ENDOCRINOLOGY

HORMONE

the chemical messengers produced by the endocrine cells that travel through the circulation to specific body cells
body cells contain receptors for specific hormones called TARGET CELLS
only those cells containing receptors will bind hormones very specific, concn dependent & reversible

CLASSIFICATION OF HORMONES
A. PROTEIN HORMONES

composed of AA (peptides, chains of 8 AA or less, amines)

synthesized in the endocrine glands as a larger precursor molecules called PREPROHORMONES contains a leader sequence of
AA called SIGNAL SEQUENCE cleaved from the molecules called PROHORMONES enzymatically cleaved to smaller molecules
active hormones packaged into secretory vesicles

does not attach to plasma CHONS & circulates in the blood as free hormone

short half life

B.

STEROID HORMONES
synthesized in the cytoplasm by multienzyme processes
derived from CHOLESTEROL
separated into groups based on the no. of carbon presents:
C 18 estrogens
C 19 androgens
C 21 gluococorticoids, mineralocorticoids & progesterone
freely diffuse across the plasma mem. & into the bloodstream
bind to specific plasma CHON w/c allows them to remain in circulation for longer than the unbound or free form of the
hormone
take longer to initiate their action & once started, the action is sustained for a prolonged period
longer half life bec. of their binding to the plasma CHON carriers

GROWTH HORMONE (GH)

composed of AA & share many of the same charac. as the CHON hormones
from indiv. cells or group of cells
has its own specific extracellular receptor since they cannot cross the plasma mem.

NEUROTRANSMITTERS (NT)

epinephrine/norepinephrine may serve as either a hormone or NT, the diff. is the site of synthesis & action

REGULATION OF HORMONE SECRETION

A. NEGATIVE FEEDBACK

the final hormone produced regulates its own secretion by inhibiting the secretion of 1 or more of the precursor hormones
TRH (Thyroid Releasing H) by hypothalamus

TSH (T Stimulating H) by pituitary gland

TH by thyroid gland
B.

POSTIVE FEEDBACK
the final hormone produced actually enhances or induces the initial hormone & causes its own prodxn to be
rare; final hormone enhances or induces initial hormone production
Oxytocin

MECHANISM OF ACTION
A. PROTEIN HORMONE ACTION

bind to extracellular receptors

activates an intracellular CHON (G) to transducer the signal to an enzyme (adenyl cyclase) to produce 2 nd messenger cAMP

2nd messenger will cause intracellular changes

B.

Bind to EC receptors Hormone-receptor complex Activate IC protein (G) transduce signal to Adenyl cyclase
(enzyme) produce 2nd messenger cAMP cause IC changes

STEROID HORMONES ACTION

diffuse across the plasma mem. to bind w/ their intracellular receptors


a heat shock CHON dissociates from the receptor after binding

hormone-receptor complex migrates into the nucleus & binds w/ a specific region on the DNA

mRNA is produced & a CHON is synthesized

DISORDERS OF THE ENDOCRINE SYS.

1.

2 categories:
1 DISORDERS

problem w/ the gland that produces the hormone (hyper/hyposecretion), the outside stimulating agents is N
Hyper more difficult to correct than hypo
Hypo not detected until 80-90% of gland is nonfunctional

2.

2 DISORDERS
the gland that produces the hormone is capable of N fxn, the outside stimulating agents are either in excess or deficient
hypersecretion of a hormone is often more difficult to correct than hyposecretion
hyposecretion is often not detected until approx. 80%-90% of the gland is nonfunctional
normal gland function, outside stimulating agents in excess or deficient

HYPOTHALAMUS
-

part of brain; under 3rd ventricle & directly above pituitary gland
secrete neuropeptides (hormones): inhibit/ stimulate hormones of Anterior Pituitary Gland (APG); regulatory hormones
neurosecretory cells secrete the neuropeptides

Hypothalamic Hormones:
Corticotropin
Releasing Hormone (CRH)

ACTH, -lipotropin, -endorphin

Thyrotropin
Releasing Hormone (TRH)

TSH

Gonadotropin Releasing Hormone (GnRH)

FSH, LH

Prolactin Inhibiting Factor (PIF=dopamine)

prolactin (PRL)

Prolactin Releasing Factor (PRF/TRH)

PRL

Growth HRH (GRH) / Somatocrinin

GH

Growth HIH (GIH) / Somatostatin (SS)

GH

Melanocyte Inhibiting Factor(MIF)

Melanocyte-Stimulating H

ADH/ Arginine Vasopressin (AVP)

reabsorption of H2O from glomerular filtrate & urine;

Vasoconstriction of Smooth Muscles

Oxytocin

stimulate uterine muscle contraction; cause contraction of the

breast muscles for the ejection of milk

 Pineal gland
on the posterior wall of the 3rd ventricle of the cerebrum
small pine-cone shaped structure
exact fxn unknown; but synthesizes MELATONIN (synthesized from serotonin; can inhibit gonadotropic hormone in lower
vertebrates {may or may not in humans})
3rd eye: regulates the circadian rhythm/ diurnal pattern
production in dim light - sleepy, tired, depressed during nighttime
Bright light inhibits melatonin active, awake during daytime

Pituitary Gland (Hypophysis)

-

connected to the hypothalamus by infundibulum or pituitary stalk through w/c the neuropeptides migrate to pit. gland
contained in a depression of sphenoid bone: SELLA TURCICA; adjacent to chiasm of optic nerve
Master Gland - secretes numerous hormones w/c triggers other glands to produce hormones
enlargement leads to loss of vision
2 main lobes:
a. Posterior Pituitary/ Neurohypophysis smaller hypothalamic lobe; storage of Oxytocin (targets the breast and the uterus) &
ADH/AVP (target organ is the kidney); synthesized in Hypothalamus; neuroectodermal in origin
b. Anterior Pituitary/ Adenohypophysis specialized secretory epith. cells: synthesize & stimulate numerous hormones
stimulates the secretion of other hormones except GH & PRL
regulate their own secretion by a (-) Feedback to Hypothalamus short loop (-) feedback
TSH, ACTH, LH,FSH, except PRL & GH - others can stimulate other adrenal glands to produce H.
TSH (thyroid stimulating hormone) T3(triiodothyronin) and T4 (thyroxin)
ACTH (adenocorticotrophic hormone)- target organ is the adrenal cortex; end hormone produced is cortisol
LH and FSH target organs are the gonads (testes for males; ovaries for females); testosterone is produced in males, estrogen
and progesterone for females
Growth factor- stimulates tissues such as cartilage, bones, muscles but these do not produce hormones
Prolactin target organ is the breast; increase the size of the breast to prepare it to produce milk
Secretory Cells of AP (staining property with H&E)
1. Acidophils - stains red; Somatotrophs (secrete GH) & lactotrophs/ mammotrophs (secrete PRL)
2. Basophils stains blue; thyrotrophs (secrete TSH) and Gonadotrophs (secrete FSH and LH)
3. Chromophobe Cells dont stain; corticotrophs (secrete ACTH)
Pituitary hormones (based on chemical configuration):
1. Polypeptides hormones with intramolecular disulfide bonds (GH & PRL)
2. Glycoproteins TSH, FSH, LH; share common -subunit, differ in -subunit; ex: human chorionic gonadotrophin (hCG)
3. Single-chain peptides hormones w/o disulfide bonds (ACTH)
POSTERIOR PITUITARY HORMONES
- ADH & Oxytocin nonapeptides: contain 9 amino acids
- both are inhibited by alcohol

1. ADH or Arginine Vasopressin (AVP)

a. Maintain bodys H2O balance by promoting H2O reabsorption in the tubules of the nephrons of kidneys less H2O in the urine
(concentrating effect); osmolality in urine compared to plasma
b. Vasoconstriction of BV vasopressin: maintain BP in traumatic injuries
Administration of ADH can help prevent von Willebrands disease because ADH can release the von Willebrand factor
1 stimulus: plasma osmolality ( Na) detected by the osmoreceptors in the Hypothalamus
RR of Plasma osmolality = 275-295 mOsm/Kg (>295 secretion of ADH)
ADH stimulation
a.
b.
c.
d.
e.

ADH (binds) to
V2 receptor (vasopressin) in distal convoluted tubules & collecting ducts activates
Adenyl Cyclase that will cause generation of
cAMP (cyclic adenosine monophosphate); (serves as the 2nd messenger: responsible for intracellular changes) initiates
phosphorylation of membrane CHON which causes
in membrane permeability to H2O

Symptoms of ADH Deficiency & Diabetes Insipidus:

1)

Polydipsia ( thirst)

2)

Polyuria ( urine output; typically >3L /24 hrs) *N=2L

Laboratory Analysis
A.
-

RIA Spec: plasma anticoagulated w/ EDTA in prechilled tubes

centrifuge blood ASAP & remove plasma from cells
plasma frozen until used for analysis
ADH levels deteriorate with prolonged storage
NV (healthy adult)= 2.3 3.1 picogm/mL or nanogram/L of plasma
plasma ADH conc. report w/ Px plasma osmolality for EVERY test

Reference Ranges for ADH:

Osmolality (mOSm/kg)

ADH (pg/mL)
270-280
280-285
285-290
290-295
295-300

<1.5
<2.5
1-5
2-7
4-12

B.
B.
B.
B.

Water Deprivation Test (Indirect ADH measure)

Procedure:
a. Weigh Px
b. Withhold H2O for 8hrs (can be done either at night or day)
c. Every 2 hrs
Weigh Px (stop test if weight falls by >5% of initial body weight)
Px empty bladder: measure urine vol & osmolality (N = 300-800 mOsm/kg H2O)
Obtain blood sample : measure plasma osmolality (stop if result is >300 mOsm/Kg dehydrated)
d. After 8hrs allow Px to drink (no more than twice urine vol. obtained in test to avoid acute hyponatremia).
Patient should be closely observed while test is being performed.
Normal: Should not have weight losses >3% & Serum/plasma osmolality w/in RR; urine osmolality must not go beyond 800
mOsm/kg of water
ADH deficiency: serum/plasma osmolality & urine osmolality over time tested (concentrating effect on plasma and
diluting effect on urine)
inversely prop: Plasma & urine osmolality
alcohol: inhibit ADH & oxytocin
cold temp: inhibit ADH

2. Oxytocin (OT)
most active in pregnant women
At term stimulates contraction of smooth muscles in the wall of the uterus (induce labor)
Synthetic oxytocin can be used to induce labor
induces lactation by stimulating contraction of the myoepethielial cells in the mammary glands (ejection of milk)
premature labor prevented by injecting alcohol intravenously
Nonpregnant women and men have basal levels of OT its role not been determined
2 Strongest Stimuli for Oxytocin release:
a. Distention of the uterus
b. Neonatal suckling of the nipple
Lab Analysis
A.
-

RIA Plasma anticoagulated w/ EDTA in prechilled tube

plasma can be frozen until used for analysis
Reference Range = 1-5 pg/mL sample

ANTERIOR PITUITARY HORMONES:

1. Prolactin (PRL)
by lactotroph (mammotroph) cells in the anterior pituitary gland
helps stimulate devt. of breast tissue needed for lactation
postpartum women: it induces synthesis of milk in the mammary gland
PRL Values
a.
-

Nonlactating women, men & children= < 20ng/mL

actual function not fully understood
Hypersecretion is associated with Hypogonadism (impaired gonads, incomplete fxn) in both men and women

b. 1st Trimester = <80 ng/mL

c. 2nd Trimester = <169 ng/mL
d. 3rd Trimester = <400 ng/mL
Secretion of PRL:
under control of PIF/ Dopamine from hypothalamus - dopamine: PRL; dopamine: PRL
No specific PRL-releasing factor, but thyrotropin releasing hormone (TRH) induce in PRL levels
PRL stress
Lab Analysis:
A. RIA method of choice, fresh nonhemolyzed serum (frozen ASAP) is used
time of collection noted (PRL in the morning)
B. IRMA (immuno-radiometric assay) doesnt recognize all forms of PRL in circulation
2. Growth Hormone (GH)
synthesized by the somatotroph cells in the AP
essential for normal growth; hormone of highest conc. in the AP
anabolic in action in most tissues; stimulate synthesis of new CHON & causing cells to divide & in size
induces Lipolysis (fat breakdown)
cartilage & bone growth & development, but action is indirect because:
a. GH stimulates Liver to produce
b. SomatomedinC (insulin-like growth factor 1 or IGF -1) binds to receptors on
c. cartliage & bone cells that stimulate
d. DNA synthesis & cell growth
Secretion of GH:
controlled by 2 hypothalamic hormones:
a. Growth hormone releasing hormone (GRH) or Somatocrinin
b. Growth hormone inhibiting hormone (GHIH/GIH) or Somatostatin
o
Other stimuli that induce the release of GH
o

a. Hypoglycemia (low blood sugar)

b. Exercise or stress
c. High protein diet
d. Acute starvation
e. Oral contraceptives and other drugs
o
GH in obesity & corticosteroid therapy
o
Growth hormones increase the body size of athletes
Prior to that, extracts from the pituitary glands of cadavers were used but it was stopped because some athletes developed
diseases to this practice

Lab Analysis:
RIA method of choice
fresh serum/ heparinized plasma (EDTA: value)
RR (female) = 0-18 ng/ml
(male) = 0-4 ng/ml

A.
-

3. TSH - glycoCHON produced by thyrothrops in AP

stimulates thyroid gland to produce
a) T4 (Thyroxin)
b) T3 (Triiodothyronine)
secretion controlled by thyrotropin releasing hormone (TRH) from hypothalamus
4. Gonadotrophins:
FSH
glycoproteins produced by gonadotroph
LH
cells in the AP; regulate the sex cells & sex
hormones from gonads of both sexes
Secretion of Gonadotropins (Major stimulus: Gonadotropin Releasing Hormone (GnRH) in hypothalamus
Women- prior to ovulation(day 14 of menstruation)

o
a.
b.

FSH stimulate follicle growth and maturation of ovum ESTROGEN

After Ovulation: LH stimulate Follicle become Corpus Luteum produce PROGESTERONE
o
Men:
a. FSH stimulates spermatogenesis in seminiferous tubules of testes
b. LH stimulates Leydig or interstitial cells to produce TESTOSTERONE
- both are not secreted in a cyclic pattern as in women
Lab analysis: (serum/plasma specimen)

A. RIA method of choice for FSH

B. IRMA(Immunoradiometric Assay) method of choice for LH: high degree of x-reactivity with hCG in RIA
*Women: interpretation is based on menstrual cycle of Px
5.
-

Adenocorticotropic Hormone (ACTH)

produced by corticotrophs in the AP
fragment of larger precursor: Proopiomellanocortin
stimulates Adrenal Cortex to secrete CORTISOL
target organ: adrenal cortex

Secretion of ACTH (1 regulated by:)

a.
b.

CRH (Corticotropin Releasing Hormone) of the Hypothalamus

Negative feedback action of Cortisol

Lab analysis: (EDTA/heparinized plasma)

A.
B.
-

RIA method of choice

IRMA
unstable in whole blood & adheres onto sides of glass tube
blood should be spun 1st in a refrigerated centrifuge remove plasma centrifuge again to remove other formed elements
(proteolytic enzymes) that can cause breakdown of ACTH during thawing and freezing process
sample should be frozen if not analyzed immediately
Shows diurnal variation: 8 AM (morning); midnight
note time of sample collection proper interpretation
RR: 8 AM (25-100 pg/mL); 6 PM (<50pg/mL)
Lowest level is at 12 midnight
PITUITARY GLAND

Clinical Applications:
1. DIABETES INSIPIDUS (Most common)
a) deficiency of ADH or
b) failure of the kidney to respond to ADH
-produce large amts of urine (polyuria) w/ low specific gravity and urine osmolality
a. function of ADH: reabsorption of H2O [DI: H2O not reabsorbed rather urine is excreted out]
symptoms: fatigue, severe dehydration, hypothermia and shock
2 types of DI
Neurogenic DI
- cause of the ADH deficiency may be a pituitary tumor, traumatic, or surgical injury, genetic, autoimmune or idiopathic
Nephrogenic DI
- normal to elevated plasma concentrations of ADH, kidney is unable to respond to the hormone.
- chronic renal dss such as chronic pyelonephritis, protein starvation, hypokalemia, sickle cell anemia, congenital defects in the
receptors in the kidney.
- other cause of excess ADH: propagene carcinoma
Diagnostic tests: plasma and urine osmolality
a. urine osmolality: low <400mOsm/kg
b. urine volume for 24hrs is (>3L)
c. normal plasma osmolality if the H2O intake has not been restricted
2.
-

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE (SIADH)

excess ADH
hypersecretion of ADH: excess H2O retention dilutional effect on the plasma components
Dilutional hyponatremia: can induce generalized weakness, mental confusion, coma and convulsions
cause: may be pituitary tumor (benign) / carcinoma (elaborates hormones)
other cause: Bronchogenic CA

3.
-

Growth Hormone DEFICIENCY

may be caused by pituitary tumors, traumatic injury, congenital disorders or idiopathic
children affected will fail to grow & be short in stature
children with true GH deficiencywill respond and grow following injections of GH

to
a.
b.
c.

prove GH deficiency:
exogenous insulin injection dangerous: induce severe hypoglycemia plasma GH coma
injection of CRH (Corticotropic Releasing Hormone)stimulate pituitary gland to secrete GH
strenuous exercise (20mins)

4. GH HYPERSECRETION
If overproduction of GH begins in childhood before the epiphyseal plates of the bones are closed: Gigantism

rapid in height w/o distortion of body proportions

hypersecretion of GH in adults is most often caused by a pituitary adenoma: Acromegaly
a.
b.
c.
d.
e.

disfiguring physical features: caused by IFG-I (somatomedin C) from the liver

growth of most body soft tissues
size of the hands & feet with coarsening of the facial features, especially development of bony ridges over the eyes, large
tongue
insulin, postprandial glucose, P & Ca
joint pain, weight gain, goiter, heat intolerance, increased sweating

Dx: serial measurements of GH

o
Why serial? -your GH secretion is episodic.
Rx: transphenoidal surgical removal of the pituitary adenoma, radiation therapy
5. PANHYPOPITUITARISM
generalized hypofunction of the pituitary gland with resulting in all pituitary hormone levels
thryoid, adrenal insufficiency, absence of gonadal fxn
SIMMONDS DSS:
Develops after destruction of the pituitary by surgery, infection, injury or tumor
extreme weight loss, dry skin, bradycardia, atrophy of the genitalia & breasts and progress to premature senility
SHEEHANS SYNDROME:
insidious (gradual) onset
caused by pituitary infarction following complications of postpartum hemorrhage (vascular spasms of the hypophyseal arteries
resulting in decreased blood flow to the pituitary, tissue hypoxia & necrosis)
o
During Pregnancy: pituitary enlarges due to demand for hormones, need for nutrients and O2 to the pituitary cells
failure of lactation ( PRL/hypoPRL)
Hypothyroidism (TSH)
postpartum amenorrhea ( FSH and LH)
6. HYPERPROLACTINEMIA
excess secretion of PRL from the pituitary often caused by a pituitary tumor
Women: concentrations of Gonadotropins & Estradiol
o
Cause continuous milk flow (galactorrhea, amenorrhea)
-

Men: enlargement of the breast tissue (gynecomastia)

o
testosterone production with atrophy of the testes
THYROID FUNCTION TESTS
THYROID STIMULATING HORMONE (TSH)
Effects of TSH on the thyroid is to increase the production and release of T4 from thyroglobulin, which in turn is converted
to T3 at the peripheral tissue
Elevated in primary hypothyroidism
If the TSH remains low or low normal in the presence of decreased TSH secondary hypothyroidism
Lab management: RIA
o
Non-isotopic immunoassay methods such as EIA and chemiluminescence
sTSH test of choice for initial diagnosis of thyroid dysfunction
o
sensitive TSH
useful for monitoring patients who are receiving
Levothyroxine or levotriiodothyronine for hypothyroidism
THYROXINE
total T4 (TT4) detect both the T4 bound to protein and the free biologically active T4

Assay for TT4 employ non-isotopic IA such as Fluorescense polarization immunoassay (FPIA) and chemilumiescence
Free Thyroxin (free T4)
o
Only 0.02%
o
Much better indicator of thyroid status than total &4
o
FT4: can enter cells and undergo conversion to the metabolically potent T3
o
Elevated in approximately 95% of hyperthyroid patients

TRIIODOTHYROININE (T3)
Total T3 useful in evaluating suspected thyrotoxicosis in which the FT4 is normal

Useful in diagnosing mild hyperthyroidism because T3 rises earlier and more markedly than does T4 in all common forms of
hyperthyroidism
Methods for measuring TT3: enzyme immunoassays (MEIA) and chemiluminescence

THYROID HORMONE-BINDING RATIO (RESIN T3 UPTAKE)

Design to reflect the unsaturated binding capacity of the TH carrier protein, primarily TBG

THRYOGLOBULIN
Storage form of the TH precursors

Measured primarily in the monitoring of patients with follicular or papillary thyroid cancer
Increased with stimulation by TSH, thyroid-simulating immunoglobulins (TSIg), TRH or hCG
The last parameter to normalize after thyrotoxicosis therefore useful in resolving thyroid history in the presence of normal
T4 and T4 but with symptoms of thyrotoxicosis
Measures by chemiluminescence

THYROID ANTIBODIES
Thyroid microsomal antibodies (TMAb)
o
Present in about 85% of px with Hashimotos thyroiditis
o
In 85% of those with Graves dieases
Anti-thyroglobulin antibodies (TgAb)
o
Found in 60% of patients with Hashimotos thyroditis
o
In 30% of patients with Graves diseases
o
*TMAba and TgAb: predictor of outcome of antithyroid drug therapy in patients with Graves disease
TSH receptor antibodies (TRAb) or Thyroid-Stimulating antibodies (TSIg)
o
*TMAb and TgAb: hemagglutination tests in which erythrocytes that have been coated with either Tg or
microsomes agglutinate when the respective antibody is present
o
*thyroid peroxidase (TPO) antibodies: main autoantigenic component of microsomes
TSH STIMULATION TEST:
Can detect abnormalities before TH concentrations are outside their reference ranges

Useful in distinguishing between pituitary and hypothalamic hypothyroidism, confirming mild hyperthyroidism in patients
whose free T3 and T4 are equivocal and yet whose other clinical findings are suggestive of thyrotoxicosis
Injecting 200-500ug of synthetic TRH after determining a baseline TSH level
15, 30 and 60 minutes TSH determinations
Side effects: headache, nausea, chest tightness and mild hypotension

CLINICAL APPLICATIONS:
HYPERTHYROIDISM
Increase in circulating TH both free and total

Can be overt or subclinical

o
Subclinical hyperthyroidism

Asymptomatic

Normal TH levels, decreased sTSH

At risk for atrial fibrillation, osteoporosis

At risk are women older than 50

o
Overt hyperthyroidism

Associated with elevated free and total T4 and T3, accompanied by a markedly decreased sTSH
o
Thyrotoxicosis

Condition that occurs when excessive amounts of TH in circulation affect peripheral tissue

Manifestations:
Decreased weight with normal appetite

Nervousness
Sweating
Palpitations
Heat intolerance
Muscle weakness
Clinical signs: enlarged thyroid (goiter), eyelid retraction and tremor

THYROID STORM:
State of thyroid crisis that requires emergency treatment

May occur following an infection, childbirth, diabetic ketoacidosis, withdrawal of antithyroid drugs or therapeutic use of
radioiodine or surgical treatment in the thyrotoxic patients
Due to sudden increase in circulating TH
Symptoms: tachycardia, heart failure, high fever, nausea, vomiting and psychiatric disorders and coma
Hyperthyroidism divided into 3 categories:
o
Excess thyroid stimulators

Primary thyroid disease

Iatrogenic and factitious causes