Block 1

Unit 1 Introduction to Endocrinology
UNIT 1
INTRODUCTION TO
ENDOCRINOLOGY
Structure
1.1 Introduction 1.5 Transport and Metabolism of
Hormones
Expected Learning Outcomes
1.6 Functions of Hormones and

1.2 Endocrine Glands
their Regulation.
1.3 Chemical Signaling
1.7 Summary
1.4 Chemical Classification of
1.8 Terminal Questions
Hormones
1.9 Answers
1.1 INTRODUCTION
Endocrinology is a scientific discipline in which we study about cell-to-cell
signaling with a focus on specific chemicals called hormones that travel
through the bloodstream to influence remote targets. Further, endocrinology
requires a multidisciplinary approach to understand hormones and their role in
the body physiology. Our body's endocrine system is composed of
hypothalamus, pituitary, pineal, thyroid, parathyroid, adrenal, pancreas,
gastro-intestinal tract and gonad (testis and ovary). Additionally, it also
encompasses many other organs that respond to, modify or metabolize
hormones. The dynamic concert of feedback regulation and cellular actions of
the hormones of the endocrine system underwrites the internal homeostasis of
the human body.
In this unit you will study about endocrine glands, different classes of
hormones secreted by them and the underlying mechanism of hormone
signaling. You will also learn about the functions and regulation of various
hormones and how they are circulated, metabolized and excreted.
7
Block 1 Hypothalamic and Pituitary Hormones

After studying this unit, you should be able to:
define and classify hormones;
explain various types of hormonal signaling;
explain the transport of hormones in the circulation and their half-lives,

metabolism and excretion; and
explain the versatile functions of hormones and their regulation.
1.2 ENDOCRINE GLANDS

The endocrine system comprises of a set of glands and organs that regulate
and control various functions of the body by producing and secreting
hormones into the extracellular fluid. The endocrine system establishes the
homeostasis in various physiological activities of the organism, regulates its
development throughout life, and helps to respond to nutritional and other
external environmental changes.
Hormones are chemical substances that gain access to the bloodstream, often
via fenestrated capillaries and act in concert as messengers and thus,
regulate and coordinate target organs throughout the body.
Endocrine gland: The hormones are secreted by the group of specific cells,
in the endocrine glands, and are carried by the circulation to exert their
actions on tissues distant from the site of their secretion. Each endocrine
gland entails an assembly of specialized cells that have a common origin in
the developing embryo.
The endocrine gland releases hormones into the bloodstream, whereas

exocrine gland secretes their contents through a duct opening onto an
external or internal surface of the body. Salivary and sweat glands are
examples of exocrine glands.
The major glands of the endocrine system produce one or more specific
hormones, are as follows:
Endocrine Hormones Molecular Target Organs Functions

Glands Characteris
tics
Hypothalamus Hypothalamic Peptide Anterior pituitary Regulate anterior

releasing and pituitary hormone
inhibiting hormones
Anterior Thyroid stimulating Glycoprotein Thyroid Stimulates thyroid

Pituitary (TSH)
Adrenocorticotropic Peptide Adrenal cortex Stimulates adrenal

cortex
Gonadotropic (FSH, Glycoprotein Gonads Sex hormone

LH) production, egg and
sperm production
Prolactin (PRL) Protein Mammary glands Milk Production
8
Growth Hormone Protein Soft Tissue, Cell division, protein
(GH) bones synthesis and bone
growth
Posterior Oxytocin Peptide Uterus, mammary Stimulates uterine

Pituitary glands contraction, breast
contraction for milk
release
Anti-diuretic Peptide Kidneys Stimulates

Hormone reabsorption of
(Vasopressin) water from kidney
tubules
Pineal gland Melatonin Serotonin Various tissues Circadian rhythm,

derived Reproduction
Thyroid Gland Thyroxine (T4) Iodinated All tissues Increase metabolic

Triiodothyronine (T3) amino acid rate, regulates
growth and
development
Calcitonin Peptide Bones, kidneys Lowers blood

and intestine calcium level
Parathyroids Parathyroid hormone Peptide Bones, kidneys Raises blood

(PTH) and intestine calcium level
Adrenal Cortex Glucocorticoids Steroid All tissues Raise blood glucose

level, stimulates
(Cortisol) breakdown of
protein
Mineralocorticoids Steroid Kidneys Reabsorb sodium

(Aldosterone, and secrete
Cortisol) potassium
Adrenal Epinephrine and Catecholami Cardiac and other Released in

Medulla Norepinephrine nes muscles emergency
situations, raises
blood glucose level,
‘fight or flight’
response
Stomach Gastrin Peptide Enterochromaffin- Stimulates secretion

like (ECL) cells of gastric acid
Pancreas Insulin Protein Liver, muscles, Lowers blood

adipose tissue glucose levels,
promotes formation
of glycogen
Glucagon Protein Liver, muscles, Raise blood glucose

adipose tissue levels
Somatostatin Protein All tissues Exerts an inhibitory

(Growth Hormone- action on numerous
inhibiting hormone) physiological
functions –
production of
hormones;
unnatural rapid
reproduction of cells
(in tumors)
Duodenum and Secretin Protein Pancreas and Regulates water

Jejunum Stomach homeostasis
throughout the body
9
Cholecystokinin Protein Gallbladder Causes the release

of digestive
enzymes and bile
from the pancreas
and gallbladder,
respectively; acts as
a hunger
suppressant
Ovary Estrogen, androgen, Steroid Gonads, skin, Stimulates female

Progesterone muscles and bone sex characteristics
Testis Androgens Steroid Gonads, skin, Stimulates male sex

(Testosterone) muscles and bone characteristics
SAQ 1
a) Tick [√] mark the correct statement:
i) Oxytocin and vasopressin are peptides and secreted by posterior

pituitary.
ii) Insulin increases blood glucose levels and promotes formation of

glycogen.
iii) Gastrin stimulates secretion of gastric acid.
b) Fill in the blanks with appropriate words:
i) Salivary and sweat glands are examples of …………………...
ii) Vasopressin is also known as ………………………..
1.3 CHEMICAL SIGNALING

In order to rapidly respond to changes in their environment, cells undergo
Chemical signals
fundamental cellular process of cell-cell signaling. Cell signaling, which is also
are molecules
secreted by cells into known as signal transduction or transmembrane signaling, is the vital process
the extracellular fluid. for communicating specific information from the cell surface to cytoplasm
The cells that respond leading to changes in gene expression in the nucleus. As a process, cell
to chemical signals
signaling denotes to a vast network of communication between and/or within
are called target cells.
Chemical signals are
the cells or with their external environment. All cells have the capacity to
accountable for accomplish this to some degree, although with an extensive variation in
utmost purpose, mechanism, and response.
communication within
the body. Chemical Cells stereotypically communicate using chemical signals, which can be
signals act proteins, short peptides, amines, nucleotides, steroids, even gases or other
as ligands that bind to molecules produced by the signaling cell, released into the extracellular
receptor ptoteins to
fluid around cells which are recognized and bound by a specific receptor
initiate a response.
protein in the target cell. The signal molecule binding to the receptor sets off
a cascade of events in the target cell. The receptors are broadly of two types –
cell surface and intracellular (Fig. 1.1).
10
Fig. 1.1: Types of Receptors. (a) Cell-surface receptors, also known as

membrane or transmembrane receptors are embedded in the plasma membrane
of cells and act in cell signaling by binding to extracellular molecules; (b)
Intracellular Receptors reside in the cytoplasm or in the nucleus. Their actions
involve membrane permeable ligands.
The cascade of signaling events can be divided into three steps:
1. Reception: Cell perceives a signaling molecule from the exterior of the

cell.
2. Transduction: Binding of signaling molecule to the receptor changes

the three dimensional configuration of receptor protein. This change
initiates the process of transduction.
3. Response: Finally, the signal triggers a specific cellular response.
In a multicellular organism, the average cell is exposed to numerous signals of

varying kinds but the cell responds to specific signals primarily depending
upon the receptors that the cell possesses. If a cell is deficit of a receptor for a
signal, it cannot respond to it. Different cells have a specific set of receptors,
so accordingly, they respond to only some signals and not others. However,
regardless of a limited set of receptors, cells respond to a stunning array of
signals with an inordinate diversity of responses because:
i. A single signal can generate a variety of responses in a target cell.
ii. Each relayed signal depends on the cell type and different cells may
respond to the same signal in a different way (Fig. 1.2).
Fig. 1.2: Cell Signaling involves a receptor, a cellular protein that recognizes the
signaling molecule and transmitted signal depends on the cell type. Different
cells respond in a diverse way to the same signal. 11
iii. Since the cell has several receptors, a given cell can receive dozens of
signals at the same time. The occurrence of one signal can affect the
response to another signal, which means the cell can have diverse
responses depending on the blends of signals received (Fig 1.3).
Fig. 1.3: Cell Signaling: Each cell type shows a set of receptors which allows it
to respond to a conforming set of signal molecules formed by other cells. These
signal molecules regulate the behavior of cells by working in combinations. As
shown here, a specific cell involves numerous signals (blue arrows) to persist
and added signals (red arrow) to divide or differentiate (green arrows). If
appropriate survival signals are not present, a cell will undergo apoptosis.
Modes of cell-cell signaling: Cell signaling can take place in different ways:
Cryptocrine system- a) Local Signaling

exudation of a
hormone into a closed i) Cell-cell contact dependent signals require interaction between
milieu and entails membrane molecules on two cells (Fig. 1. 4A).
intimacy between
cells, for instance ii) Gap Junctions form direct cytoplasmic connections between
connotation between adjacent cells (Fig. 1.4A).
Sertoli’s cells and
spermatids. iii) Autocrine signaling - a cell signals itself through a signaling
molecule that it synthesizes and to which it also responds by a
secreted chemical interacting with receptors on the surface of the
same cell (Fig. 1.4B).
iv) Paracrine signaling - a molecule released from one cell and

diffuses locally to interact with the receptors on the nearby target
cells (Fig. 1.4C). Examples:
• Release of cytokines leading to an inflammatory response in the

area.
• Release of neurotransmitters at synapses.

12
b) Long Distance Signaling
i) Endocrine signaling - hormones (chemicals secreted into the

blood) are carried through the circulatory system to act on distant
target cells (Fig. 1.4D).
ii) Neural Signaling - signaling molecules (neurotransmitters) are

released by the axon terminal of a presynaptic neuron and bind to
and react with the receptors on the dendrites of a postsynaptic
neuron (Fig. 1.4E).
Fig. 1.4: Different modes of Cell Signaling. (a) Local signaling Involves either
contact dependent signals which require interaction between membrane
molecules on two cells or via gap junctions that form direct cytoplasmic
connections between adjacent cells, (b) Autocrine signaling: the signaling
molecules act on the same cell that secreted them, (c) Paracrine signaling: the
signaling molecules released by a cell affect target cells only in close proximity,
(d) Endocrine signaling: hormones secreted by the endocrine glands or cells
into the blood and only target cells with receptors for the hormones respond to
the signals, (e) Neuroendocrine signaling involves neurotransmitters secreted
by neurons into the blood for action on distant target cells.
SAQ 2
Fill in the blanks with appropriate words:
i) Cell-surface receptors, also known as………………. are recruited in the

plasma membrane of cells.
ii) Neuroendocrine signaling involves ……………………secreted by

neurons into the blood for action on distant target cells.
iii) Release of cytokines leading to an inflammatory response in the area

is an example of ………………..
13
1.4 CHEMICAL CLASSIFICATION OF

HORMONES
Hormones can be allocated into two groups based on where they function in a
target cell:
• Hormones that do not enter cells and signal through interactions with
receptors at the cell surface. All polypeptide hormone (e.g., growth
hormone), monoamines (e.g., serotonin), and prostaglandins (e.g.,
prostaglandin E2), use cell surface receptors.
• Hormones that can enter cells and signal by binding to intracellular

receptors that function in the nucleus of the target cell to regulate gene
expression. Classic hormones that use intracellular receptors include
thyroid and steroid hormones.
Chemical Classes of Hormones: Based on chemical nature, hormones can

be classified into two major groups- those that are soluble in lipids, and those
that are soluble in water.
• Lipid-soluble Hormones: The lipid-soluble hormones comprise of

steroid hormones (eg, cortisol), and lipids (eg, prostaglandins).
• Water-soluble Hormones: The water-soluble hormones include protein

/peptide/ catecholamine / amino acid derived hormones.
A prohormone is a The chemical nature of a hormone determines:

precursor of a
hormone, such as a • How it is synthesized, stored, released and carried in the
polypeptide that blood
requires further
cleavage before the • Its biologic half-life (t½), mode of clearance and its cellular mechanism of
mature hormone is action
produced.
Protein/Peptide Hormones: Based on the differences with their chain length
protein hormones can be further classified as:
• Proteins hormones that contains 50 or more amino acids (eg,

adrenocorticotropin)
• Peptides - consist of two or more amino acids (eg, vasopressin)
• Monoamines - synthesized from the amino acid tyrosine (eg,

norepinephrine)
• amino acid derivatives (eg, triiodothyronine)
The characteristic features of the protein hormones are as follows:
• Synthesized as prehormones or preprohormones
• Hydrophilic and signal through transmembrane receptors
• Stored in membrane-bound secretory vesicles (sometimes called

secretory granules) stored in the cells of gland.
14
• Protein hormones are not secreted incessantly but are released by
exocytosis through the regulated secretory pathway (secreted in
response to a stimulus).
• Tend to circulate in blood predominantly in unbound form but may

circulate in bound form too.
Receptors for Protein Hormones:
Protein and peptide hormones, such as follicle-stimulating hormone (FSH),

gonadotropin-releasing hormone (GnRH), prolactin (PRL) and luteinizing
hormone (LH), bind to receptors entrenched in the cell membrane of receptive
cells. These receptors are large protein molecules that stereotypically have
three key domains (Fig. 1.5):
• Extracellular domain- a portion of the receptor with ligand binding site

that protrude outside the cell.
• Transmembrane domain- anchors the receptor within the plasma

membrane.
• Intracellular domain- a part of the receptor protein that resides within the
cell cytoplasm.
Fig. 1.5: Illustration of a cell surface receptor molecule displaying the ligand-
binding domain (dark purple) as a portion of the extracellular domain. The
transmembrane domain spans the plasma membrane of the cell, and the
intracellular domain outspreads into the cytoplasm.
Binding of the ligand to its receptor leads to a conformational (shape) change

in the receptor, which triggers a specific interaction amongst the cytoplasmic
proteins in the cell, triggering the release of a second messenger e.g., cAMP
and Ca2+ (the first messenger being the hormone itself) (Fig. 1.6). This
“paraphrase” of the hormonal communication to the cell’s interior is called
signal transduction. A very small quantity of hormone can be augmented to
amend thousands of molecules in the cell. Response to a protein/peptide
hormone can occur in seconds or minutes after receptor binding. 15
Fig. 1.6: Mechanism of action of a peptide hormone. Binding of a ligand to a cell

surface receptor, generally activates a G protein, triggering the release of a
second messenger (here, cAMP) that alters the activity of cytoplasmic enzymes
in a consequential manner.
Steroid hormones are a set of hormones derived from a common precursor,

cholesterol, which being fat-soluble organic molecules can effortlessly pass
through cell membranes. Steroid hormones, in general, are made by the
adrenal cortex, ovaries, testes, and placenta. The pattern of chemical bonds
and modifications on the side chain make steroid hormones structurally
diverse and thus categorized as follows:
• Progestins: 21-carbon steroids;
• Corticoids: 21-carbon steroids
• Androgens (male sex steroids): 19- carbon steroids
• Estrogens (female sex steroids): 18-carbon steroids
The characteristic features of the steroid hormones are as

follows:
• Being lipophilic, these are carried in the blood in protein-bound form, by

transport/carrier proteins which make them plasma-soluble.
• They cannot be stored in secretory vesicles due to their lipophilic nature.
• All steroid hormones are the derivative of cholesterol, which is either

taken up from the extracellular fluid by the cells or produced by
intracellular enzymes.
16
Receptors for Steroid Hormones
Steroid hormones being lipid soluble can effortlessly pass through the
phospholipid bilayer of the plasma membrane.
The receptors for the steroid hormones are present within cytoplasm or
nucleus of the target cells (Fig. 1.7). The binding of the steroid to its receptor
causes a conformational change in its receptor thereby exposing its DNA-
binding domain. The DNA-binding domain, in turn binds to a regulatory region
of a steroid-responsive gene and thus turning on or off gene transcription.
Steroid-receptor complex interacts with cofactors (nuclear proteins), which
trigger or prevent transcription. The presence of different cofactors in different
cells helps explain why the same hormone can have different effects on
various cell types. Steroid hormones, in general, take some time (at least 30
minutes) to exert their action, as they modify gene expression, and
transcription and translation of a protein and have long lasting effects.
Fig. 1.7: Mechanism of action of a steroid hormone. Lipid soluble steroid

hormone molecules pass through the plasma membrane via diffusion and bind
to receptors present in the cytoplasm or nucleus. Thereafter, the
steroid/receptor complex binds to regulatory regions of DNA, affecting the
expression of specific steroid-responsive genes.
SAQ 3
Fill in the blanks with appropriate words.
i) The ………………… nature of the steroids permits them to freely
diffuse across lipid bilayers.
ii) ……………….. is an extension of the receptor protein within the cell
cytoplasm.
iii) All steroid hormones are derived from……………………..
17
1.5 TRANSPORT AND METABOLISM OF

HORMONES
Once a hormone molecule is produced within an endocrine cell, it must be
secreted from the producing cell before yielding a physiological effect.
Because of hydrophobic nature, steroid and thyroid hormones cannot circulate

in the blood in their free-original forms contrary to the protein/peptide
hormones which are hydrophilic and water soluble, in general. But, some
protein /peptide hormones also remain bound with the carrier protein in blood.
The examples of steroid/thyroid -binding proteins are corticosteroid-binding
globulin, retinol-binding protein, sex hormone–binding globulin (SHBG),
thyroxine-binding globulin, and vitamin D– binding protein. These serum
binding proteins specially bind an exclusive class of steroid hormones.
However, protein/peptide hormones are stored inside the membrane-bound

secretory vesicles in the cells which produce them and are secreted when
required. For example, insulin is synthesized and densely packed in
pancreatic β-cells and secreted in response to stimuli such as high blood
glucose levels. Being insoluble in lipids, protein/peptide hormones do not
readily cross hydrophobic cell membranes and thus exert their actions by
binding to the receptors existing on the surface of the target cells.
Generally, once secreted, peptide hormones are not bound to carrier proteins
in the bloodstream because these hormones are soluble in aqueous solvents.
Consequently, they are rapidly degraded by serum proteases, resulting in
shorter half-life. By contrast, the nonpeptide steroid and thyroid hormones
have comparatively longer plasma half-lives as they circulate in association
with specific binding proteins. However, there are some protein/peptide
hormones like growth hormone (GH) and insulin-like growth factors (IGF-1 and
IGF-2) which do circulate in association with binding proteins.
The hormone concentration in plasma depends not only upon its synthesis
and secretion rate by the endocrine gland/cell but also upon its rate of removal
from the blood, either by excretion or by its metabolism. The excretion or
removal of hormone is required to prevent excessive, probably detrimental
effects from the continued exposure of target cells to hormones. The liver and
the kidneys are the key organs that excrete or metabolize hormones.
However, occasionally a hormone is also metabolized by the cells upon which
it acts whereby endocytosis of hormone–receptor complexes on plasma
membrane empowers the cell to remove the hormone quickly from its surface
and catabolize it intracellularly. Further, the receptors are recycled to the
plasma membrane. Additionally, specific enzymes in the blood also
breakdown some hormones, which tend to remain in the bloodstream. In
contrast, removal of the circulating steroid and thyroid hormones usually takes
relatively longer time, often several hours to days because these are protected
from excretion or metabolism by enzymes as long as they remain bound with
binding proteins. Fig. 1.8 depicts fate of a hormone.
18
Endocrine Cell
Secretes Hormone
Hormone circulating in bloodstream
Excreted in Inactivated by Activated by

urine or feces metabolism metabolism
Endocrine Cell
Binds to receptor and
produces a cellular response
Fig. 1.8: Probable fates and actions of a hormone following its secretion by an
endocrine cell. Not all paths apply to all hormones. Many hormones are
activated by metabolism inside target cells.
1.6 FUNCTIONS OF HORMONES AND

THEIR REGULATION
Hormones coordinate almost all biological activities, primarily metabolism,
growth, development and reproduction, within an organism. Functions of some
important hormones have already been tabulated in the Table 1.1.
By altering receptors, the hormones can alter the response of target cells
either by upregulating or downregulating the number of hormones receptors. Up-regulation is an
In certain cases, hormones can down-regulate or up-regulate not only their upsurge in the
specific receptors but the receptors of other hormones as well. The number of a
effectiveness of a hormone will be dropped if it is down regulated by the hormone’s receptors
receptor of another hormone. Alternatively, a hormone may induce a surge in in a cell, often due to
the number of receptors for a second hormone and consequently, extended exposure to
effectiveness of the second hormone is amplified. a low concentration of
the hormone.
This phenomenon in which one hormone is vital for another hormone to exert
its full effect on the target cell is called permissiveness. For example, in
presence of permissive amounts of thyroid hormone, epinephrine stimulates
the release of fatty acids into the blood from adipocytes (Fig. 1.9).
Down-regulation is a
decline in number of
receptors often due to
exposure to a high
concentration of the
hormone. This
momentarily declines
target-cell sensitivity
to the hormone, thus
avoiding
overstimulation.
Fig. 1.9: Permissiveness: The capability of thyroid hormone to “permit”

epinephrine-induced release of fatty acids from adipose tissue cells. Thyroid
hormone exerts this effect by causing an increased number of beta-adrenergic
receptors on the cell. Thyroid hormone by itself stimulates only a small amount
of fatty acid release. 19
1.7 SUMMARY
Let us summarize what we have learnt so far:
• The endocrine system comprises of all the glands and organs that
secrete hormones - the chemical messengers carried by the blood to
target cells somewhere else in the body.
• Based on chemical nature, hormones can be classified into two major

groups- those that are soluble in lipids, and those that are soluble in
water.
• The lipid-soluble hormones comprise of steroid hormones (eg, cortisol),

and lipids (eg, prostaglandins). The water-soluble hormones include
protein-based hormones.
• Most hormones are peptides, many of which are synthesized as larger

inactive molecules, which are then cleaved into active fragments,
whereas the steroid hormones are principally produced from cholesterol
by the adrenal cortex and the gonads.
• In general, protein/peptide hormones circulate dissolved in the

bloodstream, but steroid hormones circulate mainly bound to serum-
binding proteins.
• The liver and kidneys are the key organs involved in removal of the
hormone from the circulation by metabolizing or excreting them. The
protein/peptide hormones are rapidly removed from the blood, whereas
the steroid hormones are removed gradually, mainly because they are
bound to plasma proteins.
• After their secretion, some hormones are metabolized to more active

molecules in their target cells or other organs.
• Most receptors for steroid hormones are inside the target cells whereas
those for the peptide hormones are present on the surface of the plasma
membrane.
• Hormones can up-regulate and down-regulate their own receptors and

those of other hormones to exert increase in the effectiveness of the
hormone.
• Hormones coordinate almost all biological activities, primarily

metabolism, growth, development and reproduction of animals.
1.8 TERMINAL QUESTIONS

1. Why do only target cells respond to hormones?
2. What is the advantage of packaging peptide hormones in secretory

vesicles?
3. Why are steroid hormones not packaged into secretory

20 vesicles?
1.9 ANSWERS
Self-Assessment Questions
1. a) i) True
ii) False
iii) True
b) i) Exocrine glands
ii) Antidiuretic hormone (ADH)
2. i) Membrane or transmembrane receptors
ii) Neurotransmitters
iii) Paracrine signaling
3. i) Lipophilic
ii) Intracellular domain
iii) Cholesterol
Terminal Questions
1. A given hormone generally affects only a restricted number of cells
called target cells. A target cell responds to a specific hormone because
it bears receptors for the hormone.
2. By storing large quantities of hormone in an endocrine cell, the plasma

concentration of the hormone can be increased within seconds when the
cell is stimulated. Such rapid responses may be critical for an
appropriate response to a challenge to homeostasis. Packaging
peptides in vesicles also prevents intracellular degradation.
3. Because steroid hormones are derived from cholesterol, they are

lipophilic. Consequently, they can freely diffuse through lipid bilayers,
including those that constitute secretory vesicles. Therefore, once a
steroid hormone is synthesized, it diffuses out of the cell.
21
UNIT 2
HYPOTHALAMIC HORMONES
Structure
2.1 Introduction Corticotropin-Releasing
Hormone (CRH)
Growth Hormone-Releasing
2.2 Structure of the
Hormone (GHRH)
Hypothalamus
Somatostatin
Hypothalamic Nuclei
Hypothalamic Control of
Hypothalamic Pathways
Prolactin Secretion
2.3 Hypothalamic-Pituitary Axis
2.5 Hypothalamic Disease
2.4 Hypothalamic Hormones
2.6 Summary
Gonadotropin-Releasing
Hormone (GnRH)
2.8 Answers
Thyrotropin-Releasing Hormone
(TRH)
2.1 INTRODUCTION
In Unit 1, you learnt about the hormones, their chemical nature and role in cell
signaling. You also understood how these are transported to their specific
targets through blood and metabolized. Functions performed by various
hormones were briefed. In order to understand the mechanism and regulation
of functions performed by hormones, we shall take up detailed discussion of
the hormones secreted by different organs.
We shall begin with hypothalamus in this unit. This organ has two major roles:
homeostasis and hormones. We shall focus on hormonal aspect of the organ.
In the present unit, you will learn about various hypothalamic nuclei in
mammals along with the various connections it has with different parts of the
brain. You will also be made aware of the different hormones secreted by
these hypothalamic nuclei into the circulation system along with their structure
22 and function.
Unit 2 Hypothalamic Hormones

explain location of hypothalamus;
describe the structure and different pathways associated with the

hypothalamus;
define hypothalamo-hypophyseal portal system;
explain the structure and function of different hypothalamic hormones;

and
explain some of the important diseases associated with the

malfunctioning of hypothalamus.
2.2 STRUCTURE OF THE HYPOTHALAMUS

The hypothalamus, a relatively small-sized area in the diencephalon is located The word
below thalamus. According to the anatomy of the hypothalamus, it extends Hypothalamus is
from the level of the optic chiasm and the attached lamina terminalis to coronal derived from two
plane just posterior to the mammillary bodies. Hypothalamus is connected at Greek words: hypo-
the middle region to the pituitary gland (also known as hypophysis) by the means “under”; and
infundibular stalk, through median eminence. The median eminence, along thalamos which
with the pituitary stalk contains the portal vessels that carry releasing and literally means “bridal
inhibiting hormones from the hypothalamus to the anterior lobe of the couch”, “nuptial
hypophysis. These substances influence the secretion of the hypophyseal chamber” or
tropic hormones. “innermost room”.
2.2.1 Hypothalamic Nuclei

Hypothalamus in a broad aspect may be divided, based on antero-posterior
plane in to three regions namely, anterior or rostral hypothalamus; middle
or tuberal hypothalamus and posterior or caudal hypothalamus. Each of
these regions contains many nuclei (Fig. 2.1).
Fig 2.1: Various Hypothalamic Nuclei in Mammals. 23

These different hypothalamic nuclei are an aggregation of different size of

neurons with varied function as elaborated in Table 2.1.
Table 2.1: Generalized classification of Hypothalamic Nuclei in

mammals based on its location in the hypothalamus in to three parts
namely anterior (rostral), middle (tuberal) and posterior (caudal)
hypothalamus.
Hypothalamic Classification Hormones Functional Sexually

Nuclei of Produced by Roles Dimorphic
Hypothalamic The Nuclei Nucleus
Nuclei
Pre-Optic Area Gonadotropin Neurosecretory Males>Females
(POA) releasing regulation of
hormone Hypothalamo-
(GnRH), Thyroid hypophyseal
releasing gonadal axis,
hormone (TRH), hypothalamo-
Estrogen pituitary thyroid
receptor alpha axis, male sexual
(ERα), Estrogen behaviour
receptor beta
(ERβ),
Progesterone
receptor (PR),
Androgen
receptor (AR)
Anterior Anterior Parasympathetic

Hypothalamic Hypothalamus, control,
area (AHA) also known as thermoregulation
Rostral (control of body
Hypothalamus temperature)
Periventricular Somatostatin, Inhibition of

Nuclei Kisspeptin, ERα, Growth hormone
ERβ secretion, control
of ovulatory cycle
Suprachiasmatic Vasopressin, Biological Females>males

Nuclei (SCN) Vasoactive rhythms
intestinal peptide
(VIP)
Paraventricular Oxytocin, Electrolyte and

Nuclei (PVN), Vasopressin water balance,
Supra-optic blood pressure
Nuclei (SON) – (Vasopressin),
Magnocellular milk ejection,
Neurons uterine
contractility
(Oxytocin)
Paraventricular Corticotropin Stress

Nuclei (PVN) – releasing responses,
Parvicellular hormone (CRH), Neurosecretory
Neuron Thyroid control of
releasing Hypothalamo-
hormone (TRH), pituitary adrenal
Glucocorticoid (HPA) and
receptors GR Hypothalamo-
pituitary thyroid
(HPT) axis
Arcuate Nucleus Middle Pro- Food Intake,

Hypothalamus, opiomelanocortin energy
also known as (POMC), expenditure,
24 tuberal Neuropeptide Y neurosecretory
Hypothalamus (NPY), Agouti control of
related peptide prolactin (PRL)
(AgRP), Growth and Growth
Hormone Hormone (GH)
releasing
hormone
(GHRH),
Dopamine (DA),
Kisspeptin,
Estrogen
receptor alpha
(ERα),
Progesterone
receptor (PR),
Glucocorticoid
receptors (GR),
Leptin receptors
Ventromedial GHRH, ERα, PR Satiety, female

Nucleus (VMN) sexual behaviour
Dorsomedial Neuropeptide Y Behavioural

Nucleus (DMN) (NPY), rhythms, blood
Glucocorticoid pressure, heart
receptors (GR) rate
Lateral Appetite and

Hypothalamic body weight
Area (LHA) control
Posterior Posterior Sympathetic

hypothalamic Hypothalamus, control,
nucleus (PHN) also known as thermoregulation
caudal
Pre-mammillary Hypothalamus Emotion and
Nucleus (PMN) short-term meory
Two of the hypothalamic nuclei POA and SCN show sexual dimorphism, while
volume of the POA nuclei is more in males than in females and neurons with
suprachiasmatic nucleus in the females tend to be more elongated than in
males.
2.2.2 Hypothalamic Pathways

The hypothalamus is connected to the different regions of the brain by
different tract and pathways (Fig. 2.2), the notable being the retino-
hypothalamic tract (a connection between the eye and the hypothalamus); the
hypothalamo-hypophyseal tract (a connection between the middle region of
the hypothalamus to the pituitary); the fornix (the afferent hypothalamic
pathway connecting the hypothalamus with the hippocampus); the medial
forebrain bundle (extremely ill defined, but has connections to different parts of
the brain such as cortex etc.); stria medullaris (assemble posterior to the
anterior commissure connecting primarily the lateral preoptic area to the
habenular nuclei along the dorsomedial surface of the thalamus); stria
terminalis (innervating the bed nucleus of stria terminalis- BnST); spino-
hypothalamic tract (a connection between the spinal cord and the
hypothalamus); mammillothalamic tract (originates from the mammillary body
and splits in to mammillothalamic and mammillotegmental tracts and projects
into the anterior thalamic nuclei).
25
Cortex
Medial Forebrain Bundle
Basal Forebrain
Amygdala Hippocampus
Stria Fornix
Terminalis Septum ez Anterior
Ventral Amygdalofugal ap thalamic
fP
Pathway
u it o Nucleus
r c
Ci
Mammilo-thalamic Tract
EYE HYPOTHALAMUS
Retino-hypothalamic Tract Mammilary Hypothalamo-hypophyseal
Nucleus tract
Dorsal Longitudinal Fasciculus Midbrain Mammilo-tegmental Tract
Pituitary
Spino-hypothalamic Tract Hypothalamic-spinal Tract
Spinal Cord
Fig. 2.2: Diverse hypothalamic Pathways showing connections of the
hypothalamus with different parts of the brain.
SAQ 1
i) Eye sends input to hypothalamus through retino-hypothalamic

tract. [True/False]
ii) Pre-optic area is involved in female sexual behavior.[ True/False]
iii) Supra-chiasmatic nucleus regulates daily body rhythm.

[True/False]
iv) Hypothalamus is connected to the hippocampus by the pathway

known as Circuit of Papez. [True/False]
b) Fill in the blanks with appropriate words:
i) Hypothalamus is divided into three parts namely …………,

…………… and ….......
ii) Paraventricular and supra-optic nuclei innervate the posterior

gland and synthesize two hormones ……………
iii) Based on the structure of the hypothalamic nucleus, pre-optic area

in males show ……………… volume than the female and thus
exhibit …………………
iv) The hormone Kisspeptin is produced by ……………………….. of

the hypothalamus.
26
2.3 HYPOTHALAMIC-PITUITARY AXIS

The hypothalamus, as we have seen is connected to the pituitary gland by the
infundibulum or the pituitary stalk. Though, once pituitary was considered the
master endocrine gland, regulating widespread physiological effects
throughout the body, it itself is under the control of the hypothalamus and
hence, is no more considered as the master endocrine gland. Thus,
hypothalamic hormones regulate the secretion of the pituitary hormones via
negative feedback loops and secretions.
The pituitary gland, or hypophysis is located at the base of the brain, in a

depression of the sphenoid bone and is divided into three divisions or lobes
(Fig. 2.3).
(i) Adenohypophysis or anterior pituitary or pars distalis, contains

cords of closely compacted epithelial cells, which secrete many
hormones such as Growth hormone, Follicle Stimulating Hormone,
Leutinizing Hormone etc.;
(ii) Intermediate lobe or pars intermedia, sandwiched between the

anterior pituitary and the posterior pituitary and
(iii) Neurohypophysis or the posterior pituitary or pars nervosa. The

posterior pituitary receive neurosecretory cell nerve endings from the
hypothalamus and its hormones are synthesized by cell bodies of the
hypothalamus but released from the neural cells that populate the
posterior pituitary.
Fig. 2.3: Neuroanatomy of the Hypothalamo-Hypophyseal Axis along with the

Hypothalamo-Hypophyseal portal blood system.
27
The secretion of the anterior pituitary hormones is under the control of the
cells in the hypothalamus producing the hormones, known as releasing
hormones or in some cases releasing-inhibiting hormone. These hormones
are produced in a very small amount and impact the activity of the pars distalis
cells by special arrangement of blood vessels between hypothalamus and the
anterior pituitary, known as the hypothalamic-hypophyseal portal blood
system.
Hypothalamo-Hypophyseal Portal Blood System: In simple words,

hypothalamo- hypophyseal portal blood system is the venous blood that drains
from the hypothalamus, mixes with arterial blood and passes to anterior
pituitary before it goes into the general venous circulation. Thus, the superior
hypophysial artery provides blood supply to the median eminence and pituitary
stalk, from where blood passes via capillary loops through the long portal
vessels to the sinusoids of the pars details. The importance of this system was
confirmed by experiments showing that placing a foil barrier between the
hypothalamus and pituitary markedly inhibited the secretion of all the anterior
pituitary hormones except prolactin. The pituitary gland also receives
oxygenated arterial blood from the arterial branches of the circle of Willis.
SAQ 2
Fill in the blanks with appropriate words:
i) The pituitary gland receives oxygenated arterial blood from the arterial
branches of the …………………………..
ii) Dorsomedial nuclei secretes hormones …………………….
iii) Posterior hypothalamus comprises of hypothalamic nuclei known as

………………
iv) Suprachiasmatic artery provides blood supply to the basal part of the
…………….. just above the optic chiasm
2.4 HYPOTHALAMIC HORMONES

Hypothalamus produces various hormones known as releasing hormones (see
the Table 2.1). These are synthesized as part of larger precursor proteins,
known as pre-pro hormones encoded by mRNA transcribed from the gene for
the releasing hormone. These pre-pro hormones are proteolytically processed
within the same neuron in which they are synthesized to yield the mature
peptide. This processing takes place as the secretory vesicles containing the
maturing peptide travel from the cell body down the axon to its terminus where
the peptide will be released. Let us discuss the structure, chemical nature and
function of these hormones one by one.
2.4.1 Gonadotropin-Releasing Hormone (GnRH)

The gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide
hormone (Fig. 2.4) and its primary structure appears to be identical across all
mammals except in guinea pig, with a high degree of GnRH sequence
conservation across the vertebrates. GnRH is synthesized from precursor
protein consisting of (from the amino to the carboxyl terminus) a 23-amino acid
28
signal peptide, GnRH, a proteolytic cleavage site (GKR), and the 56-amino
acid GnRH associated peptide (GAP). This precursor protein is also highly
conserved across species. GAP is co-secreted with GnRH following
processing of the precursor into the mature peptides in the secretory granules
of the GnRH neurons.
Isoforms of GnRH have also been identified with amino acid variation in
position number 5, 7, and/or 8 which differ in species and tissue distribution.
The number of GnRH neurons is relatively few in number (approximately 600-
800) per brain.
E H W S Y G L R P G
Fig 2.4: Structure of the decapeptide, Gonadotropin Releasing Hormone (GnRH).

Left (Red colour) denotes amino terminal while right (Green colour) denotes
carboxyl terminal.
The receptor for the GnRH, the G-Protein coupled receptor (GPCR) has a
seven trans-membrane domain structure in which the cytoplasmic tail is
absent from the GnRH receptor. GnRH acts through second messenger
system by activating phospholipase C, release of IP3 and DAG
(diacylglycerol), and activation of protein kinase C. These signals are
transmitted to the nucleus through the JNK (c-jun N-terminal kinase) pathway
to activate transcription of the gene for the β-subunit of either LH or FSH. In
addition, elevated cyclic AMP and intracellular Ca2+ from activation of voltage-
sensitive calcium channels both contribute to stimulus of secretion of stored
GnRH.
GnRH is secreted in a pulsatile manner and is essential for the maintenance of

reproductive function. Absence of GnRH secretion leads to partial or complete
diminution of the two gonadotrophic hormones; the luteinizing hormone (LH)
and follicle stimulating hormone (FSH). The pulsitility of the GnRH neurons are
now thought to lie in the combination of the neuropeptides kisspeptin,
neurokinin B and dynorphin, referred to as KNDy neurons and have been
proposed to be located in the pre-optic area of the hypothalamus. These
KNDy neurons project in to the GnRH neurons of the hypothalamus and thus
help in regulating reproductive function. In recent years, it has been shown
that mutations in the kisspeptin gene lead to hypogonadism and infertility in
animals.
2.4.2 Thyrotropin-Releasing Hormone (TRH)

TRH is a tripeptide hormone Fig. 2.5 and like the GnRH, is synthesized from
the pre-pro TRH molecule. The mature thyroid releasing hormone is formed by
the process of amidation of glycine at the carboxy terminus and the
modification of the N-terminal by glutaminyl cyclase. Human preproTRH is 242
amino acids and contains six copies of the tripeptide releasing hormone within
its sequence. These progenitor TRH sequences are flanked by pairs of basic
amino acids (Lys-Arg or Arg-Arg), the signals for the prohormone convertases
(PC) 1 and 2, the proteolytic enzymes responsible for the processing of
preproTRH and proTRH.
29
E H P
Fig 2.5: Structure of the tripeptide, Thyroid Releasing Hormone (TRH). Left (Red
colour) denotes amino terminal while right (Green colour) denotes carboxyl
terminal.
The receptor for TRH, located in the target cells of the anterior pituitary as well
as elsewhere in the body, is a typical GPCR of the rhodopsin family with an
extracellular amino terminus, three extracellular loops, seven transmembrane
regions, three intracellular loops, and an intracellular carboxyl terminus. Two
forms of TRH receptor, encoded by separate genes exist namely TRH-R1 and
TRH-R2. In the pituitary, TRH-R1 mediates the TRH signal through binding to
Gq/11 and induction of protein kinase C (PKC)-, phosphophatidyl-inositol- and
Ca2+-mediated signaling pathways.
Synthesis of pre-proTRH is stimulated by norepinephrine, enabling the

hypothalamic- pituitary-thyroid axis to respond to cold and stress by increasing
the rate of metabolism, a hallmark of thyroid hormone activity. The TRH
neuron is also activated by appetite-stimulating hormones such as α-MSH and
inhibited by anorexic or appetite-suppressing peptides such as AgRP (which
binds to the α-MSH receptor and antagonizes its actions) and neuropeptide Y.
To increase food intake, the adipose hormone leptin stimulates the TRH
neuron either directly (through its receptor OB-Rb) or indirectly through the
stimulation of α-MSH. Thus, the TRH neuron integrates important information
about the environment relating to its effects on temperature, food intake, and
stress and responds by activating the hypothalamic- pituitary-thyroid axis.
Negative feedback control of TSH secretion by the peripheral hormone T3 is

thought to occur primarily at the thyrotrophs in the pituitary rather than the
hypothalamus, but thyroid hormones also play a role in the hypothalamic
neurons. T3, bound to its nuclear receptor TRβ2, inhibits the synthesis of
mRNAs encoding both prepro-TRH and the enzymes that process it into
mature releasing hormone.
TRH neurons have projections to areas of the central nervous system other
than the anterior pituitary. Some axon terminals in the spinal cord have quite
high TRH levels and contribute to the regulation of cardiovascular function.
TRH from the dorsal motor nucleus of the vagus nerve affects gastrointestinal
motility and gastric acid secretion. TRH has been identified in many peripheral
tissues such as the retina, the adrenal medulla, and the pancreas, where it
plays a role in the specialized functions of these cells.
2.4.3 Corticotropin-Releasing Hormone (CRH)

The 41 amino acid long primary structure of CRH (Fig. 2.6) is located in the
carboxyl terminus of the 196-amino acid pre-prohormone. Pre-proCRH is
encoded by the second of the two exons in its gene. Processing involves the
prohormone convertase catalyzed cleavage of CRH from the prohormone
precursor and the amidation of the carboxy terminal; this amide group is
30 required for biological activity.
CRH stimulates the secretion of adrenocorticotropic hormone (ACTH), β-

endorphin and proopiomelanocortin (POMC) derived peptides from the
corticotroph cells of the anterior pituitary gland. CRH is also an important
mediator to stress response in other areas of the brain and acts as a placental
hormone during parturition. CRH is found in other areas of the central nervous
system including the cerebral cortex, limbic system, cerebellum, brain stem,
and spinal cord.
S E E P P I S L D L T F H L L R E V L E M A
R
E
I I E M L K R N S H A Q Q A L Q
Fig 2.6: Structure of the Corticotropin Releasing Hormone (CRH). Green colour
denotes carboxyl terminal.
Gamma aminobutyric
The cell bodies of the neurons that synthesize and secrete CRH into the acid (GABA) and β-
endorphin are
hypothalamic-pituitary portal system are located in the paraventricular nucleus
naturally occurring
of the hypothalamus. Neuronal input to these CRH secreting neurons comes neuropeptides which
from the limbic system (amygdala and hippocampus) and brain stem regions have opposite roles.
governing autonomic functions. CRH secretion from nerve terminals is While GABA is
regulated by the negative feedback of glucocorticoids as well as a number of considered an
neurotransmitters and neuropeptides. β- endorphin stimulates CRH release, inhibitory
neurotransmitter
whereas GABA is inhibitory.
because it blocks, or
CRH secretion also shows a circadian rhythm, and in humans there is an inhibits certain brain
signals and
increase in CRH/ACTH/ cortisol release in the morning hours. The CRH
decreases activity of
peptide is also synthesized and released elsewhere in the brain, where it acts the nervous system;
as a neuromodulator in addition to its role in the regulation of ACTH secretion. β- endorphin are
Thus, CRH gene expression is detectable in a wide variety of brain sites, involved in relieving of
including the cerebral cortex, amygdala and lateral hypothalamus, in addition pain and stress.
to PVN.
Moreover, stress-related noradrenergic and glutamatergic excitatory signals

can activate the gene, in part via activation of the transcription factor CREB
(cyclic AMP response element binding protein). A second protein, TORC
(transducer of regulated CREB activity), plays a vital role in cyclic AMP
mediated regulation of CRH expression in these neurons. The regulation of
CRH gene expression is localization-specific; for example, in other areas of
the brain and in the placenta, glucocorticoids stimulate, rather than inhibit,
CRH gene transcription.
2.4.4 Growth Hormone-Releasing Hormone (GHRH)

GHRH is secreted by the arcuate nucleus of the hypothalamus and is derived
from a 108 amino-acid pre-prohormone yielding either GHRH (1-44) or GHRH
(1-40), shortened at the carboxyl terminal Fig. 2.7). Both forms of GHRH are
found in the human hypothalamus and since the full biological activity of
GHRH lies in amino acid residues 1–29, the physiological differences between
the two GHRH forms are likely minimal.
31
Growth hormone- Structurally, GHRH belongs to a family of proteins that includes secretin,
releasing hormone glucagon, glucagon-like peptides (GLP-1 and GLP-2), and vasoactive
(GHRH) was intestinal peptide (VIP). Following secretion from its neurons into the portal
originally isolated circulation, GHRH binds to its receptor, GHRH-R, a G-protein coupled
from ectopic tumors receptor on the somatrophs of the anterior pituitary. Increased cyclic AMP
producing it (and production leads to the increased synthesis of GH. Cyclic AMP also stimulates
thereby causing
the opening of Ca2+ and K+ ion channels, which play roles in the secretion of
observable
derangements in existing GH from the cell, in its characteristic pulsatile fashion. Phospholipid
growth), rather than signaling may also be involved in the exocytosis associated with the release of
from the GH by the somatotroph when stimulated by GHRH. In addition to its effect on
hypothalamus. Its GH secretion and synthesis by somatotrophs, GHRH stimulates proliferation of
structure was these cells through the activation of the MAP kinase pathway.
determined in 1982.
GHRH and/or its receptor also occur outside the central nervous system in
tissues such as the pancreas where it stimulates insulin, glucagon and
somatostatin release; in the gastrointestinal tract where it stimulates gastrin
release and epithelial cell division; and in tumors of many types.
Y A D A I F T N S Y R K V L G E L S A R K
L
Q
L R A R A G R E Q N S E G Q E R S M I D
Fig 2.7: Structure of the Growth Hormone Releasing Hormone (GHRH). Green
colour denotes carboxyl terminal.
2.4.5 Somatostatin
Somatotrophs are the The stimulatory effect of GHRH on GH release from the anterior pituitary
cells on anterior lobe somatotroph is countered by the GH release-inhibiting hormone, somatostatin
of the pituitary gland (SST), also known as somatotropin release inhibiting hormone (SRIH).
that produce the Somatostatin 28 and somatostatin 14 (Fig. 2.8), names based on the length of
hormone the amino acid sequence of the two forms, play the major role in the regulation
somatotropin. of pituitary function in humans.
The periventricular nucleus (located rostral to the paraventricular nucleus) is

the major site of somatostatin producing neurons in the hypothalamus. In
addition to its inhibitory effect on GH secretion by somatotrophs, for which it
was named; somatostatin also modulates a much broader range of peptides
from the pituitary (e.g., TSH), as well as from the stomach, brain, intestine,
and pancreas. For example, one of the somatostatin receptors (SSTR4) acts
in the brain to decrease the levels of Alzheimer’s related amyloid β peptide by
increasing their rate of degradation.
There are five somatostatin receptors, designated SSTR1–SSTR5. These are

encoded by separate genes on separate chromosomes. They differ in their
tissue expression patterns, their affinities for various somatostatin agonists,
and the G-proteins, and therefore the cell signaling pathways, to which they
are coupled. Clearly, this degree of variation allows somatostatin to have
diverse effects in many different target tissues. Somatostatin14 has greatest
affinity for SSTR2, which is responsible for the inhibition of the secretion of
pituitary hormones, including GH. SSTR2 activation also initiates opening of
K+ channels and closure of Ca2+channels. Both mechanisms contribute to the
32 suppression of pituitary growth hormone secretion.
S A N S N P A M A P R E R K A G C K N F F
W
C S T F T K
Fig 2.8: Structure of somatostatin hormone.
2.4.6 Hypothalamic Control of Prolactin Secretion
In mammals, the primary hypothalamic control of prolactin secretion is

predominantly through the inhibitory action of dopamine, secreted by neurons
in the dorsomedial area of the arcuate nucleus and the inferior ventromedial
nucleus of the hypothalamus. Prolactin is the only pituitary hormone regulated
in this fashion— that is, showing unrestrained secretion in the absence of
hypothalamic input.
The most immediate (within seconds) response to dopamine is increased

potassium conductance and inactivation of voltage sensitive Ca2+ channels.
The resulting diminished intracellular Ca2+ leads to reduced exocytosis of
secretory vesicles containing prolactin. Within a few minutes, inhibition of
adenyl cyclase reduces intracellular Ca2+ leading to decreased prolactin gene
expression. Sustained exposure to dopamine input leads to decreased
lactotroph proliferation.
TRH and vasoactive intestinal peptide (VIP) have also been shown to be
capable of stimulating prolactin secretion. These effects are exerted through
the signaling pathways and result in increased expression of the prolactin
gene. The physiological role of these stimulatory peptides in humans remains
somewhat unclear, however, and by far the most powerful positive influence
on prolactin secretion is neuronal one exerted by the suckling.
2.5 HYPOTHALAMIC DISEASE

Damage to the hypothalamus or to the fragile structures connecting the
hypothalamus to the anterior pituitary, the stalk and the connecting blood
portal system, can have serious and far-reaching consequences. This kind of
damage can happen through trauma to the head or through tumor invasion of
the area. These conditions can be collectively listed under panhypopituitarism
or hypothalamic hypofunction.
Many of the releasing hormones will fail to arrive at their receptors on the
plasma membranes of the specific anterior pituitary cell, and the
hypothalamic–pituitary– end organ axis will be broken. There is usually an
order to the loss of hormonal secretions in hypopituitarism. GH deficiency
occurs early followed by LH, FSH, and TSH, and ACTH deficiencies. One
rarely sees PRL deficiency. Since prolactin is under predominantly negative
control of dopamine from the hypothalamus, hyperprolactinemia is the result of
damage to the connection between the hypothalamus and the pituitary.
33
Diagnosis of disruption of hypothalamic– pituitary communication is now

possible through the availability of the releasing hormone assays. Often
patients with these syndromes are treated with the hormone of the terminal
gland in the pathway, such as the adrenal hormones, gonadal steroid
hormones, or thyroid hormones.
The isolated deficiency of GnRH leads to Kallman’s syndrome, which refers to

anosmic (lacking a sense of smell) patients with hypogonadotropic
hypogonadism. There is a cluster of genetic variations that lead to one or more
features of this syndrome, with some variants lacking some of the clinical
manifestations present in the overt syndrome. The syndrome may originate
from an arrest of the migration of the GnRH neurons from the medial part of
the nasal epithelium to the hypothalamus/ preoptic area at the appropriate
time in development. Treatment of individuals with this syndrome usually
involves pulsatile administration of GnRH.
Hypopituitarism
The hypothalamus and pituitary gland are tightly integrated. Damage to the
hypothalamus impacts the responsiveness and normal functioning of the
pituitary. Hypothalamic disease may cause insufficient or inhibited signalling to
the pituitary leading to deficiencies of one or more of the following hormones:
thyroid-stimulating hormone, adrenocorticotropic hormone, beta-endorphin,
luteinizing hormone, follicle-stimulating hormone, and melanocyte–stimulating
hormones. Treatment for hypopituitarism involves hormone replacement
therapy.
Neurogenic diabetes insipidus
Neurogenic diabetes insipidus may occur due to low levels of ADH production
from the hypothalamus. Insufficient levels of ADH result in increased thirst and
urine output, and prolonged excessive urine excretion increases the risk of
dehydration.
Tertiary hypothyroidism
The thyroid gland is an auxiliary organ to the hypothalamus-pituitary system.

Thyrotropin-releasing hormone (TRH) produced by the hypothalamus signals
to the pituitary to release thyroid-stimulating hormone (TSH), which then
stimulates the thyroid to secrete T4 and T3 thyroid hormones. Secondary
hypothyroidism occurs when TSH secretion from the pituitary is impaired,
whereas tertiary hypothyroidism is the deficiency or inhibition of TRH.
Thyroid hormones are responsible for metabolic activity. Insufficient production

of the thyroid hormones results in suppressed metabolic activity and weight
gain. Hypothalamic disease may therefore have implications for obesity.
Developmental disorders
Growth hormone-releasing hormone (GHRH) is another releasing factor

secreted by the hypothalamus. GHRH stimulates the pituitary gland to secrete
growth hormone (GH), which has various effects on body growth and sexual
34
development. Insufficient GH production may cause poor somatic growth,

precocious puberty or gonadotropin deficiency, failure to initiate or complete
puberty, and is often associated with rapid weight gain, low T4, and low levels
of sex hormones.
Diagnosis and treatment of diseases with neuroendocrine components must

always consider the multidimensional nature of the controlled neuroendocrine
system. Diseases that cause dysregulation in the neuroendocrine homeostatic
axes are considered primary, if they involve the major end organ of the axis, or
secondary, if defects occur at antecedent levels (pituitary or hypothalamus).
Neuroendocrine diseases are usually diagnosed with the aid of X-rays, MRIs
and other imaging diagnostic procedures, along with measurements of
pituitary and endorgan hormones in serum. In some cases, provocative tests
of a target- organ function are conducted with stimulatory hormone
preparations.
2.6 SUMMARY
• Hypothalamus regulates various physiological functions of the body, thus

helping in maintenance of body homeostasis.
• Based on the cytoarchitecture of the hypothalamus, it is divided into

three parts namely anterior, middle and posterior hypothalamus
containing almost 11 hypothalamic nuclei.
• Some of the hypothalamic nuclei such as pre-optic area and supra-

chiasmatic nuclei exhibit sexual dimorphism.
• The hypothalamus is connected to different parts of the brain known as

hypothalamic pathways.
• In addition to the connections with different parts of the brain, the

hypothalamus is also connected to the pituitary by the infundibulum or
the pituitary stalk, forming the hypothalamo-pituitary axis.
• Venous blood drains from the hypothalamus, mixes with the arterial
blood and passes to the anterior pituitary in to the general venous
circulation through a system known as hypothalamo-hypophyseal portal
system.
• Hypothalamus secretes various releasing and inhibiting -hormones such

as GnRH, TRH, CRH, PRL, GHIH etc. helping to maintain the various
physiological functions of the body.
• Damage to the hypothalamus or to the fragile structures connecting the

hypothalamus to the anterior pituitary, the stalk and the connecting blood
portal system may lead to disruption of many hormonal activities. These
conditions are collectively known as panhypopituitarism or hypothalamic
hypofunction. 35

1. What is hypothalamus? Explain about its parts.
2. Name the hormones produced by Pre-optic area, paraventricular nuclei

and supra-optic nuclei? What are their functions?
3. Explain the structure of thyroid releasing hormone.
4. Explain symptoms of Kallman’s syndrome.
5. Define hypothalamo-hypophyseal portal system?
2.8 ANSWERS
1. a) i) True
ii) False
iii) True
iv) False
b) i) Anterior or Rostral, Middle or Tuberal and Posterior or

Caudal hypothalamus
ii) Oxytocin and Vasopressin
iii) Greater, sexual dimorphism
iv) Periventricular and Arcuate nucleus
2. a) i) Circle of Willis
ii) Neuropeptide Y (NPY), glucocorticoid receptors (GR)
iii) Posterior hypothalamic nuclei and pre-mammillary nucleus
iv) Pre-optic area
Terminal Questions
1. The hypothalamus, a relatively small-sized area in the diencephalon is
located inferior to the thalamus. According to the anatomy of the
hypothalamus, it extends from the level of the optic chiasm and the
attached lamina terminalis to coronal plane just posterior to the
mammillary bodies. Hypothalamus is connected at the middle region to
the pituitary gland (also known as hypophysis) by the infundibular stalk,
through median eminence. Refer to the section 2.2 for more details.
2. The hormones produced by pre-optic area are gonadotropin releasing

hormone (GnRH), thyroid releasing hormone (TRH), estrogen receptor
alpha (ERα), estrogen receptor beta (ERβ), progesterone receptor (PR),
androgen receptor (AR). Major function of this nucleus is neurosecretory
regulation of hypothalamo-hypophyseal gonadal axis, hypothalamo-
36 pituitary thyroid axis and male sexual behavior. The hormones produced
by paraventricular and supra-optic nuclei, also referred to as

magnocellular neurons are oxytocin and vasopressin. Their major
functions are electrolyte and water balance, blood pressure
(vasopressin), milk ejection and uterine contractility (oxytocin).
3. TRH is a tripeptide hormone and, is synthesized from the pre-pro TRH

molecule. The mature thyroid releasing hormone is formed by the
process of amidation of glycine at the carboxy terminus and the
modification of the N-terminus by glutaminyl cyclase. Human preproTRH
has 242 amino acids and contains six copies of the tripeptide releasing
hormone within its sequence. These progenitor TRH sequences are
flanked by pairs of basic amino acids (Lys-Arg or Arg-Arg), the signals
for the prohormone convertases (PC) 1 and 2, the proteolytic enzymes
responsible for the processing of preproTRH and proTRH.
4. The isolated deficiency of GnRH leads to Kallman’s syndrome, which

refers to anosmic (lacking a sense of smell) patients with
hypogonadotropic hypogonadism. There is a cluster of genetic variations
that lead to one or more features of this syndrome, with some variants
lacking some of the clinical manifestations present in the overt
syndrome. The syndrome may originate from an arrest of the migration
of the GnRH neurons from the medial part of the nasal epithelium to the
hypothalamus/ preoptic area at the appropriate time in development.
Treatment of individuals with this syndrome usually involves pulsatile
administration of GnRH.
5. Hypothalamo- hypophyseal portal blood system is the venous blood that

drains from the hypothalamus, mixes with arterial blood and passes to
anterior pituitary before it goes into the general venous circulation. Thus,
the superior hypophysial artery provides blood supply to the median
eminence and pituitary stalk, from where blood passes via capillary
loops through the long portal vessels to the sinusoids of the pars distalis.
The importance of this system was confirmed by experiments showing
that placing a foil barrier between the hypothalamus and pituitary
markedly inhibited the secretion of all the anterior pituitary hormones
except prolactin.
37
UNIT 3
PITUITARY HORMONES
Structure
3.1 Introduction 3.4 Pathophysiology
Expected Learning Outcomes 3.5 Hormones of Posterior
Pituitary
3.2 Anatomy of the Pituitary
Gland 3.6 Feedback Regulation Cycle
3.3 Hormones of the Anterior 3.7 Diabetes Insipidus
Pituitary
3.8 Summary
Glycoprotein Hormones
Somatomammotrophic
Hormones 3.10 Answers
Pro-Opiomelanocrotin Family
Hormones
3.1 INTRODUCTION
You learnt about the hypothalamus and how it controls the activities of various
other organs by secreting the releasing hormones in Unit 2. In this unit we
shall discuss about the pituitary gland also known as hypophysis. Earlier, it
was considered as the master endocrine gland, however, as you have seen in
the previous unit, this gland is under the control of hypothalamus, hence it is
no more referred to as the Master Gland. In this unit, we shall elaborate its
anatomical division into the posterior and anterior pituitary.
Both, anterior and posterior pituitary, secrete distinct set of hormones.

Structure and physiological roles of these hormones will be explained. You will
also learn about the physiological conditions that follow due to abnormal
secretion of growth hormones. How a feedback mechanism at the level of
hypothalamus and pituitary affect the target cells in a specific manner through
their hormones will also be described. In the last section, we shall discuss
about diabetes inspidus, a disorder associated with hypothalamus- pituitary
axis, its causes, symptoms and management.
38
Unit 3 Pituitary Hormones

describe the embryonic origin of the pituitary gland;
explain why pituitary is more considered as the master endocrine gland;
describe the structure of the different parts of the pituitary gland;
categorize the different pituitary hormones and explain their functions;
explain some of the important diseases associated with the

malfunctioning of pituitary gland and its secretion.
3.2 ANATOMY OF THE PITUITARY GLAND

The embryonic development of the lobes of the pituitary gland is completely
distinct. The anterior lobe is derived from an inward invagination of the
primitive mouth cavity (oral ectoderm) known as Rathke’s pouch while the
neural lobe arises from the neural ectoderm of the floor of the developing
forebrain, the infundibulum of diencephalon. Cells of the anterior wall of
Rathke’s pouch develop into the pars distalis, containing most of the hormone-
producing cells of the adenohypophysis (Fig. 3.1).
Fig. 3.1: Embryonic development of different lobes of pituitary gland.
The pituitary gland comprises of three parts, the adenohypophysis

(alternatively referred to as the anterior lobe or the Pars Distalis), the
intermediate lobe (or Pars Intermedia) and the neurohypophysis (also called
the posterior lobe or Pars Nervosa). The adenohypophysis is primarily
39
glandular tissue and receives hormones through the hypothalamo-

PVN: Paraventricular
Nuclei, SON: Supra- hypophyseal portal system, while the neurohypophysis consists of nerve
optic Nuclei are the inputs that originate from the soma of neurosecretory neurons in the PVN and
hypothalamic nuclei SON of hypothalamus. These nerve endings travel through the median
mentioned in Unit 2. eminence that is continuous with the infundibulum, or pituitary stalk, and
ultimately release the hormones in the posterior lobe. Before we discuss about
the details of various hormones, let us learn about the anatomy of pituitary
gland.
Anatomy of the Anterior Pituitary Gland
The cell types of the The anterior pituitary gland is composed of various cell types secreting several
pituitary gland are hormones: corticotropes (adrenocorticotropic hormone; ACTH),
categorized based on somatotropes (growth hormone; GH), lactotropes (prolactin; PRL),
the type of hormones gonadotropes (luteinizing hormone; LH, and follicle-stimulating hormone;
secreted. FSH) and thyrotropes (thyroid-stimulating hormone; TSH).
The anterior lobe of the pituitary extends dorsally to form a non-secretory

tissue that wraps around the infundibular stalk known as Pars Tuberalis (Fig.
3.2). An intermediate lobe develops between the two lobes that can vary
greatly in size among different species; in humans, this regress and
disappears in adults. In many vertebrates the intermediate lobe produces
hormones that include melanotropins, such as melanocyte-stimulating
hormone (MSH) (Please refer to the Table 3.1 for details).
Fig. 3.2: Neuroanatomy of the Pars Distalis – the Anterior Pituitary Gland.
40
Anatomy of the Posterior Pituitary
The posterior pituitary primarily consists of neural tissue and it receives input
from the supraoptic and paraventricular neurons of the hypothalamus. The
axons of the neurons traverse the supraoptico-hypophyseal tract and
terminate on capillaries, where hormones are released into the circulation.
These neurons produce either vasopressin (VP) or oxytocin. The
paraventricular nucleus also contains smaller parvicellular neurons which
project through the median eminence to the primary plexus of the anterior
pituitary and co-secrete vasopressin and corticotrophin releasing hormone
(CRH). The sites of VP synthesis in the hypothalamus appear to be close to
the osmoreceptor sites, which sense changes in electrolyte (solute)
concentrations in circulation and signal release of the hormone from neuronal
terminals in the posterior pituitary (Fig. 3.3). The osmoreceptor is close to the
thirst center in the hypothalamus and interacts with the renin-angiotensin
system. Collectively, these systems appear to be the primary elements for
regulation of water balance (Please refer to the Table 3.1 for details).
Fig 3.3: Neuroanatomy of the Pars Nervosa – the Posterior Pituitary Gland.
41
Table 3.1: Hormones of the Anterior and Posterior Pituitary, their targets,
functions and hypothalamic regulators
Hormones of Cell Type Structure Target Functions Hypothalamic

the Pituitary and Location Regulators
Gland
Gonadotropic Anterior
Hormones Pituitary
(adenohypop
hysis or Pars
Distalis)
Follicle Gonadotrophs Gonads stimulates GnRH

Stimulating - Anterior Glycoprotein growth of the
Hormone Pituitary Hormones (Ovary, primary follicle
(FSH) (adenohypop testes) and estradiol
hysis or Pars secretion from
Distalis) the
ovary in
females; sperm
production and
inhibin secretion
in the testis of
males. FSH
secretion is also
regulated
locally by two
factors produced
in
folliculostellate
cells (i.e.
follistatin and
activin).
Luteinizing Gonadotrophs Gonads stimulates GnRH (LHRH)

Hormone - Anterior (Ovary, ovulation,
Pituitary testes) formation of the
(adenohypop corpus luteum
hysis or Pars and
Distalis) progesterone
secretion in
females;
stimulates
Leydig
(interstitial) cells
to secrete
androgens
(testosterone) in
males
Thyroid- Thyrotrophs - Thyroid Stimulates TRH, STT, DA

Stimulating Anterior Gland thyroxine (T4)
Hormone Pituitary and
(TSH) (adenohypop triiodothyronine
hysis or Pars (T3) secretion
Distalis) from the thyroid
gland
Growth Somatotrophs Somatomammotr Muscle, Promotes GHRH, STT

Hormone (GH) -Anterior ophic Family bone, protein
Pituitary liver, all synthesis,
(adenohypop tissues reduction
hysis or Pars
Distalis) of fat mass, and
carbohydrate
42
metabolism;
direct
stimulatory
effect on muscle
mass; increases
bone growth
by first
stimulating
somatomedin
(IGF-1) release
from the liver
Prolactin Lactotrophs - Breast, Initiates milk

Anterior gonads, production in the
Pituitary brain, mammary gland;
(adenohypop immune stimulation of
hysis or Pars cells gonads
Distalis)
Adrenocorticot Corticotrophs Adrenal Stimulates CRH, AVP

ropic Hormone - Anterior cortex glucocorticoid
(ACTH) Pituitary secretion from
(adenohypop the adrenal
hysis or Pars cortex
Distalis)
α-Melanocyte- Melanotrophs Melanocy stimulates DA

stimulating - Intermediate tes melanophores to
Hormone(α- Pituitary (Pars Proopiomelanoco darken skin
MSH) Intermedia) rtin Family color in
amphibia. Some
evidence for a
similar effect in
human, e.g. in
Addison’s
disease
β-Endorphin Melanotrophs Brain, acts as a DA

- Intermediate immune neuromodulator
Pituitary (Pars cells in the brain to
Intermedia) regulate
neurotransmitter
release, and
possibly as a
circulating
analgesic. Also
secreted from
anterior pituitary.
Oxytocin Oxytocin Smooth stimulates

Neurons - muscle of uterine muscle
Posterior mammar contractions and
Pituitary y ducts, milk ejection
(Neurohypoph uterus from the
ysis or Pars mammary
Nervosa) glands via
contraction of
myoepithelial
cells
Vasopressin Vasopressin Nonapeptide Renal elevates blood

Neurons - Hormones tubules, pressure and
Posterior vascular promotes
Pituitary smooth reabsorption of
(Neurohypoph muscle water by the
ysis or Pars cell kidneys
Nervosa)
43
3.3 HORMONES OF THE ANTERIOR

PITUITARY
As discussed earlier, the anterior pituitary gland secretes various hormones
which may be categorized into three main types.
1. Glycoprotein Hormones (LH, FSH and TSH)
2. Somatomammotrophic Hormones (GH and PRL)
3. Pro-Opiomelanocrotin Hormones (ACTH, MSH and β-Lipotropin)
3.3.1 Glycoprotein Hormones

The glycoprotein hormones of the anterior pituitary gland are heterodimeric
and share a common α-subunit and have distinct β- subunits. The α- and β-
subunits are each stabilized by disulfide bonds, and disruption of these bonds
by reducing agents alters the internal configuration of the peptide chains,
causing dissociation of the heterodimer. It is the β-subunit that confers the
specificity on the structure of the hormone so that each of the four
heterodimers interacts only with its specific receptor.
Thyroid Stimulating Hormone (TSH): TSH, also known as thyrotropin or

thyrotropic hormone, is produced in thyrotroph cells of the anterior pituitary.
TSH stimulates the synthesis and release of thyroxine (T4) and
triiodothyronine (T3) from the thyroid gland.
The gonadotropic hormones
The gonad-stimulating or gonadotropic hormones, follicle-stimulating hormone

(FSH), and luteinizing hormone (LH) are produced in the gonadotroph cells of
the anterior pituitary.
Follicle-stimulating hormone (FSH)
Follicle-stimulating hormone has a similar function in both sexes: it promotes

the development of the gametes and the secretion of gonadal hormones. In
the female, FSH stimulates the growth of the primary follicle in the ovary,
promoting development of the ovum, and the secretion of the female sex
hormone estradiol. In the male, FSH stimulates sperm production
(spermatogenesis) and the secretion of the hormone inhibin by acting on the
Sertoli cells of the testis.
Luteinizing hormone (LH)
In the female, luteinizing hormone stimulates ovulation by rupturing the follicle

and releasing the ovum. The residual cells of the follicle then form the
progesterone-secreting luteal cells (corpora lutea) in the ovary. In the male,
luteinizing hormone stimulates the Leydig cells (also called interstitial cells) to
secrete androgens such as testosterone.
3.3.2 Somatomammotrophic Hormones

Growth hormone (GH): Growth hormone is also known as somatotropin or
somatotropic hormone. The suffix –tropin – refers to a substance that has a
stimulating effect on its target organ; thus, somatotropin is a body- (soma-)
44 stimulating hormone. Growth hormone is the most abundant hormone of the
anterior pituitary and is produced in somatotroph cells. GH has effects in
almost all body cells: bone, muscle, brain, heart, fat, etc. Growth hormone has
direct effects on some cells, such as muscle, and therefore it increases muscle
mass. However, its effect on bone growth, and therefore height, occurs
indirectly by stimulating the release of somatomedin, a peptide growth factor
(also known as insulin-like growth factor; IGF-1) from the liver. GH also
stimulates the liver to increase glucose output.
Prolactin: Prolactin is produced in lactotroph (or mammotroph) cells in the

anterior pituitary. Prolactin is essential for initiating milk production in the
mammary glands and has many functions related to growth, osmoregulation,
fat and carbohydrate metabolism, reproduction, and parental behavior. In
many of these actions, prolactin interacts with other hormones, including
estradiol, progesterone and oxytocin.
3.3.3 Pro-Opiomelanocortin Family Hormones

Adrenocorticotropic hormone (ACTH): ACTH is produced in the
corticotroph cells of the anterior pituitary and acts to stimulate the synthesis
and release of glucocorticoid hormones (cortisol, corticosterone, etc.) in the
adrenal cortex. It does this with a distinct rhythm so that levels of ACTH, and
cortisol, are high in the early morning. ACTH is also involved in regulating the
immune system.
Melanocyte Stimulating Hormone (MSH) and β-Lipotropin: The POMC

molecule contains the sequences for many pituitary peptides, including ACTH,
α-MSH, β-lipotropin (LPH), and β-endorphin. First, ACTH and β-LPH are
cleaved off from the propeptide and this occurs in both the anterior and
intermediate pituitary. ACTH and β-LPH are both secreted by the anterior
pituitary, but all the ACTH in the intermediate lobe is converted to α-MSH. In
the anterior pituitary, all the β-LPH is converted to β-endorphin and γ-
lipotropin. Thus, the anterior pituitary co-releases ACTH, β-endorphin, and β-
LPH from the same corticotroph cells. In terms of hormone-like effects, β-
endorphin and γ-LPH have no known function when released into the
bloodstream, but β-endorphin has a wide range of neuropeptide functions in
analgesia, learning and memory, psychiatric diseases, feeding,
thermoregulation, blood pressure regulation, and reproductive behavior.
In amphibians, α-MSH acts on the melanophores to darken their skin to match

background color. α-MSH can also affect pigmentation in mammals, including
humans. The secretion of α-MSH from the intermediate lobe of the pituitary
may occur in the human fetus, although it has not been detected in normal
healthy adults. In patients with Addison’s disease, however, where cortisol
levels are low and ACTH secretion high, there is a pronounced darkening of
the skin that might be caused by α-MSH secreted along with ACTH. An
important non-pituitary source of α-MSH is the hypothalamus, where α-MSH
plays a critical role in influencing feeding behavior. α-MSH may also act to
modulate the immune system.
45
3.4 PATHOPHYSIOLOGY
Gigantism (Excessive GH in Childhood)
There are four types of growth patterns that can result in heights more than 2
standard deviations from the normal mean. These are: intrinsic tallness, the
expression of the genetic potential of the individual; advanced growth, where
growth occurs earlier and stops earlier at normal adult height; prolonged
growth, i.e., beyond the normal time at the end of puberty, often from a
deficiency of sex steroid hormones; and accelerated growth, due to excessive
GH levels. This last type is the one we will focus on here. Hyperproduction of
growth hormone can result from a tumor of the somatotroph (pituitary
adenoma) during growth. The resulting accelerated growth results in
gigantism, which is characterized by a height age that is greater than either
bone age or chronological age and a supranormal growth rate. This form of
GH overproduction is relatively rare. If left untreated, the tumor destroys the
functional gland, impairing the other pituitary hormones and resulting in death.
This disease often involves enlargement of the sella but is principally
manifested by unusually high circulating levels of GH. Therapy involves
removal of the tumor, radiation of the tumor, and/or a GH receptor antagonist.
Dwarfism (Growth Hormone Deficiency in Childhood)
In childhood, there are many possible causes, both genetic and

environmental, of short stature and a slow growth rate. Careful laboratory and
clinical evaluations, including measurements of IGF-1 levels, are required to
determine whether the cause is a deficiency of growth hormone. If present,
GH deficiency may be either congenital (e.g., defective GH or GHRH
synthesis or secretion) or acquired (through a tumor or injury to the head). The
GH deficiency may be isolated, i.e., GH is the only hormone involved, or there
may be disruptions in other pituitary hormones as well. GH deficiency
untreated in childhood leads to adults with proportionate extreme short stature.
The true incidence of GH deficiency, most of which is idiopathic (cause
unknown) is estimated to be around 1 in 3500 children. The child usually has a
normal birth weight but exhibits growth failure and abnormal facial
development during the first two years of life. The objective of treatment with
replacement recombinant human GH is to normalize height during childhood.
Growth rate is most accelerated during the first year of treatment (the “catch-
up” phase) with average rates of 8–10 cm/year. If, thereafter, the growth rate
slows too much, then other factors such as hypothyroidism or nutritional
factors should be considered.
Acromegaly (Excessive GH in Adults)
Excessive GH secretion in adults leads to a constellation of symptoms known

as acromegaly and most commonly results from one of several types of GH-
secreting pituitary tumors. Hypothalamic tumors that oversecrete GHRH may
also be responsible. Acromegaly is quite rare, and its incidence is not well
established. It generally has a slow progression and can be present for a
decade or more before being accurately diagnosed. Since the acromegaly is
46 of adult onset and the epiphyseal growth plates of the long bones close at the
end of puberty, the hypersecretion of GH results in excessive growth of only
those tissues still capable of responding to it. These include the mandible,
bringing about changes of facial structure and the hands and feet, which
become enlarged. These changes in appearance are often so gradual that
they are not the patient’s initial complaint upon presentation. Rather, the
headache resulting from the growing tumor is the most common symptom that
the Hypothalamus and Anterior Pituitary brings the patient to the clinic. Soft-
tissue overgrowth causes several symptoms including neuropathy;
cardiomyopathy and cardiovascular disease; debilitating arthritis; sleep apnea
due to airway obstruction; respiratory disease and, because of the role of GH
in carbohydrate metabolism, carbohydrate intolerance. Untreated acromegaly
leads to a 2- to 4-fold increase in mortality compared to age-matched controls.
The primary goal of treatment of acromegaly is to reduce excessive GH levels.
Surgery is one method to achieve this but is accompanied by serious risks,
one of which is the difficulty in removing all the tumor without damaging
nearby structures. Radiation of the tumor has also been used, but the
response in terms of lower GH levels is much slower than with surgery.
Pharmaceutical therapies include GH receptor antagonists and somatostatin
receptor ligands that block GH secretion by the tumor cells and reduce tumor
size.
3.5 HORMONES OF POSTERIOR

PITUITARY
Two important hormones are secreted from the posterior pituitary in both
males and females. These are vasopressin (VP), the antidiuretic hormone,
and oxytocin (OT), which in female mammals is important in parturition (birth)
and lactation. The two hormones are structurally closely related nonapeptides
that are derived from a common ancestral gene. Each is synthesized in a
specific group of cells in the hypothalamus and is released from the axon
termini of these neurons in the posterior pituitary. Here the hormones are
stored until the appropriate signal brings about their release into the
bloodstream.
Oxytocin
Oxytocin has two primary functions: it promotes uterine contractions during

parturition (childbirth) and it stimulates milk ejection, or letdown, from the
mammary glands during lactation. Oxytocin also has several neuropeptide
functions in the brain.
Vasopressin
Vasopressin (antidiuretic hormone, ADH) acts to raise blood pressure and to

promote water reabsorption in the kidneys – that is, it acts as an antidiuretic.
As a neuropeptide, vasopressin may enhance memory. Besides these two
hormones, the posterior pituitary releases two large proteins called
neurophysins that function as carrier proteins for oxytocin and vasopressin.
47
3.6 FEEDBACK REGULATION CYCLE

As we have learned in the previous sections, the pituitary gland is under the
control of the hypothalamus. The hypothalamus secretes various releasing
and release-inhibiting hormone, which in turn influences the function of the
pituitary gland. Thus, these hormones have specific effects on the target cells
and via feedback mechanism at the level of pituitary or hypothalamus, regulate
its actions. Fig. 3.4 a shows one long feedback loop; however short and
ultrashort feedback may also influence the hypothalamic function (Fig. 3.4 b).
Environmental Factors
Brain
Hypothalamus
RHs RIHs
OXY Median eminence
AVP
Major
Pars Pars feedback
Pars
nervosa distalis loops
intermedia
MSH GH, PRL TSH, LH, FSH,

OXY, AVP
ACTH, GH
Non-endocrine Non-endocrine Endocrine

targets targets targets
Target Effects
Effects Effects Hormones
tissues
Fig. 3.4 a: The Vertebrate endocrine system showing one long feedback loop.
Hypothalamic
GnRH GHRH TRH PrRP (?) CRH
releasing hormones
(+) (+) (+) (+) (+)

FSH PRL ACTH/αMSH Anterior pituitary
GH TSH
LH β-endorphine hormones
(−) (−) (−)
SOM DA Inhibitory hypothalamic

input
Fig. 3.4 b: Summary of the hypothalamic releasing and inhibiting hormones that
modulate the secretion of anterior pituitary hormones.
3.7 DIABETES INSIPIDUS

Lack of vasopressin action, due to damage to the hypothalamus or pituitary or
a gene mutation in either the gene for the hormone or for the receptor in the
48 kidney, leads to the condition known as diabetes insipidus (literally urine that is
tasteless). This condition is to be distinguished from diabetes mellitus (urine
that is sweet) which is due to lack of or resistance to insulin (Chapter 6).
Diabetes insipidus (DI) is characterized by polyuria (excessive urine volume)
and polydipsia (excessive thirst/water intake). The most common cause of
hypothalamic DI in both children and adults is a primary brain tumor that
impacts the hypothalamic magnocellular neurons that secrete vasopressin.
Inherited forms of DI, resulting from defects in vasopressin gene expression,
occur in both autosomal dominant and recessive forms; symptoms are
generally recognized during the child’s second year of life when parents
become more aware of the child’s need for water. In nephrogenic diabetes
insipidus (NDI) the kidney is unresponsive to vasopressin, due to a defect in
the receptor or the signaling pathway. In congenital NDI, polyuria and
polydipsia must be recognized at birth and treated immediately to avoid life-
threatening dehydration. NDI can also be acquired through chronic renal
disease, the use of one of several drugs including lithium and alcohol, and
other disease states such as multiple myeloma and sarcoidosis. Hypothalamic
DI can be treated with replacement vasopressin or its therapeutic analog
desmopressin, which has some beneficial pharmacokinetic properties.
Dosages can be tailored to the individual by monitoring urine volume and
osmolality. Treatment of nephrogenic DI is more complex since it is resistant
to hormone replacement therapy. Most approaches involve treating the
symptoms with low-sodium diet and drugs such as thiazide diuretics.
SAQ 1
i) Anterior pituitary gland develops from the infundibulum.
[True/False]
ii) Pituitary gland is the master endocrine gland. [True/False]
iii) Glycoprotein hormone are LH, FSH and TSH. [True/False]
iv) Corticotrophs produce the hormone ACTH. [True/False]
b) Fill in the blanks with appropriate words.
i) Pituitary gland is divided in to three parts as………………………
ii) Secondary capillary plexus innervates the …………… pituitary
gland.
iii) Nonapeptide hormones of the posterior pituitary gland are
…………………
iv) Pro-opiomelanocortin family hormones constitute the
………………………… hormones.
c) Fill in the blanks with appropriate words:
i) Oxytocin stimulates ……………… from the mammary glands
during …………………..
ii) Vasopressin is also known as …………. hormone.
iii) Diabetes insipidus is characterized by polyuria and …………….
iv) Excessive secretion of growth hormone in adults leads to a
disease known as ………..
49
3.8 SUMMARY
• The embryonic origin of parts of pituitary gland is distinct. The anterior

part develops from oral ectoderm known as Rathke’s pouch while the
posterior part develops from the neural ectoderm (infundibulum) of the
diencephalon.
• Pituitary gland is divided in to three parts namely anterior pituitary (Pars

Distalis); intermediate pituitary (Pars Intermedia) and Posterior posterior
pituitary (Pars nervosa) based on its embryonic development.
• The anterior pituitary has goandotrophs, thyrotrophs, lactotrophs,

somatotrophs, corticotrophs and melanotrphs cell types in its anatomical
structure.
• The hormones of the anterior pituitary belong to three families of

hormones as glycoprotein hormones, somatomammotrophic hormones
and proopiomelanocortin family of hormones.
• Posterior pituitary receives innervation from the magnocellular part (PVN

and SON) of the hypothalamus and secretes hormones oxytocin and
vasopressin.
• Thus, the pituitary is itself under the control of hypothalamus for its
various physiological functions, hence the Pituitary gland is no more
referred to as the “Master Endocrine Organ”.
• Major diseases associated with pituitary gland are dwarfism, gigantism,

acromegaly and diabetes insipidus.

1. Describe the embryonic origin of the pituitary gland.
2. What are the cell types of the anterior pituitary gland and hormones
secreted by them?
3. What is acromegaly? Explain.
4. Discuss the role of the two nonapeptides, oxytocin and vasopressin.
3.10 ANSWERS
1. a) i) False
ii) False
iii) True
iv) True
50
b) i) Pars Distalis, pars intermedia and pars nervosa
ii) Anterior
iii) Oxytocin and vasopressin
iv) ACTH, α-MSH and β-Lipotropin
c) i) Milk ejection, lactation
ii) Anti-diuretic hormone (ADH)
iii) Polydipsia
iv) Acromegaly
Terminal Questions
1. The embryonic development of the lobes of the pituitary gland is
completely distinct. The anterior lobe is derived from an inward
invagination of the primitive mouth cavity (oral ectoderm) known as
Rathke’s pouch while the neural lobe arises from the neural ectoderm of
the floor of the developing forebrain, the infundibulum of diencephalon.
Cells of the anterior wall of Rathke’s pouch develop into the pars distalis,
containing most of the hormone-producing cells of the adenohypophysis.
2. The anterior pituitary gland is composed of various cell types secreting

several hormones such as corticotropes (adrenocorticotropic hormone;
ACTH), somatotropes (growth hormone; GH), lactotropes (prolactin;
PRL), gonadotropes (luteinizing hormone; LH, and follicle-stimulating
hormone; FSH) and thyrotropes (thyroid-stimulating hormone; TSH).
These cell types may be categorized in to three types as glycoprotein
hormones (LH, FSH and TSH), proopiomelanocortin family hormones
(ACTH, MSH and β-Lipotropin) and somatomammotrophic family
hormones (GH and PRL) based on their structure.
3. Excessive GH secretion in adults leads to a constellation of symptoms

known as acromegaly and most commonly results from one of several
types of GH-secreting pituitary tumors. Hypothalamic tumors that
oversecrete GHRH may also be responsible. Acromegaly is quite rare,
and its incidence is not well established. It generally has a slow
progression and can be present for a decade or more before being
accurately diagnosed. Since the acromegaly is of adult onset and the
epiphyseal growth plates of the long bones close at the end of puberty,
the hypersecretion of GH results in excessive growth of only those
tissues still capable of responding to it. These include the mandible,
bringing about changes of facial structure and the hands and feet, which
become enlarged. These changes in appearance are often so gradual
that they are not the patient’s initial complaint upon presentation. Rather,
the headache resulting from the growing tumor is the most common
symptom that the Hypothalamus and Anterior Pituitary brings the patient
to the clinic. Soft-tissue overgrowth causes several symptoms including
neuropathy; cardiomyopathy and cardiovascular disease; debilitating
arthritis; sleep apnea due to airway obstruction; respiratory disease and, 51
because of the role of GH in carbohydrate metabolism, carbohydrate

intolerance. Untreated acromegaly leads to a 2- to 4-fold increase in
mortality compared to age-matched controls. The primary goal of
treatment of acromegaly is to reduce excessive GH levels. Surgery is
one method to achieve this but is accompanied by serious risks, one of
which is the difficulty in removing all the tumor without damaging nearby
structures. Radiation of the tumor has also been used, but the response
in terms of lower GH levels is much slower than with surgery.
Pharmaceutical therapies include GH receptor antagonists and
somatostatin receptor ligands that block GH secretion by the tumor cells
and reduce tumor size.
4. Oxytocin has two primary functions: it promotes uterine contractions

during parturition (childbirth) and it stimulates milk ejection, or letdown,
from the mammary glands during lactation. Oxytocin also has several
neuropeptide functions in the brain. Vasopressin (antidiuretic hormone,
ADH) acts to raise blood pressure and to promote water reabsorption in
the kidneys – that is, it acts as an antidiuretic. As a neuropeptide,
vasopressin may enhance memory. Besides these two hormones, the
posterior pituitary releases two large proteins called neurophysins that
function as carrier proteins for oxytocin and vasopressin.
52

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Unit 1 Introduction to Endocrinology

1.6 Functions of Hormones and

Expected Learning Outcomes

define and classify hormones;

explain various types of hormonal signaling;

explain the transport of hormones in the circulation and their half-lives,

explain the versatile functions of hormones and their regulation.

1.2 ENDOCRINE GLANDS

The endocrine gland releases hormones into the bloodstream, whereas

Endocrine Hormones Molecular Target Organs Functions

Hypothalamus Hypothalamic Peptide Anterior pituitary Regulate anterior

Anterior Thyroid stimulating Glycoprotein Thyroid Stimulates thyroid

Adrenocorticotropic Peptide Adrenal cortex Stimulates adrenal

Gonadotropic (FSH, Glycoprotein Gonads Sex hormone

Prolactin (PRL) Protein Mammary glands Milk Production

Posterior Oxytocin Peptide Uterus, mammary Stimulates uterine

Anti-diuretic Peptide Kidneys Stimulates

Pineal gland Melatonin Serotonin Various tissues Circadian rhythm,

Thyroid Gland Thyroxine (T4) Iodinated All tissues Increase metabolic

Calcitonin Peptide Bones, kidneys Lowers blood

Parathyroids Parathyroid hormone Peptide Bones, kidneys Raises blood

Adrenal Cortex Glucocorticoids Steroid All tissues Raise blood glucose

Mineralocorticoids Steroid Kidneys Reabsorb sodium

Adrenal Epinephrine and Catecholami Cardiac and other Released in

Stomach Gastrin Peptide Enterochromaffin- Stimulates secretion

Pancreas Insulin Protein Liver, muscles, Lowers blood

Glucagon Protein Liver, muscles, Raise blood glucose

Somatostatin Protein All tissues Exerts an inhibitory

Duodenum and Secretin Protein Pancreas and Regulates water

Cholecystokinin Protein Gallbladder Causes the release

Ovary Estrogen, androgen, Steroid Gonads, skin, Stimulates female

Testis Androgens Steroid Gonads, skin, Stimulates male sex

i) Oxytocin and vasopressin are peptides and secreted by posterior

ii) Insulin increases blood glucose levels and promotes formation of

iii) Gastrin stimulates secretion of gastric acid.

b) Fill in the blanks with appropriate words:

i) Salivary and sweat glands are examples of …………………...

ii) Vasopressin is also known as ………………………..

1.3 CHEMICAL SIGNALING

Fig. 1.1: Types of Receptors. (a) Cell-surface receptors, also known as

The cascade of signaling events can be divided into three steps:

1. Reception: Cell perceives a signaling molecule from the exterior of the

2. Transduction: Binding of signaling molecule to the receptor changes

In a multicellular organism, the average cell is exposed to numerous signals of

Cryptocrine system- a) Local Signaling

iv) Paracrine signaling - a molecule released from one cell and

• Release of cytokines leading to an inflammatory response in the

• Release of neurotransmitters at synapses.

i) Endocrine signaling - hormones (chemicals secreted into the

ii) Neural Signaling - signaling molecules (neurotransmitters) are

i) Cell-surface receptors, also known as………………. are recruited in the

ii) Neuroendocrine signaling involves ……………………secreted by

iii) Release of cytokines leading to an inflammatory response in the area

1.4 CHEMICAL CLASSIFICATION OF

• Hormones that can enter cells and signal by binding to intracellular

Chemical Classes of Hormones: Based on chemical nature, hormones can

• Lipid-soluble Hormones: The lipid-soluble hormones comprise of

• Water-soluble Hormones: The water-soluble hormones include protein

A prohormone is a The chemical nature of a hormone determines: