vitamin D metabolites can be used to
treat hypocalcemia. Their action is more rapid and not as prolonged as that of
vitamin D:
Calcitriol (1,25-dihydroxyvitamin D, Rocaltrol, 0.5-1 micrograms/day) is the
most active metabolite of vitamin D. The advantages of calcitriol include lack
of necessity for endogenous activation, rapid onset of action (hours), and a
biologic half-life of about four to six hours.
Alfacalcidol (1-alpha-hydroxyvitamin D3, 0.5-2.0 micrograms daily) is a
synthetic analog of vitamin D that is converted in the liver to the active
metabolite 1,25-dihydroxyvitamin D.
Dihydrotachysterol is the functional equivalent of 1-hydroxyvitamin D, only
25-hydroxylation in the liver is required to form the active drug. Is effective in
patients with chronic kidney disease.

Periodically monitoring of urinary and serum calcium and serum phosphate

are required weekly initially, until a stable serum calcium concentration (at the low
end of the normal range) is reached. Thereafter, monitoring at three- to six-month
intervals is sufficient. Some patients with hypoparathyroidism require a thiazide
diuretic (25 to 100 mg daily), with or without dietary sodium restriction, to decrease
urinary calcium excretion.

Osteoporosis is defined as a reduction in the strength of bone that leads to an
increased risk of fractures. Loss of bone tissue is associated with deterioration in
skeletal microarchitecture that results in fractures with minimal trauma. Osteoporotic
fractures are a major public health problem for older women and men in Western
society. More than 50% of fractures among postmenopausal women, including hip
fractures, occur in this group with low bone density.
Osteoporosis results from bone loss due to age-related changes in bone
remodeling as well as extrinsic and intrinsic factors that exaggerate this process.
During growth, the skeleton increases in size by linear growth and by
apposition of new bone tissue on the outer surfaces of the cortex. The latter process
is called modeling, a process that also allows the long bones to adapt in shape to the
stresses placed on them. Increased sex hormone production at puberty is required
for skeletal maturation, which reaches maximum mass and density in early
adulthood. Nutrition and lifestyle also play an important role in growth, but genetic
factors primarily determine peak skeletal mass and density.
In adults, bone remodeling, not modeling, is the principal metabolic skeletal
process. Bone remodeling has two primary functions:
(1) to repair microdamage within the skeleton to maintain skeletal strength,
(2) to supply calcium from the skeleton to maintain serum calcium.
Remodeling may be activated by microdamage to bone as a result of
excessive or accumulated stress. Acute demands for calcium involve osteoclastmediated resorption as well as calcium transport by osteocytes. Chronic demands
for calcium result in secondary hyperparathyroidism, increased bone remodeling,
and overall loss of bone tissue.
Bone remodeling is also regulated by several circulating hormones, including
estrogens, androgens, vitamin D, and parathyroid hormone (PTH), as well as locally
produced growth factors such as IGF-I, transforming growth factor (TGF-),
parathyroid hormonerelated peptide (PTHrP), interleukins (ILs), prostaglandins, and
members of the tumor necrosis factor (TNF) superfamily.
These factors primarily
modulate the rate at which new remodeling sites are activated, a process that results
initially in bone resorption by osteoclasts, followed by a period of repair during which
new bone tissue is synthesized by osteoblasts. The osteoblast, the principal boneforming cell, arises from a pool of mesenchymal stem cells in the bone marrow,
which as they differentiate, acquire a set of characteristics, including expression of
PTH and vitamin D receptors. Osteoblasts that remain within cortical bone during the
remodeling process become osteocytes. The osteoclast is a multinucleated giant
cell that is specialized for resorption of bone. Osteoclasts are terminally differentiated

cells that arise from hematopoietic precursors in the monocyte lineage and do not
divide. Osteoblasts stimulate both osteoclast formation and activation.
The cytokine responsible for communication between the osteoblasts, other
marrow cells, and osteoclasts has been identified as RANK ligand (RANKL)
[receptor activator of nuclear factor-kappa-B (NFB); RANKL]. RANKL, a member of
the TNF family, is secreted by osteoblasts and certain cells of the immune system.
The osteoclast receptor for this protein is referred to as RANK. Activation of RANK
by RANKL is a final common path in osteoclast development and activation.
Osteoblasts can also secrete osteoprotegerin (OPG) which binds and neutralizes
RANKL, leading to a block in osteoclastogenesis and decreased survival of
preexisting osteoclasts
Modulation of osteoclast recruitment and activity appears to be related to the
interplay among these three factors: OPG, RANK, RANKL. Additional influences
include nutrition (particularly calcium intake) and physical activity level.
The term primary osteoporosis denotes reduced bone mass and fractures in
postmenopausal women (postmenopausal osteoporosis) or in older men and women
due to age-related factors. The term secondary osteoporosis refers to bone loss
resulting from specific clinical disorders. There is overlap in these designations; for
example, many postmenopausal women with low bone mass have vitamin D
insufficiency or deficiency which could be considered a secondary cause of
Bone loss can occur because bone resorption is increased or bone formation
is decreased. Primary osteoporosis appears because of the following factors:
1. The central role of estrogen deficiency in the pathogenesis of osteoporosis
in postmenopausal women has been recognized for many years. Estrogen
inhibits bone resorption and, after the menopause, estrogen deficiency
results in increased bone resorption and rapid bone loss.
2. Progressive deficits in renal and intestinal function that impair the whole
body calcium economy during normal human aging.
3. The failure to reach peak bone mass as a young adult. The amount of bone
mineral present at any time in adult life represents that which has been
gained at skeletal maturity (peak bone mass) minus that which has been
subsequently lost. Bone acquisition is completed in the late teenage years
and early twenties in girls and by the second decade in boys. Heredity
accounts for most of the variance in bone acquisition. Other factors
contributing to the acquisition of peak bone mass include circulating gonadal
steroids, physical activity, and nutrient intake. The consequence of an
inadequate adolescent bone acquisition will be a lower peak bone mass and
less reserve to accommodate to future losses.
Causes of secondary osteoporosis:
I. Endocrinopathies:
Thyrotoxicosis or excess thyroid hormone replacement,
Primary hyperparathyroidism,
Glucocorticoid excess,
Diabetes mellitus.

II. Gastrointestinal/nutritional:
Vitamin D deficiency,
Chronic liver disease,
Celiac sprue because of impaired calcium and vitamin D absorption, but a
chronic inflammatory component also contributes to the bone disorder,
Parenteral nutrition.
III. Hematological disorders:
Leukemia and lymphoma,
Multiple myeloma may cause rapid bone loss because the malignant cells
produce stimulators of resorption and inhibitors of formation,
Sickle cell anemia,
IV. Medications:
Immunosuppressants (cyclosporine),
Antiseizure medications (particularly phenobarbital and phenytoin) by
impairment of vitamin D metabolism,
GnRH agonists and antagonists,
Heparin - stimulates bone resorption and inhibits bone formation,
Proton pump inhibitors.
V. Genetic disorders:
Osteogenesis imperfecta,
Homocystinuria due to cystathionine deficiency.
VI. Other:
Rheumatoid arthritis,
Chronic obstructive pulmonary disease.
Osteoporosis induced by endocrine disorders
Hypogonadism, which can occur in men or women, has multiple causes.
Patients with primary hypogonadism related to ovarian or testicular failure or
secondary hypogonadism related to hypothalamic or pituitary disease lose bone
rapidly and often have fragility fractures. The hypogonadotropic group includes
patients with anorexia nervosa, athletic amenorrhea, prolactinoma, or lesions of the
pituitary gland or hypothalamus, including tumors.
The frequency of drug-induced hypogonadism is increasing. Long-acting
progestins used for contraception in young women cause bone loss that is usually
reversible. Gonadotropin-releasing hormone (GnRH) analogues and aromatase
inhibitors, which are used to block sex hormone production in women with breast
cancer or endometriosis and men with prostate cancer, can cause rapid bone loss.
Thyroid hormone excess may increase the risk of fractures in postmenopausal women. In young women with hyperthyroidism who are treated early, only

small changes in bone mass may occur because increases in formation rates match
those of resorption.
Patients with insulin-dependent diabetes mellitus often have low bone mass
and diminished bone formation, perhaps because they lack an anabolic effect of
Disorders of calcium-regulating hormones cause bone loss in hyperparathyroidism and rickets or osteomalacia in vitamin D deficiency. Milder degrees of
parathyroid hormone (PTH) excess or vitamin D deficiency can contribute to the
pathologic changes of osteoporosis. Decreased calcium and vitamin D intake and
reduced sun exposure can lead to secondary hyperparathyroidism, which
undoubtedly plays a role in age-related bone loss. Hyperparathyroid bone disease is
associated with greater loss of cortical than trabecular bone and more preservation
of trabecular connections, as compared with osteoporosis.
Calcitonin inhibits bone resorption, and it has been thought that calcitonin
deficiency could contribute to osteoporosis. However, while bone turnover is
decreased in patients given exogenous calcitonin, endogenous calcitonin is not an
important determinant of osteoporosis.
Glucocorticoid-Induced Osteoporosis
Initiation of glucocorticoid therapy leads to rapid bone loss, resulting in
significant BMD deficits within even a few months with a greater impact on trabecular
than cortical bone. The magnitude of bone loss can be large, typically approaching
40% reduction of the initial BMD.
Approximately half of long-term glucocorticoid-treated patients suffer a
fracture. Skeletal fragility is not the only risk factor for fracture in steroid-treated
patients, because glucocorticoids (and the illnesses for which they are prescribed)
are also associated with muscle weakness, which itself creates instability and
increases the risk of falling.
Glucocorticoid-induced bone loss generally follows sustained administration of
systemic doses greater than 5 mg/d of prednisone or its equivalent. Patients
receiving maintenance hydrocortisone dosages (eg, 20 mg/d) for adrenocortical
insufficiency do not generally have an increased skeletal risk. Glucocorticoids affect
mineral balance through alterations in renal, intestinal, and skeletal function:
Renal calcium losses within a few days after initiating therapy, direct
inhibition of renal tubular calcium reabsorption leads to hypercalciuria.
Intestinal calcium losses - glucocorticoids, given in high doses for several
weeks, inhibit intestinal calcium absorption, lowering plasma ionized [Ca2+].
This is thought to stimulate compensatory hypersecretion of PTH, which
restores ionized [Ca2+] by activating bone turnover to increase delivery of
calcium to the circulation from bone.
Direct stimulation of bone resorption via increased RANK-L expression and
decreased OPG production. Glucocorticoids also inhibit osteoblastic
maturation and activity. Glucocorticoids also promote apoptosis in osteoblasts and osteocytes. In patients chronically treated with glucocorticoids,
bone formation is suppressed.
High-dose glucocorticoid administration also suppresses gonadotropin
secretion and creates a hypogonadal state in both men and women.


Clinical manifestation
Osteoporosis has no clinical manifestations until there is a fracture. This is an
important fact, since many patients with achy hips or feet assume that their
complaints are due to osteoporosis. This is unlikely to be true in the absence of
fracture. In comparison, pain is common in osteomalacia in the absence of fractures
or other bone deformities.
Osteoporotic fractures (fragility fractures, low-trauma fractures) are those
occurring from a fall from a standing height or less, without major trauma such as a
motor vehicle accident.
Vertebral fracture is the most common clinical manifestation of osteoporosis.
Most of these fractures (about two-thirds) are asymptomatic; they are diagnosed as
an incidental finding on chest or abdominal x-ray. In some patients, the presence of
vertebral fractures may become apparent because of height loss or kyphosis.
Other fractures: hip fractures are relatively common in osteoporosis and in
addition, distal radius fractures (Colles fractures) may occur. Colles fractures are
more common in women shortly after menopause, whereas the risk of hip fracture
rises exponentially with age.
There are a number of risk factors for fracture.
Nonmodifiable risk factors:
Personal history of fracture as an adult,
History of fracture in first-degree relative,
Female sex,
Advanced age,
White race,
Potentially modifiable risk factors:
Low calcium intake,
Estrogen deficiency (prolonged premenstrual amenorrhea early
menopause or bilateral ovariectomy),
Inadequate physical activity,
Current cigarette smoking,
Low body weight [BMI <18 kg/m2].
Laboratory and paraclinical investigations
Patients with a suspected acute compression fracture should be evaluated with a
plain x-ray of the dorsolumbar spine, to confirm the diagnosis. Osteoporosis may
lead to several types of vertebral abnormalities including wedge fractures, biconcave
or "codfish" deformities, and compression fractures.
Several noninvasive techniques are available for estimating skeletal mass or
density; bone mineral density - BMD. They include dual-energy x-ray absorptiometry
(DXA), single-energy x-ray absorptiometry (SXA), quantitative CT, and ultrasound
Dual-energy x-ray absorptiometry (DXA) DXA measures bone mineral content
(BMC, in grams) and bone area (BA, in square centimeters), then calculates "areal"
BMD (aBMD) in g/cm2 by dividing BMC by BA. An x-ray tube generates photon
beams of two different energy levels, thus the term "dual-energy." The difference in
attenuation (reduction in intensity) of the two photon beams as they pass through

body tissue of variable composition distinguishes bone from soft tissue and allows
quantification of BMD. DXA has become the standard for measuring bone density
because it gives very precise and accurate measurements at clinically relevant
skeletal sites (ie, those with major clinical consequences when a fracture occurs: hip,
lumbar spine and distal radius) and can be used for diagnostic classification. Tscore, the value used for diagnosis of osteoporosis, is calculated by subtracting the
mean BMD of a young-adult reference population from the patient's BMD and
dividing by the standard deviation (SD) of young-adult population. Bone mineral
density T-score criteria (WHO) for osteopenia and osteoporosis are:
Normal -1.0 SD,
Low bone mass (osteopenia): between -1.0 and -2.5 SD,
Osteoporosis -2.5 SD,
Severe (established) osteoporosis -2.5 SD and fragility fracture.
Z-score, used to compare the patient's BMD to a population of peers, is
calculated by subtracting the mean BMD of an age-, ethnicity-, and sex-matched
reference population from the patient's BMD and dividing by the SD of the reference
population it is used in children.
Quantitative computed tomography (QCT) measures volumetric BMD
(vBMD) in mg/cm3, most often at the spine. At the present time, QCT
is primarily a research tool because it is more expensive, less
reproducible, and requires a higher radiation dose than DXA.
Quantitative ultrasonography (QUS) QUS does not measure BMD,
but instead measures the reflectance of the ultrasound waves from
the bone surface. Potential advantages of QUS include low cost,
portability, and lack of radiation exposure. Measurements are most
commonly made at the calcaneus (heel). QUS cannot be used for
diagnostic classification or to monitor response to therapy.
Routine laboratory evaluation includes
complete blood count,
serum and 24-h urine calcium,
renal and hepatic function, serum albumin, cholesterol,
measurement of serum 25(OH)D level. Vitamin D levels should be
optimized in all individuals being treated for osteoporosis.
There is no established algorithm for the evaluation of women who present
with osteoporosis but in order to exclude secondary forms it can be useful:
- PTH, if hypo- or hyperparathyroidism is suspected,
- TSH, for evaluation of hyperthyroidism,
- urinary free cortisol levels or a fasting serum cortisol should be
measured after overnight dexamethasone if Cushing syndrome is a
- testosterone or E2, LH, FSH for hypogonadism,
- testing for antigliadin, antiendomysial, or transglutaminase antibodies
for celiac disease,
- serum and urine electrophoresis and evaluation for light chains in urine
in the case of suspicion for myeloma.
Several biochemical tests are available that provide an index of the overall
rate of bone remodeling. Biochemical markers usually are characterized as those
related primarily to bone formation or bone resorption. These tests measure the

overall state of bone remodeling at a single point in time. Bone formation markers
Serum bone-specific alkaline phosphatase,
Serum osteocalcin,
Serum propeptide of type I procollagen.
Bone resorption markers are:
Urine and serum cross-linked N-telopeptide,
Urine and serum cross-linked C-telopeptide,
Urine total free deoxypyridinoline.
The markers of bone resorption may help:
in the prediction of fracture risk, independently of bone density, particularly in
older individuals,
for monitoring the response to treatment (the primary use of biochemical
ensure long-term adherence to treatment.
Differential diagnosis
Although most postmenopausal women and older men do not have a
definable secondary cause, those who do can be treated more effectively. This
possibility should be considered for every patient. Other disorders that should be
consider for differential diagnosis:
rickets and osteomalacia disorders of the mineralization of newly synthesized
organic matrix determined by vitamin D deficiency,
primary bone tumor or bone metastasis,
Paget disease of bone (osteitis deformans) - a focal disorder of bone
remodeling that leads to greatly accelerated rates of bone turnover, disruption
of the normal architecture of bone, and sometimes to gross deformities of bone.
The clinical features of Paget disease are pain, fractures and bone deformity.
fibrous dysplasia of bone, a component of the McCune-Albright syndrome.
Treatment and prophylaxis of osteoporosis
Assessment of fracture risk can be estimated by using FRAX calculators that
are available online ( Patients should be educated
to reduce the impact of modifiable risk factors associated with bone loss and falling:
Women with osteoporosis (or seeking to prevent it) should exercise (prudently)
for at least 30 minutes three times per week, as exercise has been associated
with improvements in or maintenance of bone density and a reduced risk of hip
fracture in older women.
Smoking cessation because smoking cigarettes accelerates bone loss.
An optimal diet for treatment (or prevention) of osteoporosis includes an
adequate intake of calories (to avoid malnutrition), calcium, and vitamin D.
Postmenopausal women (and older men) should take adequate supplemental
elemental calcium such that their total calcium intake, including food calcium,
approximates 1200 mg/day. Women should also ingest a total of 800 IU of
vitamin D daily. Higher doses are required if they have malabsorption or rapid
metabolism of vitamin D due to concomitant anticonvulsant drug therapy.
Hip protectors may reduce fractures in high-risk populations.

Medicines that cause prolonged sedation or postural hypotension should be

avoided in elderly people. Help should be provided for designing a lifestyle that
maintains function and minimizes fracture risk.
The above measures should be adopted universally to reduce bone loss in
postmenopausal women. Postmenopausal women with osteoporosis or at high risk
for the disease should be considered for drug (or hormonal) therapy.
Pharmacologic therapy in osteoporosis can be classified in :
o Bisphosphonate: alendronate, risedronate, ibandronate, and zoledronic
o Selective estrogen receptor modulator (SERM): raloxifene,
o Denosumab,
o Tibolone, a synthetic steroid whose metabolites have estrogenic,
androgenic, and progestagenic properties. It has an excess risk of stroke.
o Calcitonin,
o Estrogen/progestin therapy HRT.
Anabolic therapy:
o Parathyroid hormone,
o Strontium ranelate,
o Anabolic steroids.
Emerging therapies.

For the treatment of osteoporosis in postmenopausal women, bisphosphonates are first-line therapy. Bisphosphonates are synthetic analogues of native
pyrophosphate that inhibit osteoclastic bone resorption. Mechanism of action:
- they attach to hydroxyapatite binding sites on bony surfaces, particularly surfaces
of active remodeling,
- bisphosphonates reduce osteoclast activity by decreasing osteoclast progenitor
development and recruitment and by promoting osteoclast apoptosis.
Bone formation is often reduced by bisphosphonates, which is probably an
indirect effect of inhibition of bone resorption.
Despite their structural similarities, there are important differences among the
bisphosphonates in potency and toxicity. The nitrogen-containing bisphosphonates,
like zoledronic acid, risedronate, ibandronate or alendronate, are approved for
prevention and treatment of osteoporosis. Some bisphosphonates have very long
retention in the skeleton and may exert long-term effects.
All the approved bisphosphonates have been shown to reduce vertebral
fractures by approximately 50% to 60%. Alendronate, risedronate, and zoledronic
acid have also been shown to reduce the risk of nonvertebral fractures. Alendronate
(70 mg) and risedronate (35 mg) are approved for weekly dosing, and risedronate
and ibandronate (150 mg) are approved for monthly dosing. Intravenous therapy can
be given conveniently for zoledronic acid (5 mg annually) and ibandronate (3 mg
Oral bisphosphonate absorption is very low, less than 1% of the administered
dose. Consequently, patients must take these medications on first arising in the
morning, on an empty stomach, with at least 250 ml of water, remain upright to
ensure passage of the pill into the stomach, and ingest nothing else for 30 minutes
for alendronate and risedronate, and 60 minutes for ibandronate.

Side-effects of the bisphosphonates are:

- upper gastrointestinal effects, most notably esophageal irritation if the pill does
not clear the esophagus hence the requirement to administer with sufficient
water and remain upright after dosing,
- osteonecrosis of the jaw,
- bone pain,
- flu-like symptoms or with intravenous bisphosphonate,
- hypocalcemia.
The contraindications of bisphosphonates are: hypersensitivity to bisphosphonates or any component of the formulation; hypocalcemia; abnormalities of the
esophagus which delay esophageal emptying such as stricture or achalasia; inability
to stand or sit upright for at least 30 minutes. None of the bisphosphonates are
recommended for use in patients with significant renal impairment (creatinine
clearance <35 mL/min).
Selective Estrogen Receptor Modulators (SERM)
In the past decade several molecules that act as estrogens on some tissues
but antiestrogens on others were developed. The only currently approved SERM,
raloxifene, is an estrogen agonist at bone and liver, that promotes conservation of
BMD and lowering of LDL cholesterol concentrations, but it is inert at the endometrium and a potent antiestrogen at the breast. Raloxifene (60 mg/day) has been
shown to decrease the vertebral fracture incidence in older osteoporotic women and
has received approval for both prevention and treatment of osteoporosis in
postmenopausal women.
Raloxifene increases the risk of venous thromboembolic events and the
occurrence of hot flashes.There are several SERMS in clinical trials for the treatment
and prevention of postmenopausal osteoporosis, including bazedoxifene and
It is a humanized monoclonal antibody against RANKL that reduces
osteoclastogenesis. RANKL, a member of the TNF superfamily of ligands and
receptors, is essential for the function of bone-resorbing osteoclasts; RANKL
accelerates osteoclastogenesis when it binds to its receptor, RANK, but is blocked
by osteoprotegerin, which is produced by osteoblasts. Denosumab has been shown
to improve bone mineral density (BMD) and reduce the incidence of new vertebral,
hip, and nonvertebral fractures in postmenopausal women. It should not be given to
patients with preexisting hypocalcemia until it is corrected. Denosumab (60 mg) is
administered by subcutaneous injection once every six months.
Calcitonin inhibits osteoclastic bone resorption if is given as a pharmacologic
agent. It is approved for postmenopausal osteoporosis treatment as a nasal spray or
as an injectable form. Calcitonin nasal spray (200 IU/d) increases modestly BMD and
reduces vertebral fractures and may provide some analgesic benefit in women with
acute or painful vertebral fractures, possibly through central nervous system effects.


Hormone replacement therapy - HRT

In the past, long-term (more than five years) unopposed estrogen and
combined estrogen-progestin therapy (postmenopausal hormone therapy, HRT) has
been routinely prescribed for prevention of coronary heart disease and osteoporosis.
The role of HRT for the prevention and treatment of osteoporosis has been
altered substantially by the findings of large clinical trials suggesting that estrogenprogestin therapy reduces fracture risk with the cost of increasing the incidence of
breast cancer, coronary heart disease (CHD), stroke, and venous thromboembolism.
Normal women have ovarian failure, or menopause, at a mean age of 51
years. Estrogen is the most effective treatment available for relief of the menopausal
symptoms that many women experience, including hot flashes, vaginal dryness,
urinary symptoms, and emotional lability. Other beneficial effects of HRT are
reduction in the risk of colorectal cancer and an improvement in lipid profiles.
However, data from the Women's Health Initiative (WHI) trial reported an increase in
CHD risk that appeared to be age dependent; women who were <10 years since
menopause or between the ages of 50 to 59 years did not have excess risk.
Estrogen deficiency results in increased bone resorption but an additional
defect in the bone formation response to increased resorption may be implicated.
The mechanisms by which estrogen regulates bone remodeling are not well
understood. It is thought to affect osteoclastogenesis and osteoclast function through
its effects on local factors. Cytokines and growth factors appear to play an important
pathogenetic role in the osteoporosis associated with estrogen deficiency.
Contraindications of HRT:
- undiagnosed abnormal vaginal bleeding;
- history of or current thrombophlebitis or venous thromboembolic disorders;
- active or recent (within 1 year) arterial thromboembolic disease (eg, stroke,
myocardial infarction);
- carcinoma of the breast;
- estrogen-dependent tumor;
- hepatic dysfunction or disease.
Postmenopausal hormone therapy is currently recommended for short-term
(2-3 years) management of moderate-to-severe vasomotor flushes. HRT is approved
for prevention but not treatment of osteoporosis. The maximum protection of bone
mass appears to occur when estrogen therapy is begun soon after menopause.
Dose equivalents for conjugated estrogen 0.625 mg, considered to be standard
estrogen dose, are: 1 mg micronized 17-beta-estradiol = 50 mcg/day transdermal 17beta-estradiol = 10 mcg ethinyl estradiol. Low dose estrogen preparations can also
be used; in general, they contain one-half the standard dose.
Endometrial hyperplasia and cancer can occur after unopposed estrogen
therapy; as a result, a progestin should be added in women who have not had a
hysterectomy. The most commonly prescribed progestin is medroxyprogesterone
acetate (MPA), typically given in a cyclic regimen (5 to 10 mg/day) or continuous
regimen (2.5 mg/day). Drospirenone, a newer progestin, has progestogenic,
antiandrogenic, and antimineralocorticoid activity (0,5-2 mg).
Parathyroid Hormone
Severe primary hyperparathyroidism is associated with fractures, skeletal
deformity, and bone pain. However, many experiences over the past two decades
indicate that administration of PTH to individuals with low BMD may not only improve

BMD but also reduce the risk of fractures. The decisive element apparently that
determines the effects of PTH to be destructive or therapeutic is whether PTH
concentrations in blood are elevated constantly or only intermittently. In severe
hyperparathyroidism, PTH concentrations remain high, varying little throughout the
day. Administration of PTH as daily pulse injections has been shown to produce a
substantial increase in trabecular bone mass with little loss or even a gain in cortical
bone in the femur.
Treatment with PTH is likely to be the most effective approach in patients who
lose bone or continue to have fractures on antiresorptive therapy.
Teriparatide or rhPTH(1-34) was approved for use in both men and
postmenopausal women with osteoporosis who are at high risk for fractures as well
as in glucocorticoid-induced osteoporosis or in patients who cannot use other
osteoporosis treatments. It is given in daily subcutaneous doses for a maximum of 2
years. The limitation is indicated because a long-term carcinogenicity study showed
that rats treated with rhPTH(1-34) showed a dose-related incidence of
Recombinant PTH 1-84 is also effective for the treatment of osteoporosis.
Strontium Ranelate
Strontium ranelate has been proposed as an anabolic agent that also may be
antiresorptive. The dose used is 2 g/day. There is evidence that strontium ranelate is
effective for reducing the risk of vertebral fractures, and to a lesser extent, nonvertebral fractures. Although side effects are minimal (e.g. diarrhea), there are
reports of rare but severe allergic reactions.
Emerging therapies
There are several novel therapies under investigation for the treatment of
osteoporosis. They are in various stages of development. As examples:
- Sclerostin inhibitors, stimulates bone formation.
- Integrin antagonists inhibits the adhesion of osteoclasts to the bone surface, an
important initial step for bone resorption.
- Cathepsin-K inhibitors inhibit bone matrix dissolution and decrease bone
The patients under treatment for osteoporosis should be monitored periodically. Markers of bone turnover are an option for patients who have conditions that
might interfere with drug absorption or efficacy, such as small bowel resections or
other types of malabsorption, or in patients who are reluctant to take antiosteoporosis medications regularly. In such patients, urinary N-telopeptide (NTX) or
serum carboxy-terminal collagen crosslinks (CTX) before and three to six months
after starting bisphosphonate or other antiresorptive therapy may be determined.
For patients starting on therapy it is also recommended to repeat DXA of the
lumbar spine and total hip every one to two years until stability is achieved, and
every two years or at less frequent intervals thereafter.



Anatom y, embryology and histology
The two adrenal glands are pyramidal-shaped glands localized in
retroperitoneum above or medial to the superior pole of the kidney. Each of them
weights about 4-6 g in adult, is protected by a fibrous capsule and consists of a
cortical part named adrenal cortex (AC) and a medullar area adrenal medulla (AM).
The blood supply of the adrenal gland is very complex and abundant; it is provided
by the aorta, but also by inferior phrenic and renal artery branches. All these small
arteries create a subcapsular arteriolar plexus, and then enter a sinusoidal system
that penetrates the cortex and medulla, draining into a single central vein in each
gland. The right adrenal vein drains directly into the posterior wall of the vena cava;
the left adrenal vein drains in the left renal vein. These anatomic features account for
the fact that it is relatively easier to catheterize the left adrenal vein than it is to
catheterize the right adrenal vein.
The adult adrenal cortex is divided histologically and functionally into three
distinct layers:
Zona glomerulosa comprises 15% of the cortex, produces aldosterone
and is clustered in cellular nests dispersed under the capsule.
Zona fasciculata is the best represented part of the cortex (75%), the
cells are larger and clear (contain more lipid) and are disposed in
columns. It produces and secretes cortisol and androgens (in lower
Zona reticularis is composed of more compact, acidophil, i.e. lipid-poor
cells, which delimit AM. It synthesizes androgens and cortisol.
The last two zones, which secrete cortisol and androgens are controlled by
ACTH, the excess or deficiency of the latter hormone influencing directly not only the
function but also the structure of these zones. It is presumed that the zona
fasciculata may respond to the acute ACTH-stimulation by increasing cortisol
production, whereas zona reticularis is responsible for basal cortisol secretion. Thus,
the excessive, chronic ACTH stimulation may be followed by the gradually loss of
clear aspect of the cells in the zona fasciculata and hypertrophy of zona reticularis.
AC derives from the primitive mesoderma, from the medial part of the
urogenital ridge. All the AC zones derive from the same cellular line characterized by
the specific expression of some transcriptional factors, such as SF-1 (steroidogenic
factor 1). During fetal life a fourth zone namely fetal cortex does exist in the cortical
region, and the whole adrenal gland is better represented reported to body weight,
compared to the adult one. From the 20th week of intrauterine life AC is under ACTH
control. The fetal cortex, which secretes mainly DHEA and DHEAS disappears
progressively after birth.


Adrenal hormone biosynthesis

All steroid hormones are derived from the cyclopentanoperhydrophenanthrene structure, that is, three cyclohexane rings and a single cyclopentane
ring. The precursor of all steroid hormones, irrespectively of the site of their
synthesis, is cholesterol which is provided mainly by the peripheral bloodstream as
LDL cholesterol (low-density lipoprotein).
It is coupled to its own membrane receptors and then it is internalized via
endocytosis; the resulted vesicles fuse with lysosomes and free cholesterol is
discharged by hydrolysis. LDL cholesterol is not the single source of cholesterol in
the adrenal gland, it can also be synthesized in the adrenal cortex from acetyl
coenzyme A. HDL cholesterol receptors have been identified recently in the adrenal.

Figure 6. Synthetic pathways for adrenal steroid synthesis

17: 17-hydroxylase (CYP17, P450c17); 17,20: 17,20 lyase (also mediated by CYP17); 3: 3hydroxysteroid dehydrogenase; 21: 21-hydroxylase (CYP21A2, P450c21); 11: 11-hydroxylase;
(CYP11B1, P450c11); 18 refers to the two-step process of aldosterone synthase (CYP11B2,
P450c11as); 17R: 17-reductase; 5R: 5-reductase; DHEA: dehydroepiandrosterone; DHEAS:
DHEA sulfate; A: aromatase (CYP19).

Free intracellular cholesterol is carried than to the external mitochondrial

membrane, where it is actively transferred to the internal mitochondrial membrane by
a protein named StAR (steroidogenic acute regulatory protein). This first step of
steroidogenesis is under ACTH control, and is schematically showed in figure 6. The
enzyme called SCC (side chain cleavage enzyme) or P450scc, with a 20,22
desmolase activity as well, catalyzes the synthesis of pregnenolone from cholesterol.
Pregnenolone is transferred then from the mitochondria in the smooth
endoplasmic reticulum, where it will be converted into progesterone or 17hydroxypregnenolone. Steroidogenesis is realized by the concerted action of more
enzymes, responsible for successive hydroxylation. All these enzymes are part of
the P450-cytochrome cluster, and the codifying genes have been characterized from
the molecular point of view and are shown in table 14. The final steps of cortisol
synthesis are realized in the mitochondria.

Table 14. Enzymes implicated in steroidogenesis



Chromosomal region

Cholesterol side-chain cleavage (SCC)



3-Hydroxysteroid dehydrogenase (3-HSD)



17-Hydroxylase/17,20 lyase









Aldosterone synthase



Androgen synthesis in the AC is represented by androstenedione and DHEA,

the latter being then reversible converted in DHEA sulphate by a sulfokinase (SK).
These are weak androgens and act mainly after transformation into more active
forms: testosterone and dihydrotestosterone (DHT).
The synthesis of aldosterone is possible only in zona glomerulosa, because
the CYP11B2 gene and enzyme capable to transform corticosterone into
aldosterone is expressed only in this zone. This zone lacks the 17Hydroxylase/17,20 lyase enzyme, so it is incapable to synthesize cortisol and
androgens. In other words, the different expression of genes codifying the enzymes
implicated in steroidogenesis is responsible for the functional stratification of AC
which correlates with the above mentioned histological and anatomical aspects.
The metabolism of adrenal hormones
The basic secretion of cortisol without stress, is 9-25 mg/day (22-69 mol/day),
that of aldosterone 100 g/day and the secretion rate of DHEA is between 10 to 30
g. The metabolism of cortisol and adrenal androgens is performed by hydroxylation
and conjugation of glucuronid groups, and sulphate in the liver. More than 90% of
resultant products are excreted by the kidneys, less than 1% of secreted cortisol
appears freely in the urine. Alteration in the cortisol metabolism appears in:
Childhood and older age a reduction of the cortisols metabolism is
Liver diseases these are followed by the reduced renal excretion of
Hypothyroidism both the excretion and metabolism of cortisol is
The cortisol clearance is reduced during pregnancy, anorexia nervosa and
starvation. A degradation to inactive metabolites of the androgens produced in the
AC does exist, but they can be converted in the periphery into more powerful
metabolic products such as testosterone and DHT. DHEA-S is produced inside the
adrenal gland but also in the liver and kidney.
The inactivation of aldosterone is realized especially in the liver where it is
transformed in tetrahydroaldosterone. Aldosterone-18-glucuronid, another metabolite
is formed in the kidney and represents 5-10% of the secreted aldosterone. DOC is
metabolized in the liver into tetrahydrodeoxycorticosterone, it is conjugated with
glucuronic acid and it is excreted in the urine.

Circulation of adrenal hormones

Both cortisol and adrenal androgens circulate mainly coupled with proteins. Thus,
10% of the total circulating cortisol is free (1g/dl), and 75% is bonded to a
transcortine named CBG (corticosteroid-binding-globulin) and the remaining part is
bonded to albumin. Adrenal androgens are bonded especially to albumin. Plasma
proteins are used as veritable circulating storage, in order to prevent large fluctuation
of free hormonal concentrations by their delayed metabolic clearance. Salivary
cortisol reflects free cortisol controlled by ACTH.
CBG levels are increased in high-estrogen states (pregnancy; estrogen or oral
contraceptive use), hyperthyroidism, diabetes, certain hematologic disorders, and on
a genetic basis. CBG concentrations are decreased in familial CBG deficiency,
hypothyroidism, and protein deficiency states such as severe liver disease or
nephrotic syndrome.
CBG increases in:
Hereditary form;
Hyperestrogenism, irrespectively to cause (pregnancy, oral contraceptive
use, estrogen secreting tumors);
Diabetes mellitus.
A reduced CBG level appears in:
Familial, hereditary CBG deficiency;
Nephrotic syndrome;
Liver failure.
The other endogenous steroid hormones do not influence the binding capacity of
cortisol to CBG and synthetic steroids, with the exception of prednisolone, do not
bind to CBG. Albumin has a much greater capacity for cortisol binding but a lower
affinity; on the other hand it binds to synthetic corticosteroids 75% of
dexamethasone is bound to albumin.
In the bloodstream aldosterone is circulating bound to CBG, but 30-50% out of
the total plasma aldosterone is free, with a half-time of 15-20 minutes. DOC, like
cortisol binds in a great amount to CBG, less than 5% being found in the free form.
The control of steroid hormone production and secretion
The main hormone which assures the trophicity of both reticular and fascicular
zones in the AC is ACTH, although a similar, but reduced action is attributed to some
neuropeptides or neurotransmitters secreted locally. ACTH is controlled by the
hypothalamus and the CNS by CRH, AVP and neurotransmitters.
The chronic ACTH stimulation determines AC hypertrophy and hyperplasia while
its deficiency inhibits steroidogenesis and it is followed by adrenal cortex atrophy.
The neuroendocrine control involves other aspects too:
1. The circadian rhythm and episodic secretion of cortisol are the result of
amplitude variation and the number of ACTH and CRH pulsatile episodes.
Plasma cortisol, following closely plasma ACTH, has low levels before
sleep, in the evening and it continues to decrease during sleep to almost
undetectable values. During the third and fifth hours of sleep there is an
increase in secretion; but the major secretory episodes begin after six to
eight hours of sleep. Cortisol secretion then gradually declines during the

day, with some secretory episodes with lower amplitudes associated with
meals and exercise. Interindividual variations do exist and biorhythm
could be lost in condition of physical stress (traumas, starvation etc.),
psychological stress (anxiety, depression), CNS and pituitary lesions, liver
and kidney failure, Cushings syndrome, alcoholism.
2. The ACTH and cortisol response to stress appear in different conditions
such as traumas, hypoglycemia and is mediated also through CRH and
CNS. This response may be reduced by high dose glucocorticoids
administered before stress.
3. Negative feedback control refers to the inhibitory effect of cortisol or
synthetic glucocorticoids (GC) on both CRH and ACTH. Continuous
administration of GC determines a lack of response of AC-pituitaryhypothalamus to stress or common stimuli, due to ACTH and CRH
suppression and the atrophy of the fasciculata and reticulata zones.
Adrenal androgens production in adults is also under the control of ACTH, both
DHEA and androstenedione having a circadian periodicity superposed on that of
ACTH and are suppressed after GC administration. On the contrary, DHEA-S does
not present diurnal fluctuations because of a much more reduced rate of metabolism.
The control of aldosterone secretion, the most important hormone with
mineralocorticoid effect is realized mostly by angiotensin II and hyperkalemia, both
having direct effect on zona glomerulosa, stimulating pregnenolone synthesis from
cholesterol and conversion of corticosterone into aldosterone. Atrial natriuretic
peptide (ANP), dopamine and heparin inhibit aldosterone secretion.
In normal individuals both renin and aldosterone release vary inversely with salt
intake hyponatremia has a stimulatory effect and hypernatremia an inhibitory
action on aldosterone release.
ACTH exerts a rapid but short stimulatory effect on aldosterone, the effect being
limited firstly by the increased secretion of DOC dependent on ACTH, hydric
retention and consecutive reduction of both aldosterone and renin.
If aldosterone is administered to a healthy person with adequate salt intake,
water and NaCl retention with K+ wasting appear initially, which determines an
elevation of blood pressure and body weight. After an approximately 3 kg weight
gain an escape phenomenon with spontaneous urine output appears and plasma
volume returns to normal, determined by atrial natriuretic peptide and hemodynamic
kidney mechanism.
Molecular mechanisms of glucocorticoids and mineralocorticoids
In contrast to the thyroid hormone receptors which are located in the nucleus,
the glucocorticoid (GC) receptors are situated intracytoplasmatic and are coupled
with hsp (heat shock protein). In target cells these proteins are dislocated when GC
bind to their own receptor after cell membrane diffusion.
Receptor-hormone complexes suffer a subsequent phosphorylation which favors
their transport into the nucleus, where they form homo- and heterodimers with other
complexes. Specific sequences of DNA-binding domains situated on the dimerized
receptors interact with hormone-responsive elements for GC (GRE), with highly
conserved structures, containing 15 nucleotides. Together with other transcription
factors, GRE stimulate or inhibit the expression of specific gene and the transcription
of specific mRNA.

Certain actions of GC, similar with the nongenomic actions of thyroid hormones,
appear more rapidly and cannot be justified by the effect on gene expression. A part
of them may be realized through some membrane or cytoplasm proteins which use
intracytoplasmic signal pathways such as Ca channels or cyclic-AMP/protein kinase.
This mechanism may explain the rapid effect of GC on immune function, apoptosis
and inhibition of ACTH secretion.
Mineralocorticoid type activity reflects both the free plasma hormone availability
and their affinity for receptors. Aldosterone and DOC have similar affinity for
mineralocorticoid receptors but aldosterone exerts a more important effect because it
exists as a free form in a higher proportion. The mineralocorticoid action of plasma
cortisol is comparable with those two, having similar affinity for receptors, but its
action is limited in certain target tissues (kidneys, colon etc.) as a consequence of
local degradation into cortisone by 11 beta hydroxysteroid dehydrogenase. Cortisone
cannot bind to mineralocorticoid receptors.
Mineralocorticoid effects are mediated by aldosterone binding to mineralocorticoid receptor in epithelial cells, mainly renal ones, followed by the transport of
these complexes into the nucleus and their coupling to specific binding domains of
some genes whose expression is thus increased. One of the most important
intermediate elements is a kinase controlled by aldosterone with a modulating effect
on apical sodium channel.
Biological effects of adrenal steroids
Steroid hormones exert their effects by binding to specific receptors, that are
present virtually in all tissues. Synthetic GC obtained by the modification of the
natural GC structure, have a lower metabolic rate and a more increased affinity for
cytosolic receptor; in addition, many of these synthetic glucocorticoids have
negligible mineralocorticoid effects.
GC effects on intermediary metabolisms consist in maintaining plasma glucose
in starvation conditions antihypoglycemic action and elevation of blood glucose in
stress period hyperglycemic action. These effects are a consequence of the
Increased liver gluconeogenesis and liver glycogen synthesis;
Inhibition of peripheral glucose uptake by the reduction of protein synthesis
and increased release of amino-acids;
Lipolysis stimulation with glycerol and free fatty acids release (amino-acids
will be used as substrate for gluconeogenesis).
GCs generally inhibit DNA synthesis, in most tissues they inhibit RNA and
protein synthesis and accelerate protein catabolism. The single exception is the liver
were both the protein and RNA synthesis are stimulated by GC.
GC effects on other tissues or functions:
1. Connective tissue. GC inhibit the proliferation of keratinocytes and fibroblasts
with formation of striae, skin thinning, poor wound healing etc.
2. Bone tissue and phosphate-calcium metabolism. GC reduce intestinal
absorption of calcium, they cause secondary hyperparathyroidism, but also
increase urinary calcium excretion, with hypercalciuria, phosphaturia. The GC
excess results in negative calcium balance, although serum calcium level is
maintained within normal range but at the expense of net bone resorption.
Osteolysis is associated with an increase in biochemical markers of bone
turnover. Glucocorticoids directly inhibit bone formation by decreasing cell

proliferation and the synthesis of RNA, protein, collagen, and hyaluronate.

Thus, osteoporosis is considered a major complication of GC excess and is
frequently described irrespectively the source.
4. Growth and development. In a physiological aspect GC accelerate
development and tissue differentiation in some organs and fetal systems (they
increase the production of surfactant, promote the development of some liver
enzyme systems etc.). GC excess inhibits growth in children by effects on
bone and a direct inhibition on GH and IGF-1.
5. Immune system. GC influence considerable both immune and inflammatory
responses: they decrease the migration capacity of inflammatory cells (PMN,
monocytes, lymphocytes) at the locus of injury. They inhibit the key enzymes
in prostaglandin synthesis and leukotriene (phospholipase A2), IL -1, IL-6 or
TNF release. They also impair antigen processing, antibody production and
clearance and other specific bone marrowderived and thymus-derived
lymphocyte functions.
6. Cardiovascular system. Glucocorticoids may increase cardiac output and they
also increase peripheral vascular tone, possibly by augmenting the effects of
other vasoconstrictors (eg, the catecholamines). Glucocorticoids also regulate
expression of adrenergic receptors. Thus, refractory shock may occur when
the glucocorticoid-deficient individual is subjected to stress. Glucocorticoids in
excess may cause hypertension independently of their mineralocorticoid
7. Renal function. GC action on water and electrolyte balance is mediated
through both mineralocorticoid receptors (with the consequent development of
sodium retention, hypokalemia and hypertension) and glucocorticoid
receptors (increase of the glomerular filtration rate).
8. CNS. Normal cortisol values maintain a normal emotional status. GC excess
determines euphoria in the first phase, then depression, considerable
emotional lability and sometimes cognitive disturbances develop. Other
central effects include increased appetite, decreased libido, and insomnia.
9. Endocrine system: GC reduce gonadotropins response to GnRH, inhibit GH
by hypothalamic effect and inhibit insulin secretion. They decrease the
majority of hormone binding proteins (CBG, TBG etc.) and stimulate
epinephrine synthesis.
10. Other effects. GC in excess determine peptic ulcer, increase intraocular
pressure, cause the development of cataract.
AC androgens have a minimal direct bioactivity, acting first of all as precursors
for active androgens: testosterone and DHT. Adrenal androgen excess can cause
premature penile enlargement and early development of secondary sexual
characteristics in boys and hypogonadotropic hypogonadism in adult male patients
as a consequence of increased aromatization of adrenal androgens, in particular
androstenedione to estrone resulting in suppression of pituitary LH and FSH
secretion. In female fetus, excessive secretion of adrenal androgens, in congenital
adrenal hyperplasia, leads to sexual ambiguity at birth and even inappropriate sex
assignment. The same excess can cause and in women with Cushings syndrome
hair excess, acne, virilism and menstrual disturbances.
Aldosterone regulates extracellular volume and influences potassium
homeostasis, determining Na+ retention and K+ excretion in the kidney. Beside these
effects, aldosterone also influences some non-epithelial cells, which include the

expression of collagen, beta TGF, plasminogen activator inhibitor type 1 genes, or

the expression of some mediator genes for inflammation. These effects are
responsible for the appearance of microangiopathy, acute necrosis and vascular
fibrosis on both renal and heart epithelium.
Laboratory evaluation of adrenal gland hormones
Measurements of cortisol in serum or occasionally plasma are extremely
useful in the diagnosis of hypercortisolism and adrenal insufficiency. Cortisol has
been measured in serum by several methods like radioimmunoassays or HPLC,
mass spectrometry. In normal subjects serum cortisol concentrations are higher in
the early morning (about 8 AM), ranging from 5 to 25 g/dL and reach a nadir <3
g/dL at about midnight, in a non-stressed subject. The total plasma cortisol
concentration is elevated when circulating estrogen levels are high (eg, during
pregnancy and when exogenous estrogens or oral contraceptives are being used), in
patients who are acutely ill, during surgery, following trauma, in depression,
starvation, anorexia nervosa, alcoholism, and chronic kidney disease. An early
morning low serum cortisol concentration (less than 3 g/dL [80 nmol/L]) is strongly
suggestive for adrenal insufficiency.
The circadian rhythm is lost in patients with Cushings syndrome. Random
morning plasma cortisol levels are of little value in making the diagnosis, whereas a
midnight cortisol level greater than >7.5 g/dL indicates Cushings syndrome. Ideally,
patients should be hospitalized for 24 to 48 hours before the midnight cortisol level is
A late evening salivary cortisol concentration can be used to establish the
diagnosis of Cushing's syndrome. Salivary cortisol concentrations are not affected by
changes in serum cortisolbinding proteins, by salivary flow or composition. Saliva is
easily collected and cortisol is stable in saliva even at room temperature for several
days. Saliva collection is noninvasive, and can be performed by the patient at home.
It is useful to evaluate at least two samples from different days. A cortisol value
greater than 2.0 ng/mL (5.5 nmol/L) has a 100% sensitivity for diagnosis of
Cushings syndrome.
The assay of unbound cortisol excreted in the urine is an excellent method for
the diagnosis of Cushing syndrome. Urine free cortisol (UFC) is measured in a 24hour urine collection by HPLC, radioimmunoassay, and by mass spectrometry. The
patient can be assumed to have Cushing's syndrome if basal urinary cortisol
excretion is more than three times the upper limit of normal (which may vary
somewhat in different assays) and one other test is abnormal. This test is not useful
in adrenal insufficiency, because it lacks sensitivity at low levels and because low
cortisol excretion is often found in normal persons.
Measurement of the urinary excretion of corticosteroid metabolites like 17hydroxycorticosteroid (17-OHCS) has been used to evaluate adrenocortical function
for many years. Urinary 17-OHCS excretion is increased in patients with all forms of
Cushing's syndrome and decreased in patients with primary and secondary adrenal
insufficiency. Various drugs interfere in the 17-OHCS assay, including
spironolactone, phenobarbital, phenytoin. These drugs should be discontinued for at
least one week, before collecting the urine specimen.
Dexamethasone suppression tests are used to assess the status of the
hypothalamic-pituitary-adrenal (HPA) axis and for the differential diagnosis of
adrenal hyperfunction.

1. Low-dose dexamethasone suppression tests:

a. the 1-mg overnight screening test Dexamethasone (1 mg, ie, two
tablets of 0.5 mg) is taken orally between 11 PM and midnight and a
single blood sample is drawn at 8 AM the next morning for assay of
serum cortisol. Cushing syndrome is excluded if the serum or plasma
cortisol level is less than 1.8 g/dL (50 nmol/L) using the 2008
Endocrine Society Guidelines or less than 5 g/dL (140 nmol/L) using
older criteria.
b. Standard two-day, 2 mg test is used to assess suppressibility in
patients with an equivocal overnight test or in patients who have not
had an overnight test. Dexamethasone, 0.5 mg is taken orally every
six hours, usually at 8 AM, 2 PM, 8 PM, and 2 AM, for a total of eight
doses. Blood is drawn six hours after the last dose for measurement
of cortisol. The normal response to the two-day test consists of a
serum cortisol concentration less than 5 g/dL (140 nmol/L) or <1.8
g/dL (50 nmol/L) using the latest guidelines criteria.
2. High-dose dexamethasone suppression test (the 2-day 8 mg DXM test). It is
used to differentiate Cushing's disease from ectopic ACTH and adrenal
tumors. The rationale for the high-dose dexamethasone suppression test is
that in Cushing's disease the negative feedback control of ACTH is reset to
a higher level than normal. Therefore, cortisol levels do not suppress with
low-dose dexamethasone but do so after high doses. The plasma cortisol is
measured at 0 and +48 hours, and a greater than 50% suppression of
plasma cortisol from the basal value has been observed in most patients
with Cushing's disease. Less commonly, 8 mg dexamethasone is given
orally at 11 PM, with plasma cortisol measured at 8 AM on the same day
(basal sample) and at 8 AM on the following morning. Some patients with
ectopic ACTH syndrome due to indolent bronchial carcinoid tumors exhibit
some suppression after high-dose dexamethasone and 10% of patients with
Cushing's disease, usually those with large, invasive ACTH-secreting
pituitary macroadenomas, show no suppression after high-dose
The tests that assess the hypothalamic-pituitary adrenal axis are used for
determining this axis response to stress:
1. The ACTH test is used for diagnosing both primary and secondary
hypoadrenalism. Cortrosyn 250, 5 or 1 g are being administered IV or IM
anytime during the day, even after meals. Cortisol measurements are
carried out before and 30 and 60 minutes after the injection. The normal
cortisol value after stimulation is 18-20 g/dl. The use of 1 g synthetic
ACTH, although is still controversial, tends to be the most sensitive test for
identifying hypoadrenalism, especially in patients with a history of prolonged
corticoid therapy.
2. The ACTH depot stimulation test Cortrosyn depot 1mg is administered IM
and the cortisol is measured before and 24 hours after the injection. In
normal cases, the cortisol level should double after 24 hours. The test can
be carried out for 2 or 5 days in order to differentiate the secondary
hypoadrenalism from the primary forms. In the former theres a progressive
cortisol rise, while in the latter theres no response.

3. The insulin tolerance test Hypoglycemia causes the central CRH release
and consequently, the ACTH and cortisol secretion. Insulin 0.05-0.15 UI/kg
is being administered and cortisol and serum glucose are measured at -30,
0, 30, 60 and 90 minutes. The normal response implies a rise in serum
cortisol to over 18 g/dl. The test is conclusive only if the serum glucose
reaches 2.2 mmol/l (40mg/dl). The ACTH response to hypoglycemia is more
than 100 pg/ml.
4. CRH stimulation test In case of primary hypoadrenalism, after the
intravenous CRH injection, theres an exaggerated ACTH response after 45
minutes. In case of pituitary failure, theres no response. This test is also
used for diagnosing Cushings disease and can be carried out after the
DXM test. An ACTH rise of 40-50% and cortisol 15-20% pleads for
Cushings disease.
The adrenal androgen measurements are used for diagnosing congenital adrenal
hyperplasia (caused by enzymatic deficits), adrenal tumors and the evaluation of
hirsutism. In adults the serum DHEA level is 0.2-1.3 g/dl (7-31 nmol/l), while the
DHEA sulphate can reach 470 g/dl (12 mol/l). Both these hormones are elevated
in case of an androgen secreting adrenal adenoma or carcinoma, but also in the
following enzymatic deficits (associated with congenital adrenal hyperplasia):
21 hydroxylase,
11 hydroxylase,
3 hydroxysteroid dehydrogenase.
On the other hand, SCC and 17 hydroxylase/17,20 lyase deficits are associated
with low or even non-detectable androgen levels. In the case of aldosterone
synthase deficiency, the androgen levels are normal.
In male patients, testosterone measurement is not significant for estimating
adrenal function, because the main percentage of this hormone is secreted by the
testis. In female patients, on the other hand, approximately 2/3 of circulating
testosterone derives from adrenal secreted precursors.
Total plasma testosterone has the following normal values:
In prepubertal patients 5-20 ng/dl (0.17-0.7 nmol/l),
In male patients 300-1000 ng/dl (10-35 nmol/l),
In female patients 20-70 ng/dl (0.7-2.6 nmol/l).
The plasma testosterone is elevated in testosterone secreting adrenal adenomas
or carcinomas, 21 hydroxylase deficiency and 11 hydroxylase deficiency; it has
normal values in CYP11B2 mutations, while in case of 3 hydroxysteroid
dehydrogenase and 17 hydroxylase deficiencies the level is very low or nondetectable including the male patients.
Although rarely used nowadays, 17 ketosteroid urinary excretion can estimate the
adrenal androgen secretion. Normal ranges are 8-10 mg/24 hours in female and 1215 mg/24 hours in male. Elevated values are caused by the same disorders as the
DHEA and DHEA-S high values. Their measurement is influenced by the use of
many drugs spironolactone, nalidixic acid, penicillin, etc. but it can be used in
monitoring the glucocorticoid substitution in congenital adrenal hyperplasia alongside
the 17 hydroxy- progesterone level.
The most frequent cause of CAH, the 21 hydroxylase deficit is confirmed by the
measurement of 17 hydroxyprogesterone. The normal values for this hormone are
under 82 ng/dl (2.5 nmol/l) in children and under 200 ng/dl (5 nmol/l) in females.

The evaluation of the renin-angiotensin-aldosterone axis has gained an

increasing importance in the evaluation algorithm of hypertensive patients, primary
aldosteronism being now considered a more frequent cause of hypertension.
Renin can be measured considering its plasmatic activity plasma renin activity
PRA with normal ranges from 1.5-2.5 ng/ml/hr or considering its mass (active
renin concentration) which has normal values from 8-35 mU/l. There are many
factors that can influence these values:
Sodium intake a reach salt intake suppresses renin,
Age theres a progressive decrease with age,
Circadian rhythm the highest renin value is in the morning,
Posture transition from supine to erect position is associated with renins
o Spironolactone, calcium channel blockers and angiotensin
converting enzyme inhibitors cause a rise in plasma renin levels,
o Beta-blockers, NSAID, clonidine and alpha-methyl-dopa lower the
renin level.
In the luteal phase of the menstrual cycle and during pregnancy the renin
has higher levels.
The measurement of serum aldosterone uses the RIA method, using high
specificity antibodies in order to avoid false-negative results. The normal range is 715 ng/dl with normal salt intake. Just like renin, the aldosterone level is influenced by
sodium intake, the circadian rhythm, pregnancy and posture.
The urinary aldosterone excretion has a normal value of 5-19 g/24 hours.
Spironolactone must be stopped 6 weeks before the measurement; the other
antihypertensive drugs must be stopped 2-4 weeks before the evaluation.
Cushing's syndrome (CS)
The diagnosis of Cushing's syndrome involves three steps: suspecting it on
the basis of the patient's symptoms and signs, documenting the presence of
hypercortisolemia and determining its cause.
Cushing's syndrome may be either corticotropin (ACTH)-dependent or
ACTH dependent: The causes of ACTH-dependent Cushing's syndrome
are associated with bilateral adrenocortical hyperplasia
Cushing's disease (pituitary hypersecretion of ACTH) the most
frequent type of Cushing's syndrome is responsible for about 70% of
reported cases. Cushing's disease is much more common in women
than in men (female-male ratio of about 8:1). Almost all patients with
Cushing's disease have a pituitary adenoma, although the tumor is
often not demonstrable by imaging; the remainder have corticotroph
Ectopic ACTH syndrome This disorder accounts for approximately
15-20% of patients with CS and is more common in men. The
production of ACTH from a tumor of nonpituitary origin may result in
severe hypercortisolism (hyperpigmentation or hypopotassemia may
be present), but many of these patients lack the classic features of

glucocorticoid excess. Bronchial carcinoid and small cell lung

carcinoma are the most frequent source of this syndrome. A wide
variety of tumors has been reported to produce ectopic ACTH:
pancreatic, thymic tumors, other carcinoid tumors, pheochromocytoma
or medullary thyroid carcinoma.
Ectopic secretion of corticotropin-releasing hormone (CRH) by
nonhypothalamic tumors or secretion of CRH from hypothalamic
tumors; both are causing pituitary hypersecretion of ACTH and
represent very rare causes of CS.
ACTH independent: The causes of ACTH-independent Cushing's
syndrome are:
Adrenocortical adenomas Primary adrenal tumors cause
approximately 10% of cases of CS. Most of these patients have benign
adrenocortical adenomas, encapsulated tumors that range in size from
1 to 6 cm. Most adrenocortical tumors are monoclonal, suggesting that
they result from accumulated genetic abnormalities.
Adrenocortical carcinomas are uncommon, with an incidence of
approximately 2 per million per year. Adrenal carcinomas are usually
greater than 4 cm when diagnosed. They may be palpable as
abdominal masses.
Primary pigmented nodular adrenocortical disease, also called bilateral
adrenal micronodular hyperplasia has a prevalence of less than 1
percent. The familial form, Carney syndrome or complex, is
characterized by pigmented lentigines and blue nevi and multiple
neoplasms, both endocrine (testicular, adrenal, pituitary, or thyroid) and
nonendocrine (cutaneous, mammary, atrial myxomas).
Bilateral ACTH-independent macronodular hyperplasia represents a
rare cause of CS, less than 1 percent. In some patients increases in
cortisol secretion are mediated by aberrant overexpression of receptors
for either gastric inhibitory polypeptide (GIP), vasopressin, betaadrenergic agonists, serotonin, luteinizing hormone/chorionic
gonadotropin. The ectopic expression of GIP receptor in zona
fasciculata cells causes "food-dependent" cortisol production - plasma
cortisol levels increase transiently following meals.
Ectopic cortisol secretion rare cases of ectopic cortisol production
from ovarian or testicular tumors have been described.
Pseudo-Cushing's syndrome appears in patients with severe obesity,
especially those with visceral obesity or polycystic ovary syndrome, in patients with a
severe major depressive disorder or with chronic alcoholism. A pseudo-Cushing's
state can be defined as the presence of some or all of the clinical features of
Cushing's syndrome together with some evidence for hypercortisolism. Resolution of
the underlying cause results in disappearance of the cushingoid state.
Iatrogenic or factitious Cushing's syndrome, which is by far the most common
cause; is usually ACTH-independent and caused by the exogenous administration of
glucocorticoids (oral, injected, topical and inhaled glucocorticoids) usually for their
anti-inflammatory effects but administration of synthetic ACTH may also be the

Clinical features
The possible presence of Cushing's syndrome is suggested by certain symptoms
and signs. Unfortunately, none of these are pathognomonic, and many are
Obesityis the most common manifestation and weight gain is usually the
initial symptom. It is classically central, affecting mainly the face ("moon"
face), neck, trunk, and abdomen, with relative sparing of the extremities. A
"buffalo hump" or dorso-cervical fat pad is common; the bulging
supraclavicular fat pads make the neck appear thick and shortened.
Growth decelerationIn children, nearly all (> 95%) show decreasing linear
growth. Weight gain accompanying decreasing linear growth in a child should
prompt an evaluation for CS.
Skin changes: atrophy of the epidermis and its underlying connective tissue
leads to thinning (a transparent appearance of the skin) and facial plethora.
There is easy bruising following minimal trauma and striae (in 50-70 %, red to
purple, depressed and wider than the pinkish-white striae that may occur with
pregnancy or rapid weight gain over 1 cm). These striae are most commonly
abdominal but may also occur over the breasts, hips, buttocks, thighs, and
axillae. Acne presenting as pustular or papular lesions may result from
glucocorticoid excess or hyperandrogenism. Minor wounds may heal slowly
and mucocutaneous fungal infections are frequent.
Hyperpigmentation of the skin is rare in Cushing's disease or adrenal tumors
but is common in ectopic ACTH syndrome.
Hypertension is a classic feature of spontaneous CS; it is present in about
75% of cases, often the diastolic blood pressure is greater than 100 mm Hg.
Muscle weakness is more often proximal and is usually most prominent in the
lower extremities (because of low fat-free muscle mass and hypopotassemia)
and it can lead to muscle wasting.
Osteoporosis patients may present with multiple fragility fracturestypically
of the feet, ribs, or vertebrae (compression fractures). Avascular necrosis of
bone has been associated with exogenous glucocorticoid administration.
Emotional lability, increased irritability, anxiety, depression, euphoria, poor
concentration, insomnia and poor memory may also be present. Severe
depression, psychosis with delusions or hallucinations and paranoia occur in
a few patients. Some patients have committed suicide.
Gonadal dysfunction in females, as a result of elevated androgens:
amenorrhea, accompanied by infertility, hirsutism (increased hair growth
occurs over the face, abdomen, breasts, chest, and upper thighs). Acne and
seborrhea usually accompany hirsutism. Virilization with temporal balding,
deepening of the voice, clitoral hypertrophy, usually occur only in girls or
women with extremely high serum concentrations of androgens due to an
adrenal carcinoma.
Decreased libido is frequent in males and some have decreased body hair
and soft testes.
Renal calculi are induced by hypercalciuria.
Thirst and polyuriaare rarely due to overt hyperglycemia but theyre usually
caused by glucocorticoid inhibition of vasopressin (antidiuretic hormone).

Laboratory and paraclinical findings

An algorithm for testing to establish the diagnosis of Cushing's syndrome is
presented in figure 7. Testing can only be interpreted in the context of sustained

Figure 7. Testing to establish the diagnosis of Cushing's syndrome

The initial diagnostic tests for hypercortisolism should be highly sensitive. After
the diagnosis of hypercortisolism is established, its cause must be determined and
this may be very challenging. Most mistakes in clinical management, leading to
unnecessary imaging or surgery, are made because the diagnostic protocol is not
followed. The laboratory diagnostic evaluation to determine if the patient has
hypercortisolism includes:
1. evidence of loss of diurnal cortisol secretion with high levels of serum or
salivary cortisol at midnight.
2. determination of urine free cortisol in a 24-hour urine collection in
Cushing's syndrome is elevated.
3. the overnight 1-mg dexamethasone suppression test normal subjects
should suppress plasma cortisol at 8 a.m. to less than 1.8 g/dL (50
nmol/L) following an overnight 1-mg test.

4. The 2-day 2 mg dexamethasone test the normal response consists of a

serum cortisol concentration less than 1.8 g/dL.
The diagnosis of Cushing's syndrome is confirmed when two tests are
unequivocally abnormal.
The first step in the evaluation of the cause of CS is to determine whether the
hypercortisolism is ACTH-dependent or ACTH-independent by measuring plasma
ACTH. This test is now best performed using a two-site immunoradiometric assay
(IRMA). Plasma ACTH concentrations are normally between 8 and 52 pg/mL at 8
AM. A low plasma ACTH concentration (<5 pg/mL) in a hypercortisolemic patient is
evidence of ACTH-independent disease. The excess cortisol secretion is ACTHdependent if the plasma ACTH concentration is above 20 pg/mL.
To determine the cause of Cushings syndrome it may be also necessary to
use the following:
High-dose dexamethasone suppression test (the 2-day 8 mg DXM test)
can distinguish between Cushing's disease and ectopic ACTH syndrome.
However, the diagnostic accuracy of this procedure is only 80-90%.
Corticotropin-releasing hormone test after basal sampling, CRH is
administered in dose of 1 g/kg body weight or a single dose of 100 g
and blood samples for ACTH and cortisol are then taken every 15 minutes
for 1 to 2 hours. In normal subjects, CRH produces a rise in ACTH and
cortisol of 15% to 20%. This response is exaggerated in Cushings
disease, in which typically an ACTH increase greater than 50% and a
cortisol rise greater than 20% over baseline values are seen.
Inferior petrosal sinus sampling simultaneous inferior petrosal sinus and
peripheral ACTH measurement before and after CRH stimulation can
reliably confirm the presence or absence of an ACTH-secreting pituitary
tumor. An inferior petrosal sinus to peripheral (IPS-P) ratio greater than 2.0
prior to CRH and greater than 3.0 after CRH is consistent with a pituitary
ACTH-secreting tumor, and an IPS-P ratio less than 1.4 supports the
diagnosis of ectopic ACTH.
Pituitary MRI is the investigation of choice once the biochemical tests have
suggested Cushing's disease. For adrenal imaging, CT offers better spatial resolution and is the investigation of choice, but MRI or ultrasound, may provide diagnostic
information in patients with suspected adrenal carcinoma. The scintigraphy is of
value in certain patients with primary adrenal pathology. The most commonly used
agent is iodine 131labeled cholesterol. In patients with occult ectopic ACTH
syndrome, high-definition CT/MRI scanning of thorax, abdomen, and pelvis may be
required to detect small ACTH-secreting carcinoid tumors. Scintigraphy with indium
111labeled octreotide may be useful in these patients. It is essential that the results
of any imaging technique be interpreted alongside the biochemical results !!
Routine laboratory examinations can show: high normal hemoglobin, hematocrit
and red cell counts; polycythemia is rare. The total white count is usually high
normal; the percentage of lymphocytes and the total lymphocyte count may be
subnormal. Eosinophils are also depressed and neutrophilia has also been
associated with Cushing's syndrome.
Serum electrolytes, with rare exceptions, are normal in Cushing disease;
however, hypokalemic alkalosis occurs when there is marked steroid hypersecretion
as is in case of ectopic ACTH syndrome.

Although fasting hyperglycemia occurs in only 10% to 15% of patients, glucose

intolerance is a relatively common finding.
Serum calcium is normal; serum phosphorus is low normal or slightly depressed.
Hypercalciuria is present in 40% of cases.
Differential Diagnosis
Before evaluation for possible Cushing's syndrome, it is essential that a
careful history excludes exogenous glucocorticoid intake. Hypercortisolism can occur
in several disorders other than Cushing's syndrome: patients with severe obesity,
especially those with visceral obesity or polycystic ovary syndrome, those with a
severe major depressive disorder and melancholic symptoms and patients with
chronic alcoholism. When such patients present with clinical features consistent with
Cushing's syndrome, they are referred to as having pseudo-Cushing's syndrome.
Of particular clinical interest has been a group of patients with cyclic
Cushing's syndrome, characterized by periods of excess cortisol production
interspersed with intervals of normal cortisol production. Most patients have been
thought to have pituitary-dependent disease.
A small number of patients have been described as having increased cortisol
secretion but without the stigmata of Cushing's syndrome. These patients are
resistant to suppression of cortisol with low-dose dexamethasone but respond to
high doses. ACTH levels are elevated and lead to increased adrenal production of
androgens and DOC. Therefore, these patients may present with the features of
androgen or mineralocorticoid excess, or both. Treatment with a dose of
dexamethasone (usually >3 mg/day) adequate to suppress ACTH results in a fall in
adrenal androgens and often returns plasma potassium and blood pressure to
normal levels. Many of these patients have been found to have point mutations in
glucocorticoid receptor.
Untreated Cushing's syndrome is frequently fatal and death may be due to the
underlying tumor itself, as in the ectopic ACTH syndrome and adrenal carcinoma.
However, in most cases, death is the consequence of sustained hypercortisolism
and its complications, including hypertension, cardiovascular disease, stroke,
thromboembolism and susceptibility to infection.
Individuals with Cushing's disease who achieve normalization of cortisol levels
as result of therapy have a standard mortality ratio similar to age-matched
The prognosis in adrenal adenomas is excellent. After the operation, it may
take time for the contralateral suppressed adrenal to recover. It is wise, therefore, to
give slightly suboptimal replacement therapy. The prognosis is almost universally
poor in adrenal carcinoma and in patients with ectopic ACTH syndrome due to the
nature of the malignancy which secretes the hormone. The prognosis is better in
patients with benign tumors that cause an ectopic ACTH syndrome.
Treatment of Cushing's disease is currently directed at the pituitary to control
ACTH hypersecretion; available methods include microsurgery, various forms of
radiation therapy, and pharmacologic inhibition of ACTH secretion. Treatment of

hypercortisolism per se by surgical or medical adrenalectomy is less commonly used

Cure of ectopic ACTH syndrome is usually possible only in cases involving the
more benign tumors such as bronchial or thymic carcinoids or pheochromocytomas.
Treatment is more difficult in metastatic tumors accompanied by severe
hypercortisolism in which therapy directed to the primary tumor is usually
unsuccessful. Severe hypokalemia may require potassium replacement in large
doses and spironolactone to block mineralocorticoid effects.
Patients with adrenal adenomas are successfully treated by unilateral
adrenalectomy and the outlook is excellent. Laparoscopic adrenal surgery has
become widely used in patients with benign or small adrenal tumors and has
significantly reduced the duration of the hospital stay. Because the hypothalamicpituitary axis and the contralateral adrenal are suppressed by prolonged cortisol
secretion, these patients require glucocorticoid therapy both during and following
Therapy in cases of adrenocortical carcinoma is less satisfactory, because the
tumor has frequently already metastasized (usually to the retroperitoneum, liver, and
lungs) by the time the diagnosis is made. Mitotane is one of the options.
In micronodular hyperplasia and in some cases of macronodular hyperplasia,
bilateral adrenalectomy is appropriate.
In patients with Cushing's syndrome who refuse surgery or have nonresectable
tumors, drugs that block steroid synthesis can be useful. These drugs may produce
hypoadrenalism and steroid secretion must be monitored and replacement steroids
given if necessary
Mitotane (6 to 12 g/d orally in three or four divided doses) is causing
mitochondrial destruction and necrosis of adrenocortical cells. The major
side effects are nausea, vomiting, anorexia and ataxia.
Ketoconazole (600 to 1200 mg daily) is an imidazole that has been widely
used as an antifungal agent but also blocks a variety of steroidogenic
enzymes and thus lowers plasma cortisol levels. It is hepatotoxic.
Metyrapone (2-4 g/day) is an 11-beta-hydroxylase inhibitor that blocks the
final step in cortisol biosynthesis. It can cause an increase in hirsutism in
women, salt retention and hypertension because of increased production
of deoxycorticosterone.
Aminoglutethimide is an anticonvulsant drug that primarily blocks the first
step in cortisol biosynthesis: cholesterol side-chain cleavage to
pregnenolone. The aminoglutethimide dose is 250 mg two or three times
a day.
Etomidate, a substituted imidazole anesthetic drug, blocks 11-betahydroxylation of deoxycortisol to produce cortisol. It may be useful in
hospitalized patients when infused intravenously in a low, nonhypnotic
dosage of 0.3 mg/kg per h.
Combinations of these drugs (for example ketoconazole, aminoglutethimide
and metyrapone) often have additive or synergistic therapeutic effects at lower
individual dosages, thereby minimizing side effects. Mifepristone is an
antiprogestational drug that, in much higher doses, competes with glucocorticoids for
binding to their receptor, thereby blocking their action.


Disorders of adrenocortical insufficiency

Primary hypoadrenalism or adrenocortical insufficiency is defined by the adrenal
being unable to secrete gluco- and mineralocorticoids. Secondary and tertiary
hypoadrenalism appear due to inadequate ACTH or CRH secretion respectively,
only glucocorticoid production being affected.
Etiology and pathogenesis
Primary hypoadrenalism is called Addisons disease and can be due to one of
the following causes, which prevalence has changed over time:
1. Autoimmune responsible for 70% of the cases. It appears sporadic or in one
of the two autoimmune polyendocrine syndromes:
o Type I or autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy syndrome (APECED) its a recessive disorder which develops
in childhood, characterized by the association of primary hypoadrenalism,
hypoparathyroidism, candidiasis, ectodermal dysplasia and sometimes
type I diabetes mellitus, gonadal failure, celiac disease or autoimmune
o Type II or Schmidts syndrome with a higher prevalence compared to
type I; it affects mainly the female sex and it associates primary
hypoadrenalism with chronic thyroiditis, type I diabetes mellitus, ovarian
failure, vitiligo, autoimmune hypophysitis and pernicious anemia.
Thrombocytopenic purpura, rheumatoid arthritis, polyserositis can
sometimes be associated.
2. Infections in case of tuberculosis, HIV infection, cytomegalovirus or fungi
(histoplasmosis, cryptococcosis). In fungi and tuberculosis infections, the
adrenal glands are enlarged and sometimes calcified; in these cases the
etiologic treatment can have direct effect on the corticoid synthesis
(ketoconazole) or metabolism (rifampicin) and can induce an adrenal crisis in
patients with insufficient resources.
3. Bilateral adrenal infarction caused by hemorrhage or adrenal vein thrombosis
which can determine adrenal crisis. It is seen primarily in cases of
meningococcal sepsis (Waterhouse-Friderichsen syndrome), but it also
appears in cases of sepsis of different origin Pseudomonas aeruginosa,
Streptococcus pneumoniae, Neisseria gonorrhoeae, Escherichia coli,
Haemophilus influenzae or Staphylococcus aureus. The major risk factors are
anticoagulation, heparin induced thrombocytopenia but also hypercoagulation states like different coagulopathies or antiphospholipidic
4. Metastatic tumors lung, breast, gastric or colon primary tumors.
5. Infiltrative amyloidosis, hemochromatosis
6. After surgery bilateral adrenalectomy
7. Drug induced via:
o Inhibition of cortisol synthesis ketoconazole, etomidate (anesthetic
agent), metyrapone, suramin (used in the treatment of some parasitic
infestations), and aminoglutethimide.
o Accelerating cortisol metabolism barbiturics, rifampicin, and phenytoin.
8. Adrenoleukodystrophy and adrenomyeloneuropathy X linked recessive
disorder, with variable phenotype. It causes CNS demyelination, cognitive

dysfunction with possible progression to dementia. The cause is excessive

increase in serum level of very long chain fatty acids VLCFAs.
9. Adrenal hypoplasia congenita (AHC) is caused by mutation in one of the
following genes:
o DAX-1 located on the X chromosome encodes a member of the
nuclear hormonal receptor family, with expression in the adrenal,
gonads and hypothalamus. The hypoadrenalism is associated with
hypo gonadotrophic hypogonadism.
o SF-1 encodes a transcription factor which plays an essential role in
steroid genesis and enhances DAX-1 expression, which at its turn has
a repressor effect on SF-1.
10. Familial glucocorticoid deficiency (FGD) or inherited unresponsiveness to
ACTH is a rare autosomal recessive cause of hypoadrenalism in which the
glucocorticoid and androgen secretion are not stimulated by ACTH.
11. Allgrove syndrome associates hypoadrenalism due to ACTH resistance,
achalasia and alacrima and sometimes mental retardation.
The most frequent cause of secondary hypoadrenalism is exogenous
administration of high doses (more than 30 mg hydrocortisone or equivalents) of
glucocorticoids for a prolonged period (exceeding 3 weeks) for different
rheumatologic or systemic disorders and sudden cessation of this treatment.
A relatively new concept with important implications in intensive care is
functional adrenal insufficiency which appears in acute, severe cases in a patient
with normal pituitary-adrenal axis. It is hard to define it from a clinical point of view
and its pathogenesis isnt completely discovered, but without adequate treatment it
might be responsible for the death of patients with acute severe diseases. The other
causes of secondary and tertiary hypoadrenalism are described in the Pituitary
failure chapter.
Clinical features
Primary hypoadrenalism manifests with mineralo- and glucocorticoid deficiency.
The renin-angiotensin-aldosterone axis remains intact in case of secondary
hypoadrenalism. Therefore there are differences between primary and central
hypoadrenalism, considering first of all the salt and water balance. Skin pigmentation
melanodermia is caused by the compensatory CRH-POMC-ACTH increase and
is described only in Addisons disease. The affected regions are most of all those
exposed to sunlight, recent scars, axillae, breast areola, palmar creases and mucous
membranes (buccal, anal, vaginal). Melanodermia is accentuated over pressure
areas such as the knuckles, toes, elbows, and knees. Vitiligo can also be associated
in case of autoimmune etiology.
Other clinical features suggestive for hypoadrenalism are weight loss,
hypotension (systolic values under 100 mmHg), muffled heart sounds, bradycardia,
auricular calcification, dry and pruritic skin (extracellular dehydration), loss of axillar
and pubic hair.
Symptoms of hypoadrenalism:
Weakness, tiredness, progressive fatigue,
Gastrointestinal anorexia, abdominal pain, diarrhea or constipation, nausea,
vomiting. An increase in gastrointestinal symptoms during an acute adrenal
crisis may confuse the diagnosis by suggesting a primary intra-abdominal

Postural dizziness, salt craving,

Muscular pain and arthralgia,
Bradymenorrhea or secondary amenorrhea, decrease in libido for both sexes,
caused by pituitary involvement or caused by the chronic consumptive
character of the disease,
In untreated long standing forms, depression, memory impairment and even
psychosis can occur.
The way a patient with hypoadrenalism presents itself depends on the clinical
form, severity and time from the debut. The secondary and tertiary forms differ from
primary hypoadrenalism through the following:
No skin pigmentation is described,
Hyponatremia can occur, but hyperkalemia is rare,
Dehydration is absent and hypotension is less severe,
Gastro-intestinal involvement is rare,
In secondary forms hypoglycemia manifested with weakness, tremor,
sweats, headache, and dizziness is frequent.

Laboratory and paraclinical findings

The electrolytic disturbances are constant in primary hypoadrenalism and absent
in the secondary form. They consist in hyponatremia, hyperkalemia and
hypercalcemia. Increased blood urea nitrogen, eosinophilia, neutropenia,
lymphocytosis and normochromic normocytic anemia can also be present. Basal
hypoglycemia is rare in adults in absence of infections or alcohol intake, but is a
constant sign in childhood hypoadrenalism.
A special chapter represents the confirmation of hypoadrenalism and
establishment of the etiology. These goals are achieved through stimulation tests
and evaluation of pituitary-adrenal resources, which were described in the chapter
functional exploration of the adrenal gland.

Basal cortisol, measured at 8 A.M. can be decreased. It is determined

by RIA, with normal range of 5-25 g/dl. A basal cortisol value greater
than 400 nmol/L (14.5 g/dL) invariably indicates an intact
hypothalamus-pituitary-adrenal axis.
The ACTH is increased in primary hypoadrenalism and normal or
decreased in secondary or tertiary forms.
Rapid ACTH stimulation test Cortrosyn 250 g, 5 g or 1g IV or IM
with cortisol measurement before administration of Cortrosyn and 30
and 60 minutes after. Normal values after stimulation are 18-20 g/dl.
Depot ACTH stimulation test Cortrosyn depot 1mg IM with plasmatic
cortisol measurements before and 24 hours after the injection. After 24
hours, the cortisol level must be double from the basal measurement.
Metyrapone test 750 mg every 4 hours, for 24 hours.
Insulin induced hypoglycemia test.
CRH stimulation test.


Figure 8. Diagnostic algorithm for the etiology of hypoadrenalism

If the autoimmune etiology is suspected, some laboratories can measure
antibodies against some enzymes involved in steroid genesis. An elevated level of
anti 21-hydroxylase antibodies can be found in 60-75% of patients with primary
autoimmune hypoadrenalism, the sporadic form or in cases of polyendocrine
autoimmune syndromes type I and II.
Abdominal scans and adrenal CT can describe calcifications and volume
enlargement of adrenal glands in case of infections, infiltrative disorders,
metastases or hemorrhage and adrenal; atrophy in case of secondary
There are specific EKG signs, caused by the dyselectrolytemia microvoltage,
verticalization of the QRS axis and, in case of hyperkalemia a tall T wave with short
QT interval, followed by prolongation of the PR interval. Enlarged QRS complexes
appear in severe cases.
Differential diagnosis
The fatigue must be differentiated from myasthenia gravis, psychiatric fatigue.
The skin pigmentation in primary hypoadrenalism must be differentiated from
other causes of melanodermia: constitutional, pregnancy pigmentation, actinic
pigmentation, renal failure, but also from hemochromatosis, porphyria, and heavy
metal poisoning (silver, lead, and mercury).
The gastro-intestinal signs impose the differential diagnosis with gastric or
duodenal ulcer, gastritis, food intake disturbances, anorexia nervosa.

Hypotension and hypoglycemia can also appear in isolated GH deficiency.

Weight loss can also appear in case of hyperthyroidism, malign tumors, and
hematological diseases.
Evolution, complications, prognosis
In the past, the most frequent cause of hypoadrenalism was dissemination from
pulmonary tuberculosis, which caused death in maximum 2 years from the onset, in
absence of gluco- and mineralocorticoid substitution. Nowadays, the predominant
etiology is autoimmune, which has an excellent prognosis with adequate treatment,
without affecting life expectancy.
Autoimmune hypoadrenalism develops gradually, in 4 steps. The autoantibody
level, especially those against the 21-hydroxylase antigen, is positively correlated
with the adrenal dysfunction. The four steps are:
1. Increase of plasma renin, with normal or low aldosterone.
2. Inadequate cortisol response to ACTH stimulation tests.
3. Increase in basal ACTH with normal cortisol maintenance.
4. Decrease of basal plasma cortisol.
The acute form of hypoadrenalism, the adrenal crisis, has a strong negative
prognosis, especially that caused by adrenal hemorrhage.
Substitution treatment overdose can cause clinical signs of hypercorticism and
osteoporosis, with subsequent increase of frailty fracture risk.
General measures avoid physical and psychological effort, normal caloric
intake, with increased salt intake, rich in fluids and adequate vitamin intake.
In chronic forms one of the following preparations can be used:
Short-acting preparations orally administered hydrocortisone 2-3 times a
day; for example 15-20 mg in the morning and 5-10mg in the afternoon; the
evening administration is to be avoided, due to side effects, such as insomnia.
This is the preferred treatment because it best mimics normal cortisol
biorhythm and has a mineralocorticoid effect as well. In children, the dose is
15-25 mg/m2/day, orally.
Long-acting formulas Prednisone 5-7.5 mg/day, Prednisolone 5 mg/day or
Dexamethasone 0.5-0.75 mg/day, once a day, in the morning. Disadvantages
of long-acting agents include the variable inter-individual metabolism of
dexamethasone, and as a result, patients may be over-treated. They are used
in patients with poor compliance to multiple daily doses.
Mineralocorticoid preparations they are used in combination with the above
mentioned drugs. The most often used drug is fludrocortisone (Astonin or
Florinef) in doses between 0.05 and 0.2 mg/day with free salt intake.
Drugs with androgenic effect there is much controversy regarding their
administration in hypoadrenalism. They are recommended in women with
persistent fatigue or malaise despite correct glucocorticoid substitution. DHEA
formulas are considered dietary supplements and can be used in doses
ranging from 25 to 50 mg/day.
Patient education is mandatory, regarding the glucocorticoid dose increase in
stressful situations infections, trauma, surgery. In case of mild diseases the usual
doses can be increased 2-3 times, for 3 days (known as the 3 x 3 rule). If the general
state does not improve, the patient must present himself to the physician.

In case of more severe trauma, the patient can administer 4 mg DXM IM until
medical assistance is available. Every patient should wear a medical alert bracelet
and should have several ready to inject syringes, for IM administration.
Medical ambulatory interventions, carried out with local anesthesia, do not
necessitate the increment of usual substitution doses. For surgical procedures with
mild stress, hemisuccinate hydrocortisone 50 mg 2-3 times a day is administered IV
the first dose with the pre-anesthetic drugs. In case of major surgery, with general
anesthesia, 100 mg HHS is given every 8 hours with dose decrement once the
clinical state allows it.
Female patients with hypoadrenalism can become pregnant, the dose increment
being usually necessary only in the third trimester and during labor, when parenteral
preparations should be administered as well.
Treatment monitoring is based mainly on clinical grounds disappearance of
mineralo- and glucocorticoid deficiency signs. Good appetite and sense of wellbeing, are the guides to the adequacy of replacement and signs of Cushing
syndrome indicate overtreatment. In primary hypoadrenalism, some authors
recommend measurement of basal ACTH level. A low ACTH level indicates
overdosage of the substitution therapy. Free urinary cortisol is not used for
monitoring the therapy.
For mineralocorticoid replacement monitoring one can use blood pressure
measurement both in recumbent and supine position, electrolyte balance and
plasma renin activity.
Acute adrenal insufficiency
It represents a medical emergency. In children and neonates, the salt-loss
syndrome can also appear in case of genetic steroid genesis disturbances, which
generate congenital adrenal hyperplasia. In adults, acute adrenal insufficiency may
occur in the following situations:
in a previously undiagnosed patient with decreased adrenal resources who
associates severe infection, trauma or other major stress;
in patients with abrupt cessation of long standing corticoid therapy and
decompensating secondary hypoadrenalism;
after pituitary infarction/apoplexy;
in a patient with known primary adrenal insufficiency who does not take more
glucocorticoid during an infection or other major illness, or has persistent
vomiting caused by viral gastroenteritis or other gastrointestinal disorders;
after bilateral adrenal hemorrhage or infarction
Clinical signs of adrenal crisis:
Marked hypotension, dehydration and hypovolemic shock; signs unjustified by
current illness severity.
Abdominal pain which can mimic acute abdomen.
Fever caused by concomitant infection or by the hormonal deficit per se.
Confusion, apathy.
Coma and death without adequate treatment.
The biochemical panel shows hyponatremia, severe hyperkalemia,
hypoglycemia, acidosis, lymphocytosis and eosinophilia.
In acute forms the treatment must be initiated as soon as the diagnosis is
suspected. The major goals are dehydration treatment, correction of hypovolemia

and dyselectrolytemias, glucocorticoid administration, general supportive measures

and treatment of the precipitating cause. The first measure should be intravenous
access with a large needle (19G) and blood sampling biochemical panel, plasma
cortisol, ACTH, renin followed by:
Saline infusion (NaCl 0.9%) 1-3 liters/day. Dextrose or glucose can be
added depending on the serum glucose.
Intravenous hydrocortisone 100 mg or DXM 4 mg every 6 hours for a day or
until the clinical state improves. After that 50 mg HHS is given every 6 hours.
When administered in supraphysiologic doses, hydrocortisone has sufficient
sodium-retaining potency so that additional mineralocorticoid therapy is not
required in patients with primary adrenocortical insufficiency.
The parenteral route can be gradually replaced by the oral one in 4-5 days, if
the clinical state allows it.
In primary hypoadrenalism mineralocorticoid drugs should also be added,
desoxycorticosterone 10 mg IM or fludrocortisone 0.1 mg, when
hydrocortisone replacement is reduced to near physiological levels.
In the case of persistent fever or if theres a suspicion of infection, antibiotics
should be added.
Congenital adrenal hyperplasia (CAH)
Congenital adrenal hyperplasia represents a group of autosomal recessive
disorders caused by inactivating mutations of the genes encoding steroid genesis
enzymes. The decreased synthesis of cortisol and/or mineralocorticoids determines
through negative feedback the marked increase of ACTH and adrenal hyperplasia.
Table 15 presents the main clinical and paraclinical traits of the 6 enzymatic defects
that cause CAH.
Clinical findings
The range of clinical findings depends on one hand on the deficient enzyme
that causes the blockage in the synthesis of certain corticosteroids and, on the other
hand on the deviation of the steroid synthesis towards certain corticosteroids which
are secreted in excess because of the high ACTH level. There are classical forms
with complete and severe enzymatic deficit and non-classical forms, late onset and
with mild severity.
The most frequent cause (90% of the CAH cases) is 21 hydroxylase deficit,
which has a prevalence of 1:15 000, followed by the 11-hydroxylase deficit, with a
prevalence of 1:100 000 newborns.
The 21 hydroxylase deficit has 3 distinct phenotypes, depending on the degree
of enzymatic deficit:
1. Salt wasting form is the most severe form, caused by a marked
enzymatic deficit. Clinically it manifests itself after day 5 of life with
electrolyte and fluid losses, hyponatremia, hyperkalemia, acidosis,
dehydration and finally vascular collapse. The clinical signs and symptoms
of salt wasting include poor feeding, vomiting, failure to thrive, lethargy,
and sepsis-like symptoms. Sexual ambiguity is also present in the female
patient (46, XX karyotype). This ambiguity can present itself with the
persistence of urogenital sinus (single orifice for the vagina and urethra),
labial fusion and clitoral enlargement (figure 9). The variable grade of

virilization of the external female genitalia is called feminine

pseudohermaphroditism. This term tends to be replaced by 46, XX DSD
disorders of sex development with female karyotype. In male patients
macrogenitosomy can be apparent at birth.
2. Simple virilizing form present at birth, is similar to the precedent, but due
to sufficient enzymatic activity, the salt wasting syndrome is absent. Both
in male and female patients, precocious puberty can become apparent if
treatment is not initiated in time. In male patients, the precocious puberty
is isosexual (sexual hair, muscle development, growth acceleration, but
with premature epiphyseal closure). In female patients heterosexual
precocious puberty is present virilization, acne, without telarche or
menarche. Final height is compromised in both sexes.
3. Non-classic or late onset form becomes apparent in adulthood or
adolescence, with virilization (muscle growth, voice deepening, clitoral
enlargement), hirsutism, acne, secondary amenorrhea, infertility. It is
estimated that this form is responsible for 5-8% of female
hyperandrogenism cases.
Other clinical findings in CAH:
High blood pressure, present from childhood, generally after 6 years of
age, appears in case of 11 hydroxylase deficiency (associated with
virilization in females) and 17 hydroxylase deficiency (without virilization,
but with primary amenorrhea and absence of secondary sexual signs in
both sexes) the defect is present in the gonads as well.
Male pseudohermaphroditism incomplete or absent virilization of the
male patient with external genitalia ambiguity and a 46, XY karyotype. This
term tends to be replaced by 46, XY DSD. It is apparent in StAR protein
deficiency lipoid adrenal hyperplasia when there is a massive
cholesterol accumulation in the cells, the whole steroid genesis being
compromised and having a severe prognosis. It is also described in 17
hydroxylase deficiency (46,XY patients usually have female external
genitalia, a blind vaginal pouch, no uterus or fallopian tubes, and
intraabdominal testes) and 3 hydroxysteroid dehydrogenase deficiency
(caused by excess DHEA, a weak androgen, which is incapable of
masculinizing the 46, XY fetus, but is responsible for a mild virilization of
the female fetus).


Table 15. Main phenotype and hormonal features of different types of CAH






Present in ,

Present in ,
Discrete in

Present in

Present in

Present in









in, in .








Blood pressure

Electrolyte balance

Na+ ; K +

Na+ ; K +

Na+; K +

Na+ ; K +

Na+ ; K +

Na+ ; K +

Deficient enzyme
External genitalia
Adrenal crisis


Figure 9 Stadialization of the external genitalia virilization Prader (1954)

Prader 0 feminine external genitalia; Prader 1 clitoral enlargement
Prader 2 clitoromegaly, partial labial fusion; Prader 3 complete labial fusion, urogenital sinus,
phallic clitoris; Prader4 masculine phenotype, micropenis, perineoscrotal hypospadias,
cryptorchidism; Prader 5 masculine external genitalia, cryptorchidism.

Laboratory and paraclinical investigations

CAH is associated with elevation of the steroids upstream from the deficient
enzyme and decrease to even non-detectable levels of the steroids downstream
from the affected enzyme (Table 14). The specificity of hormonal assessment
increases by calculating the ratio of the upstream and downstream steroids; in some
cases the ACTH or DXM tests are necessary as well.
In case of 21 hydroxylase deficiency the basal 17 OH progesterone
measurement is sometimes sufficient; the classic salt-wasting form is associated
with elevated values, sometimes over 3500 ng/dl (105 nmol/l). If the value is only
mildly elevated a late onset form is suggested. In this case the ACTH stimulation test
can be useful 250 g are administered IV with a 60 minutes rise of 17 OH
progesterone to 1000 ng/dl (30 nmol/l) in patients with nonclassic forms of the
disorder. Stimulation tests are not always required to make a diagnosis; for example,
a basal 17-OH progesterone concentration <150 ng/dL (<5 nmol/L) in the follicular
phase of the menstrual cycle effectively excludes late-onset 21-hydroxylase
The hormonal assessment is followed by adrenal imaging (ultrasonography)
that shows adrenal hypertrophy and by genotyping for identifying the CYP21A2 gene
mutation, given the fact that this genetic anomaly has a high genotype-phenotype
correlation. Other hormones have elevated levels as well: DHEA, DHEA-S,
testosterone, progesterone, urinary 17 ketosteroids.
Some countries use 17 OH progesterone filter paper screening of the
newborns for this disease. Prenatal testing is also used in case of a couple
heterozygote for the mutation.
Patients with salt-wasting syndrome have low levels of aldosterone, 11
desoxycorticosterone and high plasma renin activity.
Differential diagnosis
Salt-wasting syndrome must be differentiated from other causes of
hypoadrenalism (primary, secondary, tertiary).

External genitalia ambiguity imposes karyotyping and differential diagnosis

with other disorders of sex development, depending on that result. A recent
(European Society of Paediatric Endocrinology, 2006) classification of sex
development disorders with a revised nomenclature comprises the following:
46,XX DSD (disorders of sex development):
o Disorders of gonadal (ovary) development:
Ovotesticular DSD formerly known as true hermaphroditism,
Testicular DSD SOX9 gene duplication or SRY gene translocation,
Gonadal dysgenesis.
o Androgen excess:
CAH 21 hydroxylase, 11 hydroxylase, 3 hydroxysteroid
dehydrogenase deficit,
Aromatase deficiency (estrogen synthase),
Maternal source exogenous (androgenic drugs), ovarian secreting
tumors, luteomas,
46, XY DSD:
o Disorder of gonadal (testis) development:
Complete testis dysgenesis Swyer syndrome,
Partial gonadal dysgenesis WT1, SOX 9 or SF-1 mutations,
Testis regression.
o Disorders in androgen synthesis or action:
Disorders of androgen synthesis 17 hydroxysteroid dehydrogenase,
5 reductase, StAR, 3 hydroxysteroid dehydrogenase or 17,20 lyase
deficiency, Leydig cell hypoplasia,
Disorders of androgen action androgen insensitivity syndrome
complete or partial,
LH receptor mutations,
Defects of the anti-Mllerian hormone or its receptor (AMH, AMH-R).
Sex chromosome DSD:
o Turners syndrome and variants,
o Klinefelters syndrome and 47, XYY syndrome,
o Mixed gonadal dysgenesis 46,XX/46, XY or 45, X/46, XY.
The hirsutism and virilization of the adult female caused by the late onset 21
hydroxylase deficiency must be differentiated from other causes:
Polycystic ovary syndrome the most frequent cause,
Idiopathic hirsutism,
Exogenous administration of androgens,
Androgen secreting ovarian or adrenal tumors.
Evolution, complications, prognosis
Without treatment, the prognosis is poor, especially for the salt-wasting and
hypoadrenalism forms, death occurring in the first weeks of life, or when the
glucocorticoid substitution is not adapted in case of acute stress, trauma, surgery.
The prognosis depends on treatment compliance, considering the need for daily
administrations. One of the most frequent complication is overdosing which
determines hypercorticism side effects, manifested in children by affecting final
height, osteoporosis and weight gain.
Men with 21 hydroxylase deficiency can have testis remnants, spermatogenesis
impairment and infertility. Females with CAH, independent of the cause, can have

anovulation and reduced reproductive capacity. In virilizing forms, prenatal exposure

to elevated levels of androgens will influence girls behavior from childhood theyll
have masculine preoccupations and in adolescence and adulthood there is a more
aggressive behavior compared with the non-affected ones.
The main goal of the treatment is blocking the excess androgen synthesis by
suppressing the ACTH with concomitant adequate substitution of glucocorticoids and
mineralocorticoids if theyre deficient.
Prenatal treatment of pregnant women who are at risk of carrying a female
fetus with atypical genitalia due to 21-hydroxylase deficiency although still
controversial, is available in specialized centers, under medical supervision
and after informed consent regarding the risks and benefits. It is indicated
when both parents are heterozygotes and must be initiated early in pregnancy.
Genotyping from chorionic biopsy is available only around 8-10 weeks of
pregnancy and therefore the treatment is begun without knowing if the fetus
will be affected. DXM is administered to the mother, 20 g/kg/day, throughout
the pregnancy, only if the molecular diagnosis confirms CAH in the female
Neonate and childhood treatment in case of adrenal crisis the treatment is
the one described in hypoadrenalism. Hydrocortisone is usually used in
children, in doses of 20-25 mg/sqm with adequate adjustment in case of
stress, trauma, etc. In salt-wasting forms, fludrocortisone is also administered
in doses adjusted depending on the electrolyte balance, ranging from 0.05-0.2
mg/day, with sodium supplementation (1-3 g/day) added in food. Therapy can
be monitored by steroid determinations, for example, the measurement of 17OH progesterone and androstenedione but also with growth velocity and bone
maturation every 4-12 months. The dose of mineralocorticoid should be
adjusted so that the electrolytes and blood pressure, as well as the plasma
renin activity, are in the normal range.
There is an evaluation ongoing for a new therapeutic scheme a combination
of flutamide (antiandrogen), testolactone (aromatase inhibitor inhibits
estrogen formation from testosterone, the former being responsible for the
premature epiphyseal closure), hydrocortisone and fludrocortisone in more
physiologic doses.
Surgical correction of external genitalia ambiguity is controversial considering
both the moment and the exact procedure. Vaginoplasty and clitoroplasty are
performed only in Prader stage 3-5.
In adult patients DXM 0.25-0.75 mg or prednisolone 5-7.5 mg/day is
administered in a single dose, in the evening, before sleep. Monitoring the
therapy implies 17 OH progesterone, DHEA-S, androstendione, testosterone
and urinary 17 ketosteroids measurement. For those with concomitant
mineralocorticoid deficit fludrocortisone treatment is continued with periodical
measurements of PRA, blood pressure and electrolyte balance.
The late onset forms, with their symptomatology resembling that of polycystic
ovary syndrome benefit from oral contraceptive treatment for bradymenorrhea
and antiandrogens (cyproterone acetate) for hirsutism and virilization.
Treatment with evening doses of glucocorticoids is indicated in women only in

cases of anovulation, pregnancy desire

spermatogenesis disturbances and infertility.

and in



cases of

Primary aldosteronism
In the past, clinicians would not consider the diagnosis of primary
aldosteronism unless the patient presented with spontaneous hypokalemia.
Nowadays it is estimated that approximately 5-13% of all patients with hypertension
have low plasma renin activity (PRA) because of an increased production of
aldosterone and many of them have normal electrolytes. It appears mostly in women
who are in the third to sixth decade.
Hypertension, suppressed plasma renin activity and increased aldosterone
excretion characterize the syndrome of primary aldosteronism which can be
determined by:
Aldosterone-producing adenoma (APA)- Conns disease, 30% of the cases (in
the past it was considered that it was responsible for 60-70% of all primary
aldosteronism cases), more frequent in the left adrenal. The tumor is more
frequently small (under 3 cm), composed of glomerular cells, partially
autonomous, meaning that the circadian aldosterone production rhythm is
maintained, but with no response to angiotensin II.
Bilateral idiopathic hyperplasia (IHA) 60% of cases; incompletely elucidated
mechanism, possibly an increase of the glomerular region sensibility to
angiotensin II.
Primary (unilateral) adrenal hyperplasia (PAH) 2% of cases.
Aldosterone-producing adrenocortical carcinoma -<1% of cases, voluminous
tumor (larger than 6 cm), with distant metastases.
Familial Hyperaldosteronism (FH):
o Type I glucocorticoid-remediable hyperaldosteronism, <1%, with an
autosomal dominant inheritance, appears because of a chimeric gene
duplication that results from unequal crossing-over between the
promoter sequence of CYP11B1 gene (encoding 11 -hydroxylase)
and the coding sequence of CYP11B1 gene (encoding aldosteronesynthase). The result is an ectopic expression of aldosterone synthase
activity in the cortisol-producing zona fasciculata, which is controlled by
o Type II, <2%, aldosterone-producing adenoma or bilateral idiopathic
hyperplasia which appear in a familial context;
Ectopic aldosterone-producing adenoma or carcinoma (in the ovaries or the
kidney), extremely rare, <0,1% of cases.
The rise of aldosterone production, with no regard to its origin, leads to an
increased sodium reabsorption, an increase in circulating and intracellular sodium,
an increase in water reabsorption, a potassium depletion that leads to an increased
renal secretion of hydrogen ions, a rise of plasma bicarbonates and alkalosis. The
large magnesium depletion and the alkalosis are responsible for the tetany.
Consecutively, there is a suppression of the renin-angiotensin system.


Clinical presentation
The patients are in their third to sixth decade, have high systolic-diastolic
blood pressure (a constant sign), with an average of 160-180/110-120 mmHg,
usually considered resistant to drugs (there is no significant BP decrease when the
standard doses of 3 hypotensive drugs are administered, including a diuretic).
In patients with hypokalemia the following clinical signs can also appear:
Asthenia, muscular weakness, sometimes myasthenia-like,
Acute tetany with facial paresthesia and muscular cramps,
Palpitations (premature ventricular contractions),
Polyuria, polydipsia, nocturia resistance to ADH and, in time, kaliopenic
nephropathy (with degenerative lesions in small arterial vessels and
proximal tubes),
Periodic paralysis is rare, except in the Asian population.
Edema is not present in these patients, even though water and sodium
retention exists, because of the mineralocorticoid escape. Left heart hypertrophy is
an usual finding. When matched for age, blood pressure, and duration of
hypertension, patients with primary aldosteronism have greater left ventricular mass
by echocardiographic measurements than patients with other types of hypertension
(eg, pheochromocytoma, Cushing syndrome, or essential hypertension).
Laboratory and paraclinical exams:
In classical forms we find:
Hypokalemia the blood must be collected during a diet with a normal
amount of sodium, without a tourniquet and with spironolactone
discontinued at least 6 weeks before testing.
Hyperkaliuria more than 30 mEq/24 h, with a low urinary Na/K ratio.
Hypernatremia can be absent, Na can be normal or just slightly high.
What needs to be underlined is the fact that hypokalemia is inconstant in
patients with primary aldosteronism. In 2008, Endocrine Society elaborated
diagnosis guides and set the categories of hypertensive patients in which a primary
aldosteronism should be ruled out:
Hypertension in young persons, or in persons with a family history of
hypertension at a young age,
Hypertension with adrenal incidentaloma,
Hypertension and spontaneous hypokalemia, or hypokalemia after small
doses of diuretics,
Severe hypertension (systolic >160 mm Hg or diastolic >100 mmHg) or
hypertension resistant to treatment,
Hypertension and family history of primary aldosteronism (first degree
Laboratory investigations should be done in more steps: first identifying the
patients by concomitantly dosing plasma aldosterone concentration and plasma
renin activity, usually followed by confirmation tests and establishment the
etiopathological subtype.

Hormonal tests:
1. Plasma aldosterone concentration, collected under strict conditions:
normal salt intake, 1g salt/day supplemented 4 days before collecting the
blood, spironolactone discontinued 6 weeks before. The rest of medication
needs a 2 to 4 weeks discontinuation. Only drugs that do not interfere with
renin-angiotensin/aldosterone feedback loops can be used (prazosin,
guanetidine). The blood kalium levels should be normal because
hypokalemia decreases the aldosterone production. The normal values in
the morning are between 7 and 15 ng/dl, higher values confirming the
hyperaldosteronism, but not differentiating between primary and
secondary forms.
2. PRA is low and does not rise after diuretics. Normal values 1,5-2,5
ng/ml/h, and 6-8 ng/ml/h after stimulation.
3. The best screening test for hyperaldosteronism is the dosing of both PAC
and PRA and calculating the ratio between the two. The blood samples
are taken in the morning, between 8 and 10 AM. ACE inhibitors can falsely
elevate PRA. Therefore, in a patient treated with an ACE inhibitor, the
finding of a detectable PRA level or a low PAC/PRA ratio does not exclude
the diagnosis of primary aldosteronism. Each laboratory has a detection
limit for PRA (usually under 0,1 ng/mL/h). The medium values of PAC/PRA
in patients with essential hypertension are between 4 and 10, in
comparison with 30-50 in those with primary aldosteronism. Because PRA
is low in a significant number of patients with essential hypertension, PAC
>15 ng/dL (416 pmol/L) represents an additional diagnosis criteria for
primary aldosteronism.
4. Other tests: 18-hydroxicorticosterone, urinary aldosterone or its
metabolites, especially aldosterone 18-glucuronide.
The confirmatory tests are necessary and they highlight the inadequate
secretion of aldosterone; the PAC/PRA ratio is not considered a diagnostic test, but
only a screening test. The suppression tests are:
Oral sodium loading test: Only after controlling hypertension and
hypokalemia, patients should receive a high-sodium diet for 3 days, with a goal
sodium intake of 5000 mg Na (12.8 g NaCl). In the third day a 24h urine specimen is
collected. Urinary sodium has to be >200 mEq and urinary aldosterone more than 12
mg/24 hours in order to prove an autonomous secretion of aldosterone).
Intravenous saline infusion test. In this test 2 liters of 0.9% sodium chloride
solution are infused intravenously with an infusion pump over 4 hours with the
patient in a recumbent position. Blood pressure and heart rate are monitored during
the infusion. At the completion of the infusion, blood is drawn for measurement of
PAC. PAC levels in normal subjects decrease to less than 5 ng/dl; most patients with
primary aldosteronism do not suppress to less than 10 ng/dl. Post-saline infusion
PAC values between 5 and 10ng/dl are indeterminate and can be seen in patients
with IHA.
Fludrocortisone suppression test is no longer used by most centers.
Captopril test: 2 hours after the administration of 25 mg Captopril, PAC
decreases in adrenal hyperplasia and in normal persons, while in Conns syndrome
the values remain the same.
The last step in diagnosing primary aldosteronism is establishment of its
etiology. First, abdominal CT scan, emphasizing the adrenals, has a higher

sensibility in comparison with MRI. The aldosterone-producing adenoma is a welldefined hypodense tumor, more than 1cm in diameter.
Other imagistic investigations are abdominal ultrasound and I131-cholesterol
scintigraphy. Sometimes differentiating a unique adenoma from an idiopathic
bilateral hyperplasia can be challenging, especially because surgery should only be
performed in the former. What needs to be done is adrenal venous sampling with
bilateral dosing of PAC and cortisol, with calculation of the ratio or correction of
aldosterone/cortisol and a comparison between the values obtained from the two
veins. A ratio greater than 4:1 suggests a unilateral secretion.
Differential diagnosis
Primary aldosteronism hypertension has to be differentiated first from the
essential hypertension. Attention should be paid to secondary hyperaldosteronism
with high PRA, with a different physiopathological mechanism and a clinical picture
that sustains the diagnosis. Secondary hyperaldosteronism appears in:
Congestive heart disease;
Renovascular hypertension (PAC/PRA ratio<10);
Malignant hypertension;
Prolonged treatments with diuretics associated with low-sodium diet;
Pregnancy associated hypertension or contraceptive-induced
Coarctation of the aorta.
If both PRA and PAC values are small, a weak mineralocorticoid excess is
suspicioned (generally aldosterone precursors), or a cortisol excess which ends up
in stimulating mineralocorticoid receptors. Usually these forms are rare:
Congenital adrenal hyperplasia: 11-Hydroxylase deficiency (with
Exogenous mineralocorticoid administration;
DOC-secreting tumors;
Primary resistance to glucocorticoids;
Liddle syndrome appears as a consequence of the activation of Na+
amiloride sensible channels form the collecting tubes. Clinically the
presentation is similar to hyperaldosteronism. Hypokalemia does not
respond to spironolactone, but only to triamterene or amiloride (it
specifically inhibits the Na+ channels);
dehydrogenase type 2 (11HSD-2) deficit, hereditary or acquired (licorice
or carbenexolone ingestion). 11HSD-2 inactivates cortisol in the kidney,
transforming it into cortisone. A rise of the cortisol/cortisone ratio is
responsible for binding the cortisol to mineralocorticoid receptors. In the
secondary form the enzyme is inhibited by the ingestion of carbenexolone
or an increased ingestion of glycyrrhizic acid, the active principle of licorice
root (Glycyrrhiza glabra), used as a sweetener in candies, chewing gum
and some sodas.
Cushings syndrome:
o Exogenous excess of glucocorticoids,

o ACTH-dependent, pituitary adenoma or ectopic secretion of ACTH,

o ACTH-independent (uni or bilateral adrenal hyperplasia).
Evolution, complications and prognostic
The excessive production of aldosterone is associated with an increased risk
of cardiovascular disease because of the left heart hypertrophy, acute myocardial
infarction and cerebral vascular disease. The complications of hypertension are
present when treatment is lacking. Normalization of blood pressure should not be the
only goal in managing a patient who has primary aldosteronism. Most patients with
long-standing primary aldosteronism have some degree of renal failure.
The treatment goals in primary aldosteronism are the normalization of the
aldosterone level, the correction of hypopotassemia and the normalization of the
blood pressure. Establishing the correct subtype diagnosis is essential since the
treatment of primary aldosteronism is based upon whether the adrenal aldosterone
hypersecretion is unilateral or bilateral:
Unilateral adrenalectomy, for aldosterone-producing adenoma or unilateral
adrenal hyperplasia, usually performed laparoscopically.
Pharmacologic treatment is indicated for idiopathic bilateral forms, but also for
unilateral forms, if surgery is contraindicated or refused by the patient:
o Aldosterone antagonists: Spironolactone, 200- 400 mg/day initially,
then 50-100 mg/day (can have adverse reactions as gynecomastia,
decreased libido and erectile dysfunction in men because of the
antagonic effect at the testosterone receptor, or menstrual irregularity
in women). Serum electrolytes and creatinine must be checked
frequently in the first 4 to 6 weeks of treatment. Eplerenone, a highly
selective mineralocorticoid receptor antagonist, can be used in doses
of 2 x 25 mg/day
o Potassium-sparing diuretics (Amiloride 2 x 5-15 mg/day or
Triamterene) can have a good effect on hypopotassemia and
hypertension, but are not considered first-line treatments in primary
aldosteronism because of persistence of hyperaldosteronism with its
possible deleterious cardiovascular effects. Thiazides can be
associated in low doses (12,5-50 mg hydrochlorothiazide) in order to
reduce hypervolemia.
o In order to control the hypertension ACE inhibitors are used: Enalapril
or Captopril (25-50 mg/day) decrease the aldosterone secretion.
Calcium channel blockers can also be prescribed (Nifedipine,
o Low-sodium diet (under 100 mEq/day), regular exercise, maintaining a
normal BMI, and avoiding the alcohol excess and smoking contribute
to the success of the pharmacological treatment.
In glucocorticoid-remediable aldosteronism chronic treatment with physiologic
doses of a glucocorticoid normalizes blood pressure and corrects
hypokalemia (hydrocortisone or dexamethasone). Usually hydrocortisone is
used (10-12 mg/m2).
Cisplatin or Trilostan are used in the malignant forms.


Anatom y, embryology and histology
The adrenal medulla occupies the central portion of the adrenal gland, without a
clear demarcation from adrenal cortex. The adrenal medulla accounts for 10% of
total adrenal gland volume.
Adrenomedullar cells are called chromaffin cells or pheochromocytes. These
cells stain brown with chromium salts and are arranged in nests or cords around a
rich network of capillaries and venous sinusoids that drain blood from the adrenal
cortex. Their cytoplasm contains large numbers of vesicles (granules) that measure
100 to 300 nm in diameter and contain catecholamines (epinephrine and/or
norepinephrine) but also proteins, lipids, adenosine triphosphate (ATP), chromogranins, neuropeptide Y and proopiomelanocortin.
The pheochromocytes as well as the sympathetic nervous system arise in the
fetus from the primitive cells of the neural crest (sympathogonia). A large number of
these cells migrate to form paraganglia, collections of chromaffin cells located on
both sides of the aorta. The largest cluster of chromaffin cells outside the adrenal
medulla is located near the level of the inferior mesenteric artery and is referred to as
the organ of Zuckerkandl; it is quite prominent in the fetus and is a major source of
catecholamines during the first year of life. Pheochromocytomas are tumors that
arise from the adrenal medulla, whereas nonhead-neck paragangliomas arise from
extra-adrenal sympathetic ganglia. Pheochromocytomas can secrete excessive
amounts of both epinephrine and norepinephrine, whereas paragangliomas secrete
only norepinephrine.
Biosynthesis, secretion and circulation of catecholamines
The catecholamines have a catechol nucleus and are represented by dopamine,
norepinephrine, and epinephrine. They are synthesized from tyrosine, which may be
derived from ingested food or synthesized from phenylalanine in the liver.
Tyrosine enters neurons and chromaffin cells by an active transport mechanism
and is converted to l-dihydroxyphenylalanine (l-DOPA). The reaction is catalyzed by
tyrosine hydroxylase and represents the rate-limiting step in catecholamine
synthesis. Tyrosine hydroxylase activity may be inhibited by alpha methyltyrosine
(metyrosine) which is sometimes used in the therapy of metastatic or unresectable
DOPA is than converted to dopamine by the enzyme aromatic l-amino acid
decarboxylase (dopa decarboxylase).
Dopamine is actively transported into granulated vesicles to be hydroxylated to
norepinephrine by the enzyme dopamine -hydroxylase. The enzyme is structurally
similar to tyrosine hydroxylase; both are stimulated by glucocorticoids.
In the adrenal medulla, norepinephrine is released from the granule into the
cytoplasm, where the cytosolic enzyme phenylethanolamine N-methyltransferase
(PNMT) converts it to epinephrine. Epinephrine is then transported back into another
storage vesicle. In normal adrenal medullary tissue, approximately 80% of the
catecholamines released is epinephrine. PNMT expression is regulated by the
presence of glucocorticoids, which are in high concentration in the adrenal medulla.

Therefore, catecholamine-secreting tumors that secrete primarily epinephrine are

localized to the adrenal medulla.
Catecholamines are stored in electron-dense granules that contain catecholamines, ATP, as well as several neuropeptides, calcium, magnesium, and watersoluble proteins called chromogranins.
Preganglionic nerve fibers terminate in adrenal medullary cells, where they
release acetylcholine at synapses and stimulate adrenal medullary receptors.
Activation of the receptors depolarizes the cell membranes and causes an influx of
calcium ions. The increased intracellular concentration of calcium triggers exocytosis
of the neurosecretory vesicles with consequent release of their contents. Adrenal
medullary catecholamine secretion increases with exercise, angina pectoris,
myocardial infarction, hemorrhage, ether anesthesia, surgery, hypoglycemia, anoxia
and asphyxia, and many other stressful stimuli.
Following release into the circulation, approximately one half of the catecholamines bind to albumin and other proteins with low affinity and high capacity.
Therefore, plasma concentrations of catecholamines fluctuate widely. Catecholamines are quickly removed from the bloodstream and have a circulating half-life of
10-100 seconds.
Catecholamine Metabolism and Inactivation
Catecholamines are removed from the circulation either by reuptake in
sympathetic nerve terminals or by metabolism through two enzyme pathways
followed by sulfate conjugation and renal excretion. Catechol-O-methyltransferase
(COMT) converts epinephrine to metanephrine and converts norepinephrine to
normetanephrine through meta-O-methylation. Metanephrine and normetanephrine
are oxidized by monoamine oxidase (MAO) to vanillylmandelic acid (VMA) by
oxidative deamination. MAO also may oxidize epinephrine and norepinephrine to
dihydroxymandelic acid, which is then converted by COMT to VMA. Dopamine is
also metabolized by MAO and COMT to the final metabolite, homovanillic acid (HVA)
Catecholamines actions
The adrenergic receptors are G proteincoupled receptors activated by
norepinephrine and epinephrine. Most cells in the body have adrenergic receptors;
they mediate the fight or flight response also called the "acute stress response".
Epinephrine is the major catecholamine secreted by the normal adrenal
medulla, and its secretion is unique to the adrenal medulla. In sympathetic neurons
norepinephrine is released into the synapse by exocytosis where is either
reabsorbed or leaks out of the synapse into the circulation. Such synaptic leakage
accounts for the majority of circulating norepinephrine in normal individuals.
Adrenergic receptors were originally classified into two groups: and . This
classification has been expanded as subtypes of the and receptors have been
discovered (Table 16)


Table 16. Example of catecholamine receptors: location and actions

Catecholamine Tissue Location
Vascular smooth




Preganglionic nerves
Adipose cells
Adipose cells
Most tissues
Vascular smooth
Bronchiolar smooth
Intestinal smooth
Pancreatic islet cells
Adipose cells
Vascular smooth
Sympathetic nerves
Pituitary lactotrophes
Gastrointestinal tract

Action Following Receptor Activation

Increases vasoconstriction (increases blood
Increases pilomotor smooth muscle contraction
(erects hairs)
Increases contraction and ejaculation
Increases gravid uterus contraction
Increases sphincter tone and relaxes smooth
Decreases the release of neurotransmitter
Decreases lipolysis
Decreases norepinephrine release
Increases force and rate of contraction
Increases lipolysis
Increases calorigenesis
Decreases vasoconstriction (increases blood
Decreases contraction (bronchial dilation)
Increases glycogenolysis and gluconeogenesis
Decreases intestinal motility; increases
sphincter tone
Increases release of insulin and glucagon
Increases lipolysis
Decreases vasoconstriction (vasodilation);
Inhibits synaptic release of norepinephrine
Inhibits prolactin release
Paracrine functions

The adrenergic receptors can undergo sequestration, downregulation or

phosphorylation, a phenomenon that has been called desensitization, tolerance or
tachyphylaxis. This can explain why some of the patients with pheochromocytomas
and paragangliomas have no hypertension despite having chronically elevated
serum norepinephrine levels. Adrenergic desensitization appears to be one cause of
the cardiovascular collapse that can occur abruptly following the removal of a
pheochromocytoma in some patients.
Pheochromocytoma and paraganglioma
Catecholamine-secreting tumors that arise from chromaffin cells are
pheochromocytomas and "catecholamine-secreting paragangliomas" ("extra-adrenal
pheochromocytomas" or nonhead-neck paragangliomas). Pheochromocytomas are
tumors that arise from the adrenal medulla, whereas nonhead-neck
paragangliomas arise from the sympathetic ganglia. Pheochromocytomas are more
common (85%).
Nonhead-neck paragangliomas are often intra-abdominal (75%) and can be
sometimes nonsecreting.They arise most commonly in the perinephric, periaortic

and bladder regions but can be found in the chest arising in the anterior or posterior
mediastinum or the heart. Pelvic paragangliomas may involve the bladder wall and
obstruct the ureters. Non-chromaffin parasympathetic paragangliomas are typically
found in the head and neck. Unlike chromaffin sympathetic paragangliomas, usually
these tumors do not secrete catecholamines.
Catecholamine-secreting tumors are rare neoplasms, probably occurring in
less than 0.2 percent of patients with hypertension. It is estimated that the annual
incidence of pheochromocytoma is approximately 2 to 8 per million people, but this is
likely an underestimation. Although pheochromocytomas may occur at any age, they
are most common in the fourth to fifth decade and are equally common in men and
Most pheochromocytomas occur sporadically. The "rule of tens" for
pheochromocytomas states that about 10% are bilateral, 10% are extra-adrenal, and
10% are malignant.
Based on family history, it was formerly thought that only about 10% of
patients with these tumors developed it as part of a genetic syndrome. With genetic
testing, it is now clear that about 25% of patients with pheochromocytomas or
paragangliomas carry a germline mutation associated with a familial syndrome.
There are several familial disorders associated with pheochromocytoma, all of
which have autosomal dominant inheritance:
von Hippel-Lindau (VHL) syndrome. The VHL phenotype includes
pheochromocytoma (frequently bilateral), paraganglioma (rarely),
cystadenoma, renal and pancreatic cysts, pancreatic neuroendocrine
tumors, and renal cell carcinoma.
MEN 2 - activating mutations throughout the RET proto-oncogene
Neurofibromatosis type 1 characterized by neurofibromas, cafe au lait
spots, axillary and inguinal freckling, and iris hamartomas (Lisch
Familial paraganglioma is an autosomal dominant disorder characterized by
paragangliomas that are located most often in the head and neck but also in the
thorax, abdomen, pelvis, and urinary bladder. Most cases of familial paraganglioma
are caused by mutations in the succinate dehydrogenase (SDH) subunit genes
(SDHB, SDHC, SDHD, SDHAF2, SDHA), which compose portions of mitochondrial
complex II.
Pheochromocytomas are typically encapsulated and firm in texture. The
average diameter is 3-5 cm. Larger tumors frequently contain large areas of
hemorrhagic necrosis that have undergone cystic degeneration. Malignant
pheochromocytomas are histologically and biochemically the same as benign ones.
The only reliable clue to the presence of a malignant pheochromocytoma is local
invasion or distant metastases, which may occur as late as 20 years after resection
Clinical manifestations
The symptoms of pheochromocytomas are the consequence of the
hemodynamic and metabolic effects of tumoral hypersecretion of epinephrine,
norepinephrine and dopamine. The classic triad of symptoms in patients with a
pheochromocytoma consists of episodic headache, sweating, and tachycardia.
Blood pressure patterns vary among patients with pheochromocytomas:

About half of the patients have what appears to be essential sustained

Paroxysmal hypertension with very high blood pressure is described in
one third of the patients. The typical duration of a pheochromocytoma spell
is 15 to 20 minutes, but it may be much shorter. Spells may occur multiple
times daily or infrequently, like once a month. Attacks can occur
spontaneously or may be precipitated by postural change, medications
(e.g., -adrenergic antagonists, metoclopramide, anesthetic agents , MAO
inhibitors, ionic radio-contrast media, chemotherapy, phenothiazines), or
maneuvers that increase intra-abdominal pressure (e.g., exercise,
defecation, trauma). Hypertensive crises may also be triggered by eating
foods containing tyramine (the precursor to catecholamines): aged
cheeses, meats, fish, beer, wine, chocolate, bananas or by micturition
(with bladder paragangliomas).
About 13% of patients may be completely normotensive.
Orthostatic hypotension (with presyncope or syncope) may dominate the
presentation, especially in patients with epinephrine- or dopaminepredominant tumors The lability in blood pressure can be attributed to
episodic release of catecholamines, chronic volume depletion, and
impaired sympathetic reflexes.
Headache is a common manifestation, occurring in 90% of cases. It is of
moderate to severe intensity, lasting from hours to days. Generalized sweating
occurs in up to 60 to 70 percent of symptomatic patients.
Other symptoms associated with catecholamine-secreting tumors:
Anxiety, fear of impending death and panic attack-type symptoms,
Palpitation (forceful heartbeat) in epinephrine secreting tumor,
Increased sense of body heat,
Paresthesia, numbness,
Nausea and vomiting,
Visual changes,
Epigastric and chest pain.
Other signs associated with catecholamine-secreting tumors:
Tachycardia or dysrhythmias there can be initial tachycardia
during a paroxysm, followed by reflex bradycardia,
Peripheral vasoconstriction associated with a spell results in
cool or cold hands and feet and facial pallor,
Weight loss (rare),
Fever (infrequent).
Cardiomyopathy and congestive heart failure are the symptomatic
presentations caused by pheochromocytoma that are most frequently unrecognized
by clinicians. Some of the cosecreted hormones that may dominate the clinical
presentation include ACTH (Cushing's syndrome), parathyroid hormone-related
peptide (hypercalcemia), vasopressin (syndrome of inappropriate antidiuretic
hormone secretion), vasoactive intestinal peptide (watery diarrhea), and growth
hormonereleasing hormone (acromegaly).


About 13% of patients with pheochromocytomas and paragangliomas have no

hypertension despite having high circulating levels of catecholamines, this most
likely reflects adrenergic receptor desensitization related to chronic stimulation. The
acute attack with high blood pressure and dysrhythmias may be the first
manifestation of the disease during an anesthesia and surgery procedure.
Laboratory and paraclinical investigations
The diagnosis is typically confirmed by measurements of urinary and plasma
fractionated metanephrines and catecholamines. The metabolism of catecholamines
is primarily intratumoral, with formation of metanephrine from epinephrine and
normetanephrine from norepinephrine. Most laboratories now measure fractionated
catecholamines (dopamine, norepinephrine, and epinephrine) and fractionated
metanephrines (metanephrine and normetanephrine) by high-performance liquid
chromatography (HPLC) with electrochemical detection or tandem mass
Blood samples should ideally be drawn from a previously positioned intravenous cannula while the patient is fasting and resting supine (to avoid venipuncture
A 24-hour urine specimen is collected for fractionated catecholamines,
fractionated metanephrines, dopamine and creatinine. The container is acidified with
10 to 25 mL of 6 N HCl for preservation of the catecholamines; the acid does not
interfere with metanephrine assays.
Plasma and urinary metanephrines are much more sensitive than they are
specific. Most patients with elevated levels of fractionated metanephrines do not
harbor a pheochromocytoma if their levels are less than three times the upper limit of
the reference range.
Smoking can elevate plasma free metanephrine assays and coffee increases
plasma normetanephrine. Drugs that can interfere with the plasma free
metanephrine assay include tricyclic antidepressants, levodopa, epinephrine-like
drugs, cocaine, amphetamines, lidocaine, MAO inhibitors and acetaminophen.
Some tumors (mostly paragangliomas) fail to secrete catecholamines or
metanephrines. Serum chromogranin A (CgA) is a useful test to diagnose and
monitor such nonsecretory tumors. Urinary VMA determinations have an overall
lower diagnostic sensitivity for pheochromocytoma
Clonidine suppression test represents a confirmatory test. This test is
intended to distinguish between pheochromocytoma and false-positive increases in
plasma catecholamines and fractionated metanephrines. Clonidine is a centrally
acting alpha(2)-adrenergic receptor agonist that normally suppresses the release of
catecholamines from neurons but does not affect the catecholamine secretion from a
pheochromocytoma. Clonidine (0.3 mg) is administered orally, and plasma
fractionated metanephrines are measured before and three hours after the dose. In
patients with essential hypertension, plasma normetanephrine concentrations
decrease (into normal range or >40 percent decrease). However, these
concentrations remain increased in patients with pheochromocytoma.
Due to advances in the methodology of measuring catecholamines and
metanephrines, phentolamine, glucagon, histamine, metoclopramide and tyramine
tests are rarely needed. This kind of stimulation testing is no longer used since it can
cause dangerous hypertension.

There are several available imaging modalities for pheochromocytoma and

Computed Tomography it is useful to perform an initial non-enhanced
(without intravenous contrast) CT of the adrenals because the density of
an adrenal tumor can be better approximated without intravenous contrast.
An adrenal mass with a density of less than 10 Hounsfield units (HU) is
unlikely to be a pheochromocytoma. CT scanning of the entire abdomen
(from the diaphragm through to the pelvis) is obtained with intravenous
contrast-enhanced and delayed contrast-enhanced imaging. An adrenal
protocol that specifically determines the rate of contrast washout is
needed, because pheochromocytomas tend to have a slower contrast
washout than adrenocortical adenomas. CT scanning is less sensitive for
the detection of small adrenal pheochromocytomas (less than 1 cm) or
extra-adrenal paragangliomas (less than 2 cm). Hypertensive crises have
been provoked in pheochromocytoma patients receiving ionic intravenous
contrast agents; so initiating an alpha-blocking agent before the CT scan is
highly recommended.
MRI is useful in the diagnosis of adrenal pheochromocytomas,
paragangliomas, and metastatic disease. It may be used with or without
gadolinium contrast. Intravenous gadolinium contrast does not cause
hypertensive crisis. On MRI T1-weighted images, pheochromocytomas
have a dull signal (due to lack of fat cells), similar to kidney and muscle,
distinguishing it from adrenal cortical adenomas, which contain fat and
therefore have an intensely bright signal on T1-weighted images. The
hypervascularity of pheochromocytomas makes them appear bright on
MRI T2-weighted images. MRI is the scanning technique of choice in
children and during pregnancy, because it involves no radiation exposure.
MRI is helpful in visualizing paragangliomas that are intracardiac,
juxtacardiac, or juxtavascular in order to detect vascular invasion.
Metaiodobenzylguanidine scanning (123I-MIBG Scintigraphy). If the results
of abdominal imaging are negative, scintigraphic localization with 123IMIBG is indicated. This radiopharmaceutical agent accumulates
preferentially in catecholamine-producing tumors; however, this procedure
is not as sensitive as was initially hoped. Thyroid uptake of 123I should be
blocked with the administration of an iodide preparation (e.g., Lugol's
solution). The medications that may interfere with 123I-MIBG uptake (e.g.,
tricyclic antidepressants, labetalol, calcium channel blockers) must be
discontinued for 2 weeks before imaging is performed.
Positron Emission Tomography (PET). Advanced scanners can perform
PET and CT scanning simultaneously to produce accurate threedimensional anatomic imaging. It can be done with 18F-FDG (fluorodeoxyglucose), that is absorbed by tissues with active metabolism,
including tumors. For this reason it detects other tumors besides
pheochromocytoma/paraganglioma and is, therefore, less specific than
I-MIBG scanning. PET scanning may also be performed using
radioisotope-tagged dopamine: 18F fluorodopamine (18F-FDA). This scan is
more specific for paraganglioma and metastatic pheochromocytoma than
the previous one, because dopamine is a substrate for the norepinephrine
transporter in tumor tissue.

Octreoscan with 111In-pentetreotide or with 111In labeled octreotide, known

as somatostatin receptor imaging may be useful when paragangliomas or
metastases are suspected, particularly if MIBG scanning is negative.
Other tests. Patients with pheochromocytoma are frequently found to have:
o an increased white blood count with a high absolute neutrophil
count and sometimes eosinophilia,
o hyperglycemia, but overt diabetes mellitus is uncommon,
o hypercalcemia which may be caused by bone metastases or
tumoral secretion of PTHrP.
Genetic testing is advisable for all patients with a pheochromocytoma or
paraganglioma and is strongly recommended if a patient has one or more of the
a.) paraganglioma,
b.) bilateral/multifocal adrenal pheochromocytoma,
c.) unilateral adrenal pheochromocytoma and a family history of
pheochromocytoma/ paraganglioma,
d.) unilateral adrenal pheochromocytoma with onset of symptoms before age
45 years,
e.) other clinical findings suggestive of one of the previously discussed
syndromic disorders.
An asymptomatic person at risk for disease on the basis of family history of
pheochromocytoma/paraganglioma should have genetic testing only if an affected
family member has a known mutation.

Differential diagnosis
Among patients suspected to have a pheochromocytoma, the diagnosis is
rarely confirmed. The differential diagnosis must be made especially with:
Pseudopheochromocytoma or hyperadrenergic spells, with paroxysmal
hypertension an abrupt elevation of blood pressure associated with
palpitations, flushing, anxiety and increase in plasma catecholamines
documented during attacks. Differentiation can be done by clonidine test.
Antihypertensive and psychopharmacologic agents or psychological
intervention can control pseudopheochromocytoma.
Severe anxiety and panic disorders.
Primary hypogonadism (menopausal syndrome).
Carcinoid syndrome - patients present with flushing and diarrhea rather
than pallor with associated pheochromocytoma-like symptoms.
Pharmacologic causes
o Withdrawal of adrenergic-inhibitor, like clonidine because of the
rebound effect,
o Sympathomimetic drug ingestion (amphetamine),
o Illegal drug ingestion (cocaine, phencyclidine, lysergic acid
diethylamide LSD ). Cocaine inhibitis the norepinephrine reuptake
by blocking the presynaptic reuptake pumps (transporters) and may
also enhance the release of catecholamines from central and
peripheral stores.
o Combination of a monoamine oxidase inhibitor and foods contain
relatively high concentrations of tyramine.

The treatment of choice for pheochromocytoma is complete surgical
resection which requires an experienced team consisting of an endocrinologist,
anesthesiologist and endocrine surgeon. Careful preoperative pharmacologic
preparation is very important.
Preoperative management it takes 7 to 10 days (a longer duration is
indicated for patients with catecholamine cardiomyopathy). It should be started with
-adrenergic blockade. The beta-adrenergic blocker should never be started first
because blockade of vasodilatory peripheral beta-adrenergic receptors with
unopposed alpha-adrenergic receptor stimulation can lead to a further elevation in
blood pressure. On the second or third day of -adrenergic blockade, patients are
encouraged to start a diet high in sodium content (5 g/day) because of the
catecholamine-induced volume contraction and the orthostasis associated with adrenergic blockade. This degree of volume expansion may be contraindicated in
patients with congestive heart failure or renal insufficiency. After adequate adrenergic blockade has been achieved, -adrenergic blockade is initiated, typically
2 to 3 days preoperatively.
Alpha-adrenergic blockade - Phenoxybenzamine is the preferred drug for
preoperative preparation. It is an irreversible, long-acting, nonspecific -adrenergic
blocking agent. The initial dosage is 10 mg once or twice daily (with maximum final
dosage of 100 mg daily). The patient should be warned about the orthostasis and
marked fatigue that occur in almost all patients. With their more favorable side effect
profiles, selective 1-adrenergic blocking agents (e.g., prazosin, terazosin,
doxazosin) are preferable to phenoxybenzamine when long-term pharmacologic
treatment is indicated. However, treatment with these agents is not routinely used
preoperatively because of incomplete -adrenergic blockade.
Beta-adrenergic blockade is indicated to control the tachycardia and
should be administered only after -adrenergic blockade is effective. It should be
used cautiously and at a low dose (e.g.10 mg of propranolol every 6 hours)
Combined - and -adrenergic blocking agent Labetalol, with the
inconvenience of a stronger beta-blocker effect than the alpha-blocker one.
Catecholamine synthesis inhibitor Metyrosine inhibits catecholamine
synthesis by blocking the enzyme tyrosine hydroxylase. It should be used with
caution and only in patients who cannot be treated with the typical combined - and
-adrenergic blockade protocol. Metyrosine may be added to - and -adrenergic
blockade if the resection will be difficult or if destructive therapy is planned. The main
side effect with short-course therapy is hypersomnolence.
Calcium channel blockers - block norepinephrine-mediated calcium transport
into vascular smooth muscle. Nicardipine is the most commonly used calcium
channel blocker in this setting (2x30 mg/day). It is used to supplement the combined
- and -adrenergic blockade protocol.
Acute hypertensive crises may occur before or during an operation,
and they should be treated with intravenously administered drugs:
Phentolamine is a short-acting, nonselective -adrenergic blocker. An initial
test dose of 1 mg is administered and is followed, if necessary, by repeat 5-mg
boluses or continuous infusion. The response to phentolamine is maximal 2 to 3
minutes after a bolus injection and lasts 10 to 15 minutes.

Nicardipine can be started at an infusion rate of 5 mg/hour and titrated for

blood pressure control.
Sodium nitroprusside has a rapid onset of action and a short duration of
effect. It is administered as an intravenous infusion, 2 mcg/kg of body weight per
minute and adjusted every few minutes
Anesthesia and surgery. Surgical resection of a catecholamine-secreting
tumor is a high-risk surgical procedure and an experienced surgeon-anesthesiologist
team is required. The last oral doses of - and -adrenergic blockers can be
administered early in the morning on the day of the operation. Fentanyl, ketamine,
atropine, halothane and morphine should be avoided. The laparoscopic approach to
the adrenal gland is currently the procedure of choice for patients with solitary intraadrenal pheochromocytomas smaller than 8 cm in diameter. For larger tumor or in
cases of difficult dissection open adrenalectomy in indicated.
Hypotension may occur during and after surgical resection of the
pheochromocytoma, and it should be treated with fluids and colloids and then
intravenous pressor agents if necessary. Preoperative preparation with calcium
channel blockers or alpha blockade reduces the risk of shock. If both adrenal glands
were manipulated during surgery, adrenocortical insufficiency should be considered
as a potential cause of postoperative hypotension. Because hypoglycemia can occur
in the immediate postoperative period, fluid given intravenously should contain 5%
Evolution, prognosis and complications
More than one-third of pheochromocytomas cause death prior to diagnosis.
Death usually results from a fatal cardiac arrhythmia, myocardial infarction or stroke.
In patients late diagnosed with pheochromocytoma dilated cardiomyopathy, left
ventricular hypertrophy and cardiac failure can occur.
Approximately 1 to 2 weeks after surgery, urinary fractionated catecholamines
and metanephrines should be measured. If the levels are normal, the resection of
the pheochromocytoma should be considered complete. A postoperative 123I-MIBG
scan or PET scan is recommended for all patientsbut especially for those in whom
there is any doubt about complete resection of the pheochromocytoma and for any
patients with multiple tumors. The 24-hour urinary excretion of fractionated
catecholamines and metanephrines or plasma fractionated metanephrines should be
checked annually for life. Follow-up CT or MRI is not needed unless metanephrine or
catecholamine levels become elevated.
Malignant Pheochromocytoma about 10 percent of all catecholaminesecreting tumors are malignant. Malignant pheochromocytomas are histologically
and biochemically the same as benign ones. The only reliable clue to the presence
of a malignant pheochromocytoma is local invasion or distant metastases, which
may occur as long as 20 years after resection. Distant metastases most commonly
are found in lungs, bone or liver. Malignancy is common in those with familial
paraganglioma caused by mutations in SDHB gene.
Treatment of malignant pheochromocytoma or paraganglioma includes the
following options: tumor mass reduction, alpha blockers for symptoms,
chemotherapy and nuclear medicine radiotherapy (131I-MIBG treatment using 200mCi doses at monthly intervals over three to six cycles). Thrombotic therapy,
radiofrequency ablation and cryoablation are other options to be considered.

Pheochromocytoma in children. Affected children are more likely to have

multiple tumors, extra-adrenal paragangliomas and genetic conditions associated
with pheochromocytomas and paragangliomas. Over 80% of children exhibit
hypertension that is usually sustained. Among hypertensive children, the incidence
of surgically confirmed disease has ranged from 1 to 2 percent.
Pheochromocytoma in pregnancy. A tumor that is unrecognized carries a
severe prognosis, with a reported 40% maternal mortality and a 56% fetal mortality.
MRI (without gadolinium enhancement) is the preferred imaging modality. The
treatment of hypertensive crises is the same as for nonpregnant patients, except that
use of nitroprusside should be avoided. Although the most appropriate management
is debated, adrenal pheochromocytomas should be removed promptly if diagnosed
during the first or second trimester of pregnancy. The preoperative preparation is the
same as for a nonpregnant patient. If the pregnancy is already in the third trimester,
a single operation is recommended, to perform a cesarean section and remove the
adrenal pheochromocytoma at the same time. Spontaneous labor and delivery
should be avoided.
Adrenal incidentaloma
An adrenal incidentaloma is a mass lesion greater than 1 cm in diameter,
accidentally discovered by radiologic examination. This entity is the result of
technological advances in imaging such as computed tomography and magnetic
resonance imaging.
Autopsy series have found the prevalence of adrenal adenomas greater
than 1 cm in diameter to be between 1.5% and 7%.
Incidentalomas are uncommon in young patients but increase in frequency
with age. Clinically, two issues arise: whether the lesion is functional (i.e., secreting
hormones) and whether it is malignant. In more than 85% of cases, these lesions are
nonfunctioning, benign adenomas. Occasionally they represent myelolipomas, cysts,
hamartomas, or granulomatous infiltrations of the adrenal, functioning tumors
(pheochromocytomas and those secreting cortisol, aldosterone, or sex steroids) and
carcinomas. Some incidentalomas cause abnormal hormone secretion without
obvious clinical manifestations of a hormone excess.
All patients with incidentally discovered adrenal masses should undergo
appropriate endocrine screening tests:
measurement of 24-hour urinary metanephrines,
free cortisol level,
overnight dexamethasone suppression tests,
circulating levels of plasma renin activity and aldosterone in
hypertensive patients,
17-OH progesterone after ACTH stimulation tests.
The possibility of malignancy should be considered in each case: metastases
(up to 27% of patients with cancer have adrenal metastases), adrenal carcinoma
(rare), neuroblastoma, lymphoma etc.
Size appears to be predictive of malignancy: incidentalomas larger than 5 cm
have a greater risk to be malignant. Smooth, homogeneous adenomas on an
enhanced adrenal scan with a Hounsfield unit score (a marker of radiodensity) less

than 10 HU are invariably benign; malignancy is suspected in irregular,

inhomogeneous adenomas with a score greater than 20 HU.
Adrenalectomy is indicated for functional tumors and for tumors larger than 5
cm in diameter. Repeat CT scanning in patients with smaller tumors can be used to
guide management. Laparoscopic adrenalectomy is the treatment of choice.



Sex determination is the process whereby the bipotential gonad develops into a
testis or an ovary. Sex differentiation requires the developing gonad to function
appropriately to produce peptide hormones and steroids.
1. Chromosomal sex - refers to the differences regarding heterosomes between
the two sexes. In females two identical heterosomes (XX) are found in
addition to the 44 autosomes, while in the male these heterosomes are
different (XY). In humans, chromosomal sex usually is determined at the time
of fertilization, when two haploid gametes fuse. There is a marked
discrepancy between chromosome X and Y, related to the size and gene
content. The phenomenon of dosage compensation refers to the inactivation
of one of the two X chromosomes in females, a phenomenon that can be
highlighted by the Barr test.
2. Gonadal sex. The primitive gonad has a double potential, it can develop in
both testis or ovary. The key gene of testicular differentiation is the SRY gene
that encodes a DNA-binding protein, testis determining factor (TDF),
responsible for the differentiation of spermatogonia (primordial germ cells),
Leydig and Sertoli cells. A number of genes have been identified that are
essential for development of both ovaries and testes. For testis development
particularly strong evidence exists for the importance of the following genes:
SF1, SOX9, WT-1, AMH and for ovary the DAX1 and WNT4 genes are the
most important. The gonad begins to differentiate as a testis at 7-8 weeks of
gestation while the onset of ovarian differentiation starts later, at 10 weeks.
3. Differentiation of Genital Ducts or internal genitalia (IG). Under the action of
testosterone and AMH (Anti-Mllerian hormone) Wolffian ducts differentiation
(which form the epididymis, deferens duct, seminal vesicles and prostate) and
Mllerian ducts regression occur. In the presence of an ovary or in the
absence of a functional fetal testis, Mllerian structures persist to form the
fallopian tubes, uterus, and upper portion of the vagina and the Wolffian ducts
4. Differentiation of External Genitalia (EG). Testosterone and especially
dihydrotestosterone (DHT, converted from testosterone in the target cells by
the enzyme 5 alpha-reductase), will determine the development of the
urogenital sinus derivatives along male lines: fusion of the urethral folds and
formation the penis, glans development from genital tubercle, merging genital
folds to form the scrotum. In the absence of androgens (as in normal females
or when both gonads are missing), the development of external genitalia is
female (the genital tubercle becomes the clitoris, the urogenital swellings form
the labia majora, and the urethral folds fuse to form the labia minora).
5. Psychosexual development determines gender identity (refers to a person's
identification as male or female), sex-typical behaviors, sexual orientation
(refers to choice of sexual partner).
6. Secondary sex characteristics - the last phase in the continuum of
development of gonadal function will take place at puberty. External genitalia
is completely developed and the secondary sexual characteristics will
complete the phenotype for each gender, resulting in the striking sex
dimorphism of mature individuals.

Nomenclature and Classification of Disorders

of Sex Development
In 2006 a Consensus Statement on management of intersex disorders was
developed that has reviewed the nomenclature and classification of these conditions.
It is recommended not to use terms such as intersexuality, pseudohermaphroditism,
hermaphroditism, sex reversal syndrome, considered potentially offensive to the
patient. Instead the term "disease/disorder of sex development", DSD was proposed
for all congenital conditions in which development of chromosomal, gonadal and
anatomic sex is atypical. The need for this reassessment lies in identifying the
genetic causes of sexual abnormalities and changing moral concepts in modern
society. This classification includes three categories:
46,XX DSD - gonads are usually represented by the ovary, but EG and IG
have varying degrees of virilization or masculinization.
Disorders of ovarian development:
Ovotesticular DSD - with the old name of true
Testicular DSD: SOX9 gene duplication or SRY gene
translocation the phenotype is male with signs of
hypogonadism, infertility and/or testicular dysgenesis (in this
situation ambiguous EG occurs);
46, XX Gonadal Dysgenesis.
Syndromes caused by androgen excess:
deficiency, 11 beta-hydroxylase deficiency and 3-beta
hydroxysteroid dehydrogenase deficiency.
P-450 aromatase (estrogen synthetase) deficiency. The
enzyme, expressed in the placenta, ovary, bone, adipose
tissue, CNS, is responsible for the conversion of
testosterone to estradiol. In the absence of aromatase,
estrogen cannot be synthesized by the placenta, and
large quantities of placental testosterone and
androstendione are transferred to the fetal and maternal
circulation, resulting in androgenization of the female
fetus and virilization of the mother during pregnancy. At
puberty, affected subjects develop hypergonadotropic
hypogonadism with gradual virilization.
Maternal androgen excess. It can have different sources:
exogenous intake (iatrogenic), endogenous source from
adrenal and ovarian tumors.
Other conditions: bicornate uterus, uterine hemiagenesis or hypoplasia,
or uterine agenesis. Congenital absence of the uterus and the upper
one-third of the vagina is termed the Mayer-Rokitansky-Kster-Hauser
(MRKH) syndrome. If Mllerian agenesis is associated with renal and
cervical spine abnormalities it is referred to as the MURCS syndrome.


46, XY DSD - originally testes are present but EG or/and IG are

Disorder of testis development:
o Pure gonadal dysgenesis, also called Swyer syndrome. The testes
are dysgenetic and do not secrete testosterone and AMH, so
Mllerian derivatives develop, the phenotype is female with female
IG (uterus, fallopian tubes), sexual infantilism and primary
o Partial gonadal dysgenesis (mutations in WT1, SOX9, SF-1 genes):
Denys-Drash syndrome, mutations in the WT1 suppressor
gene, associates Wilms tumor, degenerative nephropathy
and ambiguity of EG with persistent Mllerian duct.
WAGR syndrome (Wilms tumor, Aniridia, Genitourinary
abnormalities and mental Retardation) caused by 11p13
campomelic dysplasia (SOX9 mutations) with short,
dysplastic and curved limbs, the phenotype of EG is variable.
o Testicular regression syndrome (congenital anorchia, "vanishing
testes syndrome") refers to the situation when although male EG
and IG are present, testis are missing. A testicular torsion or other
vascular cause, after the 20th week of intrauterine development,
may be the cause. Testosterone has low values, with no rise after
stimulation with hCG and the gonadotropins are increased. Surgical
exploration is usually recommended after CT or MRI. Sometimes
ambiguity of EG is found, which suggests a degree of gonadal
Disorders of androgen biosynthesis and action:
o Defects in androgen synthesis StAR deficiency, 3 betahydroxysteroid
17Hydroxylase/17,20-Lyase deficiency (all are described in
CAH) or 17-hydroxysteroid dehydrogenase deficiency and
5-reductase deficiency;
o Mutations in the LH/hCG receptor (Leydig cell hypoplasia);
o Disorders of androgen action total or partial androgen
insensitivity syndrome;
o Persistent Mllerian duct syndrome is the presence of a
uterus in an otherwise normal male. This condition can result
from mutations in AMH or its receptor (AMH-R).
Undescended testis may occur and sometimes infertility can
be described, due to testicular degeneration.
o Other conditions: cryptorchidism, isolated hypospadias.
Sex chromosomes DSD:
o Turner syndrome with all the cytogenetic variants;
o Klinefelters syndrome and 47, XYY syndrome;
o Mixed gonadal dysgenesis 45, X/46, XY.


Ovotesticular DSD
This is an extremely rare syndrome, with only about 500 cases being reported
so far. Ovotesticular DSD (formerly called true hermaphroditism) occurs when both
an ovary and a testis, either in the same gonad (ovotestis) or different gonads are
found in one individual. Phenotype is highly variable, most commonly EG are
ambiguous with hypospadias, or at least one testis is palpable in the inguinal canal.
At puberty, menses usually occur (rudimentary uterus or hemiuterus are present in
the ipsilateral ovary or ovotestis part) and breast development occurs also, with
possible virilization or feminization depending on the predominance of one of the two
tissues. Karyotype may be 46, XX/46, XY in 20% of cases, 46, XX in 75% of cases
and 46, XY in the rest. Management of these cases depends of the ambiguity of EG.
If female gender is chosen, testicular tissue must be removed. If the phallus size and
masculinization of EG is adequate, ovarian tissue requires removal at puberty.
Defects in testosterone synthesis and action
17-hydroxysteroid dehydrogenase type 3 deficiency - the enzyme responsible
for conversion of androstendione to testosterone has several isoforms, one of which
is expressed in the testes and its deficiency is responsible for the absence of the
virilization of EG. In most cases, the phenotype is female with rudiment of the vagina
and the testes are present in the inguinal canals. Typically, gynecomastia and
pronounced virilization occur in puberty due to increased peripheral conversion of
androstendione to testosterone.
Steroid 5-reductase type 2 deficiency is similar to the previous, testes are
normally differentiated, but the enzyme that converts testosterone into DHT
(considered the active hormone, about 50 times stronger than testosterone) is
missing. The optimal masculinization of EG cannot take place. These patients can
present with microphallus, small scrotum, hypospadias, urogenital sinus and blindending vagina. IG are male. Increased virilization appears again at puberty but
without acne and gynecomastia. The explanation lies in the presence of two
isoenzymes. The type I enzyme is expressed in the skin and type II isoenzyme in the
EG and prostate. The T/DHT ratio is abnormally high and confirms the diagnosis.
Leydig cell hypoplasia occurs due to mutations in the LH/hCG receptor with
variable phenotype. EG are frequently female, but hypospadias, microphallus and
cryptorchidism (with small testes) can occur. Mllerian duct derivatives disappear
due to normal Sertoli cell function. Pubertal masculinization is missing.
Androgen insensitivity syndromes.
Mutations in the androgen receptor (AR) cause resistance to androgen
(testosterone, DHT) action or the androgen insensitivity syndrome (AIS). The
disorder is inherited as a X-linked recessive trait.
46, XY individuals with complete AIS (CAIS, formerly called testicular
feminization syndrome) have:
o unambiguously female external genitalia with normal or slightly
underdeveloped labia and clitoris; short and blind-ending vagina,
o testes, that may be located in the abdomen, the inguinal canals, or the
o absent or hypoplastic Wolffian ducts derivates.
At puberty LH synthesis is augmented with subsequent increases in plasma
testosterone (normal male range) which will be aromatized to estradiol in peripheral
tissues thus normal breast development occurs, but axillary and pubic hair is

markedly decreased or absent (hairless women). The absence of menarche (primary

amenorrhea) is constant and the height is usually above average.
Before puberty the syndrome can be suspected in a girl with an inguinal
hernia or a labial mass (containing testes). Gonadectomy sometimes is performed,
as there is a low risk of malignancy, and estrogen replacement is prescribed at
puberty. Alternatively, the gonads can be left in situ until breast development is
complete. Psychological development is feminine, including typical maternal
Partial AIS (PAIS, Reifenstein's syndrome) results from less severe AR
mutations. Patients often present in infancy with microphallus, perineoscrotal
hypospadias and small undescended testes and with gynecomastia at the time of
puberty. A rudimentary vagina is present but the uterus is absent. Azoospermia and
infertility in otherwise normal men have also been described in association with
mutations in the androgen receptor and are considered the mildest form of PAIS.
Post puberty, as in individuals with complete androgen resistance, LH, testosterone
and estradiol are elevated.
Those individuals raised as males require hypospadias repair in childhood
and breast reduction in adolescence. In several adult men with Reifenstein's
syndrome, the administration of high doses (500 mg) of testosterone esters intramuscularly improved masculinization. More severely underandrogenized patients
present with clitoral enlargement and labial fusion and may be raised as females.
The surgical and psychosexual management of these patients is complex and
requires active involvement of the parents and the patient.
Turner syndrome
Turner syndrome is the only viable monosomy and also one of the most
common chromosomal abnormalities in humans, occurring in approximately 1/25001/3000 female new-born.
Clinical features
Before puberty, diagnosis is based on the cardinal feature of this syndrome,
major growth retardation, with a height that is below -3 SD. It may be present at birth
but often becomes evident after the first three years of life. In the absence of
treatment with recombinant GH the final height of these girls does not exceed 145
cm, with a slight tendency to obesity.
In addition, numerous anomalies may occur:
o congenital lymphedema, which can be present at any age, often at
birth and when treatment with growth hormone or estrogen is started,
o shield-like chest, wide space between the nipples,
o epicanthal folds, sometimes ptosis,
o prominent low-set ears, high-arched palate,
o frequent pigmented nevi,
o short neck, broad and webbed - pterygium coli (skin fold on the side of
the neck),
o very low occipital hair insertion,
o cubitus valgus, knee abnormalities, exostosis,
o short fourth metacarpals and metatarsals,
o nail hypoplasia,
o renal malformations: horseshoe kidney,

o cardiac malformation: bicuspid aortic valve, coarctation of the aorta,

aortic stenosis, hypertension.
Gonadal dysgenesis is a cardinal feature of patients with a 45,X chromosome
constitution. The gonads at adolescence are typically streak-like and usually contain
only fibrous stroma. It manifests with:
o absence or reduced secondary sexual characteristics: amastia or
hypomastia, infantile external genitalia, absence of pubic or axillary
hair ,
o primary amenorrhea with primary infertility.
Most patients with Turner syndrome have normal intelligence. Patients may
have hearing loss and mental retardation (it is described in ring X chromosome).
Learning disabilities involving spatial relationships, nonverbal problem-solving, and
attention are often present in these girls.
Paraclinical and laboratory
Karyotype is essential for the positive diagnosis: in 50-60% of cases it shows a
homogeneous monosomy 45,X; in 25% of cases different types of mosaicism occur:
45,X/46,XX or 45,X/46,XX/47,XXX and in other cases structural abnormalities of
chromosome X are present: isochromosomes X for long or short arm, Xp and Xq
deletions, ring chromosomes. Sometimes mosaicism with a 45,X and a Y-bearing
cell line (45,X/46,XY) or a structurally abnormal Y chromosome is identified, in which
case bilateral gonadectomy is necessary because of the risk of malignancy.
Cytogenetic diagnosis can be used for prenatal diagnosis of this syndrome.
The absence of the short arm of X chromosome determines short stature and
congenital malformations, while the loss of long arm is accompanied by gonadal
Plasma estrogen levels are low and gonadotropins (LH, FSH) are elevated hypergonadotropic hypogonadism. Gynecological exam and pelvic ultrasound show
uterine hypoplasia and absence of ovarian follicles, streak-like gonads. A cardiac
evaluation with echocardiogram or MRI should be done.
Differential diagnosis
Noonan syndrome has a similar phenotype (short stature, same facies,
pterygium coli) but cardiac malformations (pulmonary stenosis) are more severe,
mental retardation is frequently present and gonadal dysgenesis may be missing.
Other diseases to be excluded include: hypothyroidism, other causes of short
stature, pure gonadal dysgenesis (karyotype 46, XY).
Evolution and prognosis
In childhood, heart or kidney malformations can give different complications. In
adulthood, women with Turner syndrome may present more common than the
general population: hearing loss, hypertension, obesity, non-insulin-dependent
diabetes mellitus, autoimmune thyroiditis.
Early diagnosis enables treatment with recombinant growth hormone. The
doses required in Turner syndrome are close to double of those used in patients with
GH deficiency for achieving predictive height (the existence of a resistance to the
action of GH/IGF is suspected). The safety profile of this treatment is good, with

exceptions related to the risk of intracranial hypertension, the decrease in glucose

tolerance and type II diabetes occurrence and the slipped femoral epiphysis. It
requires an adaptation of GH doses based on monitoring of IGF-I levels.
Peripubertal estrogen-progestin replacement therapy requires a progressive
administration, starting with low doses of estrogen (2, then 5, 10 and 20 mcg
ethinylestradiol/day for 6-12 months each) and the introduction of a progestin along
with the first menstrual bleeding (norethisterone, medroxyprogesterone acetate 5 mg
or 10 mg for 7-10 days). The timing and dosing of estrogen therapy should be
selected to reflect normal puberty. Beginning treatment with low-dose estradiol
around age 11 or 12 years of age permit a normal timing of puberty without
compromising adult height. Growth hormone and estrogen are given together until
epiphyseal fusion occurs.
Klinefelter's syndrome
This syndrome is the clinical manifestation of a male who has an extra X
chromosome. The most common genotype is 47,XXY, but greater numbers of X
chromosomes have also been reported. Prevalence is 1 in 500-600 male newborns.
Many cases remain undiagnosed because of reduced phenotypical changes. This
syndrome is the most common congenital abnormality causing primary
hypogonadism or infertility.
Clinical features
Before puberty clinical diagnosis is difficult. In some cases it may be suspected
because of high stature and school difficulties. At puberty it becomes obvious
following characteristic phenotype:
Tall stature, with long limbs (eunuchoid habitus) or gynoid habitus, with close to
normal proportions,
A normal intellectual development in most cases, learning disorder with
Behavioral disorders, irritability, immaturity, difficulties in social integration due
to lack of adaptation,
Gonadal dysgenesis with seminiferous tubules hyalinization occurs constantly
and is manifested by:
in 40-60% bilateral gynecomastia occurs, often asymmetrical (because
of testosterone deficiency and consecutive LH hypersecretion with
stimulating estradiol production in the testes); breast cancer risk is 20
times higher than in normal men.
absence of secondary sexual characteristics:
absence of facial, axillary and troncular hair growth,
a reduced pubic hair growth with horizontal hair insertion (triangular),
a gynoid habitus, with biacromial diameter smaller than bitrochanteric,
normal or low muscle mass, constant low muscle strength,
high pitched voice.
small testes (length does not exceed 2-3 cm), firm, painless,
permanent azoospermia with primary infertility,
normal or small penis,
sometimes cryptorchidism, hypospadias,
a decline in potency and libido as age is increasing.
Paraclinical and laboratory

Karyotype reveals: free homogeneous trisomy X: 47,XXY in 85% of cases; a

mosaic can be found, the most common: 46, XY/47,XXY and rarely other karyotypes
48,XXXY or 49,XXXXY. In 60% of cases the additional X chromosome comes from
the father, as a result of nondisjunction in meiosis I. In mosaicism, trisomy is
secondary to the mitotic nondisjunction in a male embryo. The presence of a greater
number of X chromosomes is associated with increased severity of dimorphic
changes and mental retardation.
Semen analysis emphasizes aspermia, azoospermia or oligospermia. Plasma
testosterone is often low, with normal or increased LH and greatly increased FSH
(inhibin production is low due to damage of seminiferous tubules).
Testicular biopsy reveals hyalinization of the seminiferous tubules, severe
deficiency of spermatogonia, and pseudo-adenomatous clumping of Leydig cells. In
mosaicism the histological alterations are more attenuated, with even germ cells and
spermatogenesis - these patients may be fertile.
Sometimes the patients present impaired glucose tolerance, hyperlipidemia,
Differential diagnosis
It is made with other causes of primary or secondary male gonadal deficiency.
Evolution and prognosis
Klinefelters syndrome may be associated with chronic lung disease
(emphysema, chronic bronchitis), mediastinal tumors, varicose veins,
cerebrovascular disease, obesity, autoimmune thyroiditis, hypothyroidism, diabetes
mellitus, peptic ulcer, leukemia, osteoporosis, taurodontism with early decay.
Patients have a high mortality rate from lung cancer, non-Hodgkin lymphoma but a
lower death rate than expected from prostate cancer.
Therapy with testosterone in the hypogonadal patient will enhance secondary
sexual characteristics and sexual performance, increases muscle mass, prevents or
helps ameliorate osteopenia/osteoporosis and possibly prevents the development of
gynecomastia. Androgen substitution is initiated at the age of 11-12 years. There are
different options:
testosterone enanthate (Testoviron): 50-100 mg every 3-4 weeks
initially, increase dose by 50 mg every 2-3 weeks to a maintenance dose
(200-250mg/2-3 weeks).
testosterone undecanoate or a testosterone patch or gel form.
Fertility has been achieved by using in vitro fertilization in men with
oligospermia or with intracytoplasmic sperm injection (ICSI) after retrieval of
spermatozoa by testicular sperm extraction techniques.


Normal puberty
Cognitive, psychosocial and biologic maturation of the individual takes place
at the age of adolescence. The most remarkable biologic transformations in this
period are growth spurt and the appearance of secondary sexual characteristics. In
the same time, changes in body composition, the gain of reproductive function,
changes in bone mineralization and structure, and in cardiovascular system also
During embryo-fetal development, the hypothalamic-pituitary-gonadal axis is
activated, but shortly after birth there is a decrease in pituitary gonadotropins and
they remain inhibited until puberty. This suppression is realized at the level of CNS
by the tonic inhibition of the pulsatile GnRH generator situated in the arcuate nucleus
of the hypothalamus. The pituitary maintains its sensibility to GnRH during this
period. The intrinsic inhibitory mechanism of the CNS responsible for prepubertal
blockade of the GnRH pulse generator is realized mainly by gamma-amino-butyric
acid (GABA) but also by dopaminergic, serotoninergic or opioid mechanisms.
Puberty matches with the disinhibition of the pulsatile GnRH secretion translated in
nocturnal LH secretion in boys and cyclic LH and FSH secretion in girls.
In addition, other neural structures are involved in the onset of puberty and
leptin (produced and secreted by adipocytes) is an essential component of pubertal
development, although it doesnt seem to play a major role in the onset of puberty.
Stages of pubertal development are described for both sexes, in a succession
of physiologic changes with large chronologic limits. The whole period lasts for 4-5
years and starts at ages 9-10 years old in girls and 10-11 years in boys.
In girls breast development (telarche), pubic hair development (pubarche) and
the onset of menses (menarche) are observed according to Tanner and Marshall
pubertal stages. Breast development stages (B1-B5) are presented in Figure 10:
o stage B1: prepubertal,
o stage B2: breast bud stage, elevation of breast
and papilla as a small mound; enlargement of
areolar diameter,
o stage B3: further enlargement of breast and
areola with no separation of their contour,
o stage B4: projection of areola and papilla to
form a second mound above the level of the
o stage B5: mature stage, projection of papilla
only, resulting from recession of the areola to
the general contour of the breast.

Figure 10. Stages of breast development B1-B5

(according to Marshall, WA, Tanner, JM, Arch Dis Child


Pubic hair development P1-P5 is presented in Figure 11:

o stage P1: prepubertal, there is no pubic hair,
o stage P2: sparse, slightly pigmented hair, straight or slightly curled along the
o stage P3: hair is darker, coarser and curlier, and spreads over the pubic
o stage P4: hair is now adult type, but there is no spread to the medial surface
of the thighs,
o stage P5 : similar to P4, distributed as inverse triangle.

Figure 11. Stages of female (left) and male (right) pubic hair development, P2-P5,
(according to Marshall, WA, Tanner, JM, Arch Dis Child 1970)

First sign of puberty in girls is telarche, followed by pubarche along with vulvar
development (vaginal opening becomes horizontal, there is thickening and
pigmentation of the labia, the clitoris becomes erectile). The uterus, vagina and
ovaries enlarge in relationship with secondary sexual characteristics and menarche
occurs after an average of 2.6 years after the onset of telarche
The onset of puberty in girls is influenced by genetic and environmental factors
(including endocrine disruptors). In the last years the onset of puberty and also the
age of menarche have decreased due to improvement of socioeconomic status and

Figure 12. Stages of male genital development, G1-G5

(according to Marshall, WA, Tanner, JM, Arch Dis Child 1970)

The assessment of sexual maturation in boys includes: measurement of

testicular volume with an orchidometer (ellipsoids made of plastic or wood ranging
from 1 to 25 ml), pubic hair development staging, according to Tanner P1-P5
(Figure 11) and male genital development staging, Tanner stages G1-G5 (Figure
Pubic hair development stages are:
stage P1: prepubertal, no pubic hair,
stage P2 : sparse growth of long, slightly pigmented hair, straight or
slightly curled at the base of penis,
stage P3: hair is darker, coarser, curlier, spreads towards the pubis,
stage P4: hair is now adult in type, with no spread to the medial face of
stage P5: similar to P4 stage, distributed as inverse triangle, spreads to
the medial face of thighs and linea alba.
For the external genitalia the stages are:
stage G1: prepubertal, penis, testes and scrotum about the same size
as in early childhood,
stage G2: enlargement of scrotum and testes (diameter > 2 cm),
scrotal skin shows a change in texture (more wrinkled),
stage G3: growth of penis (mainly in length), further growth of testes
(diameter> 3 cm) and scrotum,
stage G4: the penis is further enlarged in length and breadth with
development of glans, enlargement of testes (> 4 cm), scrotum
becomes pigmented and wrinkled,
stage G5: genitalia are adult in size and shape, testes > 5 cm in
Growth of testes is usually the first sign of puberty in boys followed by the
appearance of pubic hair. The prostate and seminal vesicles are developed, and
ejaculation occurs. Axillary, troncular and facial hair appears gradually, along with
deepening of the voice.
During the development of secondary sexual characteristics there is an
acceleration of growth in both sexes termed growth spurt, determined by the GHIGF1 axis, thyroid hormones and gonadal steroids. In girls, growth spurt starts earlier
and maximum velocity is reached at the age of menarche, while in boys it starts later
and ends 2 years after the girls growth has ceased. Estrogens are the major
hormones responsible for maturation of chondrocytes and osteoblasts which leads to
epiphyseal fusion in both sexes.
Precocious puberty
The appearance of any sign of secondary sexual development before the age
of 9 in boys and 8 in girls is considered precocious puberty.
Gonadotropin-dependent precocious puberty (GDPP), true or central
(complete) precocious puberty in this situation there is a pulsatile
GnRH secretion and the hypothalamic-pituitary axis is activated

Gonadotropin-independent precocious puberty (GIPP) or peripheral

precocious puberty when there is an autonomous secretion of sexual
steroids (of gonadal or adrenal origin) in both sexes, which are
independent of the hypothalamic GnRH or pituitary gonadotropin
Incomplete precocious puberty refers to the situation when a partial
development of the secondary sexual characteristics occurs, it is
considered usually a variant of normal puberty.
If precocious puberty is accompanied by early feminization in girls or
masculinization in boys, it is considered isosexual (central precocious puberty is
always isosexual). On the other hand, early virilization in girls or feminization in boys
is known as contrasexual precocious puberty.
Etiology of true or central precocious puberty:
1. Idiopathic 80-90 % of cases, more frequent in girls; no anatomic lesion
or other cause of the pulsatile GnRH secretion can be identified. It can be
2. CNS tumors or developmental abnormalities of the hypothalamus, mostly
hamartomas of tuber cinereum (through TNF alpha secretion that
mediates the release of GnRH), but also optic gliomas in
neurofibromatosis type I, hypothalamic astrocytomas, ependymomas,
pineal tumors.
3. Other lesions of CNS: encephalitis, cranial abscess, arachnoid cysts,
vascular lesions, myelomeningocele, trauma, tuberculoid or sarcoid
granulomas, hydrocephalus, cranial irradiation. The latest can cause
associated GH deficit.
4. True precocious puberty due to prolonged exposure to sex steroids, like in
poorly or late treated virilizing congenital adrenal hyperplasia.

Clinical manifestations
Clinically, in GDPP, first signs are those of sexual maturation with the
appearance of secondary sexual characteristics earlier, but in the same order as in
normal puberty (in girls telarche precedes pubarche, and in boys testis enlargement
is followed by pubic hair development). Gametogenesis occurs in both sexes.
Individuals with a peripheral source of gonadal hormones (GIPP) are more likely to
display deviations from the normal sequence of puberty.
Central and peripheral precocious puberty is accompanied by increased
height velocity, somatic development and rate of skeletal maturation. If treatment is
delayed this accelerated epiphyseal activity can lead to rapid growth in the first
phase followed by the closing of epiphyseal cartilages and compromising of the final
stature. This is the paradox of a tall child compared to those of his/her generation
who will end as an adult with short stature. In addition, emotional distress due to
intellectual immaturity is constant.
Paraclinical explorations and laboratory findings
Serum estradiol, testosterone, basal FSH and LH are often measured in
children with precocious puberty. Levels of LH and sex steroids should be measured
using assays with detection limits adapted to the pediatric age group (LH detection
limits near 0.1 mIU/mL). In most laboratories, prepubertal levels of LH are below 0.1

Children with GDPP can be distinguished from those with GIPP (and from
normal prepubertal children) on the basis of measurements of serum LH
concentrations, at baseline and after administration of exogenous gonadotropinreleasing hormone (GnRH).
In GDPP, basal levels of LH and FSH are often at pubertal levels and will
increase with GnRH stimulation. Peak LH levels above 5 to 8 mIU/mL suggest
GDPP. In GIPP, LH and FSH levels are low at baseline (prepubertal range) and will
not increase with GnRH stimulation.
Imaging for bone age radio-carpal X-rays show a progress of bone age by
at least one year compared to the chronologic age in precocious sexual
development. If the patient has a normal bone age, he or she is unlikely to have
For differential diagnosis additional tests including thyroid function studies,
cortisol, DHEA, DHEAS, 17-hydroxyprogesterone and hCG in boys are used
In girls, pelvic (uterus, ovaries) ultrasound is mandatory: it can identify the
presence of an ovarian cyst or tumor. Uterus volume > 1.8 ml, or a length of the
uterus above 34 mm suggest progressive puberty. Ultrasound examination of the
testes is indicated in boys with GIPP to evaluate for the possibility of Leydig-cell
Radiologic exploration by CT or MRI of the CNS, hypothalamic-pituitary
region, pineal gland, is required considering the possible tumoral etiology (more
frequent in boys). A diagnosis of idiopathic GDPP is a diagnosis of exclusion.
Differential diagnosis
True, central precocious puberty must be differentiated from other forms of
sexual precocity:
1. In both sexes peripheral precocious puberty can occur in severe,
untreated hypothyroidism (probably by the TSH directly acting on FSH
receptors and activating them), in McCune-Albright syndrome (initially
peripheral sexual precocity, it can be transformed into true, central
precocious puberty) or after administration of medication, cosmetics or
even food containing sex steroids (iatrogenic effect),
2. Isosexual precocious puberty in girls, GIPP can be determined by:
functioning ovarian cysts,
estrogen secreting ovarian or adrenal tumors,
Peutz-Jeghers syndrome (it is associated with perioral
hyperpigmentation and intestinal polyposis with malignant potential)
3. Isosexual precocious puberty in boys appears in :
hCG secreting tumors that can occur in the gonads, brain
congenital adrenal hyperplasia (21-alpha-hydroxilase or 11hydroxilase deficiency),
virilizing adrenal tumors,
Leydig cell tumors or adenoma,
familial testotoxicosis: autosomal dominant syndrome, manifested
only in boys, caused by activating mutations of the LH receptor
gene, which results in premature Leydig cell maturation and

testosterone secretion. Affected boys present around 2 years of

cortisol resistance syndrome.
4. Incomplete precocious puberty, usually represents variants of normal
pubertal development:
premature telarche occurs in girls: unilateral or bilateral breast
enlargement, usually before age of 3, growth velocity is normal,
estrogen levels are slightly higher, with normal LH, FSH; can
regress spontaneously.
premature adrenarche occurs in both sexes, with appearance of
premature pubarche and axillary hair; the source is the adrenal
cortex, with higher DHEA and DHEA-S levels, but normal
gonadotropins and sex steroids; differential diagnosis should be
made with late onset CAH; it represents a risk factor for polycystic
ovary syndrome in girls.
premature menarche it is supposed to be an exaggerated
sensitivity of uterus to estrogens. Isolated menarche occurs, without
any other sign of puberty
In incomplete forms bone age determination is indicated. If the clinical findings
are consistent with incomplete precocious puberty and the bone age is normal,
follow-up rather than further evaluation usually is appropriate. These cases should
be followed because 10-20% of the isolated forms can progress towards true
precocious puberty.
5. Contrasexual precocious puberty:
In girls, early virilization requires differential diagnosis with:
o congenital adrenal hyperplasia (21-hydroxilase, 11hydroxilase, 3 beta-hydroxysteroid-dehydrogenase deficits)
o Cushing syndrome (virilizing adrenal neoplasm)
o virilizing ovarian tumors
o cortisol resistance syndrome
o Iatrogenic: administration of androgens
Feminization in boys occurs in:
o estrogen secreting adrenal tumor
o chorionepithelioma
o testicular tumor (Peutz-Jeghers syndrome)
o iatrogenic: exposure to estrogens
Evolution, complications, prognosis
Besides the general and local complications of non-idiopathic forms, short
stature caused by premature epiphyseal fusion and psychological issues about
premature sexual maturation should be considered.
In tumoral cases surgery is elective followed by radio- or chemotherapy
depending on the nature of the tumor.
In true precocious puberty GnRH agonists treatment is safe and effective.
These agents have been shown to downregulate GnRH receptors and reduce
pituitary gland response to GnRH, functioning as transient pharmacological
gonadectomy. The available preparations are:

o Nafareline - with subcutaneous (4 g/kg/day) or intranasal administration,

o Leuprolide (25-50 g/kg/day, SC) or depot-intramuscular, 11.25 mg every
3 months,
o Triptorelin (Dypherelin) SC or depot-IM (3.75 mg at 28 days for children
above 20 kg, or half of the dose for children under 20 kg)
o Histerelin a new formula, administered as a slow-release (1year) implant
Adverse effects are rare, consisting of bronchospasm in the case of intranasal
administration, or local abscess with depot formulas. Long term effects on
hypothalamic-pituitary axis after cessation of treatment are not described.
Other therapeutic options:
o Medroxyprogesterone acetate, administered orally, for long term,
inhibits LH, FSH secretion by its action on hypothalamic GnRH
secretion. It has the disadvantage of anabolic effect that produce
weight gain by increasing appetite.
o Cyproterone acetate has antiandrogenic, antigonadotropic and
progestational properties, it is administered per os in dose of
o In McCune-Albright syndrome and familial testotoxicosis agents like
testolactone and letrozole can be used (they produce inhibition of
androgen to estrogen aromatization); spironolactone (which has
antiandrogenic effect); ketoconazole through steroidogenesis-inhibiting
Patients should be evaluated every three to six months. If treatment is
effective growth rate reduction appear but also normalization of sex steroids and
involution of secondary sexual characteristics.
Delayed puberty
Delayed puberty is clinically defined by the absence or incomplete
development of secondary sexual characteristics until the age of 14 in boys and 13
in girls.
The constitutional form of delayed puberty affects boys more frequent then
girls and it is associated with short stature (constitutional delay in growth and
adolescence). The onset of puberty can be spontaneous, occasionally after the age
of 16. A family history of a similar pattern of development supports the diagnosis.
Every form of prepubertal hypogonadism (both hypogonadotropic and
hypergonadotropic) will manifest as delayed puberty and should be included in the
differential diagnosis. Short stature and bone age can be the guiding elements: in
constitutional delay bone age is always retarded compared to chronologic age, but
appropriate compared to stature, and rate of growth corresponds to bone age.
Adrenarche and gonadarche (the onset of sex steroid secretion from gonads) are
Patients with hypogonadotropic hypogonadism have normal height, bone age
is appropriate for age, but they lack the pubertal growth spurt. Adrenarche is
installed at normal age, but gonadarche is absent.
Measurement of gonadotropins, together with estradiol (females) or
testosterone (males) helps in the diagnosis of hypergonadotropic hypogonadism
(increased LH, FSH levels with low or undetectable estradiol and testosterone) but

cannot differentiate delayed puberty from hypogonadotropic hypogonadism (both

share low baseline gonadotropin and sex steroid levels). Only periodic evaluation will
finally make the distinction between these two, and sometimes treatment may be
initiated before the etiology is clear. For the exclusion of organic causes PRL and
thyroid hormone levels should be measured and imagistic exploration of
hypothalamic-pituitary region and gonads should be performed. Chronic hepatic or
renal disease, exposure to medication, irradiation, anorexia nervosa or pathologic
obesity should be considered before the final diagnosis (in fact, by exclusion) of
delayed puberty is made.
Treatment is not indicated until the age of 14 and is used mainly in patients
expressing a marked anxiety about the delay; others recommend only periodical
evaluation and reassurance of families and patients of the absence of organic
In boys, testosterone enanthate (Testoviron) can be administered, 50
mg/month for 3 to 6 months and revaluation after 6 months of break. In constitutional
delay there will be an enlargement of testicular volume, an increase of plasma
testosterone and secondary sexual characteristics will appear, progressing to normal
In girls, a 6 months regimen of ethinylestradiol 5 g/day or conjugated
estrogens 0.3mg/day can induce the development of breast tissue without inducing
In both sexes, the absence of progression of pubertal characteristics when
treatment is discontinued (2 courses of therapy can be prescribed) or after reaching
adult age are highly suggestive for hypogonadotropic hypogonadism.



Adult testis has a volume of 15-30 ml, with an average length of 4.6 cm (range
between 3.5 to 5.5 cm) and a width of 2.1 to 3.2 cm. The testes are located in the
scrotum, which has a protective role and also maintains testicular temperature
approximately 2C below the core temperature.
Testis has two functional compartments:
Germinal represented by seminiferous tubules (80-90% of
testicular mass) - contains seminal cells line and Sertoli cells, with
nutritional and hormonal function.
Endocrine formed by interstitial Leydig cells that produce sex
o androgen (19 C): testosterone (T), dihydrotestosterone
o estrogen (18 C): 17 -estradiol, estrone (small amounts),
o progestagen (21 C): pregnenolone, 17 -pregnenolone, 17progesterone, progesterone (small amounts).
There are several steroidogenic enzymes involved in androgen synthesis. The
rate-limiting process in testosterone synthesis is the delivery of cholesterol by the
StAR protein to the inner mitochondrial membrane and then the formation of
pregnenolone. The five major enzymatic steps involved in testosterone synthesis are
summarized in Fig.1.
Sertoli cells produce:
- AMH (MIF) anti Mllerian hormone/ Mllerian inhibition factor
- inhibins A and B (regulatory peptide that inhibits the secretion of FSH)
Testosterone circulates bound to SHBG - sex hormone binding globulin (60%)
and albumin (38%), while the free fraction that is directly accessible to the tissues
represents only 2%. Plasma SHBG is increased by estrogen, tamoxifen, phenytoin,
hyperthyroidism, cirrhosis and decreased by androgens, glucocorticoids, GH,
hypothyroidism, acromegaly and obesity, thus influencing plasma levels of total
Testosterone is converted to DHT (an androgen that is more potent than
testosterone) by 5-reductase and to estradiol through aromatase. Aromatization of
testosterone to estradiol occurs in adipose tissue, brain, bone, breast, liver, blood
vessels and testes (Sertoli cells and Leydig cells). In the liver, T is converted to
androsterone and etiocholanolone, that will be removed as urinary 17-ketosteroids
(20-30% of them come from testicular androgen metabolism, the rest of them from
adrenal androgens). DHT is metabolized in androstenetriol and androstendiol.
In the target cells androgen action is achieved via intracellular androgen
receptor (AR), a ligand-regulated transcription factor. The AR is structurally related to
the nuclear receptors and is distributed in both the cytoplasm and the nucleus. T or
DHT binding to the AR determine it to translocate into the nucleus, where it binds to
DNA or other transcription factors already bound to DNA, initiating transcription of
specific androgen-dependent genes.
T-AR complex regulates:
- internal male genital system differentiation by Wolffian duct virilization,
- secretion of gonadotropins: FSH and LH,

metabolic action: skeletal and muscle development, protein anabolic effect,

increase LDL- and decrease HDL-cholesterol, stimulation of erythropoiesis.
DHT-AR complex regulates:
- prenatal differentiation and puberty virilization of external male genital system,
- development of larynx and pilo-sebaceous follicle function,
- development and maintenance of secondary sexual characteristics.
Male sexual behavior is determined prenatally, develops during puberty and is
permanently stimulated by T and estradiol in the CNS.
Androgen production is primarily regulated by LH that is stimulated by
intermittent GnRH secretion (pulses released every 90 minutes) from hypothalamus.
High levels of T inhibit pituitary LH secretion and hypothalamic GnRH release,
through negative feedback, after aromatization to estradiol. T reduces pulsation
amplitude and frequency of Gn-RH and estradiol reduces their amplitude.
Spermatogenesis is a complex process with endocrine and paracrine
components, controlled by T and DHT, in which Sertoli cells are crucial. Androgens
are required for meiosis and spermatogenesis can be maintained by them if it is
initiated by FSH. Sertoli cells have receptors for FSH and testosterone, but not for
LH. At puberty, FSH initiates spermatogenesis by acting on germinal epithelium in
the presence of adequate levels of intratubular T, while stimulating the formation of
LH receptors on Leydig cells. Negative feedback control is provided by inhibin B and
estradiol (produced by Sertoli cells from T by aromatization), which inhibits secretion
of FSH. Thus, elevated levels of FSH are a true indicator for severe abnormalities of
spermatogenesis, its determination being essential in evaluating male infertility

Figure 13. The steps involved in

testosterone synthesis

Morphological and functional exploration of the testis

1. Male external genitalia examination is essential in assessing male
- The penis should be examined for the presence of malformations:
hypospadias, chordee (abnormal angulation due to a fibrous plaque).
- Testicular volume is estimated by Prader orchidometer (in normal adult the
volume is greater than 15mL). A low volume can suggest a disorder of the
seminiferous tubules development or their regression.
- Testicular consistency: small and firm testes are suggestive for hyalinization
processes and fibrosis (Klinefelters syndrome). Small, rubbery testes are
normally found in prepubertal males but in adults it may indicate a lack of
gonadotropin stimulation. Soft testis are characteristic for post-pubertal
testicular atrophy.
- Epididymis and vas deferens are appreciated by palpation.
- Scrotum should be wrinkled, pigmented and the cremasteric reflex should be
- The presence of secondary sexual characteristics should be always
2. Semen analysis. Sperm is collected by masturbation in special containers or in
condoms without spermicide, after 2-3 days of sexual abstinence. Semen specimen
should be examined 20 minutes to 2 hours after collection. Fever, exercise,
psychological trauma, convalescence, various drugs can temporarily affect
spermatogenesis and therefore at least three samples should be collected one to
two weeks apart. Normal sperm parameters (WHO 2010) are presented in Table17.
3. Hormonal evaluation plasma concentrations of total and free T, DHT, FSH, LH,
PRL and E2 should be measured.
- Total plasma testosterone:
o Prepubertal:5-20 ng/dL (0.17 -0.7 nmol / L)
o Post-pubertal: 300-1000 ng/dL (10-35 nmol / L),
- Free testosterone = 50-210 pg/mL; DHT = 15 -75 ng/mL; FSH = 5-25
mIU/mL; LH = 2.5 -15 mIU/mL; Estradiol (E2) = 15-40 pg/mL; PRL = 1-16
ng / ml.
4. Testicular ultrasound appreciates testicular volume and structure, its homogeneity
and can identify in situ carcinoma. Doppler ultrasound is useful when varicocele is
present. The transrectal ultrasound can highlight aplasia or agenesis of seminal
5.Cytogenetic and molecular evaluation (sex chromatin, karyotype, FISH etc.)
determine the number and structure of chromosomes, structural chromosomal
abnormalities, microdeletions of the Y chromosome. It is indicated in sexual
ambiguity and male infertility with azoospermia or extreme oligospermia.


Table 17. Normal sperm parameters

Sperm volume

1,5-5 mL

Aspermia no sperm
Hypospermia < 1,5 ml
Hyperspermia > 5 ml

Sperm color




> 15 million/mL

Oligospermia: <15 million/mL

Azoospermia: no spermatozoa
Asthenospermia: < 32% rapid
progressive motility


4% normal forms
(by strict criteria
excluding sperm with
mild abnormalities)

Liquefaction time
Sperm fertilizing


> 40% total motility

32% rapid
progressive sperm

Prostate disorders
prostate stones
Acute and chronic

Teratospermia: < 25% normal

Necrospermia: > 25% dead

3-25 minutes
Migration, survival
and vitality tests,
acrosome reaction
carnitine, fructose,
citric acid, zinc, acid


Functions of
prostate, seminal

6. Testicular biopsy is primarily indicated in hypogonadal men with normalsized testes and azoospermia in order to distinguish between spermatogenic failure
and ductal obstruction. Testicular sperm extraction for possible intracytoplasmic
sperm injection (ICSI) into ova may be performed at the same time.
7. hCG stimulation test (LH-like action). Plasma T is determined before and
after 4 days of daily hCG (2000-5000 IU) administration. Normal response: T is
doubled after the last administration of hCG. It is used for differential diagnosis
between bilateral cryptorchidism and bilateral anorchia.
Male Hypogonadism
Hypogonadism in a man refers to a decrease in one or both of the two major
functions of the testes: sperm production and testosterone production. These
abnormalities usually result from disease of the testes (primary hypogonadism) or
disease of the pituitary or hypothalamus (central, secondary or tertiary
hypogonadism). Sometimes disorders can affect all levels (combined hypogonadism:
in the elderly, in alcoholism, hemochromatosis).


Primary male hypogonadism

1. Congenital primary hypogonadism in male can associate varying degrees of
Klinefelters syndrome and other chromosomal abnormalities (eg. Male
46, XX),
Bilateral anorchia (vanishing testes syndrome),
Enzymatic defects in synthesis of testosterone, pure gonadal
Incomplete androgen insensitivity,
Leydig cell hypoplasia (LH receptor defect),
Noonan syndrome (male Turner syndrome) has autosomal dominant
inheritance with variable penetrance. The genotype and phenotype is
male with physical stigmata of classic Turner syndrome.
Uncorrected cryptorchidism it primarily affects spermatogenesis.
Myotonic dystrophy - familial form of muscular dystrophy in which 80% of
affected men have primary hypogonadism. Clinical features: progressive
fatigue, atrophy of facial muscles and extremities, infertility.
"Sertoli cell only " or germinal aplasia. Clinical features: infertility, mild or
moderate testicular atrophy, normal secondary sexual characteristics.
Labs: azoospermia, FSH, normal T and LH. Testicular biopsy shows
only mature Sertoli cells in seminiferous tubules, without any germ cells.
Deletions of portions of the Y chromosome may be the cause.
2. Acquired disorders - evolve without genital ambiguity:
gonadal irradiation,
Infectious diseases (mumps, tuberculosis, syphilis, sexually transmitted
trauma, testicular torsion,
autoimmune processes,
administration of drugs (chemotherapy, ketoconazole),
bilateral orchiectomy,
chronic systemic disease: renal failure, cirrhosis, HIV infection,
Clinical manifestations
Because testosterone has different roles during sexual life, the manifestations
of androgen deficiency differ depending on the stage of sexual development.
Prepubertal hypogonadism is characterized by the absence of development of male
secondary sexual characteristics and behavior:
- eunuchoidism: excessively long arms and legs relative to height.
- testes are small and hypotrophic, microphallus,
- scrotum is poorly developed and lacks rugal folds and pigmentation,
- absence of a male hair pattern in all body areas (facial, chest, abdominal),
- pubic hair pattern is more typical of females with the shape of an inverted
- no acne,
- prepubertal fat distribution (predominantly in the face, chest, and hips),
- gynecomastia/adipomastia,

poorly developed muscle mass, diminished strength and physical

- lordosis, kyphosis, scoliosis can occur,
- high-pitched voice,
- infertility,
- reduced motivation and initiative
Arm span exceeds height, and the distance from the symphysis to the floor
exceeds that from the crown of the head to the symphysis pubis, both differences
being greater than 5 cm. The absence of testosterone (and as a result estradiol)
during puberty causes a delay in epiphyseal closure so that the continued presence
of growth hormone results in an increase in the length of the long bones. This
relationship persists even after testosterone treatment. As a result, the finding of
eunuchoid proportions in an adult male at any age indicates prior prepubertal
If testosterone deficiency develops after puberty the normal male morphotype
is preserved, there is an involution of secondary sexual characters with variable
intensity (demasculinization), sexual dysfunction (diminished libido, erectile
dysfunction), energy deficiency, infertility. Other signs and symptoms: fine facial skin
wrinkling (lateral to orbits and mouth), hot flushes, sweats.
Paraclinical and laboratory explorations
Primary hypogonadism evolves with abnormal sperm parameters, normal or
low T, increased FSH and LH (hypergonadotropic hypogonadism). Barr test,
karyotype and post-pubertal semen analysis are performed. Sometimes it is
necessary to perform ultrasound and/or testicular biopsy. Patients with azoospermia
require urological evaluation to rule out a ductal obstruction. The absence of fructose
in semen means either the absence of seminal vesicles or bilateral obstruction of
DEXA osteodensitometry is required in all types of hypogonadism regardless
the etiology, osteoporosis being one of the complications of untreated forms.
Measurement of urinary 17-cetosteroids, DHEA and pregnantriol are used for
diagnosing CAH, which involves enzymatic defects of steroidogenesis in adrenal
and/or gonads.
Differential diagnosis
The most important is to differentiate the primary form from hypogonadotropic
male hypogonadism. The latter can be congenital:
GnRH deficiency or isolated congenital hypogonadotropic
hypogonadism - may be the consequence of GnRH deficiency,
mutations in the GnRH receptor, the FSH or LH subunits.
Kallman De Morsier syndrome hypogonadotropic hypogonadism
Mutations in the leptin or leptin receptor genes cause
hyperphagia, obesity and central hypogonadism.
Syndromes with mental retardation and hypogonadism: PraderWilli, Bardet-Biedl syndrome
Isolated LH deficiency - Pasqualini syndrome - fertile eunuchs
syndrome. FSH production is maintained and intact, the testes

have a quasinormal volume, but Leydig cells are absent.

Isolated FSH deficiency - rare, masculinization seems normal but with infertility.
Pituitary failure due to combined deficiencies - mutations in HESX1, Prop-1.
Acquired forms of secondary hypogonadotropic hypogonadism occur in:
central hypothalamic-pituitary lesions: inflammation, trauma,
tumors, pituitary adenomas, surgery, infiltrative disease, radiation
and other forms of anterior pituitary insufficiency,
suppression of gonadotropins by:
administration of GnRH, sex steroids in high doses,
chronic disease, type II diabetes.
The central forms can coexist with GH and TSH deficiency (dwarfism + central
hypothyroidism). Gynecomastia occurs less frequent than in the primary form (LH
and FSH are not increased and do not stimulate testicular aromatase).
In the central form semen analysis is constantly abnormal, T and
gonadotropin levels are low or inappropriately normal, prolactin may be increased.
Dynamic tests with GnRH and clomiphene can provide information regarding the
cause of pituitary or hypothalamic deficit. Full assessment of anterior and posterior
pituitary is required, as well as a neuro-ophthalmologic and imaging (MRI)
Primary hypogonadism benefits from androgen replacement therapy:
Testosterone enanthate or cypionate 50-100 mg/month IM with gradually
dose increment (50 -100 mg every 2-3 weeks) until the adult dose is
achieved (200 mg IM every 2 weeks)
Testosterone propionate a short acting form, can be used to initiate
treatment in elderly patients;
Testosterone undecanoate (Undestor, for oral administration 2-3x40-80
mg/day or Nebido, a long-acting oily solution, IM, 1 g /3 months);
Transdermal delivery via membranes impregnated with testosterone
(Androderm). or testosterone gel (AndroGel 1%) results in physiologic
concentrations of testosterone ,
A buccal preparation applied twice daily under the upper lip is also
Testosterone pellets (Testopel) may be implanted subcutaneously for a
longer duration of the effect.
Contraindications to treatment with androgens:
high risk: prostate cancer and metastatic breast cancer
moderate risk:
- benign severe prostatic hyperplasia,
- inexplicably high levels of PSA,
- polycythemia (hematocrit > 50%),
- severe obstructive sleep apnea,
- severe congestive heart failure (NYHA III/IV).
Possible side effects of androgen replacement therapy: polycythemia, acne,
reduction of spermatogenesis and fertility, gynecomastia, alopecia, induction or
worsening of obstructive sleep apnea, impaired liver function and decreased HDL195

cholesterol, pain at the injection site, skin reactions at the application site. Androgen
therapy may cause premature fusion of the epiphyses in an adolescent.
Defined as unilateral or bilateral absence of the testicle in the scrotum, due to
their retention on the normal path of descent. The incidence varies in preterm infants
(20-25%) compared with full term infants (2-4%). In many cases of cryptorchidism
noted at birth, spontaneous testicular descent occurs during the first year of life,
reducing the incidence to 1% by 1 year of age. Unilateral cryptorchidism is 5 to 10
times more common than bilateral.
Localization of the cryptorchid testes:
50% are located at the external inguinal ring or in a high scrotal
19% lie within the inguinal canal, between the internal and external
inguinal rings;
9% are intra-abdominal.
Ectopic testes are located outside the defined normal path of testicular
descent, in most cases being found superficially above the external inguinal ring, in
Scarpa's triangle or perineum.
Testicle and epididymis descent into the scrotum takes place between 7-9
months of intrauterine life, therefore at birth the testes should be present in the
scrotum or get there no later than 1 year of age. The pathogenesis of cryptorchidism
is not fully understood. Some of the possible causes are the following:
GnRH hyposecretion or decreased pituitary sensitivity to GnRH - in case of
hypothalamic-pituitary diseases;
primary testicular damage: in Klinefelter's syndrome, 46, XY DSD;
environmental endocrine disruptors with estrogen or antiandrogen activity,
such as phthalates or bisphenol A, have been proposed as a cause of the
increased incidence of cryptorchidism seen in recent years.
idiopathic - probably multifactorial etiology, candidate genes: Insulin-like factor
3 (INSL3)
The whole fetal hypothalamic-pituitary-gonadal axis participates in the normal
descend process as well as inhibin (required for differentiation of gubernaculum
testis) and anti-Mllerian hormone. Low intra-abdominal pressure and mechanical
obstacles (tight inguinal canal in 3% of cases) may deviate testes from their normal
trajectory, leading to ectopic testes.
Clinical features
A careful physical examination should be performed to assess the location of
testes within the scrotum or inguinal canal. Clinical signs of hypogonadism or
ambiguity of EG (hypospadias, micropenis, etc.) may be present. The examination
should be performed with warm hands, in a calm atmosphere, sometimes after
scrotal warming or a hot bath to facilitate testicular descent. For detection of a
retractile testes, applying continuous pressure over the lower abdomen in the
direction of the inguinal canal may be helpful. The volume of the undescended testis
is usually lower. Other malformations, especially renal should always be sought.

Paraclinical and laboratory explorations

T, FSH, LH levels can be normal, except in hypogonadism and anorchia
stimulation with hCG increases plasma T, but is ineffective in bilateral
anorchia; the test is used to exclude bilateral anorchia in the case of
bilateral cryptorchidism
AMH- children with no testicular tissue have very low levels,
17-OH progesterone and electrolyte to exclude 21 hydroxylase deficiency,
abdominal ultrasound, CT, MRI - especially in obese children,
exploratory laparoscopy



Differential diagnosis
Retractile testes (pseudo-cryptorchidism) is due to hyperactive cremasteric
reflex. Testes can be lowered into the scrotum, but they return to the inguinal
canal after release. Low temperatures, fear, inadequate palpation can activate
this reflex (more pronounced between 5 and 6 years).
Ectopic testes: are outside the normal path of descent.
Bilateral anorchia: is associated with increased gonadotropins, decreased T
and lack of response to hCG stimulation test.
Congenital adrenal hyperplasia - virilization forms. Female infants with severe
forms at birth may have an apparent male phenotype with bilateral
cryptorchidism. Electrolyte and karyotype is recommended because of the
possible disastrous consequences (acute adrenal insufficiency).

Evolution and complications

The most common complications are: inguinal hernia (about 90% of
cryptorchid males have associated ipsilateral inguinal hernia, rarely symptomatic),
testicular torsion, trauma.
Infertility has a high incidence in men with cryptorchidism. The degree of
germ-cell dysfunction in case of cryptorchidism is correlated with the duration of
suprascrotal location of the testes and whether one or both testes are affected.
A cryptorchid testis is eight times more likely to undergo malignant
degeneration than a normal testis. The incidence of such tumors is greater in
patients with intraabdominal testes (most commonly seminomas). Testicular
malposition is not the only factor in the development of testicular cancer because
sometimes these tumors occur in the contralateral, normally descended testicle.
The hormonal or surgical correction should be undertaken ideally before 24
months of age.
1.Hormonal treatment:
- Intramuscular chorionic gonadotropin therapy. One protocol consists of the
administration of 1500 to 2500 units twice weekly for four weeks. The
treatment has less than 25% success rate but may be tried prior to
- Intranasal GnRH therapy three times a day for 28 days by nasal spray. It
has been shown to be as effective as chorionic gonadotropin injections in
correcting cryptorchidism in some patients.

2. Surgery: orchiopexy should be performed as early as possible, in order to

preserve fertility. If cryptorchid testicle is diagnosed after puberty, orchiectomy can
be recommended, because the fertility rate is low and the risk of malignancy is very

Male sexual dysfunction

Sexual dysfunction in men includes the following:
o disturbances of libido: loss of sexual desire.
o erectile dysfunction (ED) is the inability to achieve or maintain an
erection of sufficient duration and firmness to complete satisfactory
sexual activity in more than 25% of attempts.
o disorders of ejaculation: premature or retrograde ejaculation, failure to
o orgasmic dysfunction
Penile erection occurs when blood flow to the penile erectile tissue
(corpora cavernosa and spongiosum) increases as a result of dilation of the
penile artery, following psychogenic or sensory stimuli transmitted to the limbic
system and then to the thoracolumbar and sacral autonomic nervous system.
The relaxation of the cavernosal arterial and cavernosal trabecular sinusoidal
smooth muscle occurs following stimulation of the sacral parasympathetic (S24) nerves, which results in the release of acetylcholine, vasoactive intestinal
peptide, and an endothelial cell-derived nitric oxide. Nitric oxide is released from
the nonadrenergic, noncholinergic (NANC) autonomic nerve supply and
increases the production of cyclic 3',5'-guanosine monophosphate (cyclic GMP),
which induces relaxation of smooth muscle. As the sinusoids become engorged,
the subtunical venous plexus is compressed against the tunica albuginea,
preventing egress of blood from the penis. Contraction of the bulbocavernosus
muscle through stimulation of the somatic portion of the S2 to S4 pudendal
nerves further increases the intracavernosal pressure. These processes result
in the distention, engorgement, and rigidity of the penis that constitute erection.
Cyclic GMP is gradually broken down by phosphodiesterase type 5 (PDE5). Inhibitors of PDE-5 such as the oral medications sildenafil, vardenafil, and
tadalafil maintain erections by reducing the breakdown of cyclic GMP.
ED appears through different basic mechanisms: (1) failure to initiate
(psychogenic, endocrinologic, or neurogenic), (2) failure to fill (arteriogenic), and
(3) failure to store adequate blood volume within the lacunar network (venous
incompetence) (4) mechanically interferences with erection in local urogenital
disorders such as Peyronie disease (idiopathic fibrosis of the covering sheath of
the corpus cavernosum).
These categories are not mutually exclusive, and multiple factors
contribute to ED in many patients. Diabetic, atherosclerotic, and drug-related
causes account for >80% of cases of ED in older men.
The psychogenic cause should be considered in all cases. The most
common causes of psychogenic ED are performance anxiety, depression,
relationship conflict, loss of attraction and sexual inhibition.


Table 18 lists various pathological conditions and drugs that may be associated with erectile dysfunction.

Table 18. Organic causes of erectile dysfunction

Diabetes mellitus
Adrenal insufficiency
Feminizing tumors

Pelvic vascular
Sickle cell
Venous leaks
Aorto-illiac or



temporal lobe
Spinal cord



Drugs and other causes

Selective serotoninreuptake inhibitors
Anticonvulsants Lithium,
Tricyclic antidepressants
H2-receptor antagonists
Other:Tobacco, Alcohol,
Opioids, Amphetamines,

Clinical manifestations
Patients may complain of constant or episodic inability to initiate or
maintain an erection, decreased penile turgidity, decreased libido, or a
combination of these difficulties. The differentiation between psychogenic and
organic erectile dysfunction can usually be made on the basis of the patients
Physical examination should include the following: a search for visual
field defects, patient's secondary sexual characteristics, presence of
gynecomastia. A careful assessment of femoral and peripheral pulses is also
important, as well as the search for evidence of peripheral or autonomic
neuropathy, a search for penile plaques indicative of Peyronie's disease,
examination of the testicles, evaluation of the cremasteric reflex (this is elicited
by stroking the inner thighs and observing ipsilateral contraction of the scrotum).
Clinically, men with androgen deficiency most commonly present reduced
sexual desire and erectile dysfunction. ED with normal libido advocates for
vascular or neurogenic causes. If libido and erection are maintained, but
premature ejaculation occurs the psychogenic form is very likely.
Paraclinical and laboratory explorations
1. Routine laboratory exams: blood count, lipid profile, parameters of liver
and kidney function, PSA (prostate specific antigen), fasting and 2-hour
postprandial blood glucose measurements
2. Hormonal determinations: T, FSH, LH, PRL, TSH, FT4, cortisol, etc.
3. Specialized tests at selected patients on the basis of established
psychiatric and psychological evaluation,
nocturnal penile tumescence testing,
vascular investigations: Doppler ultrasonography with
spectral analysis following intracorporeal injection of a
vasoactive drug, penile arteriography, cavernosometry
pelvic and pituitary CT or MRI .
The treatment of underlying risk factors (eg weight loss, exercise, stress
reduction, smoking cessation) and comorbidities (effective therapy of an
underlying systemic or endocrine disorder) may improve erectile function.
Available treatment options for male sexual dysfunction:
1. Oral agents. PDE5 inhibitors (Sildenafil Viagra 25-100 mg, tadalafil
Cialis or vardenafil Levitra) are taken orally about 1 hour before
anticipated intercourse.
the relaxant effect of NO on smooth muscle is prolonged,
improving erection quality and duration but does not stimulate the
these agents are absolutely contraindicated in men receiving oral
contraindications: association with alpha adrenergic antagonists
(can cause long-term hypotension, simultaneous therapy is strictly
prohibited), after heart attack or stroke,
side effects include headache, facial flushing, visual disturbances.

2. Vasoactive drugs including prostaglandin E1 (alprostadil), papaverine

hydrochloride, and phentolamine mesylate, either alone or in
combination, may induce an erection following intracavernous injection.
Side effects include penile pain, penile fibrosis priapism and dizziness.
One other option is: intraurethral insertion of a pellet containing
3. Devices have been developed that use suction to induce penile
engorgement and constrictive bands to maintain the ensuing erection.
4. Surgically implanted semirigid or inflatable penile prosthesis.
5. Repair of venous leaks and microsurgical revascularization of arterial
lesions have had variable success rates.
6. Aphrodisiac substances to increase libido:
Yohimbine by blocking presynaptic alpha-2-adrenergic
Apomorphine (Uprima), -MSH (Melanotan-II) or Melanocortin
receptor agonists with central dopamine agonist mechanism.
7. For psychogenic erectile dysfunction, simple reassurance and
explanation, formal psychotherapy, and various forms of behavioral
therapy may have success.
8. For premature ejaculation: selective serotonin reuptake inhibitors
(SSRIs) as first-line therapy but clomipramine may be also beneficial.
It is defined as breast enlargement in men, due to diffuse hyperplasia of
breast tissue, exceeding the diameter of 0.5 cm. All the mechanisms involved in the
occurrence of gynecomastia require an imbalance between estrogen and
testosterone concentrations or action at the mammary gland level. Gynecomastia
occurs by proliferation of ducts and connective stroma.
Gynecomastia can be a normal physiologic phenomenon:
in the newborn: in 30-40% of infants, due to transplacental transfer of
maternal and placental estrogens; it regresses spontaneously within a few
weeks after birth.
during puberty: with a frequency of 40-70%, by increasing the secretion of
LH and high ratio of estrogen to androgen in early stages of puberty,
spontaneously withdraws in 2 to 3 years after onset.
with aging due to decrease of androgen secretion and increased
peripheral conversion of androgens into estrogens.
Pathological gynecomastia occurs regardless of age, fails to resolve
spontaneously and may have multiple causes:

Endocrine diseases or conditions with a pathological biosynthesis or

hormonal excesses:
o congenital or acquired primary or central hypogonadism,
o androgen resistance syndromes: estrogen action in breast glandular
tissue through reduction/absence of androgen action,
o familial aromatase excess syndrome
o hyperprolactinemia - acts likely indirectly by inhibiting gonadotropins
and consequently reducing androgen secretion, thereby developing a
hormonal imbalance in favor of estrogen,

o thyroid pathology: hypothyroidism and especially hyperthyroidism (by

increasing SHBG, stimulation of peripheral aromatase, increasing LH)
o adrenal dysfunction: feminizing adrenocortical tumors, Cushing
syndrome, Addison's disease (rarely)
o testicular tumors: choriocarcinoma, trophoblastic tumors (by hCG),
Leydig cell tumors (estrogen excess),
o ectopic secretion of hCG in hepatoma, lung, gastric, and renal
Liver disease: cirrhosis by increasing the production rate of androstenedione
from the adrenals, enhancing aromatization of androstenedione to estrone,
and increasing the conversion of estrone to estradiol
Lung, thoracic or mediastinal processes: tumors, abscess, pleural effusion
Spinal cord injury
Drugs: estrogen (used to treat prostate cancer), androgens, antiandrogens
(eg cyproterone acetate), spironolactone (reduces production of testosterone,
antagonizes the peripheral androgens action, interacts with estrogen
receptors in breast), cortisol derivates, vitamin D, digitalis (estrogen-like
effect), phytoestrogens in marijuana. Phenothiazines, methyldopa and
reserpine cause gynecomastia by increasing PRL.
Patients with severe malnutrition or chronic disease (type 1 diabetes,
tuberculosis, AIDS, chronic renal failure) may develop gynecomastia during
refeeding or remission period of the disease (by oscillations of gonadotropins
Acute or chronic excessive stimulation of Leydig cells by gonadotropin
secretion favors a relative excess of estrogens and their precursors compared with
the production of testosterone. This mechanism would be responsible for
gynecomastia in patients with Klinefelters syndrome, Leydig cell insufficiency in
adults, gynecomastia occurring at puberty, but also that of the trophoblastic or
nontrofoblastic hCG secreting tumors (in addition, some of these tumors are able to
convert estrogen precursors in estradiol).
Clinical manifestations
Signs and symptoms:
Localization: uni- or bilateral, symmetrical or asymmetrical, concentric
enlargement of the glandular tissue directly beneath the areolar area.
The nipples and areolas are often hyperpigmented, sometimes with
enlargement of the mammary areola,
Consistency: rubbery to firm disk of tissue, often mobile,
Can be spontaneously painful or on palpation,
Rarely galactorrhea or nipple discharge occur
Paraclinical and laboratory explorations
Once physiological and drug-induced gynecomastia have been excluded the
following tests should be performed in all patients with gynecomastia:
- plasma levels of T, estradiol, LH, hCG,
- biochemical screening for liver and kidney diseases,
- if those are normal, levels of PRL, SHBG, -feto-protein, TSH, FT4,
- imaging investigations (breast, testicular, adrenal, thoracic, abdominal,

The differential diagnosis

Pathological gynecomastia must be distinguished from:
1. Breast lipomas, neurofibromas usually unilateral, painless and eccentric.
2. Breast cancer rarely occurs in men, but has a very rapid evolution. It is
typically eccentric to the nipple-areolar complex, firm to hard in texture, and
may be associated with skin dimpling, nipple discharge and regional
2. Leukemic infiltration.
3. Adipomastia can sometimes be difficult to differentiate (it needs palpation,
breast ultrasound) it is less firm, diffuse, without glandular structure,
4. Physiologic gynecomastia
Evolution and prognosis
It is good for the drug-induced gynecomastia after cessation of treatment.
There are no complications other than possible psychological damage from the
cosmetic defect. Physiological gynecomastia is monitored clinically.
If possible it should be etiological: ablation of the hCG and estrogen secreting
tumors, androgen replacement in case of hypogonadism, treatment of
For most adolescents with gynecomastia, only observation is recommended
with reevaluation in three to six months.
In pathological forms of gynecomastia there are several options:
1. Drug therapy that can be beneficial:
- anti-estrogenic drugs, SERM: tamoxifen (10-30 mg / day), raloxifene 60
- aromatase inhibitors: testolactone
- nonaromatizable androgen like dihydrotestosterone (DHT)
- in hyperprolactinemia: dopamine agonists (bromocriptine, cabergoline).
2. Surgery reduction mammoplasty for cosmetic reasons in patients with
gynecomastia with long evolution, recurrent, refractory to conservative treatment, or
in the fibrotic stage.
3. Radiotherapy prophylactic low-dose bilateral breast radiotherapy in
patients with prostate carcinoma before initiation of GnRH agonists.
Andropause and Partial Androgen Deficiency
Age-associated hypogonadism does not develop as clearly in men at
andropause as in women at menopause. The key difference is the gradual, often
subtle change in androgen levels in men compared with the precipitate fall of
estrogen production in women. In men there is a decline in serum total testosterone
concentrations that begins after the age of 40 years. The higher decline in free
testosterone levels is related to the increase in the levels of sex hormonebinding
globulin (SHBG) with age.
The decline in testosterone levels, when associated with signs and symptoms
of androgen deficiency, has been called andropause, but this term may be better

replaced by LOH late onset hypogonadism, ADAM (androgen deficiency in aging

male) or PADAM (partial androgen deficiency in aging male).
Many symptoms have been attributed to the male andropause, including
decreased libido and potency, emotional instability, fatigue, decreased strength,
decreased concentrating ability, vasomotor instability (palpitations, hot flushes,
diaphoresis), and a variety of diffuse aches and pains. There are usually no
associated signs unless the testicular injury is severe. In such patients, a decrease in
testicular volume and consistency may be present as well as gynecomastia.
Because of the increase in SHBG with age, it is not surprising that the serum
free testosterone concentration decreases with increasing age to a greater degree
than the total testosterone. As men age, serum gonadotropin concentrations
increase, FSH more than LH, but the rise is not so great as one would expect from
the fall in testosterone, suggesting that the fall in testosterone with age is due to both
secondary and primary hypogonadism. Oligospermia is usually present. Bone
mineral density may be decreased.
In the absence of known pituitary or testicular disease, testosterone therapy is
recommended only for men with low serum testosterone concentrations on more
than one occasion and clinically important symptoms of testosterone deficiency
(such as fatigue and sexual dysfunction).
Physicians must discuss the risks and benefits of testosterone therapy before
recommending this approach. The target serum testosterone concentration in these
men should be lower than that for younger men, to minimize the potential risk of
testosterone-dependent diseases. If treatment is undertaken, the man should be
screened before treatment and monitored during treatment for evidence of
testosterone-dependent diseases, such as prostate cancer.


Ovary is a paired intrapelvic organ that has the size of 2.5 2 1 cm and
weight of 4-8 g (variable during the ovarian cycle), located on the posterior surface of
the broad ligament. Adult ovary is covered by a coating germinal epithelium and by a
thin conjunctival capsule, and consists of two parts: outer cortex and central medulla.
The cortical area contains a conjunctival stroma that includes ovarian
follicles in different stages of maturation and albicans corpora.
The medullary area contains vessels and medullary nerves. Near the hilum
(the place where blood and lymphatic vessels, as well nerves enter into the
ovary), the medullary area contains cells with similar morphology to
testosteron-producing Leydig cells.
Ovarian follicle, the morpho-functional unit of mature ovary coordinates the
two gonadal functions:
the release of a mature oocyte (egg) every 28-30 days,
the production of specific steroid hormones: estrogens, progesterone
(necessary for endometrial nidation) and small amounts of androgens.
The hypothalamus plays a fundamental role in regulating hormones during
female reproductive period. Ovarian functionality is ensured by hypothalamic
pulsatile secretion of GnRH with a stimulatory effect on pituitary production of
gonadotropins (LH and FSH). In adult women the pulse frequency of GnRH varies
during menstrual cycle (a pulse at every 60-90 minutes in the follicular phase, and at
every 1 to 3-5 hours in the luteal phase). GnRH stimulation in combination with
feedback regulation of ovarian hormones (estrogens exert a negative feedback
mechanism by GABA during the follicular phase, and a positive one in the
preovulatory stage) generates a phasic secretion of LH and FSH (monthly or
circatrigintan biorhythm) in pituitary gonadotrophic cells.
Ovarian cycle with a duration of 28-30 days, includes a follicular phase
dominated by the secretion of estrogens and a luteal phase dominated by the
production of estrogens and progesterone. Ovulation takes place between these two
phases. Luteal phase length is relatively constant between 12 and 14 days in normal
cycles; thus, the major variability in cycle length is due to variations in the follicular
phase. Estrogens, produced primarily in follicular phase of the ovarian cycle,
modulate GnRH secretion and pituitary sensitivity to GnRH. This increased pituitary
responsiveness to GnRH is responsible for the preovulatory surge of LH.
Progesterone is primarily secreted by the corpus luteum; its high serum level
reduces the pulse frequency of GnRH secretion by increasing hypothalamic
concentrations of opioid peptides (beta-endorphins) with inhibitory effects. Its level
starts to increase preovulatory being responsible at least in part for the increase of
FSH and its coordination with the LH preovulator peak.
Follicular phase is initiated by the increase of FSH in the first 5 days of the
cycle which "selects" a dominant follicle (privileged); this will undergo full
maturation, from a stock of follicles "recruited" by virtue of a genetic program of
development incompletely elucidated. After selection, FSH decreases, and the rest
of the follicular maturation process goes on through paracrine coordination.
Through the cooperation between theca and granulosa cells - the ovarian follicle
produces and releases large amounts of estrogens, the plasma concentration of
which increases exponentially and produces simultaneously a new and mild FSH

On the 14th day a rapid elevation of LH production - the LH surge - triggers

ovulation, i.e. the release of the mature oocyte. In the preovulatory stage, almost
simultaneously with LH peak a milder FSH surge occures, which plays an important
role in ovulation by inducing LH receptors on granulosa cells, and than will ensure
the proper formation and function of the corpus luteum. After ovulation the loading
with a yellow pigment - lutein (morphological luteinization) as well as progesterone
and estrogens secretion (functional luteinization) take place in granulosa cells.
The corpus luteum reaches its peak luteal function in 7 days after ovulation
(21 day of the cycle). Its survival depends on small amounts of LH. If no pregnancy
occurs, corpus luteum regresses, by virtue of its genetic program which gives a
lifetime limit of 14 days and becomes corpus albicans through fibrosis.
Ovarian steroid biosynthesis involves the concerted activity of the theca and
granulosa cells, known as "the two-cells theory":
the internal cell layer (theca cells) contains receptors for LH and all the
enzymatic equipment necessary for the biosynthesis of androgens,
testosterone and androstenedione from cholesterol.
the granulosa cell layer disposes of receptors for FSH and aromatase enzyme
that converts androgen with 19 carbon atoms to estrogens with 18 carbon
atoms. Granulosa cells takes over the androgens and form estrogens through
The woman has an additional source of estrogen, besides the ovarian one,
that resulted from the conversion (aromatization) of adrenal androgens to estradiol or
estrone in adipose tissue, and little amounts in the liver and brain. These last
sources are the only reserve of estrogen during the postmenopausal period that are
not influenced by physiological mechanisms involved in the regulation of ovarian
Besides steroid hormones, the ovary produces peptide hormones involved in
the endocrine and paracrine control of its function:
inhibins (A and B) are important inhibiting factors of FSH, independent of
estradiol, during the menstrual cycle,
activin A and B are involved in paracrine control of estrogen secretion,
AMH is produced by granulosa cells and, like inhibin B, is a marker of ovarian
The vast majority of circulating estrogens and androgens are carried in the
blood bound to carrier proteins, which restrain their free diffusion into cells and
prolong their clearance. High-affinity binding proteins include sex hormone-binding
globulin (SHBG), which binds androgens with somewhat greater affinity than
estrogens, and corticosteroid-binding globulin (CBG), which also binds progesterone.
Modulations in binding protein levels by insulin, androgens, and estrogens contribute
to high bioavailable testosterone levels in PCOS (polycystic ovary syndrome) and to
high circulating estrogen and progesterone levels during pregnancy.
Estradiol is converted to estrone and then hydroxylated in the liver in estrone
or estrone sulfate that are excreted in urine. Progesterone is converted to
pregnanediol in the liver and then excreted by the kidneys.
The mechanism of action of estrogen and progesterone involves diffusion of
these steroids in the target cell, coupled with a specific cytoplasmic receptor and
translation of estrogen-receptor and progesterone-receptor complexes to the
nucleus. By binding to a specific sequence of nuclear DNA, the complex initiates the

transcription and translation of structural proteins or enzyme, through which target

cells respond to hormonal message.
Estrogens are tasked to develop progesterone receptors on target cells of the
reproductive system, which explains the need of an "optimal" estrogen-progestin
sequence for a proper function of this system.
Morpho-functional exploration of the ovary

Barr test - highlights the sexual chromatin in buccal mucosa cells. Normally, Barr
corpuscle is present in 20-80% of female cells and in 0.4% of male cells;
Karyotype counts the number and analyses the morphology of chromosomes is useful in the diagnosis of gonadal dysgenesis.
Ovulation tests:
Basal body temperature monitoring - basal temperature (oral or rectal measuring
at the same time of the day) increases postovulatory (after plasma progesterone
increases) by about 0.4 degrees and it maintains itself during the luteal phase,
cervical mucus smear,
cytovaginal exam aims histological and tinctorial changes of vaginal epithelium
cells, depending on the phases of the menstrual cycle,
ovarian ultrasound - monitors the development and maturation of ovarian follicles,
demonstrate the presence of ovarian tumors,
Measurement of LH surge by ovulation strips (colorimetric determination of LH
amount in urine in the midcycle period),
progesterone measurement in day 21 of the menstrual cycle (if
progesterone level >5 ng/mL ovulation is likely).
Hormonal measurements are presented in table 19.
Table 19. Hormonal measurements in female

Investigated hormone
Estradiol (E2)
follicular phase
ovulatory peak
luteal phase
follicular phase
luteal phase

Normal values

Utility, interpretation

< 50 pg/ml
50 100 pg/ml
200 400 pg/ml
50 150 pg/ml
< 50 pg/ml

To monitor ovulation induction therapy in assisted


0,5 5 ng/ml
10-27 ng/ml
20-70 ng/dl
(0.7- 2.6 nmol/l)

To investigate infertility

follicular phase
ovulatory peak
luteal phase

1,5 15 U/l
60 80 U/l
1,5 15 U/l
> 80U/l

FSH prepubertal, pituitary or hypothalamic

FSH menopause, gonadotropin-secreting
adenoma, primary ovarian failure

follicular phase
ovulatory peak
luteal phase

5 - 25 U/l
60 100 U/l
5 25 U/l

LH prepuberty, pituitary or hypothalamic

LH menopause, primary ovarian failure,
gonadotropin-secreting adenoma,
PRL pregnancy, lactation
Organic or functional hyperprolactinemia


To diagnose virilizing syndromes, PCOS

< 20 ng/ml
< 480 microUI/ml


In certain clinical conditions dynamic tests may be applied:

Progestin withdrawal test: in amenorrhea 10-20 mg/day Duphaston
(dydrogesterone) or 5 mg/day medroxyprogesterone acetate (MPA) is
given for 10 days. If the endometrium has minimal estrogenic
impregnation, a withdrawal uterine bleeding occurs directly proportional to
the degree of impregnation. The presence of withdrawal bleeding within 7
days after treatment indicates that the outflow tract is intact and sufficient
estrogen was present at the outset to stimulate endometrial growth.
- Estrogen-progestin test. The combined administration of estrogen (2
mg/day oral micronized estradiol for 21 days) with progestin (5 mg/day
MPA for 10 days started from the 16th day) will result in endometrial growth
followed by vaginal bleeding if the uterine compartment is normal. The test
is negative in Mllerian duct agenesis (uterus, cervix agenesis), uterine
- Clomiphene test: 100 mg/day of clomiphene citrate for 5 days. The test
can prove the occurence of ovulation by biochemical, clinical and
ultrasound examinations in polycystic ovary syndrome (PCOS). It is
negative in hypothalamic-pituitary lesions.
- GnRH test: administration of 100 micrograms GnRH with measurement of
FSH and LH at baseline, at 30 and 60 minutes after injection. Normally LH
and FSH increase at least 2 times. The test is positive in hypothalamic
anomalies and negative in pituitary lesions. In PCOS, LH is high and FSH
does not change.

Female hypogonadism
The classification of female hypogonadism is based on etiopathogenesis and
clinical appearance which vary considerably according to the time of onset
(prepubertal or postpubertal):
Hypergonadotropic hypogonadism (primary or gonadal
Hypogonadotropic hypogonadism (tertiary/hypothalamic or
secondary/ pituitary cause).
Hypergonadotropic hypogonadism (premature ovarian failure - POF)
The physiopatological mechanisms of POF are the accelerated follicular
atresia and inadequate stimulation of the ovarian follicle. Premature ovarian failure
(POF) is a heterogeneous syndrome defined as the occurrence of ovarian
insufficiency before the age of 40 years. In this category we find the following clinical
Turner syndrome, with all its cytogenetic variants.
Ovarian agenesis - lack of development of the ovaries, of unknown cause.
46,XX gonadal dysgenesis the ovaries are dysgenetic, beign replaced with
fibrous streaks. Turner stigmata and short stature are absent.
46,XY gonadal dysgenesis (Swyer syndrome) and mixed gonadal dysgenesis
(45,X/46,XY) - in both cases the testicle becomes inactive before internal and
external genitalia develops, so the phenotype is female. Gonads harbour a 10208

30% risk for malignancy due to the presence of Y chromosome and their
removal is indicated.
Certain forms of CAH: deficiency of StAR (with severe adrenal insufficiency),
17-hydroxylase (association of hypertension, hypokalemia and sexual
infantilism), aromatase deficiency (with concomitant maternal virilization during
Translocations, submicroscopic deletions or polysomies (like 47,XXX or other
variants) of chromosome X.
FMR1 gene premutation carriers (the gene is responsible for the appearance of
the fragile X syndrome). It is estimated that in 3-16% of women with POF the
number of CGG repeats in the promoter of this gene is between 55 and 200
Iatrogenic or exposure to toxins (alkylating agents, smoking), radiation, viral
infections (cytomegalovirus, mumps virus), bilateral oophorectomy.
Autoimmune POF - occurs especially in the context of autoimmune
pluriglandular syndromes type I and II, when it may be associated with
autoimmune thyroid disease or adrenal insufficiency. Immunosuppressive
therapy can restore ovarian function in rare cases.
Galactosemia - it is thought to be caused by the toxic effects of galactose
Resistant ovary syndrome - controversial entity, where the ovarian
gonadotropin receptors may be affected (FSH or LH receptor mutations have
been described in some cases). Ovarian biopsy may reveal numerous
primordial follicles, without further development.

Clinical signs
Physical examination and morphogram appreciate waist, chest perimeter, the
relationship between certain distances (pubis-ground, pubis-vertex) and diameters
(bitrochanteric, biacromial) enrolling them in a graph and then correlating them to a
standard morphograme. An assessment of breast development (eg, by Tanner
staging B1-B5) and of pubertal hair development (eg, by Tanner staging P1-P5)
should be performed. Evaluation for the classic physical features of Turner syndrome
should be noted but also examination of the skin for hirsutism, acne, striae,
hyperpigmentation and vitiligo.
If the onset is prepubertal, the most common features are:
primary amenorrhea,
amastia or hypomastia,
rare/absent pilosity or thinned axillary or pubic hair,
infant, rudimentary external genitalia (vulva, vagina, clitoris)
congenital malformations or Turner stigmata.
Postpubertal estrogen deficiency is characterized by normal female
morphotype conservation, but:
involution of primary (genitalia) and secondary sexual characteristics, in
variable degree,
decreased libido and sexual dysfunction,
energy deficit,
menstrual cycle disturbances (hypo-, oligomenorrhea or secondary
amenorrhea) with chronic anovulation and infertility,

symptoms of estrogen deficiency such as vasomotor symptoms and vaginal

dryness are common.

Paraclinical and laboratory explorations

Barr test and karyotype should be performed. E2 is low and gonadotropins are
high. Ovarian and uterine ultrasound can provide additional information and is
mandatory in ovarian dysgenesis. In some selected cases the following parameters
should be determined: antiovarian antibodies, TSH, fT4, TPO antibody, basal and
stimulated cortisol, ESR, glucose, serum calcium and phosphate (for exclusion of
autoimmune diseases). Although no longer routinely indicated, exploratory
laparotomy with histopathological examination of the ovary may be necessary.
Untreated forms can lead to osteoporosis and DXA scan is required in
hypogonadism regardless of etiology. Determination of urinary 17-cetosteroids,
DHEA, pregneneolone and other metabolites are reserved to investigate CAH, that
may involve enzymatic defects of steroidogenesis in adrenal and/or gonads.
Differential diagnosis
POF should be differentiated from hypogonadotropic hypogonadism. This
category includes congenital or acquired hypothalamic causes:
GnRH deficiency or isolated congenital hypogonadotropic hypogonadism 5 times more rare in girls than in boys, it appears in the absence of GnRH
secretion in hypothalamic neurons or an impaired GnRH action on
pituitary, caused by receptor mutations. Childhood growth is normal, but
at puberty an eunuchoidal habitus develops (arm span exceeds height by
more than 5 cm)
Kallmann De Morsier Syndrome - hypogonadotropic hypogonadism with
anosmia/hyposmia following olfactory bulb agenesis or hypoplasia.
Leptin or leptin receptor mutations - cause hyperphagia, obesity and
central hypogonadism.
Syndromes associated with mental retardation: Prader-Willi syndrome,
Bardet-Biedl syndrome - see chapter hypothalamus.
Functional hypothalamic amenorrhea.
Acquired forms occurring in the context of central hypothalamic lesions
craniopharyngiomas), surgery, infiltrative disease, radiation.
The pituitary causes are:
Pituitary insufficiencies due to combined genetic deficiencies (mutations in
HESX1, Prop-1).
Selective FSH deficiency rare, caused by FSH gene mutations.
Acquired forms occurring in the context of central pituitary lesions:
inflammation, trauma, tumors, surgery, infiltrative disease, radiation.
macroprolactinomas). Prolactin has a double effect: inhibits ovarian
androgen aromatization (the estradiol levels and corpus luteum activity are
decreased, reducing the production of progesterone), but also disrupts the
secretion of LH and FSH at the central level by inhibiting directly GnRH
Determination of basal concentrations of E2, FSH and LH allow differential

diagnosis between primary hypogonadism (low E2, increased FSH and LH ) and
central one (low E2, low or inadequately normal FSH, LH). The differential diagnosis
should include all cases of primary and secondary amenorrhea.
Primary hypogonadisms benefit from combined estrogen-progestin therapy. In
prepubertal forms, the scope is the development of secondary sexual characteristics;
hormone replacement therapy requires a progressive administration, starting with
low doses of estrogen (2, then 5, 10 and 20 mcg/day ethinyl estradiol, each dose for
6-12 months) and introduction of a progestine when withdrawal bleeding is present.
Then standard preparations as oral contraceptive or hormone replacement therapy
(HRT) used in menopause are indicated.
In HRT several types of estrogen may be continuously administered; the
equivalent doses are :
1 mg/day micronized 17-estradiol, per os =
0.625 mg/day conjugated estrogens, per os =
10 g/day ethinyl estradiol, per os =
50 g/day 17-estradiol valerate transdermal administered.
Most women have an intact uterus, so progestin preparations are
administered cyclically, for 10-14 days per month (synthetic progestin preparations:
5-10 mg/day medroxyprogesterone acetate, 10-20 mg/day dydrogesterone or natural
micronized progesterone). Some newer progestin preparations are in use:
drospirenone, with antimineralocorticoid and antiandrogenic action, at doses of 0.5 to
2 mg/day. Treatment is usually indicated until about age of 50 years, the average
age of normal menopause, in order to prevent cardiovascular and skeletal
complications resulting from the absence of estrogens. Breast cancer risk is not
higher than in women with normal ovarian function.
Amenorrhea can be primary (PA), if a girl has not had at least one
menstruation by age of 16 years, or secondary (SA), if menstrual period is absent for
at least 6 months in a woman who had previously menses.
Primary amenorrhea may be due to:
1. Hypothalamic and pituitary etiology (represent 25% of all PA) - both were
discussed at hypogonadotropic hypogonadism. Constitutional delayed
puberty is included in this group.
2. Ovarian causes are responsible for 50% of PA; see hypergonadotropic
(especially ovarian dysgenesis), and polycystic ovary
syndrome (PCOS).
3. Uterine or vaginal etiology (causes 20% of PA) - in case of congenital
anomalies, agenesis of the uterus, cervix or in:
Mayer-Rokitansky-Kuster-Hauser Syndrome agenesis of the uterus and
the upper portion of the vagina, with normal sexualisation.
Imperforate hymen is associated with cyclic pelvic pain and hematocolpos.
Transverse vaginal septum.
4. Other causes, due to receptor or enzyme defects: complete androgen
insensitivity syndrome, 17 alpha-hydroxylase deficiency, 5-alpha reductase
deficiency etc

In the case of secondary amenorrhea physiological causes should firstly be

excluded: pregnancy and menopause. A diagnostic algorithm is showed in figure 14.
The causes of SA may be:
hypothalamic and pituitary in 55% of cases,
ovarian in 40% of cases,
other etiology, including uterine causes in the remaining 5%.

Figure 14. A diagnostic algorithm for amenorrhea.

DHEAS: Dehydroepiandrosterone-sulfate; FSH: follicle-stimulating hormone; FT4: free
thyroxine; hCG: human chorionic gonadotropin; LH: luteinizing hormone; PCOS:
polycystic ovarian syndrome; PRL: prolactin; TSH: thyroid-stimulating hormone.

One of the hypothalamic causes of amenorrhea is the functional hypothalamic

amenorrhea. It is characterized by decreased frequency and amplitude of GnRH,
with low or normal LH and FSH, but inadequate levels for E2. The cause of
functional hypothalamic amenorrhea often remains unclear, but in many cases it is
preceded by psychologic stress, strenuous exercise, or poor nutrition (it was
described in the functional deficit of GnRH in hypothalamic pathology chapter).
The abnormal GnRH secretion characteristic for functional hypothalamic

amenorrhea leads to decreased pulses of gonadotropins, absence of normal

follicular development, absent midcycle LH surges, anovulation, and low serum
estradiol concentrations. Serum FSH exceeds LH, similar to prepubertal period.
Pathogenic mechanisms in hypothalamic amenorrhea are not fully elucidated
but may be involved:
decreased leptin levels, known to stimulate GnRH pulses,
increased CRH resulting in high ACTH and cortisol secretion, that have a nonspecific inhibition on gonadotropins and GnRH,
functional hyperprolactinemia, stress related with the same effect on GnRH.
The female athlete triad is characterized by disordered eating, amenorrhea,
and osteoporosis. These patients have very low body fat. It is assumed that there is
a critical level of fat for optimal reproductive function in women.
A common cause of SA is hyperPRL (see pituitary chapter). Among the
ovarian causes PCOS is responsible for 20% of SA and is associated with
hyperandrogenism. While gonadotropins are often normal, ample increase in LH with
an LH/FSH ratio over 3 can occur but is no longer considered a diagnostic criterion
for PCOS.
The diagnosic algorithm of SA must take into account the role of other
endocrinopathies: hypo- and hyperthyroidism, Cushing syndrome, adrenal
insufficiency, virilizing adrenal tumors, which often induce oligomenorrhea or
secondary amenorrhea.
Among uterine causes of SA, uterine synechiae or Asherman syndrome arise
from endometrial infections, postpartum bleeding requiring deep curettage. In these
cases anamnesis may be very useful and estrogen-progestin test is negative - the
deprivation bleeding does not occur.
Should be individualized according to the etiology. Estrogen status can be
determined by means of the progesterone withdrawal test or by measurement of
serum estradiol (<50 pg/mL). If withdrawal bleeding does not appear or estradiol is
less than 50 pg/mL, HRT or combined contraceptive hormones should be instituted.
If withdrawal bleeding occurs, any cyclic progestin therapy is adequate to combat
unopposed estrogen action and to prevent endometrial hyperplasia.
If fertility is desired, in some forms Clomiphene can be used to induce
ovulation. It acts as an anti-estrogen determining the increase of gonadotropins. It is
administered from the fifth day of bleeding for 5 days in doses of 50 mg/day with the
possibility of repeated courses and increase the dosage to 250 mg/day in case of
failure. The treatment may be continued for maximum 6 cycles. With the same
purpose it may be used gonadotropins or pulsatile GnRH therapy. The treatment of
PCOS is discussed later.
Premenstrual and intermenstrual syndrome (PMS)
Women during the reproductive period may present in late luteal phase a
collection of physical and behavioural manifestations that was named premenstrual
syndrome (PMS); it has a self-limited character in most cases. Premenstrual
dysphoric disorder (PMDD) is an exacerbated form of this syndrome, with a
prevalence of 3-5% in the general population which may require specialized
psychiatric treatment.

PMS is manifested by the appearance of the following signs and symptoms,

with 7-10 days before menstrual bleeding which resolve in 2-3 days after:
Feeling sad, hopeless,
Feeling tense, anxious, or "on edge",
Marked lability of mood interspersed with frequent tearfulness,
Persistent irritability, anger, and increased interpersonal conflicts,
Decreased interest in usual activities, concentration difficulties, memory
Feeling fatigued, lethargic, or lacking in energy,
Marked changes in appetite,
Other physical symptoms, such as breast tenderness or swelling, headaches,
acne, joint or muscle pain, a sensation of bloating, weight gain.
A significant proportion of women have regular menstrual cycles; in case of
irregular bleedings, endocrinological and gynecological examination is necessary.
The cause of this syndrome is unknown, but the interaction of cyclic changes
in ovarian steroids with central neurotransmitters (serotonin, beta-endorphin,
gamma-aminobutyric acid) seem to be implicated.
Intermenstrual syndrome occurs at mid-cycle with ovulation, has a lower
intensity and duration than PMS and may be associated with spotting.
The treatment of PMS consists of:
administration of progestin preparations 10 days/month, on days 16-25 of
cycle - Utrogestan, Duphaston, Medroxyprogesterone - but their effectiveness
is inconstant;
Oral contraceptives, such as Yasmin (drospirenone + estradiol);
Serotonin reuptake inhibitors (SSRI - fluoxetine, sertraline, citalopram) and
benzodiazepine (alprazolam) administered during the luteal phase only are
considered the most effective;
GnRH agonists;
NSAIDs for pain, diuretics (spironolactone).
Benign mastopathy
Benign breast disorders are very common in women between 30 and 50
years. Mammary gland is composed of epithelial structures, adipose tissue and
fibrous stroma. Epithelial component is one that responds to hormonal stimuli but
numerous paracrine interactions may exist between it and the stroma.
Benign breast lesions are classified histologically into three categories:
1. Nonproliferative lesions - are not considered to increase significantly the risk
of malignant transformation. Different terms are used to define these changes:
fibro-cystic disease, fibrocystic mastopathy, benign mammary dysplasia.
Simple or complex breast cysts are also included in this category. Aspiration,
and in some cases cytological examination are required.
2. Proliferative lesions, without atypia. These lesions are associated with a mildly
increased risk of breast cancer, with about 1.5 to 2 times to the general
population, but preventive chemotherapy is not indicated. Breast
fibroadenomas (FA) are found in this category, these can be simple, giant,
juvenile or complex. They are solid, mobile masses, requiring puncture biopsy
for confirmation. FA are usually excised but can also be monitored (if they are
small). Their etiology is not fully known, it seem to be hormone-dependent

(occuring frequently in women between 15 and 35 years of age, getting more

frequent during pregnancy or estrogen therapy). Cryoablation is an alternative
therapeutical method through surgery.
3. Atypical hyperplasia (AH) may be lobular or ductal. Excisional biopsy for
diagnosis is required. The relative risk for invasive breast cancer is 3 to 6
times higher, but it can reach up to 10 times in multifocal extension, especially
in those associated with calcifications. Patients with confirmed diagnosis are
advised to reduce risks, avoiding excessive alcohol consumption, oral
contraceptives, HRT. Preventive chemotherapy with tamoxifen or raloxifene
may be indicated based on the Gail model for breast cancer. This model
incorporates atypical proliferative disease into a risk calculation tool in order to
identify women who are appropriate candidates for this therapy. These lesions
have some, but not all, of the features of ductal or lobular carcinoma in situ.
Clinical manifestations
One of the constant manifestations of benign breast pathology is breast pain.
It may be cyclical or noncyclical. Cyclic breast pain occurs with 7-10 days before
menstruation, is bilateral, especially in the external quadrants. The stimulatory action
of estrogens on ductal elements, the effect of progesterone on the stroma and
sometimes the action of PRL to increase ductal secretion could be responsible for
this pain. It is accompanied by swelling and tender nodules of the breasts, with a
characteristic consistency. Palpatoric changes and pain subside when menstrual
bleeding occurs.
Nipple discharge is another sign that may appear in breast pathology, being
described in both benign and malignant diseases. It may be serous, sero-citrine or
bloody, uni- or bilateral.
Inspection and palpatoric examination of the breast are the first diagnostic
steps. Palpation should be performed both pre- and postmenstrual. The chest wall,
mammary glands and regional lymph nodes (supraclavicular, cervical, bilateral
axillary) are all examined.

Paraclinical and laboratory exploration

Imagistic investigations are essential in the diagnosis of breast pathology:
Breast ultrasound is indicated to both young people and the elderly,
complementary to mammography. It identifies cystic lesions and distinguishes
them from the solid, parenchymatous lesions. Suspicious nodules on
ultrasonography are usually solid, with irregular borders and inomogenous
structure, with microcalcifications, axillary lymphadenopathy and perilesional
Mammography is rarely indicated under the age of 35 years, it has a high
resolution and fidelity in the identification of suspicious lesions and is the most
widely used imaging technique for breast cancer screening. Routine
mammogram involves taking two views (craniocaudal and mediolateral
oblique) of each breast. Suspicious lesions are spiculated soft tissue masses;
opacities with irregular borders, parenchymal asymmetry, clustered
microcalcifications. The radiologist will provide data related to the relative
likelihood of a normal, benign, or malignant diagnosis and recommendations
for further management.
Breast MRI is not routinely indicated.

Fine needle aspiration (FNA) evaluates breast lumps. Cytology is indicated

only in cystic lesions with bloody or unclear fluid.
Breast core needle biopsy (CNB) is made with thicker needles ( 18 gauge
biopsy needles), sometimes under ultrasound guidance. Compared to FNA,
core needle biopsy offers a more reliable histological diagnosis. Stereotactic
biopsy can also be made.
Excisional biopsy requires surgical excision of all suspicious breast masses.
Hormonal determinations must include: TSH, fT4, PRL, possible LH and FSH,
as well as E2 and progesterone in the luteal phase (21th day of the menstrual cycle).
The determination of serum tumour markers (CA 15-3 or CA 27.29) is not indicated
in the early diagnostic steps of a suspicious nodule.

Differential diagnosis
The most important aspect is to differentiate benign lesions from breast
cancer. The last one has several clinical features: single lesion, rapid increase,
invasive, infiltrating, becoming adherent to adjacent tissues. The orange peel skin
appearance or nipple retraction may become visible. Locoregional, especially
axillary, sub- and supraclavicular lymphadenopathy is present. Bloody nipple
discharge is another suggestive sign for both the intraductal lesions or ductal ectasy.
Other breast tumors should also be excluded, usually benign lesions: breast
lipoma, fat necrosis (posttraumatic or postsurgical, can mimic the clinical appearance
of a breast carcinoma), galactocele (a milk-filled cyst occuring frequently in lactating
or pregnant women), idiopathic granulomatous mastitis or other infiltrative lesions
Cyclic breast pain can be treated with NSAIDs. In non-responder cases other
drugs are used:
Tamoxifen 10-20 mg/day, with the benefit of reducing the risk of breast
carcinoma. But long-term treatment increases the risk of uterine carcinoma,
thromboembolism or development of cataract. Side effects: hot flashes, joint
Raloxifene 60 mg/day.
Danazol 100-400 mg/day is the drug of choice for severe symptoms; due to
androgenic effect it can cause clinical signs of virilization, acne, seborrhea,
liver disorders, weight gain, amenorrhea.
Bromocriptine (2.5 to 7.5 mg/day) - only in the case of hyperprolactinemia.
GnRH agonists.
Topic ointments with progesterone or NSAIDs.
Some observational studies have shown some improvement of breast pain by
changing lifestyle (low fat diet, reducing coffee consumption), using vitamin E or
evening primrose oil, but so far data are not considered conclusive.


Polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine
disorders, its prevalence being estimated between 1.5 and 10% of the female
population, with an ascension observed in the last decades.
The syndrome has a peripubertal onset, characterized primarily by chronic
anovulation and hyperandrogenism, clinically expressed by virilisation, menstrual
disorders and infertility. Obesity is associated in approximately 50% of cases.
Etiopathogenesis and physiopathology
The symptomatic polymorphism of polycystic ovarian syndrome suggests the
existence of several pathophysiological mechanisms and therefore different
ethiological sources. Various genetic anomalies, the hypothalamus and pituitary,
endocrine pancreas, adrenals and of course, the ovaries are involved in the
formation of ovarian cysts. It is difficult to establish the initiator mechanism and the
way in which ovarian follicles are forced to cystic transformation.
PCOS is now thought to be a complex genetic trait, similar to cardiovascular
disease, type 2 diabetes mellitus and the metabolic syndrome, where multiple
genetic variants and environmental factors interact in development of the disorder.
Principal genetic targets for the responsible variants proposed include genes
regulating gonadotropin secretion and action, insulin secretion and action, weight
and energy regulation, and androgen biosynthesis and action.
A central feature of PCOS is hyperandrogenism, which is primarily of ovarian
origin, although the adrenal cortex often overproduces androgens as well.
Irrespective to the primary cause of the disease, pathophysiological
mechanisms tend to perpetuate in vicious circle until the therapeutic intervention
interrupt this.
Large and frequent pulses of GnRH stimulate the production of pituitary LH,
but not that of FSH. LH increases androgen production in the theca cells, and
reduced FSH-levels arrest follicular maturation, ovulation, corpus luteum formation
and progesterone secretion. The follicle becomes a cyst at a certain stage of the
developmental process, if the mediocyclical pulsation of LH is lacking. Androgens in
excess cause follicular atresia.
Increased circulating androgens determine clinical signs, but they also reduce
circulating SHBG which elevates free fraction of testosterone and prolactin. In
adipose tissue androgen aromatization results in large amount of estrogens, that
escapes from physiologic control. Thus estrogens stimulate adipocyte development
resulting in obesity with hyperinsulinism and insulin resistance. Folliculogenesis
alteration is caused by the synergistic action of increased LH and hyperinsulinism.
Estrogens converted from androgens determine abnormalities in monoaminergic
control of GnRH secretion (suppressing dopamine and opioid inhibitory tonus) and
amplify the pulses and frequency of GnRH discharge.

Clinical manifestations
Oligomenorrhea/secondary amenorrhea, or dysfunctional uterine
Premenstrual syndrome occurs in one third of women with PCOS;
Chronic anovulation with secondary infertility;
Signs of hyperandrogenism: hypertrichosis - increased hair growth
density, but without exceeding the normal distribution areas, hirsutism 217

defined as excessive terminal (thick, pigmented) body hair in a male

distribution, commonly noted on the upper lip, chin, around the nipples
(periareolar), and along the linea alba of the lower abdomen, acne affecting especially the face, back, shoulders and neck; male pattern
balding (alopecia); virilization signs of the female phenotype (increased
muscle mass, deepening of the voice, or clitoromegaly may occur, but
these findings are suggestive of other causes of virilization, such as a
neoplasm of the ovary or adrenal gland).
Obesity: overweight is positively correlated with clinical signs of androgen
excess and with the extent of menstrual cycle disturbances and infertility.
In women with PCOS obesity is usually moderate, with central or
abdominal distribution in about 75% of cases.
Acanthosis nigricans.
Women with PCOS may be more likely to have mood disorders
(depression and anxiety), when compared to women of similar BMI
without PCOS.

Paraclinic and laboratory explorations:

free and total plasma testosterone are increased;
LH may be increased with normal or low FSH and LH/FSH ratio may be
over 2.5 - 3;
low SHBG;
Estrogens are generally within normal limits (E1/E2 ratio increases);
Progesterone is low due to chronic anovulation;
Hyperprolactinemia (in 30% of cases);
17-OH progesterone is normal (excludes congenital adrenal
DHEA and androstenedione can be moderately increased;
IR index (insulin resistance = glucose X insulin/25) is increased in 50%
of cases; in these situations OGTT (oral glucose tolerance test) indicates impaired
glucose tolerance or even diabetes mellitus.
Transvaginal ultrasound of the ovary shows:
o an increased ovarian volume;
o 10-12 microcysts (10 mm in diameter) distributed at the
periphery of the ovary and increased stromal volume;
o absence of mature follicles at mid-cycle;
o endometrial hyperplasia.
Diagnostic criteria for PCOS require the presence of at least two of the
following three changes:
Chronic oligo- or anovulation,
Clinical or biochemical signs of hyperandrogenism,
Ultrasound appearance of polycystic ovaries.
Differential diagnosis

Anovulation and amenorrhea of primary ovarian lesions (increased

FSH, low estrogen).

Hypothalamic-pituitary dysfunction with amenorrhea/anovulation.

Asherman syndrome (uterine synechiae normal hormone levels, lack

of response to estrogen-progestin test).

Ovarian or adrenal androgen secreting tumors (like Cushings
Iatrogeny drugs that induce hirsutism (some progestins, phenytoin,
diazoxide, metirapon etc).
Idiopathic hirsutism.

Evolution, complications and prognosis

Insulin resistance, hyperinsulinemia, hyperandrogenism and chronic
anovulation cause long-term risks in patients with untreated polycystic ovary
o impaired glucose tolerance (or type 2 diabetes),
o low HDL-cholesterol and high triglyceride concentrations,
consistent with insulin resistance as well as an increase in LDLcholesterol, these will lead to an increased risk of
cardiovascular disease. All cardiovascular risk factors should
be considered for evaluation and treatment.
o nonalcoholic steatohepatitis (NASH),
o obstructive sleep apnea;
o development of endometrial adenocarcinoma.
The goals of PCOS therapy are focused on two aspects: improvement of
symptoms (menstrual irregularities, acne, hirsutism) and prevention or minimization
of long-term complications, which may occur in adulthood (infertility, endometrial
complications). The therapy of PCOS includes:
weight loss, lowering the body mass index (BMI) below 30;
estro-progestin therapy with oral contraceptives (CO) inhibits secretion of FSH
and of LH, decreases plasma free testosterone, reduces the level of DHEAS,
increases SHBG level and has protective effects on the endometrium by
regulating the bleedings. Most patients tolerate the combination of an
estrogen (30-35 g estradiol) with a progestin that have low or no androgenic
properties (desogestrel, gestodene, drospirenone). Progestin preparations
with androgenic effect (such as levonorgestrel, norgestrel) should be avoided.
Diane 35 is the contraceptive of choice in women with PCOS and acne.
Contraindications: pregnancy, thromboembolism or stroke, estrogendependent tumors, hypertriglyceridemia, undiagnosed uterine bleeding, active
liver disease, smoking women over 35 years.
Patients with contraindication for oral contraceptive therapy will be treated
only with progestin (eg. medroxyprogesterone acetate, 5-20 mg/day, 10 days
Cyproterone acetate (in combination with estradiol in Diane 35 or as
Androcur 25-100 mg in the first 10 days of treatment with oral contraceptive)
is an antiandrogen, with a progestative effect, usefull in 50-75% of cases of
Agents that increase insulin sensitivity. From this class of substances the
most used and most studied compound is Metformin (1500-2000 mg/day). It
produces a reduction in testosterone, improves jeun plasmatic insulin,

increases SHBG, decreases body mass index, and makes an improvement in

acne and hirsutism. Common side effects are digestive: nausea, diarrhea,
abdominal discomfort and lactic acidosis (rare). In the same class are
thiazolidinediones: rosiglitazone or pioglitazone. They may cause weight gain.
Other antiandrogens that are effective include: Spironolactone, a weak
diuretic, inhibits androgen biosynthesis and competes with them for binding to
androgen receptor sites in target organs (hair follicle, sebaceous gland, etc.);
Finasteride a 5-alpha-reductase type 2 inhibitor or Flutamide, a nonsteroid
androgen receptor antagonist, with hepatotoxicity risk.
GnRH agonists and antagonists have clinical applications in hirsutism. They
suppress gonadotropins and gonadal steroid secretion. Their topical
preparations have medium anti-androgenic effect.
For patients aiming pregnancy:
o ovulation can occur as a response to clomiphene citrate; the usual
therapeutic doses are of 50-100 mg/day (administered 5 days/cycle in
the follicular phase), with a success rate of 75% in terms of ovulation
induction, and of 35-40% in terms of pregnancy. The lack of
therapeutic response does not contraindicate the subsequent course of
clomiphene citrate although there is a risk of ovarian overstimulation
syndrome. The addition of metformin may be useful in women who do
not respond to clomiphene alone. In women resistant to
clomiphene citrate or metformin combined with clomiphene the next
step is gonadotropin therapy.
o Ovarian wedge resection, as ovulation induction therapy is reserved for
cases where other therapy have failed. Several methods of
electrocauterisation (also known as diathermy), laser "drilling" and
multiple biopsy.
o In vitro fertilization.
In addition to oral contraceptives, traditional antiacneic therapy can be used:
topical benzoyl peroxyde, topical or systemic antibiotics, topical or systemic
retinoids. Isotretinoin has teratogenic effects so it may be used only
associated with effective contraception.
Androgenic alopecia is improved by combined treatment with topical minoxidil
or spironolactone associated with oral contraception.
Patients being under treatment for PCOS should be consulted initially at 3-6
months, then every 6 months in order to encourage patients compliance and to
monitor the effect of the antiandrogenic therapy.
Menopause is a physiological stage in the natural life cycle of women. It
means permanent cessation of menses due to loss of ovarian follicular activity. By
convention, the diagnosis is made retrospectively after 12 months of amenorrhea or
after 3 months of non bleeding response after progesterone administration. The
average age of menopause onset is 50-51 years ranging between 42 and 60 years,
depending on race, but without being influenced by age of menarche, parity, socioeconomic conditions, and without any changes in the last century. The age of
menopause is reduced by about two years in smoking women. Although clinical

observations suggest the onset of menopause at around the same age in mother
and daughter, large studies could not demonstrate this.
Perimenopause refers to the time period preceding menopause, when fertility
wanes and menstrual cycle irregularity increases, until the first year after cessation of
menses. The onset of perimenopause precedes the final menses by 2 to 8 years, with
a mean duration of four years.
Early menopause is a premature ovarian failure, the term is no longer in
The main pathogenic mechanism of menopause is a decreasing ovarian
follicular reserve (by apoptosis - genetically programmed cell death), reaching a
critical threshold, when accelerated follicular depletion is present.
Three stages of menopause are considered:
perimenopause - a relative excess of estrogen through the lack
of progesterone,
menopausal estrogen deprivation,
In perimenopause the responsiveness of ovarian follicles to gonadotropins
decreases, resulting in a decline in progesterone production in the luteal phase and
inhibin B, with a consequent rise in FSH firstly and than in LH. As follicular atresia
progresses, estradiol levels show a great fluctuation presenting very high or very
low values.
Follicular maturation being impaired there is no more ovulation; anovulatory
cycles with a short follicular phase induces progesterone deficiency, and relative
hyperestrogenism with frequent bleedings. The tendency for anovulatory cycles
that produce this hyperestrogenic, hypoprogestagenic environment may be
responsible for the increased incidence of dysfunctional uterine bleeding,
endometrial hyperplasia or carcinoma and leiomyoma among women of
perimenopausal age. Benign mastopathies can exacerbate. Later on, irregular
menses turn into secondary amenorrhea due to the significant reduction of
estradiol synthesis.
Menopause is not a complete lack of estrogens. Androstenedione secreted
by adrenal gland and by ovarian stroma under the influence of elevated LH levels,
is converted to estrone by aromatization in adipose tissue. Estrone through
peripheral conversion forms small amounts of estradiol. This explains why estrogen
deficiency is less severe in obese women, so they are more prone to endometrial
The cause of hot flashes is unknown. They are thought to be due to thermoregulatory dysfunction, initiated in the hypothalamus by estrogen withdrawal. The
close proximity of the medial preoptic area (the major thermoregulatory area in
mammals) and a high density of GnRH containing neurons suggest the possibility
of simultaneous activation of a burst of GnRH release and thermoregulatory
A speculative mechanism for the initiation of hot flashes is endogenous
opioid peptide withdrawal. Estrogen increases central opioid peptide activity, and
estrogen deficiency may be associated with decreased or absent endogenous
central opioid activity.


Clinical manifestations
1. Precocious clinical features:
Bleeding patterns anovulatory bleeding and endometrial hyperplasia
cause oligomenorrhea (irregular cycles) and episodes of heavy
dysfunctional bleeding. It should be noted that menorrhagia requires an
evaluation to rule out uterine disorders.
Vasomotor symptoms the most common acute change during
menopause is the hot flash, which occurs in up to 75 percent of women.
They are self-limited, usually resolving without treatment within one to
five years, although some women will continue to have hot flashes until
after age 70. Hot flashes typically begin as the sudden sensation of heat
centered on the upper chest and face that rapidly becomes generalized.
The sensation of heat lasts from two to four minutes, is often associated
with profuse perspiration and occasionally palpitations, and is often
followed by chills and sometimes a feeling of anxiety. Hot flashes usually
occur several times per day, although the range may be from only one or
two each day to as many as one per hour during the day and night. Hot
flashes are particularly common at night.
Genitourinary symptoms: The epithelial lining of the vagina and urethra
are very sensitive to estrogen, and estrogen deficiency leads to thinning
of the vaginal epithelium. This results in vaginal atrophy (atrophic
vaginitis), causing symptoms of vaginal dryness, itching and often,
dyspareunia. Recurrent urinary tract infections are also a problem for
many postmenopausal women.
Skin changes The collagen content of the skin and bones is reduced by
estrogen deficiency. Decreased cutaneous collagen may lead to
increased aging and wrinkling of the skin. Hirsutism can occur.
Psycho affective disorders anxiety, irritability, insomnia, depression,
decreased ability to concentrate and generally a decrease in selfconfidence can be present but with great variability.
2. Long-term issues. Gradual weight gain and fat redistribution that becomes
predominant at a visceral level, associated to dyslipidemia with atherogenic effect,
result in an increased risk of ischemic heart disease and stroke. Accelerated bone
loss, especially in women with other risk factors, causes osteoporosis.
Paraclinical and laboratory investigations
Initially in perimenopause, during anovulatory cycles: low levels of
progesterone and inhibin;
In menopause gonadotropins are increased, especially FSH>50
U/l; repeated measurements are necessary because the secretion
of gonadotropins has ultradian rhythm;
Estradiol is low, its main source remains the peripheral conversion
of estrone. Serum estradiol is 10-20 pg/ml;
Estrone/estradiol ratio increases;
DHEA decreases with age, testosterone and androstenedione
remain relatively constant until late postmenopause. Androgens
are aromatized in estrone in tissues (especially in the fat one).
Finally all circulating androgens will decrease but less dramatically
comparing to estrogens.
Androgen/estrogen ratio increases in comparison with

premenopausal stage, which explains the relative excess of

androgens and hirsutism in menopause.
Differential diagnosis
Positive diagnosis is suggested by clinical manifestations: oligomenorrhea,
amenorrhea, hot flushes, genitourinary trophic changes and confirmed by elevated
FSH> 50 U/l and low estradiol. Other causes of secondary amenorrhea, like
hypothyroidism and thyrotoxicosis, pheochromocytoma, carcinoid syndrome should
be excluded.
For women with irregular or heavy menses during perimenopause progestin
can be indicated for a short period of time. Although progestins neither regularize
cycles nor reduce the number of bleeding days, they reduce the volume of
menstrual flow. Progestins are administred for 10-14 days/month from day 16 of
the menstrual cycle. Side effects: breast pains, flatulence, nausea, edema, anxiety,
irritability, depression.
Medroxyprogesterone acetate 5-10 mg/day;
Dydrogesterone - Duphaston 10 to 20 mg/day;
Lynestrenol Orgametril 5-10mg/day;
Natural oral micronized progesterone - Utrogestan 100-200 mg/day.
When the bleeding does not occur anymore on progestative treatment, it
means that estrogen secretion is deficient and estrogens association is indicated.
Estrogen therapy provides the best treatment for severe vasomotor
symptoms, reducing their frequency and severity. Estrogen is available in many
forms: oral tablets, transdermal, topical gels and lotions, subcutaneous implant,
intravaginal creams and tablets, and vaginal rings.
Estrogen administered orally has a greater effect on the liver due to the firstpass effect, because intestinal absorption leads to portal vein concentrations that
are initially substantially higher than those after transdermal administration. Many
oral preparations of estrogen are available: sulfoconjugated equine estrogens
(Premarin), oral micronized estradiol, esterified estrogens but also estrone sulfate
and ethinyl estradiol, the estrogen used in all oral contraceptive preparations (much
more potent, and therefore, is used in very low doses).
Available transdermal estrogen preparations contain 17-beta estradiol.
Vaginal estrogen is most commonly used in very low doses for the management of
vaginal atrophy. Side effects of estrogen: breast pains, nausea, stomach
Low-dose estrogen regimens and ultra-low doses of estrogen can achieve
reduction in vasomotor symptoms in some women and may be associated with
fewer risks and side-effects.
Endometrial hyperplasia and cancer can occur after as little as six months of
unopposed estrogen therapy; as a result, a progestin should be added in women
who have not had a hysterectomy. Women who have undergone hysterectomy
should not receive a progestin.
Cyclic combined regimens have daily estrogen (continuously) and progestins
on days 1 to 14 of each month. Eighty to 90 percent of women receiving cyclic
combined hormone regimens have monthly withdrawal bleeding.

Unlike cyclic therapy, continuous estrogen-progestin therapy (both

hormones given every day) induces amenorrhea in most women (daily progestin
eventually results in an atrophic endometrium). For contraindications and
complications of HRT see also osteoporosis.
Results from the WHI (the Women's Health Initiative) trial in 2002 significantly
reduced the indications for HRT in recent years. Estrogen therapy in
postmenopausal women relieves menopausal symptoms, but has risks for some
women, including breast cancer, coronary heart disease, stroke, and venous
thromboembolism. For most peri- and postmenopausal women with clinically
significant menopausal symptoms, postmenopausal hormone therapy is still a good
option when used at low doses for a short period of time (<5 years). The decision to
use HT should be made only after first carefully reviewing its risks and benefits for
the individual.
Alternative approaches includes:
tibolone 2.5 mg/day - synthetic steroid with weak estrogenic, androgenic and
progestogenic properties, reduces hot flashes, headache, insomnia,
increases the libido but also the risk of stroke.
the selective serotonin reuptake inhibitors (SSRIs, like fluoxetine) and
selective serotonin norepinephrine reuptake inhibitors (SNRIs, like
venlafaxine) also relieve the symptoms of vasomotor instability and are one
of our first choices in women who are not taking estrogen.
gabapentin (300900 mg/day) mimics the physiologic effects of the
neurotransmitter gamma-aminobutyric acid (GABA).
clonidine (0.10.2 mg/day),
vitamin E (400800 IU/day),
veralipride, a dopamine antagonist,
the consumption of soy-based products, black cohosh (Actaea racemosa or
Cimicifuga racemosa) or other phytoestrogens may also alleviate vasomotor
symptoms, although some clinical trials suggest that they are ineffective. In
women with breast cancer and hot flashes, phytoestrogens and black
cohosh are not indicated!



Adipose tissue endocrine role

Traditionally, adipocytes have been viewed as energy depots that store
triglycerides during feeding and release fatty acids during fasting to provide fuel for
other tissues. However, adipose tissue secretes numerous proteins that have
important physiologic functions:
Leptin. The ob or Lep gene codes for a protein called leptin, that is produced
in fat cells, gut, and the placenta and is secreted it into the bloodstream.
Leptin has pleiotropic effects on food intake, hypothalamic neuroendocrine
regulation, reproductive function, immune function and energy expenditure.
There is a direct relationship between plasma leptin concentrations and BMI
or body fat percentage. Therefore, plasma leptin concentrations reflect
adipose tissue mass and are influenced by energy balance. Congenital leptin
deficiency due to a mutation in the leptin gene, produces massive obesity with
profound hyperphagia and hyperinsulinemia. Most obese people, however,
are not leptin deficient but have a high serum leptin concentrations and
apparent leptin resistance.
Resistin is another signaling polypeptide secreted by adipocytes that probably
links obesity to diabetes by inducing insulin resistance.
Adiponectin, an abundant adipose-derived protein whose levels are reduced
in obesity, enhances insulin sensitivity and lipid oxidation and it has vascularprotective effects.
Selected Cytokines: both TNF- (Tumor Necrosis Factor-) and IL-6, may
contribute to systemic inflammation and insulin resistance.
Prothrombotic agents such as plasminogen activator inhibitor I.
Estrogens. Adipose tissue has P450 aromatase activity. The conversion rate
of androstenedione into estrone increases with age and obesity.
Physiologic Regulation of Energy Balance
Substantial evidence suggests that body weight is regulated by both
endocrine and neural components that ultimately influence energy intake and
expenditure. Within the brain, there are several important regions in processing
information about food and relating it to body weight:
The nucleus of the tractus solitarius, the hindbrain area in which vagal and
other neural inputs are integrated.
The arcuate nucleus at the base of the hypothalamus integrates leptin
signals, perhaps the best characterized hypothalamic nucleus involved in
the control of energy balance.
The paraventricular nucleus (PVN) plays a central role in regulation of food
The ventromedial hypothalamus, the destruction of which leads to
increased food intake and profound obesity.
The lateral hypothalamus which, if damaged, may decrease feeding and
lower body weight.

Selected regions of the amygdala.

Stimulators of food intake:

neuropeptide Y (NPY) is one of the most potent stimulators of food
intake known. It is a neurotransmitter found in the central and
peripheral nervous systems, released from cells of the arcuate
agouti-related peptide (AGRP) is an antagonist of MC4R
(melanocortin-4 receptor), and competes with -MSH (melanocytestimulating hormone) for binding to MC4R. Leptin signals through
proopiomelanocortin (POMC) neurons in the hypothalamus to
induce increased production of MSH, this will act as an agonist
on melanocortin-4 receptors to inhibit appetite, therefore binding of
AGRP to MC4R leads to increased food intake.
melanin-concentrating hormone (MCH),
orexin-A and orexin-B (also called hypocretin) also stimulate food
growth hormone-releasing hormone, norepinephrine,
Ghrelin, a 28 amino acid peptide, is secreted into the bloodstream
by endocrine cells lining the fundus of the stomach. Ghrelin
secretion is stimulated by fasting, increases preprandially, and is
suppressed by food intake. Ghrelin is orexigenic, increasing food
intake when administered peripherally, and acts in part by directly
modulating the activity of the NPY/AGRP neurons in the arcuate
nucleus of the hypothalamus.
Inhibitors of food intake A number of hormones inhibit food intake.
Leptin and melanocortin system. Leptin binds to its receptors on two
populations of neurons in the arcuate nucleus of the hypothalamus: the
orexigenic AGRP/NPYexpressing neurons, and the anorexigenic POMCexpressing neurons. These two groups of neurons have projections mainly
to the paraventricular nucleus of the hypothalamus. The PVN has a dense
neuronal population that expresses MC4R. When leptin binds its receptors
on POMC neurons, -MSH, a cleavage product of POMC, is released.
Activation of MC4R in the PVN by -MSH relays a satiety signal and
causes a decrease in food intake. AGRP is an antagonist of MC4R, and
competes with -MSH for binding to MC4R. Binding of AGRP to MC4R
leads to increased food intake. Leptin activates POMC neurons and
inhibits AGRP neurons, resulting in a net decrease in food intake.
Cholecystokinin (CCK) is secreted by intestinal cells into the bloodstream
in response to the presence of fat and proteins. CCK stimulates gut
motility, contraction of the gallbladder, pancreatic enzyme secretion and
suppresses food intake.
CART cocaine and amphetamine regulated transcript.

PYY, a 36 amino acid peptide is released into the bloodstream by

intestinal endocrine cells of ileum and colon after food ingestion and
reduces food intake.
GLP-1, glucagon-related peptide-1 with a very short half-life (2 minutes), is
degraded by dipeptidyl peptidase-4. It increases insulin secretion in a
glucose-dependent manner and decreases food intake.

Etiopathogeny of Obesity
Obesity is a state of excess adipose tissue mass. Although often viewed as
equivalent to increased body weight, this need not be the caselean but very
muscular individuals may be overweight by numerical standards without having
increased adiposity. Obesity more effectively defined by assessing its linkage to
morbidity or mortality.
Many surveys performed especially in the United States have found a
significant increase in the prevalence of overweight and obesity over the past 30
years. The percentage of the American adult population with obesity (BMI >30) has
increased from 14.5% (between 1976 and 1980) to 33.9% (between 2007 and
2008). Obesity is more common among women and in the poor, and among blacks
and Hispanics; the prevalence in children is also rising at a worrisome rate.
Although not a direct measure of adiposity, the most widely used method to
diagnose obesity is the body mass index (BMI), which is equal to weight/height2 (in
kg/m2). Other approaches to quantifying obesity include anthropometry (skinfold
thickness), densitometry (underwater weighing), CT or MRI, and electrical
Table 20. Weight Classification by Body Mass Index (BMI)
BMI (kg/m2)
Obesity class 1
Obesity class 2
Obesity class 3


The distribution of adipose tissue in different anatomic depots also has

substantial implications for morbidity. Specifically, intraabdominal and abdominal
subcutaneous fat have more significance than subcutaneous fat present in the
buttocks and lower extremities. This distinction is most easily made clinically by
determining the waist-to-hip ratio, with a ratio >0.9 in women and >1.0 in men being
abnormal. Many of the most important complications of obesity are linked more
strongly to intraabdominal and/or upper body fat than to overall adiposity. The
mechanism underlying this association is unknown but may relate to the fact that
intraabdominal adipocytes are more lipolytically active than those from other depots.
Release of free fatty acids into the portal circulation has adverse metabolic actions,
especially on the liver.

Role of genetic factors in obesity

Obesity is commonly seen in families, inheritance is usually not Mendelian
and the heritability of body weight is similar to that for height, ranging between 0.6
and 0.9. In addition to the heritability of weight, metabolic rate, thermic response to
food, and spontaneous physical activity are to some extent heritable. A number of
single gene defects that cause human obesity have been uncovered. The BardetBiedl and Prader-Willi syndromes are probably the best known examples of these
traits Other single gene defects causing Mendelian forms of obesity are in genes of
the leptin-melanocortin system (mutations in POMC, MC4R, Leptin, Leptin receptor
The genes that contribute to the more common forms of obesity have been
difficult to identify. Genome wide association studies in large populations have
identified polymorphisms in genes that are associated with obesity risk: a variant in
the FTO gene (fat mass and obesity associated) may account for approximately 22
percent of common obesity. Common variants near MC4R were associated with
increasing body mass index in both children and adults. This suggests that there
may be overlap in the genetic determinants of monogenic and multifactorial forms of
The gene for peroxisome-proliferator-activated receptor (PPAR) gamma 2, a
transcription factor has a key role in adipocyte differentiation. Mutations identified in
this gene accelerate the differentiation of adipocytes and are associated with obesity
in some subjects.
Environmental effects in obesity
It is clear that environment plays a key role in obesity, as evidenced by the
fact that famine prevents obesity even in the most obesity-prone individual.
Cultural factors are importantthese are related to both availability and
composition of the diet and to changes in the level of physical activity. In industrial
societies, obesity is more common among poor women, whereas in underdeveloped
countries, wealthier women are more often obese. In children, obesity correlates to
some degree with time spent watching television. Although the role of diet
composition in obesity continues to generate controversy, it appears that high-fat
diets may promote obesity when combined with diets rich in simple, rapidly absorbed
Additional environmental factors such as sleep deprivation and night-eating
syndrome, cessation of smoking may contribute to the increasing obesity
prevalence. Binge-eating disorder is a psychiatric illness characterized by
uncontrolled episodes of eating that usually occur in the evening.
The weight gain may be precipitated by a number of events, including
pregnancy, oral contraceptive therapy, and menopause.
A number of drugs can cause weight gain, including psychoactive drugs
(thioridazine, risperidone, clozapine), lithium, antidepressants (amitriptyline, doxepin
and imipramine), antiepileptic drugs (valproate, carbamazepine), antihyperglycemic
agents (thiazolidinediones, insulin). Other drugs associated with weight gain include
cyproheptadine (an antihistamine), beta blockers and glucocorticoids.
Neuroendocrine and metabolic disorders
Neuroendocrine and metabolic disorders associated with obesity are:

o Hypothyroidism - should be considered, but it is an uncommon cause

of obesity. Much of the weight gain that occurs in hypothyroidism is
due to myxedema. In one study of children, obese subjects had a
higher serum TSH, which fell to normal levels with weight loss,
suggesting the higher TSH was a result of obesity and not the cause.
o Cushing's syndrome a common clinical feature in patients with
Cushing's syndrome is progressive central (centripetal) obesity, usually
involving the face, neck, trunk, abdomen and, internally, the mesentery
and mediastinum. The extremities are usually spared and are often
o Insulinoma - patients with insulinoma often gain weight as a result of
overeating to avoid hypoglycemic symptoms. The increased substrate
plus high insulin levels promote energy storage in fat.
o Polycystic ovary syndrome about 50 percent of women with the
polycystic ovary syndrome (PCOS) are obese.
o Growth hormone deficiency - in adults is associated with an increase
in abdominal and visceral fat.
o Disorders that affect the reproductive axis are associated with obesity
in both men and women. Male hypogonadism is associated with
increased adipose tissue, often distributed in a pattern more typical of
o Disorders involving the hypothalamus - tumors, trauma or inflammation
can cause varying degrees of obesity by affecting the systems
controlling satiety, hunger, and energy expenditure.
Pathologic Consequences of Obesity
Obesity has major adverse effects on health. Obesity is associated with an
increase in mortality mostly due to cardiovascular causes. Mortality rates rise as
obesity increases, particularly when obesity is associated with increased
intraabdominal fat.
o Hyperinsulinemia is characteristically associated with obesity. This
hyperinsulinemia is linked to insulin resistance (ie, the decrease in
insulin-stimulated glucose utilization). One of the major consequences
of this obesity-associated insulin resistance is the requirement for
increased insulin secretion. While the majority of obese individuals can
secrete sufficient insulin to accommodate the insulin-resistant state, in
genetically predisposed individuals type 2 diabetes (T2DM) results.
o Cardiovascular complications - higher cardiovascular disease risk has
been linked to visceral adiposity with several distinct mechanisms
including inflammation, thrombosis, hyperglycemia, atherogenic
dyslipidemia, and adipocytokines. Obesity has been implicated as one
of the major risk factors for hypertension, heart failure, and coronary
heart disease. Overweight and obese individuals develop left
ventricular dilation and hypertrophy and left atrial enlargement. These
structural abnormalities increase the risk of heart failure and of atrial

o Metabolic syndrome. The two most consistent characteristics of

persons with this syndrome are insulin resistance and central
abdominal obesity. The International Diabetes Federation (IDF)
proposed a set of metabolic syndrome criteria in 2004- see table 21.
Table 21. Diagnostic criteria for metabolic syndrome
Waist 94 cm (men) or 80 cm (women)
And 2 of:
-Fasting plasma glucose 100 mg/dL or diagnosed diabetes
-Triglycerides >150 mg/dL (1.7 mmol/L) or treatment for elevated triglycerides
-HDL cholesterol <40 mg/dL in men or <50 mg/dL in women or drug treatment for
low HDL-C
-Systolic blood pressure >130 mmHg, diastolic blood pressure >85 mmHg or drug
treatment for hypertension
O Obesity is frequently associated with the nonalcoholic fatty liver
disease (NAFLD) and steatohepatitis, cholesterol gallstones,
O Obstructive sleep apnea (OSA) is associated with severe obesity and
other features of the metabolic syndrome.
O Several cancers have been linked to obesity, including breast,
endometrial, colorectal, prostate, and renal cell carcinomas. Putative
mechanisms for breast and endometrial cancer include higher
hyperandrogenism. The relationship between obesity and colon cancer
is stronger in men than women.
O Obesity is associated with an increased risk of osteoarthritis, venous
stasis, psychiatric disorders and infertility in both women and men.
Management of the Obese Patient
Currently available weight-loss treatments include dietary intervention,
increased physical activity, behavior modification, pharmacotherapy, and surgery.
Dietary Intervention. The primary focus of diet therapy is to reduce overall
calorie consumption. It is recommended to initiate treatment with a calorie deficit of
5001000 kcal/day compared with the patient's habitual diet. This calorie deficit can
be accomplished by suggesting alternatives to the diet. Examples include choosing
smaller portion sizes, eating more fruits and vegetables, consuming more wholegrain cereals, selecting leaner cuts of meat and skimmed dairy products, reducing
fried foods and other added fats and oils, and drinking water instead of caloric
beverages. High-fat foods such as pretzels, cheese, egg yolks, potato chips, and red
meat should be avoided.
The guidelines recommends 4565% of calories from carbohydrates, 2035%
from fat, and 1035% from protein. One aproach is the use of low-carbohydrate,
high-protein diets for weight loss but sustained adherence to the diet rather than diet
type is likely to be the best predictor of weight-loss outcome. Occasionally, very low

calorie diets (VLCDs) are prescribed as a form of aggressive dietary therapy but they
need close metabolic monitoring.
Physical Activity Therapy . Exercise can improve glycemic control and insulin
sensitivity, has beneficial effects on serum lipoprotein concentrations, body
composition, and aerobic capacity and also reduces feelings of depression and
anxiety. The recommendations for heart disease prevention are at least 150
min/week. A high amount of physical activity (more than 300 min of moderateintensity activity a week) is often needed to lose weight and sustain weight loss.
Behavioral Therapy. Cognitive behavioral therapy is used to help change and
reinforce new dietary and physical activity behaviors.
Drug therapy. It can be considered for those with a BMI greater than 30
kg/m2, or a BMI of 27 to 30 kg/m2 if they have comorbid conditions. Weight loss
medications are often associated with many undesirable side effects. Currently there
are four main categories of weight loss medications: adrenergic agents, serotonergic
agents, combination of both adrenergic/serotonergic agents, and lipase inhibitors.
The classic sympathomimetic adrenergic agents (like phentermine) function
by stimulating norepinephrine release or by blocking its reuptake. In contrast,
sibutramine functions as a serotonin and norepinephrine reuptake inhibitor. It can
cause dry mouth, insomnia, tachycardia, high BP.
Fluoxetine, a selective serotonin reuptake inhibitor, approved for the treatment
of depression, may facilitate weight loss in the short run.
Orlistat is currently the only available drug that alters fat digestion. It does so
by inhibiting pancreatic lipases. As a result, ingested fat is not completely hydrolyzed
to its constituent fatty acids and glycerol, and fecal fat excretion is increased. The
recommended dose is 120 mg three times daily. A lower dose (60 mg), over-thecounter version is approved and available in some countries. Side effects: diarrhea,
flatulence, fecal urgency and incontinence, abdominal pain, dyspepsia.
Other medications:
o Metformin is a biguanide that is approved for the treatment of diabetes
mellitus, produces modestly weight loss.
o Leptin - leptin resistance can be overcome with high doses of leptin,
but whether the effect can be sustained is not known. Leptin therapy is
effective in some patients with lipodystrophy.
o Bupropion is a drug approved for the treatment of depression and for
the use in prevention of weight gain when trying to stop smoking.
o Rimonabant, an endocannabinoid receptor antagonist, was successful
in producing modest weight loss and improving metabolic
complications. However, adverse central nervous system side effects
of rimonabant including depression and anxiety precluded introduction
of this drug into clinical practice.
o short- or long-acting GLP1 agonists (exenatide, liraglutide), used for
diabetes are associated with a decrease in body weight.
Bariatric surgery .There are three main types of bariatric surgeries:
1. restrictive - includes horizontal gastroplasty, vertical banded
gastroplasty, adjustable gastric banding.
2. malabsorptive - include the oldest of all bariatric procedures, the
jejunoileal bypass, biliopancreatic diversion etc.
3. those that have both a restrictive and a malabsorptive component - is
the most commonly used bariatric surgery worldwide. The Roux-en-Y

gastric bypass procedure (RYGB), which involved stapling the upper

stomach into a small 30-mL pouch and attaching it to the jejunum
bypassing the lower stomach and duodenum. This procedure can be
done with an open surgical approach, or now more commonly with a
laparoscopic approach.
Indications for the surgical management of severe obesity:
Be well-informed and motivated,
Have a BMI >40,
Have acceptable risk for surgery,
Have failed previous nonsurgical weight loss,
Some guidelines also suggested that adults with a BMI >35 who have serious
comorbidities such as diabetes, sleep apnea, obesity-related cardiomyopathy or
severe joint disease may also be candidates.
Contraindications to bariatric surgery include patients with untreated major
depression or psychosis, binge-eating disorders, current drug and alcohol abuse,
severe cardiac disease with prohibitive anesthetic risks, severe coagulopathy, or
inability to comply with nutritional requirements including life-long vitamin
The restrictive-malabsorptive procedures increase risk for micronutrient
deficiencies of vitamin B12, iron, folate, calcium, and vitamin D. Patients with
restrictive-malabsorptive procedures require lifelong supplementation with these
Liposuction Removal of fat by aspiration after injection of physiologic saline
has been used to remove and contour subcutaneous fat. While this can result in a
significant reduction in fat mass and weight, it does not appear to improve insulin
sensitivity or risk factors for coronary heart disease.
Complementary and alternative medications such as herbs, vitamins,
nutritional supplements, and meal replacement therapies are commonly used by the
general public for weight loss. Examples of dietary supplements ephedra, green tea,
chromium. However the efficacy and safety of these herbal remedies has not been
well studied.