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Module 2
CORE KNOWLEDGE
HYPO/HYPERPITUITARISM
GIGANTISM, ACROMEGALY, PROLACTINEMIA,
DIABETES INSIPIDUS & SIADH
DIABETES MELLITUS
HYPO/HYPERTHYROIDISM (MYXOEDEMA, CRETINISM, THYROIDITIS,
THYROTOXICOSIS)
HYPER/HYPO PARATHYROIDISM
HYPER/HYPO CORTISOLISM
CUSHING’S DISEASE/SYNDROME
ADDISON’S DISEASE
HYPER/HYPO ALDOSTERONISM
PHAEOCHROMOCYTOMA
HORMONES RELATED TO STRESS
Hamdan Noor
Cyberjaya University College of Medical Sciences
ENDOCRINE PHYSIOLOGY Module 2
Module 2: The Hypothalamic and
Pituitary Hormones
Sub-topics:
Summary
Conclusion
Appendix
2
Learning Outcomes:
Additional objectives
1. Contrast the anterior and posterior pituitary lobes with respect to cell types, vascular supply, development,
and innervation.
2. List the target organs or cell types for oxytocin and describe its effects on each.
3. Name the stimuli for oxytocin release during parturition or lactation.
4. List the target cells for vasopressin and explain why vasopressin is also known as antidiuretic hormone
(ADH).
5. Describe the stimuli and mechanisms that control vasopressin secretion
6. Identify disease states caused by a) over-secretion, and b) under-secretion of vasopressin and list the
principle symptoms of each.
7. Describe the biosynthesis, structure, and actions of the glycoprotein hormones FSH, LH, and TSH.
8. Describe the biosynthesis, structure, actions, and metabolism of the GH/prolactin family.
9. Describe the biosynthesis, structure, and actions of the POMC family: ACTH, MSH, (-lipotropin, (-
endorphin.
10. Identify appropriate hypothalamic factors that control the secretion of each of the anterior pituitary
hormones, and describe their route of transport from the hypothalamus to the anterior pituitary.
11. Diagram the short-loop and long-loop negative feedback control of anterior pituitary hormone secretion.
Predict the changes in secretory rates of hypothalamic, anterior pituitary, and target gland hormones caused
by over-secretion or under-secretion of any of these hormones or receptor deficit for any of these hormones.
12. Explain the importance of pulsatile and diurnal secretion.
3
Learning Resources:
Terms to Know:
Please list down all the terms that you need to know and write down their meaning.
4
Learning Activities
1. Functional Anatomy of the Hypothalamus and Pituitary Gland
1.1. The hypothalamus
The hypothalamic and pituitary hormones play central roles in physiologic processes. The
target cells for most of these hormones are themselves endocrine cells. Thus, a seemingly
small initial signal is amplified to cause widespread effects on many cells and tissues,
affecting physiological processes effectively.
The hypothalamus is located in the middle of the base of the brain, and encapsulates the
ventral portion of the third ventricle (Fig. 2.1).
• Enlarge the diagram of the hypothalamus to show its association with the pituitary gland.
• Why are hypothalamic and pituitary neurons influential over physiological processes?
• What characterise the target cells for hypothalamic and pituitary hormones?
5
The hypothalamus is involved in coordinating the physiologic responses of different organs
that together maintain homeostasis. It does this by integrating signals from the external
environment, from other brain regions, and from visceral afferents and then stimulating the
appropriate neurological and endocrine responses (Fig. 2.2). In doing so, the hypothalamus
influences many aspects of daily function, including food intake, energy expenditure, body
weight, fluid intake and balance, blood pressure, thirst, body temperature, and the sleep cycle.
Most of these hypothalamic responses are mediated through hypothalamic control of pituitary
function.
Some of the neurons that make up the hypothalamic nuclei are neurohormonal in nature, i.e.
they synthesize neuropeptides that function as hormones and release these neuropeptides
from axon terminals in response to neuronal depolarization. Two types of neurons are
important in mediating the endocrine functions of the hypothalamus: the magnocellular and
parvocellular neurons (Fig. 2.2).
6
Activity 2.2: The hypothalamic nuclei
Magnocellular neurons are located predominantly in the paraventricular and supraoptic nuclei
of the hypothalamus. The unmyelinated axons form the hypothalamo-hypophysial tract that
traverses the median eminence ending in the posterior pituitary. These neurons synthesize the
neurohormones oxytocin (mainly by paraventricular nucleus) and ADH (mainly by
supraoptic nucleus) which are transported down the hypothalamo-hypophysial tract and
stored in the posterior pituitary (Fig. 2.3).
Parvocellular neurons are small in size and have projections that terminate in the median
eminence, brain stem, and spinal cord. They release small amounts of releasing or inhibiting
neurohormones (hypophysiotropic hormones) that control anterior pituitary function. These
are transported in the long portal veins to the anterior pituitary, where they stimulate the
release of pituitary hormones into the systemic circulation (Fig. 2.3).
7
Activity 2.3. Secretion from the
hypothalamic nuclei
In summary, the hypothalamus is part of the central nervous system that plays a very
important role in controlling many functions the body. Various inputs from the external and
internal environment are integrated by the hypothalamus which then produce outputs to the
effectors via the electrical (autonomic nervous system) and hormonal messages to affect
physiological functions. The hormones synthesised by the hypothalamic neurons are listed in
Section 2.
8
1.2. The Pituitary
The pituitary gland, also known as the hypophysis, is a roundish organ that lies immediately
beneath the hypothalamus, resting in a depression of the base of the skull called the sella
turcica ("Turkish saddle").
The anterior pituitary and posterior pituitary have separate embryological origins. Anterior
pituitary is derived from diencephalon, thus consists of neural tissue (pituicytes that are
modified astrocytes). Anterior pituitary develops from evagination of epithelial cells from
nasal pharynx which develops upwards forming Rathke’s pouch which later forms anterior
pituitary. Thus posterior pituitary consists of neural tissue whereas anterior pituitary consists
of epithelial tissue.
• The superior hypophyseal artery ramifies into a capillary bed in the lower
hypothalamus, and hypothalamic hormones destined for the anterior pituitary are
secreted into that capillary blood.
• Blood from those capillaries drains into hypothalamic-hypophyseal portal veins
(Portal veins are defined as veins between two capillary beds). The hypothalamic-
hypophyseal portal veins branch again into another series of capillaries within the
anterior pituitary.
• Capillaries within the anterior pituitary, which carry hormones secreted by that gland,
coalesce into veins that drain into the systemic venous blood. Those veins also collect
capillary blood from the posterior pituitary gland.
This pattern of vascular connections is presented diagrammatically in Fig. 2.6. The utility of
this unconventional vascular system is that minute quantities of hypothalamic hormones are
carried in a concentrated form directly to their target cells in the anterior pituitary, and are not
diluted out in the systemic circulation.
Note: The inferior hypophyseal artery supplies the posterior pituitary and the veins transport
posterior pituitary hormones to the general circulation.
9
Fig. 2.5. The hypothalamo-pituitary axis.
Anterior pituitary: Small-bodied (parvocellular nuclei including the supraoptic and paraventricular nuclei) neurons in the
hypothalamus secrete releasing and inhibitory factors into capillaries that penetrate the median eminence and surround the
infundibular recess. The capillaries (primary plexus), which are outside of the blood-brain barrier, coalesce into long portal veins
that carry the releasing and inhibitory factors down the pituitary stalk to the anterior pituitary. Other neurons secrete their
releasing factors into a capillary plexus that is much further down the pituitary stalk; short portal veins carry these releasing
factors to the anterior pituitary. There, the portal veins break up into the secondary capillary plexus of the anterior pituitary and
deliver the releasing and inhibitory factors to the "troph" cells that actually secrete the anterior pituitary hormones (GH, TSH,
ACTH, LH, FSH and PRL) that enter the systemic bloodstream and distribute throughout the body.
Posterior pituitary: Large neurons (magnocellular nuclei) in the paraventricular and supraoptic nuclei of the hypothalamus
actually synthesize the hormones ADH and oxytocin. These hormones travel down the axons of the hypothalamic neurons to the
posterior pituitary where the nerve terminals release the hormones, like neurotransmitters, into a rich plexus of vessels supplied
by the inferior hypophyseal artery.
10
Fig. 2.6. The hypothalamo-pituitary axis
• List down the nuclei and regions in the hypothalamus that contain small-bodied neurons that
secrete releasing and inhibiting factors. Name the factors (neurohormones) involved.
Describe the flow of the hormones down to the anterior pituitary.
• List down the nuclei in the hypothalamus that contain large neurons that synthesise hormones
in their soma and transport them along their axons to the posterior pituitary. Name the
hormones.
• Describe the system of blood flow to the hypothalamus and to the pituitary. What is the
advantage of this unconventional vascular system?
11
2. Overview of Hypothalamic and Pituitary Hormones
Hypothalamic releasing and inhibiting hormones are secreted from various hypothalamic
nuclei and are carried directly to the anterior pituitary gland via hypothalamic-hypophyseal
portal veins. Specific hypothalamic hormones bind to receptors on specific anterior pituitary
cells, modulating the release of the hormone they produce (Table 2.1 and Fig. 2.8).
12
Fig. 2.8. Relationship between hypothalamic hormones, pituitary hormones and hormones from the peripheral
endocrine glands.
• Why is the pituitary considered as the “master” gland or the “king” of the endocrine gland?
• What is the advantage of having hormones affecting other endocrine glands before targeting the
final body tissues for the physiological effect?
• List down all hypothalamic hormones, describe their chemistry and synthesis, and discuss their
mechanism of actions on the target cells.
• Briefly describe the mechanism of action of the anterior pituitary hormones on the target cells
and indicate the physiologic responses of the target cells.
13
2.2. Regulation of hypothalamic hormone release
As part of the nervous system, the hypothalamus receives and integrates afferent signals from
multiple brain regions (Fig.2.9).
• Some of these afferent signals convey sensory information about the individual's
external environment such as light, heat, cold, and noise. Among the environmental
factors, light plays an important role in generating the circadian rhythm of hormone
secretion through melatonin released by the pineal gland.
• Other signals perceived by the hypothalamus are visceral afferents that provide
information to the central nervous system from peripheral organs such as the
intestines, the heart, the liver, and the stomach.
The hypothalamus is a center for integration of the information that the body is continuously
processing. The neuronal signals are transmitted by various neurotransmitters released from
the afferent fibers, including glutamate, norepinephrine, epinephrine, serotonin,
14
acetylcholine, histamine, -aminobutyric acid, and dopamine. In addition, circulating
hormones produced by endocrine organs and substrates such as glucose can regulate
hypothalamic neuronal function. All of these neurotransmitters, substrates, and hormones
can influence hypothalamic hormone release.
What is the meaning of negative feedback system? Compare it to positive feedback system.
Give examples of both. Which one is more commonly found in real life? Why?
Based on Fig. 2.10, give a few examples to illustrate the negative feedback mechanism of
hormone secretion.
Table 2.2 summarizes the major hormones synthesized and secreted by the pituitary gland,
along with summary statements about their major target organs and physiologic effects.
Based on the chemical nature of the pituitary hormones and their functions, predict the mechanism of
action of the hormones on the target organs.
16
As seen in the Table 2.2, the anterior pituitary synthesizes and secreted 6 major hormones. A
final point to be made is that individual cells within the anterior pituitary secrete a single
hormone (or possibly two in some cases). Thus, the anterior pituitary contains at least five
distinctive endocrinocytes (Table 2.3).
• those belonging to the GH and prolactin family. Released from the somatotrophs, an
abundant (50%) cell type in the anterior pituitary.
In summary, when stimulated by various external and internal factors, the magnocellular
nuclei of the hypothalamus produce neurohormones (ADH and oxytocin) that are stored in
the posterior pituitary. These hormones will be secreted appropriately under certain
conditions. On the other hand, the parvocellular nuclei produce neurohormones that would
stimulate or inhibit secretion from the anterior pituitary.
Next we’ll look in more detail at individual hormones produced by the anterior pituitary.
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3. Anterior Pituitary Hormones
3.1. Growth Hormone (Somatotropin)
Growth hormone, also known as somatotropin, is a protein hormone of about 190 amino
acids that is synthesized and secreted by cells called somatotrophs in the anterior pituitary. It
is a major participant in control of several complex physiologic processes, including growth
and metabolism. Growth hormone is also of considerable interest as a drug used in both
humans and animals.
Keeping this distinction in mind, we can discuss two major roles of growth hormone and its
minion IGF-I in physiology.
Effects on growth
Growth is a very complex process, and requires the coordinated action of several hormones.
The major role of growth hormone in stimulating body growth is to stimulate the liver and
other tissues to secrete IGF-I. IGF-I stimulates proliferation of chondrocytes (cartilage cells),
resulting in bone growth. Growth hormone does seem to have a direct effect on bone growth
in stimulating differentiation of chondrocytes.
IGF-I also appears to be the key player in muscle growth. It stimulates both the
differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and
protein synthesis in muscle and other tissues.
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Fig. 2.12. Functions of GH on liver, muscle and adipose tissues.
Metabolic effects
Growth hormone has important effects on protein, lipid and carbohydrate metabolism. In
some cases, a direct effect of growth hormone has been clearly demonstrated, in others, IGF-I
is thought to be the critical mediator, and some cases it appears that both direct and indirect
effects are at play.
• Protein metabolism: In general, growth hormone stimulates protein anabolism in
many tissues. This effect reflects increased amino acid uptake, increased protein
synthesis and decreased oxidation of proteins.
• Fat metabolism: Growth hormone enhances the utilization of fat by stimulating
triglyceride breakdown and oxidation in adipocytes.
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• Carbohydrate metabolism: Growth hormone is one of a battery of hormones that
serves to maintain blood glucose within a normal range. Growth hormone is often said
to have anti-insulin activity, because it suppresses the abilities of insulin to stimulate
uptake of glucose in peripheral tissues and enhance glucose synthesis in the liver.
Somewhat paradoxically, administration of growth hormone stimulates insulin
secretion, leading to hyperinsulinemia.
Growth hormone secretion is also part of a negative feedback loop involving IGF-I. High
blood levels of IGF-I lead to decreased secretion of growth hormone not only by directly
suppressing the somatotroph, but by stimulating release of somatostatin from the
hypothalamus.
Growth hormone also feeds back to inhibit GHRH secretion and probably has a direct
(autocrine) inhibitory effect on secretion from the somatotroph.
Integration of all the factors that affect growth hormone synthesis and secretion lead to a
pulsatile pattern of release. Basal concentrations of growth hormone in blood are very low. In
children and young adults, the most intense period of growth hormone release is shortly after
the onset of deep sleep.
20
Fig. 2.14: Synthesis and
release of growth hormone
releasing hormone (GHRH)
and somatostatin, and the
control of growth hormone
(GH) release.
21
3.1.4. GH abnormality
States of both growth hormone deficiency and excess provide very visible testaments to the
role of this hormone in normal physiology. Such disorders can reflect lesions in either the
hypothalamus, the pituitary or in target cells. A deficiency state can result not only from a
deficiency in production of the hormone, but in the target cell's response to the hormone.
The effect of excessive secretion of growth hormone is also very dependent on the age of
onset and is seen as two distinctive disorders:
• Gigantism is the result of excessive growth hormone secretion that begins in young
children or adolescents. It is a very rare disorder, usually resulting from a tumor of
somatotropes. One of the most famous giants was a man named Robert Wadlow. He
weighed 8.5 pounds at birth, but by 5 years of age was 105 pounds and 5 feet 4 inches
tall. Robert reached an adult weight of 490 pounds and 8 feet 11 inches in height. He
died at age 22.
• Acromegaly results from excessive secretion of growth hormone in adults. The onset
of this disorder is typically insidious. Clinically, an overgrowth of bone and
connective tissue leads to a change in appearance that might be described as having
"coarse features". The excessive growth hormone and IGF-I also lead to metabolic
derangements, including glucose intolerance.
In years past, growth hormone purified from human cadaver pituitaries was used to treat
children with severe growth retardation. More recently, the virtually unlimited supply of
recombinant growth hormone has lead to several other applications to human and animal
populations.
Human growth hormone is commonly used to treat children of pathologically short stature.
There is concern that this practice will be extended to treatment of essentially normal children
- so called "enhancement therapy" or growth hormone on demand. Similarly, growth
hormone has been used by some to enhance athletic performance. Although growth hormone
therapy is generally safe, it is not as safe as no therapy and does entail unpredictable health
risks. Parents that request growth hormone therapy for children of essentially-normal stature
are clearly misguided.
The role of growth hormone in normal aging remains poorly understood, but some of the
cosmetic symptoms of aging appear to be amenable to growth hormone therapy. This is an
active area of research, and additional information and recommendations about risks and
benefits will undoubtedly surface in the near future.
.
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Activity 2.9. Growth hormone
• What is the chemical nature of GH? How is it synthesized in the anterior pituitary? What
regulates the synthesis?
• Which body cells have the receptor for GH? What is the nature of the receptor for GH?
Describe the signal transduction mechanism after the receptor is activated by GH. What are
the direct physiological effect of GH?
• Describe the involvement of somatomedins in mediating the action of GH. How are
somatomedins synthesized? What are the effects on the target cells?
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3.2. Prolactin (PRL)
Prolactin is synthesized as a prohormone. Following cleavage of the signal peptide, the length
of the mature hormone is between 194 and 199 amino acids, depending on species. Hormone
structure is stabilized by three intramolecular disulfide bonds.
The conventional view of prolactin is that its major target organ is the mammary gland, and
stimulating mammary gland development and milk production pretty well define its
functions.
It is difficult to point to a tissue that does not express prolactin receptors, and although the
anterior pituitary is the major source of prolactin, the hormone is synthesized and secreted in
many other tissues. Overall, several hundred different actions have been reported for
prolactin in various species. Some of its major effects are summarized here.
In the 1920's it was found that extracts of the pituitary gland, when injected into virgin
rabbits, induced milk production. Subsequent research demonstrated that prolactin has two
major roles in milk production:
• Prolactin induces lobuloalveolar growth of the mammary gland. Alveoli are the
clusters of cells in the mammary gland that actually secrete milk.
• Prolactin stimulates lactogenesis or milk production after giving birth. Prolactin,
along with cortisol and insulin, act together to stimulate transcription of the genes that
encode milk proteins.
The prolactin receptor is widely expressed by immune cells, and some types of lymphocytes
synthesize and secrete prolactin. These observations suggest that prolactin may act as an
autocrine or paracrine modulator of immune activity.
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3.2.2. Control of prolactin secretion
Estrogens provide a well-studied positive control over prolactin synthesis and secretion. The
increasing blood concentrations of estrogen during late pregnancy appear responsible for the
elevated levels of prolactin that are necessary to prepare the mammary gland for lactation at
the end of gestation.
• What is the chemical nature of PRL? How is it synthesized in the anterior pituitary? What
regulates the synthesis?
• Which body cells have the receptor for PRL? What is the nature of the receptor for PRL?
Describe the signal transduction mechanism after the receptor is activated by PRL. What are the
direct physiological effects of PRL?
Thyroid-stimulating hormone (TSH), also known as thyrotropin, is secreted from cells in the
anterior pituitary called thyrotrophs, finds its receptors on
epithelial cells in the thyroid gland, and stimulates that gland
to synthesize and release thyroid hormones.
Secretion of thyroid-releasing hormone, and hence, TSH, is inhibited by high blood levels of
thyroid hormones in a classical negative feedback loop (Fig. 2.17).
Additional information about TSH and its effects and control are presented in the Module on
Thyroid Gland.
.
Activity 2.11. Thyroid stimulating hormone (TSH)
• What is the chemical nature of TRH and TSH? How is it synthesized in the anterior pituitary?
Describe the negative feedback mechanisms involved in the regulation of TSH synthesis.
• Which body cells have the receptor for TSH? What is the nature of the receptor for TSH?
Describe the signal transduction mechanism after the receptor is activated by TSH. What are
the direct physiological effects of TSH?
26
3.4. Adrenocorticotropic Hormone (ACTH)
Within the pituitary gland, ACTH is synthesized as part of a much larger precursor protein
that contains not only ACTH but also several other hormones. A large precursor protein
named proopiomelanocortin (POMC, "Big Mama") is synthesized and proteolytically
chopped into several fragments as depicted in Fig. 2.19. Not all of the cleavages occur in all
species and some occur only in the intermediate lobe of the pituitary.
The major attributes of the hormones other than ACTH that are produced in this process are
summarized as follows:
• Lipotropin: Originally described as having weak lipolytic effects, its major
importance is as the precursor to beta-endorphin.
• Beta-endorphin and Met-enkephalin: Opioid peptides with pain-alleviation and
euphoric effects.
27
• Melanocyte-stimulating hormone (MSH): Known to control melanin pigmentation
in the skin of most vertebrates.
• Corticotropin-like intermediate peptide (CLIP):
What is the chemical nature of ACTH? How is it synthesized in the anterior pituitary? What regulates
the synthesis?
What is POMC? What is the significance of increased POMC in patients having Cushings disease in
terms of signs and symptoms?
Which body cells have the receptor for ACTH? What is the nature of the receptor for ACTH?
Describe the signal transduction mechanism after the receptor is activated by ACTH. What are the
direct physiological effects of ACTH?
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are called gonadotropins
because they stimulate the gonads - in males, the testes, and in females, the ovaries. They are
not necessary for life as such, but are essential for reproduction. These two hormones are
secreted from cells in the anterior pituitary called gonadotrophs. Most gonadotrophs secrete
only LH or FSH, but some appear to secrete both hormones.
LH, FSH and TSH are large glycoproteins composed of alpha and beta subunits (Fig. 2.17).
The alpha subunit is identical in all three of these anterior pituitary hormones, while the beta
subunit is unique and endows each hormone with the ability to bind its own receptor.
Physiologic effects of the gonadotropins are known only in the ovaries and testes. Together,
they regulate many aspects of gonadal function in both males and females.
In both sexes, LH stimulates secretion of sex steroids from the gonads. In the testes, LH binds
to receptors on Leydig cells, stimulating synthesis and secretion of testosterone. Theca cells
in the ovary respond to LH stimulation by secretion of testosterone, which is converted into
estrogen by adjacent granulosa cells.
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Follicle-Stimulating Hormone (FSH)
As its name implies, FSH stimulates the maturation of ovarian follicles. Administration of
FSH to humans and animals induces "superovulation", or development of more than the usual
number of mature follicles and hence, an increased number of mature gametes.
This regulatory loop leads to pulsatile secretion of LH and, to a much lesser extent, FSH. The
number of pulses of GnRH and LH varies from a few per day to one or more per hour. In
females, pulse frequency is clearly related to stage of the cycle.
Numerous hormones influence GnRH secretion, and positive and negative control over
GnRH and gonadotropin secretion is actually considerably more complex than depicted in
Fig. 2.20. For example, the gonads secrete at least two additional hormones - inhibin and
activin - which selectively inhibit and activate FSH secretion from the pituitary.
Elevated blood levels of gonadotropins usually reflect lack of steroid negative feedback.
Removal of the gonads from either males or females, as is commonly done to animals, leads
to persistent elevation in LH and FSH. In humans, excessive secretion of FSH and/or LH
most commonly the result of gonadal failure or pituitary tumors. In general, elevated levels of
gonadotropins per se have no biological effect.
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3.5.4. Pharmacologic manipulation of Gonadotropin secretion
Normal patterns of gonadotropin secretion are absolutely required for reproduction, and
interfering particularly with LH secretion is a widely-used strategy for contraception. Oral
contraceptive pills contain a progestin (progesterone-mimicking compound), usually
combined with an estrogen. As discussed above, progesterone and estrogen inhibit LH
secretion, and oral contraceptives are effective because they inhibit the LH surge that induces
ovulation.
Another route to suppressing gonadotropin secretion is to block the GnRH receptor. GnRH
receptor antagonists have potent contraceptive effects in both males and females, but have not
been widely deployed for that purpose.
• What is the chemical nature of LH and FSH? How are they synthesized in the anterior pituitary?
What regulates the synthesis?
• Which body cells have the receptor for LH and FSH? What is the nature of the receptor for LH
and FSH? Describe the signal transduction mechanism after the receptor is activated by LH and
FSH. What are the direct physiological effect of LH and FSH?
As with most endocrine organs, alterations in function of the anterior pituitary can be due to
excess or deficient production of pituitary hormones or to altered responsiveness to hormone
effects at the target organ.
Small pituitary adenomas can cause manifestations of excess tropic hormone production,
whereas larger tumors can produce neurologic symptoms by mass effect in the sellar area.
30
effective in lowering serum prolactin levels, restoring gonadal function, decreasing tumor
size, and improving visual fields. Hyperprolactinemia can also be due to drug-induced
inhibition of dopamine release.
Hypopituitarism
GH deficiency and retarded growth may result from impaired release of GH from the
pituitary gland because of diseases of the hypothalamus or pituitary gland or genetic
predisposition. Alternatively, mutations in the gene for the GH receptor can cause
insensitivity to GH and growth retardation with low serum IGF-I concentrations.
GH insensitivity
Measurements of anterior pituitary hormone concentrations and of the respective target gland
hormone levels are used to assess the functional status of the system (Table 3.4). For
example, paired measures of TSH and thyroid hormone, FSH and estradiol, and ACTH and
cortisol are used to evaluate the integrity of the respective systems. In addition, stimulation
and inhibition tests can be used to assess the functional status of the pituitary gland. These
tests are based on the normal physiologic feedback mechanisms that control tropic hormone
release. For example, insulin-induced hypoglycemia is used to elicit an increase in GH
release in patients with suspected GH deficiency. In contrast, suppression tests can be used to
31
diagnose Cushing syndrome, a clinical state resulting from prolonged, inappropriate exposure
to excessive endogenous secretion of cortisol. Cushing syndrome is characterized by loss of
the normal feedback mechanism of the hypothalamo-pituitary-adrenal axis and the normal
circadian rhythm of cortisol secretion. The basis of the test is that, in most situations, the
corticotroph tumor cells in Cushing disease retain some responsiveness to the negative
feedback effects of glucocorticoids, whereas tumors ectopically secreting ACTH do not.
Table 3.4. Pituitary Tropic Hormone and Target Organ Hormone Pairs
32
4. Posterior Pituitary Hormones
4.1. Synthesis and release of
posterior pituitary hormones
4.2.1. Introduction
Roughly 60% of the mass of the body is water, and despite wide variation in the amount of
water taken in each day, body water content remains incredibly stable. Such precise control
of body water and solute concentrations is a function of several hormones acting on both the
kidneys and vascular system, but there is no doubt that ADH is a key player in this process.
Antidiuretic hormone, also known as vasopressin, is a nine amino acid peptide. Within
hypothalamic neurons, the hormone is packaged in secretory vesicles with a carrier protein
called neurophysin, and both are released upon hormone secretion. The circulating
concentrations of ADH range from 1.5 to 6 ng/L.
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4.2.2. Physiologic Effects of Antidiuretic Hormone
The single most important effect of antidiuretic hormone is to conserve body water by
reducing the output of urine. Antidiuretic hormone binds to receptors in the distal or
collecting tubules of the kidney and promotes reabsorption of water back into the circulation.
In the absence of antidiuretic hormone, the kidney tubules are virtually impermeable to water,
and it flows out as urine.
Fig. 2.22. Cellular mechanism of ADH action in the collecting tubules and ducts.
34
Table 2.3. Key Features of Aquaporins
Aquaporin Features
AQP1 Constitutively expressed in apical and basolateral membranes of
epithelial cells of proximal tubules and descending limb of Henle's
loop. Involved in 90% of water reabsorption.
Given: GFR = 180 L/day; 90% reabsorption of water in the proximal tubule.
• How much water remains in the renal tubule without the presence of ADH?
Effects on the vascular system
• How much urine is produced per day?
• In many species,
How much waterhigh concentrations
is reabsorbed of antidiuretic
in the distal hormone
tubule and collecting cause
duct in thewidespread constriction
presence ofADH?
of arterioles, which leads to increased arterial pressure. It was for this effect
• Explain the mechanism of ADH action on the renal tubule starting from receptor activationuntilthat the name
vasopressin
reabsorptionwas coined.
of water In place.
takes healthy humans, antidiuretic hormone has minimal pressor effects.
• 4.2.3.
WhatControl
is “syndrome of inappropriate
of Antidiuretic ADH (SIADH)”?
Hormone secretionWhat would happen in a patient withthis syndrome?
When plasma osmolarity is below a certain threshold, the osmoreceptors are not activated and
antidiuretic hormone secretion is suppressed. When osmolarity increases above the threshold,
the osmoreceptor cells shrink (the cells loses water to the interstitium) and start producing
action potentials. These action potentials are transmitted to median preoptic nucleus which
acts as the control centre. This control centre also receives information from baroreceptors
(aortic arch and carotid body) and volume receptors (atria) (Fig. 2.24). Information from the
osmoreceptros, baroreceptors and volume receptors then induce the control centre to
stimulate the cells in the supraoptic nucleus. Action potentials produced by the cells of the
35
supraoptic nucleus reach the axon terminals and induce exocytosis of ADH.
Another potent stimulus of antidiuretic hormone is nausea and vomiting, both of which are
controlled by regions in the brain with links to median preoptic nucleus of the
hypothalamus.
• What are the stimuli for ADH release? Hint: high osmolarity, low blood volume,
nausea/vomiting.
• Where is the control centre? Hint: Supraoptic nucleus (SON).
• How is the afferent information transmitted to the control centre? Hint: From the
osmoreceptor direct synapse with the neurons in the SON. From the baroreceptors via
the vagus and glossopharyngeal nerves vasomotor centre SON
• Describe the mechanism of ADH secretion by nerve endings of the neurons originating from
the SON and terminating in the posterior pituitary. Hint: action potentials stimulating voltage
gated Ca2+ channels causing exocytosis of vesicles containing ADH.
There is an interesting parallel between ADH secretion and thirst. Both phenomena appear to
be stimulated by hypothalamic osmoreceptors, although probably not the same ones. The
osmotic threshold for antidiuretic hormone secretion is considerably lower than for thirst, as
if the hypothalamus is saying "Let's not bother him by invoking thirst unless the situation is
bad enough that antidiuretic hormone cannot handle it alone."
In summary, ADH is a very important hormone secreted from the posterior pituitary (albeit
produced by neurons in the hypothalamic supraoptic nucleus). Secretion of ADH is
stimulated by high plasma osmolarity (via osmoreceptor) and low blood volume (via
baroreceptor) which induces ADH stored in the nerve endings in the posterior pituitary to be
secreted. ADH binds to its receptor in the cells of the renal distal tubules and collecting
ducts. Activation of the receptor leads to signal transduction mechanism that causes
migration of aquaporin 2 to the luminal membrane to increase water reabsorption, thus
compensating the high osmolarity and low plasma volume.
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.
4.3. Oxytocin
4.3.1. Introduction
• Stimulation of milk ejection (milk letdown): Milk is initially secreted into small sacs
within the mammary gland called alveoli, from which it must be ejected for consumption
or harvesting. Mammary alveoli are surrounded by smooth muscle (myoepithelial) cells
which are a prominent target cell for oxytocin. Oxytocin stimulates contraction of
myoepithelial cells, causing milk to be ejected into the ducts and cisterns.
• Stimulation of uterine smooth muscle contraction at birth: At the end of gestation, the
uterus must contract vigorously and for a prolonged period of time in order to deliver the
fetus. During the later stages of gestation, there is an increase in abundance of oxytocin
receptors on uterine smooth muscle cells, which is associated with increased "irritability"
of the uterus (and sometimes the mother as well). Oxytocin is released during labor when
the fetus stimulates the cervix and vagina, and it enhances contraction of uterine smooth
muscle to facilitate parturition or birth.
In cases where uterine contractions are not sufficient to complete delivery, physicians
sometimes administer oxytocin ("psilocin") to further stimulate uterine contractions.
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Activity 2.18:
Physiologic effects
and regulation of
oxytocin release.
Both sexes secrete oxytocin - what about its role in males? Males synthesize oxytocin in the
same regions of the hypothalamus as in females, and also within the testes and perhaps other
reproductive tissues. Pulses of oxytocin can be detected during ejaculation. Current evidence
suggests that oxytocin is involved in facilitating sperm transport within the male reproductive
system and perhaps also in the female, due to its presence in seminal fluid. It may also have
effects on some aspects of male sexual behavior.
The most important stimulus for release of hypothalamic oxytocin is initiated by physical
stimulation of the nipples or teats. The act of nursing or suckling is relayed within a few
milliseconds to the brain via a spinal reflex arc. These signals impinge on oxytocin-secreting
neurons, leading to release of oxytocin.
A number of factors can inhibit oxytocin release, among them acute stress. For example,
oxytocin neurons are repressed by catecholamines, which are released from the adrenal gland
in response to many types of stress, including fright. As a practical endocrine tip - don't wear
a gorilla costume into a milking parlor full of cows or set off firecrackers around a mother
nursing her baby.
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Both the production of oxytocin and response to oxytocin are modulated by circulating levels
of sex steroids. The burst of oxytocin released at birth seems to be triggered in part by
cervical and vaginal stimulation by the fetus, but also because of abruptly declining
concentrations of progesterone. Another well-studied effect of steroid hormones is the
marked increase in synthesis of uterine (myometrial) oxytocin receptors late in gestation,
resulting from increasing concentrations of circulating estrogen.
Fig. 2.27. Effect of suckling on the release of prolactin, oxytocin, and gonadotropin-releasing hormone
(GnRH). Suckling has four effects. First, it stimulates sensory nerves, which carry the signal from the breast to
the spinal cord where they synapse with neurons that carry the signal to the brain. Second, in the arcuate nucleus
of the hypothalamus, the afferent input from the nipple inhibits neurons that release dopamine (DA). DA
normally travels via the hypothalamic-portal system to the anterior pituitary where it inhibits prolactin (PRL)
release by lactotrophs. Thus, inhibition of DA release leads to an increase in PRL release. Third, in the
supraoptic and paraventricular nuclei of the hypothalamus, the afferent input from the nipple triggers the
production and release of oxytocin in the posterior pituitary. Fourth, in the preoptic area and arcuate nucleus, the
afferent input from the nipple inhibits GnRH release. GnRH normally travels via the hypothalamic-portal
system to the anterior pituitary, where it stimulates the synthesis and release of follicle-stimulating hormone
(FSH) and luteinizing hormone (LH). Thus, inhibiting GnRH release inhibits FSH and LH release, and thereby
inhibits the ovarian cycle.
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Activity 2.19. Oxytocin
• What is the chemical nature of oxytocin? How is it synthesized in the hypothalamus? What
regulates the synthesis?
• Which body cells have the receptor for oxytocin? What is the nature of the receptor for
oxytocin? Describe the signal transduction mechanism after the receptor is activated by
oxytocin. What are the direct physiological effects of oxytocin?
In summary, oxytocin plays important roles in milk secretion and parturition. The stimulus
for milk secretion is the suckling act of the baby which stimulates the mechanoreceptor.
Afferent impulses are sent to the hypothalamus where neurons in the paraventricular nucleus
are stimulated. On reaching the nerve endings in the posterior pituitary, the impulses cause
increased intracellular Ca2+ which triggers exocytosis of oxytocin from the granules.
Either excess or deficiency of ADH can result in clinical disease. The concentrations of ADH
may be altered in various chronic pathophysiologic conditions, including congestive heart
failure, liver cirrhosis, and nephritic syndrome. The most frequent abnormality is a decrease
in ADH release in diabetes insipidus, a clinical syndrome resulting from the inability to form
concentrated urine. This condition can arise from either of two situations:
Diabetes insipidus is characterized by the excretion of abnormally large volumes (30 mL/kg
of body weight per day for adult subjects) of dilute (<250 mmol/kg) urine and excessive
thirst. Some patients produce as much as 16 liters of urine per day! If adequate water is
available for consumption, the disease is rarely life-threatening, but withholding water can be
very dangerous. Hypothalamic diabetes insipidus can be treated with exogenous antidiuretic
hormone e.g. desmopressin.
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Activity 2.20. Antidiuretic hormone (ADH)
• What is the chemical nature of ADH? How is it synthesized in the hypothalamus? What
regulates the synthesis?
• Which body cells have the receptor for ADH? What is the nature of the receptor for ADH?
Describe the signal transduction mechanism after the receptor is activated by ADH. What is the
direct physiological effect of ADH?
• Compare and contrast between hypothalamic (“central”) diabetes insipidus and nephrogenic
diabetes insipidus.
1. Hydration test
This test determines the ability of the body to increase the production and release of ADH
during water deprivation. Fluids are withheld from the individual, and the rise in urine
osmolality, which indicates the response of the body to conserve fluid, is measured. Normal
function consists of an increase in urine osmolality and a decrease in urine output during
water deprivation alone.
4. As in screening for other endocrine pathologies, plasma levels of ADH are determined
using radioimmunoassay. The values obtained are interpreted together with the indirect
assessment of antidiuretic activity triggered by a dehydration test.
An increase or excess in the release of ADH, also known as the syndrome of inappropriate
ADH secretion (SIADH), may be the result of tumor production of the hormone. The tumor
can be located in the brain, but malignancies of other organs such as the lung have also been
shown to produce high levels of ADH. The excess production of ADH results in the
production of very small volumes of concentrated urine. Retention of water may lead to
hyponatremia. Management of this condition entails fluid restriction and in some cases the
use of saline solutions to restore adequate plasma sodium levels.
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Summary
Table 2.5. Summary of anterior pituitary hormones
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Conclusions
Please write down your comments on the achievement of the objectives of this module.
Objectives Comments
1. Describe the gross anatomy and
microanatomy of the hypothalamus and
pituitary, including the hypothalamo-
pituitary axis, in terms of their endocrine
functions.
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