ENDOCRINE PHYSIOLOGY

Module 2

The Hypothalamic and

Pituitary Hormones

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

Prof. Dr. Hamdan Noor

March, 2017

Hamdan Noor
Cyberjaya University College of Medical Sciences
ENDOCRINE PHYSIOLOGY Module 2
Module 2: The Hypothalamic and
Pituitary Hormones

Sub-topics:

1. Functional Anatomy of the Hypothalamus and Pituitary Gland

1.1. The hypothalamus
1.2. The pituitary
1.3. The hypothalamo-pituitary axis

2. Overview of Hypothalamic and Pituitary Hormones

2.1. The hypothalamic hormones
2.2. Overview of the pituitary hormones

3. Anterior Pituitary Hormones

3.1. Growth Hormone
3.2. Prolactin
3.3. Thyroid Stimulating Hormone
3.4. Adrenocorticotropic Hormone
3.5. Gonadotropins: Luteinizing Hormone and Follicle Stimulating Hormone
3.6. Diseases pertaining to anterior pituitary hormones

4. Posterior Pituitary Hormones

4.1. Synthesis and release of posterior pituitary hormone
4.2. Antidiuretic Hormone (Vasopressin)
4.3. Oxytocin
4.4. Diseases pertaining to posterior pituitary hormones

Summary

Conclusion

Appendix

2
Learning Outcomes:

At the end of this Module you should be able to:

1. Describe the gross anatomy and microanatomy of the hypothalamus and pituitary,
including the hypothalamo-pituitary axis, in terms of their endocrine functions.
2. Describe the hypothalamic hormones in terms of their chemistry, biosynthesis, origin,
target cells, regulation of release, mechanism of action and the effect of over and
under secretion of the hormones.
3. Describe the anterior pituitary hormones in terms of their chemistry, biosynthesis,
origin, target cells, regulation of release, mechanism of action and the effect of over
and under secretion of the hormones.
4. Describe the posterior pituitary hormones in terms of their chemistry, origin,
biosynthesis, target cells, regulation of release, mechanism of action and the effect of
over and under secretion of the hormones.

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:

Notes in this Module

Boron and Boulpaep, Ch. 46
Widmaier, Raaf and Strang (Vander’s Human Physiology) Ch. 11
Marieb. Ch. 17
Tortora and Derrickson. Ch. 18
Guyton and Hall. Ch. 74
Ganong. Ch.18
Patricia E. Molina Endocrine Physiology, 2nd Edition (Access Medicine)

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).

Fig. 2.1. Locations of hypothalamus and pituitary gland

Activity 2.1: Hypothalamus and pituitary

• Label all the parts in Fig. 2.1.

• Note the location of the hypothalamus, pituitary gland, sella turcica.

• Enlarge the diagram of the hypothalamus to show its association with the pituitary gland.

• Explain the anatomy of hypothalamus and pituitary in terms of strategies in solving

physiological problems.

• Why are hypothalamic and pituitary neurons influential over physiological processes?

• What characterise the target cells for hypothalamic and pituitary hormones?

• What is the advantage of having a hormone affecting the activity of hormone-producing

cells?

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).

Fig. 2.2. The hypothalamus and pituitary gland

6
 Activity 2.2: The hypothalamic nuclei

• What is the meaning of “neurohormonal

nuclei”? Give examples that can be
found in the hypothalamus.

• Discuss the relationship between the

hypothalamus and pituitary in terms of
endocrine functions.

• Discuss the vasculature of the

hypothalamo-pituitary axis and relate it
to hormone transport.

The superior hypophysial artery (SHA), medial

hypophysial artery, and inferior hypophysial
artery (IHA) provide arterial blood supply to the
median eminence and the pituitary.
Magnocellular neurons of the supraoptic nuclei
(SON) and paraventricular nuclei (PVN) have
long axons that terminate in the posterior
pituitary

Fig. 2.3. The hypothalamus and pituitary gland

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

• Compare and contrast between the

magnocellular and parvocellular neuron.

• What is the advantage of having the

posterior pituitary as a storage place for
ADH and oxytocin?

• What is the advantage of releasing

hypophysiotropic hormone into the portal
vein?

• Discuss the factors that affect

hypothalamic secretion.

Fig. 2.4. Secretion from magnocellular and parvocellular neurons

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 pituitary is composed of two distinctive parts:

• The anterior pituitary (adenohypophysis) is a classical gland composed

predominantly of cells that secrete protein hormones.
• The posterior pituitary (neurohypophysis) is not really an organ, but an extension of
the hypothalamus. It is composed largely of the axons of hypothalamic neurons which
extend downward as a large bundle behind the anterior pituitary. It also forms the so-
called pituitary stalk, which appears to suspend the anterior gland from the
hypothalamus.

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.

1.3. The hypothalamo-pituitary axis

A key to understanding the endocrine relationship between hypothalamus and anterior

pituitary is to appreciate the vascular connections between these organs. As will be
emphasized in later sections, secretion of hormones from the anterior pituitary is under strict
control by hypothalamic hormones. These hypothalamic hormones reach the anterior
pituitary through the following route:

• 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

Activity 2.4: The hypothalamus-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?

• Use examples to explain the flow chart depicted in Fig. 2.6.

In summary, it is important to study the anatomy of the hypothalamus-pituitary axis because

of its physiological significance. The magnocellular nuclei in the hypothalamus produce
ADH and oxytocin that are delivered to the posterior pituitary via the axons. They are
transported into the circulation via the veins from the capillaries supplied by inferior
hypophyseal artery. The parvocellular nuclei secrete various neurohormones that are taken
up by the capillary bed in the median eminence supplied by superior hypophyseal artery and
delivered directly to the anterior pituitary where they influence its secretion.

11
2. Overview of Hypothalamic and Pituitary Hormones

The pituitary gland is often portrayed as the "master gland" or

“king of the endocrine gland” because the anterior and posterior
pituitary secrete a battery of hormones that collectively influence
all cells and affect virtually all physiologic processes. However,
the power behind the throne is actually the hypothalamus. As
discussed in Section 1, some of the neurons within the
hypothalamus - neurosecretory neurons - secrete hormones that
strictly control secretion of hormones from the anterior pituitary
(Fig. 2.7). The hypothalamic hormones (or hypophysiotropic
hormones) are referred to as releasing hormones and inhibiting
hormones, reflecting their influence on anterior pituitary
hormones (Table 2.1).

Fig. 2.7. Relationship between

hypothalamus, pituitary and systemic
target organs

2.1. The hypothalamic 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).

Table 2.1. Key aspects of hypophysiotropic hormones

Hypophysiotropic Predominant Anterior pituitary Target cell

hormone hypothalamic nuclei hormone controlled
Thyrotropin-releasing Paraventricular nuclei Thyroid-stimulating Thyrotroph
hormone (TRH) hormone and prolactin
Gonadotropin-releasing Anterior and medial Luteinizing hormone and Gonadotroph
hormone (GnRH) hypothalamus; preoptic follicle-stimulating
septal areas hormone
Corticotropin-releasing Medial parvocellular Adrenocorticotropic Corticotroph
hormone (CRH) portion of paraventricular hormone
nucleus
Growth hormone- Arcuate nucleus, close to Growth hormone Somatotroph
releasing hormone median eminence
(GHRH)
Somatostatin or growth Anterior paraventricular Growth hormone Somatotroph
hormone-inhibiting area
hormone
Dopamine Arcuate nucleus Prolactin Lactotroph

12
Fig. 2.8. Relationship between hypothalamic hormones, pituitary hormones and hormones from the peripheral
endocrine glands.

Activity 2.5. Hypothalamic hormones

• Why is the pituitary considered as the “master” gland or the “king” of the endocrine gland?

• Why is the hypothalamus considered as the “power behind the throne”?

• 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

A robust control system must be in place to prevent over- or under-secretion of

hypothalamic and anterior pituitary hormones because secretion of many other
hormones depend on them. A prominent mechanism for control of the releasing and
inhibiting hormones is negative feedback, as described in general in Module 1. Details
on the control of specific hypothalamic and anterior pituitary hormones are presented
later in the discussion of those hormones.

Activity 2.6: Factors influencing

hypothalamic functions

• List the factors that influence

hypothalamic functions. Discuss
how these factors affect
hypothalamic functions and body
functions in general.

• Give examples of how information

from the limbic system, the
thalamus, the visceral organs, the
reticular formation and hormones
from the circulation affect the
hypothalamic functions.

• What are “hypophysiotropic

hormones”? Discuss briefly how
these hormones affect hormone
secretion from the anterior
pituitary and posterior pituitary.

Fig. 2.9. Factors influencing endocrine function of the hypothalamus.

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.

Therefore, hypothalamic hormone release is under environmental, neural, and hormonal

regulation. The ability of the hypothalamus to integrate these signals makes it a center of
command for regulating endocrine function and maintaining homeostasis.

Review of feedback mechanism of hormone release

Hormones can signal the hypothalamus to either inhibit or stimulate hypophysiotropic

hormone release. This control mechanism of negative feedback regulation consists of the
ability of a hormone to regulate its own cascade of release. For example, cortisol produced
from the adrenal gland can inhibit the release of CRH, thus inhibiting the production of
ACTH and consequently decreasing adrenal gland synthesis of cortisol. This loop of
hormonal control and regulation of its own synthesis is critical in maintaining homeostasis
and preventing disease. A shorter loop of negative feedback inhibition also exists, that
depends on the inhibition of hypophysiotropic neuropeptide release by the pituitary hormone
that it stimulates. In this case, an example would be the ability of ACTH to inhibit CRH
release by the hypothalamus. Some neuropeptides also possess an ultra-short feedback loop,
in which the hypophysiotropic neuropeptide itself is able to modulate its own release. As an
example, oxytocin stimulates its own release (via uterine smooth muscle contraction),
creating a positive feedback regulation of neuropeptide release.

Fig. 2.10. Negative feedback mechanism

Activity 2.7: Principles of negative feedback system of hormone secretion

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.

Discuss why negative feedback is very important in regulating hormone secretion.

15
This continuous regulation of hormonal release is dynamic; it is continuously adapting to
changes in the environment and in the internal milieu of the individual. Throughout a given
day, the hypothalamus integrates a multitude of signals to ensure that the rhythms of hormone
release are kept in pace with the needs of the organism. Disruption of these factors can alter
the patterns of hormone release. For example, a patient in the intensive care unit, where the
lights are on 24 hours of the day, will have a disrupted cycle of hormone release. Other
situations that disrupt the normal cycles of hormone release are travel across time zones and
night-shift employment.

In summary, regulation of hypothalamic hormone release is brought about by various sensory

inputs from the external and internal environments. After integrating them, the hypothalamus
dispenses efferent outputs to the effectors via the autonomic nervous system and the
hypothalamic neurohormones. The neurohormones act on anterior pituitary cells to
stimulate/inhibit secretion of pituitary hormones which then control various peripheral target
glands/tissues.

2.3. Overview of the pituitary hormones

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.

Table 2.2. The pituitary hormones

Gland Hormone Major target organ(s) Major Physiologic

Effects
Anterior Pituitary Growth hormone Liver, adipose tissue, Promotes growth
most body cells (indirectly), control of
protein, lipid and
carbohydrate
metabolism
Thyroid-stimulating Thyroid gland Stimulates secretion of
hormone thyroid hormones
Adrenocorticotropic Adrenal gland (cortex) Stimulates secretion of
hormone glucocorticoids
Prolactin Mammary gland Milk production
Luteinizing hormone Ovary and testis Control of reproductive
function
Follicle-stimulating Ovary and testis Control of reproductive
hormone function
Posterior Pituitary Antidiuretic hormone Kidney Conservation of body
water
Oxytocin Ovary and testis Stimulates milk ejection
and uterine
contractions

Activity 2.7. Predicting mechanism of action of hormones

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).

Table 2.3. The regulatory hypothalamic factors

Anterior pituitary cells Hypothalamic factor Pituitary hormone produced

Lactotrophs Dopamine Prolactin
Corticotrophs CRH POMC: ACTH, β-LPH, α-MSH, β-
endorphin
Thyrotrophs TRH TSH
Gonadotrophs GnRH LH and FSH
Somatotrophs GHRH GH

The hormones of the anterior pituitary can be classified into 3 families:

• The glycoproteins - heterodimers consisting of a common α-subunit and a unique β-

subunit, which confers the biologic specificity of each hormone. They include TSH,
FSH, LH, and human chorionic gonadotropin produced by the placenta.

• those derived from proopiomelanocortin (POMC). POMC is a precursor pro-

hormone produced by the corticotrophs of the anterior pituitary. Corticotrophs
account for 10% of the secretory cells of the anterior pituitary. POMC is post-
translationally cleaved to ACTH; β-endorphin, an endogenous opioid peptide; and α-,
β- and -melanocyte-stimulating hormones (MSH). The biologic effects of POMC-
derived peptides are largely mediated through melanocortin receptors (MCRs).

• 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.

17
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.

3.1.1. Physiologic effects of Growth Hormone

A critical concept in understanding growth hormone

activity is that it has two distinct types of effects:
• Direct effects are the result of growth hormone
binding its receptor on target cells. Fat cells
(adipocytes), for example, have growth hormone
receptors, and growth hormone stimulates them to
break down triglyceride and suppresses their ability
to take up and accumulate circulating lipids.
• Indirect effects are mediated primarily by an
insulin-like growth factor-I (IGF-I) aka
somatomedin, a hormone that is secreted from the
liver and other tissues in response to growth
hormone. A majority of the growth promoting
effects of growth hormone is actually due to IGF-I
acting on its target cells.
Fig. 2.11. Direct and indirect effect of GH

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.

18
 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.
19
 • 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.

3.1.2. Mechanism of action of Growth Hormone

Size of GH: 190 a.a.; half-life: 25 minutes

GH receptor: 620 a.a.; tyrosine kinase-associated receptor. This tyrosine kinase triggers a
series of protein phosphorylation that modulate target cell activity.

3.1.3. Control of Growth Hormone secretion

Production of growth hormone is modulated by many factors, including stress, exercise,

nutrition, sleep and growth hormone itself. However, its primary controllers are two
hypothalamic hormones and one hormone from the
stomach:
• Growth hormone-releasing hormone
(GHRH) is a hypothalamic peptide that
stimulates both the synthesis and secretion
of growth hormone.
• Somatostatin (SS) is a peptide produced by
several tissues in the body, including the
hypothalamus. Somatostatin inhibits
growth hormone release in response to
GHRH and to other stimulatory factors
such as low blood glucose concentration.
• Ghrelin is a peptide hormone secreted from
the stomach. Ghrelin binds to receptors on
somatotrophs and potently stimulates
secretion of growth hormone. Fig. 2.13. Control of pituitary secretion

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.

Small-bodied neurons in the

arcuate nucleus of the
hypothalamus secrete GHRH, a
43-amino acid peptide that
reaches the somatotrophs in the
anterior pituitary via the long
portal veins. GHRH stimulates
the somatotrophs to release GH
stored in secretory granules by
raising [cAMP]i and [Ca2+]i.
Neurons in the periventricular
region of the hypothalamus
synthesize somatostatin, a 14-
amino acid neuropeptide.
Somatostatin, which also travels
to the anterior pituitary via the
long portal vessels, is a potent
inhibitor of GH secretion.
Somatostatin acts by inhibiting
adenylyl cyclase and thus
lowering [Ca2+]i. AC, adenylyl
cyclase; PKA, protein kinase A;
SS, somatostatin.

Key aspects of GH physiology can be summarized as follows:

• GH is produced and stored in somatotrophs in the anterior pituitary.

• The production of GH is pulsatile, mainly nocturnal, and is controlled by GHRH and
somatostatin.
• Circulating levels of GH increase during childhood, peak during puberty, and fall with
aging.
• GH stimulates lipolysis, amino acid transport into cells, and protein synthesis; inhibits
glucose uptake.
• GH stimulates the production of IGF-I, which is responsible for many of the activities
attributed to GH.

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.

Clinically, deficiency in growth hormone or receptor defects are manifested as growth

retardation or dwarfism. The manifestation of growth hormone deficiency depends upon the
age of onset of the disorder and can result from either heritable or acquired disease.

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.

3.1.5. Pharmaceutical and biotechnological uses of Growth Hormone

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.
.

22
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?

• Describe the clinical consequence of hyposecretion and hypersecretion of GH.

In summary, GH is secreted by the somatotrophs of the anterior pituitary and regulated by

GHRH and somatostatin released by the hypothalamus. GH works on various effectors
(muscle, liver, adipose tissues) either directly or via IGF-I by stimulating protein synthesis,
lipolysis and amino acid transport into cells. Deficiency in GH would result in growth
retardation or dwarfism, whereas excessive secretion of GH would result in gigantism (in
young children) or acromegaly (in adults).

23
3.2. Prolactin (PRL)

Prolactin is a single-chain protein hormone closely related to growth hormone. It is secreted

by lactotrophs in the anterior pituitary. It is also synthesized and secreted by a broad range of
other cells in the body, most prominently various immune cells, the brain and the decidua of
the pregnant uterus.

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.

3.2.1. Physiologic effects of prolactin

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.

Mammary gland development, milk production and reproduction

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.

Effects on immune function

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.

A considerable amount of research is in progress to delineate the role of prolactin in normal

and pathologic immune responses. It appears that prolactin has a modulatory role in several
aspects of immune function, but is not strictly required for these responses.

24
3.2.2. Control of prolactin secretion

In contrast to what is seen with all the other pituitary

hormones, the hypothalamus tonically suppresses prolactin
secretion from the pituitary. In other words, there is usually a
hypothalamic "brake" set on the lactotroph, and prolactin is
secreted only when the brake is released. If the pituitary stalk
is cut, prolactin secretion increases, while secretion of all the
other pituitary hormones fall dramatically due to loss of
hypothalamic releasing hormones.

Dopamine serves as the major prolactin-inhibiting factor or Fig. 2.15. Regulation of

brake on prolactin secretion. Dopamine is secreted into portal prolactin release
blood by hypothalamic neurons, binds to receptors on
lactotrophs, and inhibits both the synthesis and secretion of prolactin. Agents and drugs that
interfere with dopamine secretion or receptor binding lead to enhanced secretion of prolactin.

In addition to tonic inhibition by dopamine, prolactin secretion is positively regulated by

several hormones, including thyroid-releasing hormone, gonadotropin-releasing hormone and
vasoactive intestinal polypeptide. Stimulation of the nipples and mammary gland, as occurs
during nursing, leads to prolactin release. This effect appears to be due to a spinal reflex arc
that causes release of prolactin-stimulating hormones from the hypothalamus.

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.

3.2.3. PRL abnormality

Excessive secretion of prolactin - hyperprolactinemia - is a relatively common disorder in

humans. This condition has numerous causes, including prolactin-secreting tumors and
therapy with certain drugs.
Common manifestations of hyperprolactinemia in women include amenorrhea (lack of
menstrual cycles) and galactorrhea (excessive or spontaneous secretion of milk). Men with
hyperprolactinemia typically show hypogonadism, with decreased sex drive, decreased sperm
production and impotence. Such men also often show breast enlargement (gynecomastia), but
very rarely produce milk.

Activity 2.10. Prolactin (PRL)

• 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?

• Describe the clinical consequence of hyposecretion and hypersecretion of PRL.

25
3.3. Thyroid-Stimulating Hormone (TSH or Thyrotropin)

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.

TSH is a glycoprotein hormone composed of two subunits

which are non-covalently bound to one another (Fig. 2.16).
The alpha subunit of TSH is also present in two other
pituitary glycoprotein hormones, follicle-stimulating
hormone (FSH) and luteinizing hormone (LH), and, in
primates, in the placental hormone chorionic gonadotropin.
Each of these hormones also has a unique beta subunit,
which provides receptor specificity. In other words, TSH is
composed of alpha subunit bound to the TSH beta subunit,
and TSH associates only with its own receptor. Free alpha Fig. 2.16. Subunits of glycoprotein
hormones
and beta subunits have essentially no biological activity.

The most important controller of TSH secretion is

thyrotropin-releasing hormone, TRH.

Thyrotropin-releasing hormone is only three

amino acids long. Its basic sequence is glutamic
acid-histidine-proline, where both ends of the
peptide are modified. TRH binds to a Gq
protein–coupled receptor, which activates Fig. 2.17. Control of TSH secretion
phospholipase C, leading to increased
phosphoinositide turnover, calcium mobilization,
and release of TSH into the circulation. TSH binds to a Gs protein–coupled receptor in the
thyroid gland, activating adenylate cyclase, which leads to increased intracellular cAMP
formation and stimulation of the protein kinase A signaling pathway. TSH stimulates all the
events involved in thyroid hormone synthesis and release, especially stimulation of thyroid
peroxidase.

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)

Adrenocorticotropic hormone stimulates the adrenal cortex to

secrete glucocorticoids such as cortisol, and has little control
over secretion of aldosterone, the other major steroid
hormone from the adrenal cortex. Another name for ACTH is
corticotropin.

ACTH is secreted from the anterior pituitary in response to

corticotropin-releasing hormone (CRH) from the
hypothalamus. CRH is secreted in response to many types of
stress, which makes sense in view of the "stress management"
functions of glucocorticoids. CRH itself is inhibited by
glucocorticoids, making it part of a classical negative
feedback loop (Fig. 2.18). Fig. 2.18. Control of ACTH
secretion

Additional information on the role of ACTH in regulation of adrenal steroid secretion is

presented in the Module 3 on the adrenal gland.

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.

Fig. 2.19. Protein precursor of ACTH, MSH, endorphin and met-enkaphalin

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):

Activity 2.12. Adrenocorticotropic hormone (ACTH)

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?

3.5. Gonadotropins: Luteinizing hormone (LH) and Follicle Stimulating

Hormones (FSH)

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.

3.5.1. Physiologic effects of Gonadotropins

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.

Luteinizing Hormone (LH)

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.

In females, ovulation of mature follicles on the ovary is induced by a large burst of LH

secretion known as the preovulatory LH surge. Residual cells within ovulated follicles
proliferate to form corpora lutea, which secrete the steroid hormones progesterone and
estradiol. Progesterone is necessary for maintenance of pregnancy, and, in most mammals,
LH is required for continued development and function of corpora lutea. The name
luteinizing hormone derives from this effect of inducing luteinization of ovarian follicles.

28
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.

FSH is also critical for sperm production. It

supports the function of Sertoli cells, which in
turn support many aspects of sperm cell
maturation.

3.5.2. Control of Gonadotropin secretion

The principle regulator of LH and FSH

secretion is gonadotropin-releasing hormone
or GnRH (also known as LH-releasing
hormone). GnRH is a ten amino acid peptide
that is synthesized and secreted from
hypothalamic neurons and binds to receptors
on gonadotrophs.

As depicted in Fig. 2.20, GnRH stimulates

secretion of LH, which in turn stimulates Fig. 2.20. Control of gonadotropin secretion
gonadal secretion of the sex steroids
testosterone, estrogen and progesterone. In a classical negative feedback loop, sex steroids
inhibit secretion of GnRH and also appear to have direct negative effects on gonadotrophs.

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.

3.5.3. LH and FSH abnormality

Diminished secretion of LH or FSH can result in failure of gonadal function (hypogonadism).

This condition is typically manifest in males as failure in production of normal numbers of
sperm. In females, cessation of reproductive cycles is commonly observed.

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.

29
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.

Activity 2.13. Gonadotropins

• 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?

• Describe the clinical consequence of hyposecretion and hypersecretion of gonadotropins.

3.6. Diseases of the Anterior Pituitary

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.

Hormone-producing pituitary adenomas

The most common cause of excess production of pituitary hormones is a hormone-producing
pituitary adenoma.
• Prolactinomas are the most common (40–45%),
• Somatotroph (20%),
• Corticotroph (10–12%),
• Gonadotroph (15%), and
• Thyrotroph (rarely: 1–2%).

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.

Patients with a prolactinoma present with elevated levels of prolactin (hyperprolactinemia),

milk secretion (galactorrhea), and reproductive dysfunction. In males, prolactinomas may
cause infertility by producing hypogonadism. In most cases, dopamine agonists are extremely

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.

GH-secreting adenomas can be associated with acromegaly or bone and soft-tissue

overgrowth in adults, and with gigantism in children.

Corticotropin-releasing adenomas are associated with excess cortisol production or Cushing

syndrome; patients present with central obesity, proximal myopathy, hypertension, mood
changes, dorso-cervical fat pads, and hyperglycemia, among other clinical signs and
symptoms.

Gonadotroph pituitary adenomas are frequently inefficient in hormone production.

Thyrotropin-secreting tumors are rare and are frequently large when diagnosed.

Hypopituitarism

Hypopituitarism, or deficiency of anterior pituitary hormones, can be congenital or acquired.

Isolated GH and gonadotropin deficiencies are the most common. The most frequent cause of
pituitary insufficiency is trauma, such as that associated with surgery, penetrating injury, or
automobile accidents. Severe blood loss and hypoperfusion of the pituitary can also lead to
pituitary insufficiency. Ischemic damage to the pituitary gland or hypothalamic-pituitary stalk
during the peripartum period leads to Sheehan syndrome, manifested as hypothyroidism,
adrenal insufficiency, hypogonadism, GH deficiency, and hypoprolactinemia.

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

Growth failure can be the result of decreased GH release, decreased GH action, or GH

insensitivity syndrome, also known as Laron syndrome. The syndrome is characterized by
deletions or mutations in the GH receptor gene, resulting in failure to generate IGF-I and
IGFBP-3. The typical manifestation is short stature or dwarfism, which can be prevented by
IGF-I treatment. The study of these patients has provided much of our understanding of the
differential effects of GH and IGF-I.

Evaluation of anterior pituitary function

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

Pituitary tropic hormone Target organ hormone

ACTH (8:00 AM) <80 pg/mL (<80 pmol/L)
GH 2–6 ng/mL (<5 g/L)
FSH
Female: 5–25 IU/L (3–35 mIU/mL)
Male: 5–20 IU/L (5–20 mIU/mL)
LH (adult, premenopausal)
Female: 5–20 IU/L (20–50 mIU/mL)
Male: 5–20 IU/L (20–50 mIU/mL)
TSH 0.4–5 mU/L (0.4–5 U/mL)
Prolactin 2–15g/L (25 ng/mL)
Cortisol (8:00 AM) 140–690 nmol/L (5–25 g/dL)
IGF-I 140–400 ng/mL
Estradiol
Female: 70–220 pmol/L (20–60 pg/mL)
Male: <180 pmol/L (50 pg/mL)
Progesterone
Female: luteal peak >16 nmol/L (75 ng/mL)
Male: <6 nmol/L (<2 ng/mL)
Testosterone
Female: <3.5 nmol/L (<1 ng/mL)
Male: 10–35 nmol/L (3–10 ng/mL)
Thyroxine 64–154 nmol/L (5–12g/dL)
Triiodothyronine 1.1–2.9 nmol/L (70–190 ng/dL)

Table 3.5. Relative Frequency of Occurrence of Pituitary Tumors

Lactotroph (PRL) 30%

Somatotroph (GH) 15%
Combined GH/PRL 8%
Corticotroph (ACTH) 15%
Thyrotroph (TRH) 1%
Pleurihormonal 4%
Nonfunctioning 27%

32
4. Posterior Pituitary Hormones
4.1. Synthesis and release of
posterior pituitary hormones

Hormones released by the posterior

pituitary include ADH and oxytocin. They
are synthesized in the endoplasmic
reticulum (ER) of hypothalamic
magnocellular neurons as pre-prohormones
(Fig. 2.21). In the Golgi apparatus (GA),
they are packaged in secretory granules and
are transported down the axons of the
hypothalamo-hypophysial tract. During
transport, the precursor hormones are
processed, yielding the final hormone and
the respective neurophysins (carrier
proteins). The contents of the
neurosecretory vesicles are released by
exocytosis from the axon terminals in the
posterior pituitary. Exocytosis is triggered
by the influx of Ca2+ through voltage-gated
channels that are opened during neuronal
depolarization. The rise in Ca2+ allows
docking of the secretory vesicles on the
axonal plasma membrane and release of the
neuropeptides into the interstitial space.
Fig. 2.21. Synthesis and release of posterior pituitary
hormones

4.2. Antidiuretic Hormone (ADH)

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.

33
4.2.2. Physiologic Effects of Antidiuretic Hormone

Effects on the kidney

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.

Antidiuretic hormone stimulates water reabsorption by stimulating insertion of "water

channels" or aquaporins into the membranes of kidney tubules (Fig. 2.22). These channels
transport solute-free water through tubular cells and back into blood, leading to a decrease in
plasma osmolarity and an increase osmolarity of urine. Acting through cAMP, ADH causes
vesicles containing aquaporin 2 to fuse with the apical membrane of principle cells of the
collecting tubules and ducts.

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.

AQP2 Exclusively expressed in the collecting ducts. The only aquaporin

directly regulated by ADH. Binding to the V2 ADH receptor stimulates
insertion into the luminal membrane.

AQP3, AQP4 Constitutively expressed in the basolateral membranes of epithelial

cells in the collecting ducts. Enhance water reabsorption following
AQP2 insertion into the luminal membrane.

Activity 2.14: Effect of ADH on urine formation

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?

Effects on the vascular system

In many species, high concentrations of antidiuretic hormone cause widespread

constriction of arterioles, which leads to increased arterial pressure. Mechanism: ADH binds
to V1 receptor on arteriolar smooth muscle  activating PLC via Gq DAG and IP3
Intracellular Ca++ contraction. It was for this effect that the name vasopressin was coined.
In healthy humans, antidiuretic hormone has minimal pressor effects.

4.2.3. Control of Antidiuretic Hormone secretion

The most important variables regulating antidiuretic hormone secretion is plasma

osmolarity, (the concentration of solutes) and blood volume. Osmolarity is sensed by
neurons known as an osmoreceptors in the subfornical organ and the organum
vasculosum (anteroventral area of the third ventricle) of the hypothalamus (Fig.2.23). The
osmoreceptor cells are in the vicinity of capillaries that have no blood brain barrier.

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.

Activity 2.15: Effect of osmolarity on ADH

release

Name 2 factors that trigger ADH release. Hint: high

osmolarity and low blood volume.

What is the plasma osmolarity threshold level that

would trigger ADH release? Hint: refer to Activity 2.14.
When would this happen?

Where are the chemoreceptors that detect plasma

osmolarity situated?

How does high osmolarity stimulate chemoreceptors to

fire action potentials? Where are the action potentials
transmitted to?

What is the effect of the action potentials transmitted in

the neurons originating from the supraoptic nuclei?
Describe the mechanism of ADH release from the
terminal ends of these neurons (i.e. in the posterior
pituitary).
Fig. 2.23. Effect of osmolarity on ADH release

Activity 2.16: Effect

of low blood
volume on ADH
release.

What could be the

causes of reduced
blood volume?

How does blood loss

(>10%) affect ADH
secretion?

Hint: Blood loss and a

decrease in mean arterial
blood pressure (MABP)
greater than 10% signal
the hypothalamus to
increase the release of
AVP. The afferent signals
are transmitted by the 9th
and 10th cranial nerves.
These signals increase
sympathetic tone,
therefore decreasing
magnocellular neuron
inhibition and stimulating
ADH release.

Fig. 2.24. Signals that trigger ADH release.

36
 Fig. 2.25. The ADH secretion pathway

Activity 2.17. Summary of mechanism of ADH secretion

Refer to Fig. 2.25.

• 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.

37
.
4.3. Oxytocin

4.3.1. Introduction

Oxytocin in a nine amino acid peptide that is synthesized in hypothalamic paraventricular

neurons and transported down the axons in posterior pituitary for secretion into the blood.
Oxytocin is also secreted within the brain and from a few other tissues, including the ovaries
and testes. Oxytocin differs from ADH in two of the nine amino acids. Both hormones are
packaged into granules and secreted along with carrier proteins called neurophysins.

4.3.2. Physiologic effects of Oxytocin

Oxytocin mediates three major effects:

• 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.

Circulating oxytocin binds to G(q)-coupled oxytocin receptors on the plasma membrane

of uterine smooth muscle cells, triggering the phospholipase C cascade. Formation of IP3
leads to Ca2+ release from internal stores and increase in intracellular Ca2+. This activates
calmodulin which stimulates MLCK to phosphorylate the regulatory light chain, causing
contraction of uterine smooth muscle cell.

• Establishment of maternal behavior: During parturition, there is an increase in

concentration of oxytocin in cerebrospinal fluid, and oxytocin acting within the brain
plays a major role in establishing maternal behavior.

38
Activity 2.18:
Physiologic effects
and regulation of
oxytocin release.

List and explain factors

that stimulate oxytocin
release. What are the
receptors?

Where are the afferent

signals sent to?

Why is the loop called

“positive feedback”?

How is uterine muscle’s

responsiveness
enhanced?

The increased number of

oxytocin receptors, the
increased number of gap
junctions between smooth
muscle cells, and the
increased synthesis of
prostaglandins enhance
the responsiveness of the
uterine muscle.

What are the final

physiological effects of
oxytocin?

Fig. 2.26. Physiologic effects of oxytocin and the control of parturition

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.

4.3.3. Control of Oxytocin secretion

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.

39
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.

40
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?

• Describe the clinical consequence of hyposecretion and hypersecretion 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.

4.4. Diseases pertaining to the posterior pituitary

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:

• Hypothalamic ("central") diabetes insipidus results from a deficiency in secretion of

antidiuretic hormone from the posterior pituitary. Causes of this disease include head
trauma, and infections or tumors involving the hypothalamus.
• Nephrogenic (renal) diabetes insipidus occurs when the kidney is unable to respond to
antidiuretic hormone. Most commonly, this results from some type of renal disease,
but mutations in the ADH receptor gene or in the gene encoding aquaporin-2 have
also been demonstrated in affected humans.

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.

41
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?

• Describe the clinical consequence of hyposecretion and hypersecretion of ADH.

• Compare and contrast between hypothalamic (“central”) diabetes insipidus and nephrogenic
diabetes insipidus.

Diagnosis of diabetes insipidus

Evaluation of ADH status

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.

2. Synthetic ADH challenge.

Individuals with normal pituitary function do not exhibit a further increase in urine
osmolality following the administration of a synthetic ADH analog (desmopressin).
Individuals with central diabetes insipidus have a greater than 9% increase in urine
osmolality following desmopressin administration, indicating that the body is not capable of
producing maximal release of ADH and consequently does a better job when a synthetic
analog of ADH is administered.

3. Response to osmotic stimulation produced by the intravenous infusion of hypertonic (5%)

saline solution.

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.

Syndrome of inappropriate ADH secretion (SIADH)

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.

42
Summary
Table 2.5. Summary of anterior pituitary hormones

ACTH GH Prolactin TSH LH FSH

Receptor ACTH-receptor GH receptor Prolactin TSH LH FSH
(melanocortin- receptor receptor receptor receptor
2-receptor)
Source Corticotropes Somatotrop Lactotropes Thyrotrop Gonadotro Gonadotro
(pituitary) es (pituitary) (pituitary) es pes pes
(pituitary) (pituitary) (pituitary)
Hypothala CRH, AVP GHRH TRH TRH GnRH GnRH
mic (ghrelin)
releasing
hormone
Target Adrenal gland Liver Mammary Thyroid Ovary Ovary
(production gland gland (theca cell, (granulosa
of IGF-1), ganulosa cell) / testis
peripheral cell, luteal (Leydig
tissue cell) / testis cell)
(Sertoli
cell)
Function Stimulating Stimulating Stimulating Stimulatin Stimulating Regulating
cortisol release growth lactation g thyroid estrogen / theca- and
(direct and hormone testosteron Sertoli cell
indirect release e function
effect via production
IGF-1)

43
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.

2. Describe the hypothalamic hormones in

terms of their chemistry, biosynthesis, origin,
target cells, regulation of release, mechanism
of action and the effect of over and under
secretion of the hormones.

3. Describe the anterior pituitary hormones in

terms of their chemistry, biosynthesis, origin,
target cells, regulation of release, mechanism
of action and the effect of over and under
secretion of the hormones.

4. Describe the posterior pituitary hormones in

terms of their chemistry, biosynthesis, origin,
target cells, regulation of release, mechanism
of action and the effect of over and under
secretion of the hormones.

44