INTRODUCTION ENDOCRINAL

SYSTEM PHYSIOLOOGY

DR. MASIKA
2023
 ENDOCRINAL SYSTEM PHYSIOLOOGY

Introduction
1.  General principles of endocrinal system
2.  Endocrinal functions of hypothalamus and pituitary
gland
3.  Thyroid gland
4.  Endocrinal control of calcium metabolism and bone
physiology
5.  Adrenal glands
6.  Pancreatic and gastrointestinal hormones
7.  Endocrinal functions of other organs and local
hormones
 Introduction
• Biological functions of the multicellular living organisms
are very well co-ordinated.
• This co-ordination is achieved by two main control
systems, nervous system and the endocrinal system.
• Nervous system is principally related with functions of
the body in an external and internal environment.
Through transmission of electrochemical impulses via
nerve fibres.
• Endocrinal system is mainly concerned with different
metabolic functions of the body, especially the chemical
reactions and transport of various substances. The
endocrinal functions are accomplished through
hormones.
 Relationship between endocrine and neural physiology
• The nervous system and the endocrine system have
important functional similarities.
• The nervous system and the endocrine system often respond
together to incoming stimuli so as to integrate the organism’s
response to changes in its external and internal environment.
• A significant decrease in the circulating blood volume is
sensed by baroreceptors, the cardiac atria, the kidney and
the brain.
• The sympathetic nervous system, a neurohormone from the
posterior pituitary gland and hormones from the cardiac atria
and ventricles, the adrenal medulla, the adrenal cortex and
the kidneys act on target cells in blood vessels and kidneys to
restore blood volume. 
 Relationship between endocrine and neural physiology cont’

• Relationship between the nervous and endocrine systems is illustrated:

• Nervous and endocrine cells can both secrete substances into the
bloodstream.
• Some endocrine cells and neurons generate electrical potentials and
can be depolarized.
• Peptides originally discovered as products of endocrine cells have
neurotransmitter function as well. Likewise, molecules normally
considered to be neurotransmitters can act as hormones.
• Both biogenic amine neurotransmitters and peptide hormone
molecules can be produced by a single cell.
• Certain factors such as neurogenin and nerve growth factor play a role
in the development of both endocrine cells as well as nervous system.
• Structural similarities exist between the receptors for hormones and
neurotransmitters.
 Organization of endocrine system

• The neurosecretory cells of hypothalamus secrete certain

neurohormones called releasing and inhibitory factors which
influence the secretion of hormones from other endocrine glands.
• Certain other substances act as neurotransmitters in the brain and
influence the secretion of neurosecretory cells of hypothalamus.
The environmental factors through these neurotransmitters
influence the whole endocrine system.
1. Pituitary gland (hypophysis). It has two main parts:
adenohypophysis and neurohypophysis. 
Adenohypophysis secretes growth hormone (GH) or somatotropins,
follicle-stimulating hormone (FSH), luteinizing hormone (LH),
prolactin, thyrotropin or thyroid-stimulating hormone (TSH) and
corticotropin or adrenocorticotropic hormone (ACTH).
Neurohypophysis stores the antidiuretic hormone (ADH) or
vasopressin and oxytocin synthesized by the hypothalamus.
 Organization of endocrine system cont’

2. Thyroid gland. It has two lobes and an isthmus (bridge) connecting the
lobes. It secretes thyroxine (T4) and triiodothyronine (T3). The C cells or
parafollicular cells which are scattered in the spaces between the follicles of
the thyroid gland secrete calcitonin.
3. Parathyroid glands. These are four in number; very small glands situated
behind the lobes of the thyroid gland and secrete parathormone.
4. Adrenal glands. These are situated on the upper poles of the two kidneys
(suprarenal glands). The outer cortex region of the adrenal glands secretes
cortisol, aldosterone and sex steroids, and the inner medullary region
secretes catecholamines (adrenaline and noradrenaline).
5. Pancreatic islets (islets of Langerhans). These are small groups of cells
which secrete insulin, glucagon, pancreatic polypeptide and somatostatin.
6. Gonads. These include ovaries in females and testes in males. The ovaries
secrete oestrogens and progesterone (female sex steroids), and testes
secrete male sex hormone (testosterone).
 Organization of endocrine system cont’
7. Pineal gland. It is a small gland present in the roof of third ventricle
in the brain. It secretes melatonin and other biogenic amines.
8. Placenta. Secretes various hormones like human chorionic
gonadotropin (HCG), oestrogen, progesterone, somatotropins and
relaxin.
9. Gastrointestinal mucosa: secretes various hormones collectively
known as gastrointestinal (GIT) hormones, e.g. gastrin, secretin,
cholecystokinin-pancreozymin (CCK-PZ), etc.
10. Kidneys. The kidneys secrete erythropoietin, prostaglandins and
1,25-dihydroxycholecalciferol, and also help in activation of
angiotensin production.
11. Atrial muscle cells. These secrete atrial natriuretic peptides (ANP)
and many other peptides.
12. Skin. This is also considered to act as an endocrine structure by
producing vitamin D, which is a hormone.
 GENERAL PRINCIPLES OF ENDOCRINAL SYSTEM
• The word hormone is derived from the Greek
word hormaein, which means to execute or to arouse.
• In the classic definition, hormones are secretory products of the
ductless glands which are released in catalytic amounts into
bloodstream and transported to specific target cells/ organs,
where they elicit physiologic, morphologic and biochemical
responses.
• In reality, the requirement that hormones be secreted into the
bloodstream is too restrictive, because they can also act locally.
1. Endocrine hormones.
• These include the chemical messengers whose function is the
transmission of a molecular signal from a classic endocrinal cell
through the bloodstream to a distant target cell
 2. Neurocrine hormones

• Nervous communication involves the release of chemical

messengers from nerve terminals, which may reach their target
cells via one of three routes:
• Neurotransmitters can be released directly into the intercellular
space, cross the synaptic junction and inhibit or activate the
postsynaptic cell, e.g. acetylcholine and norepinephrine.
• Neural signals can be transferred via gap junction, which is a
membrane stabilization between the nerve cells, between nerve
terminals and endocrine cells and between endocrine cells.
• Neurohormones or peptides are released from a neurosecretory
neuron into the bloodstream and then carried to a distant target
cells . E.g., oxytocin and antidiuretic hormone (ADH). The effector
sites of neurohormones are not always endocrine cells.
 3. Paracrine hormones
• Chemical messengers are secreted by a cell, are carried over
short distance by diffusion through the interstitial spaces (ECF)
to act on the neighbouring different cell types as or a regulatory
substance. E.g.,, in islets of Langerhans, somatostatin secreted
by the delta cells acts on the alpha and beta cells.
4. Autocrine hormones: Refer to those chemical messengers
which regulate the activity of neighbouring similar type of cells.
E.g., of autocrine hormones are prostaglandins.
6. Cytokines are peptides secreted by cells into the ECF and can
function as autocrines, paracrines, or endocrine hormones. E.g.,
of cytokines include the interleukins and other lymphokines that
are secreted by T-helper cells and act on other cells of the
immune system. Cytokine hormones (e.g., leptin) produced by
adipocytes are sometimes called adipokines.
FIGURE: 1-
1Different types
of hormones (by
their mechanism
of action)
are: A, endocrine
hormone; B, neur
ocrine
hormone; C, para
crine hormone;
and D, autocrine
hormone.
 NOTE

• According to the route by which it is transmitted, the same

chemical messenger may act as endocrinal hormone
(bloodstream conveyance), or as a paracrine, or as an
autocrine hormone (local conveyance), e.g. insulin secreted
by beta cells in the pancreatic islets may act as:
• Endocrine hormone. When released into bloodstream, insulin
acts on the adipose tissue, muscle, liver and brain to regulate
energy stores, carbohydrate, fat and protein metabolism.
• Paracrine hormone. Insulin, when released into the islets
interstitial fluid, inhibits the neighbouring alpha cells of the
islets.
• Autocrine hormone. The insulin released in the islets
interstitial fluid can regulate growth and function of beta cells
themselves as they possess insulin receptors.
 Classification of hormones
A. Depending upon the chemical nature

1. Amines or amino acid 2. Proteins and polypeptides

i. Short-chain polypeptides include:
derivatives, e.g.
• Catecholamines (epinephrine - Posterior pituitary hormones
and norepinephrine), - Antidiuretic hormone (ADH) and
• Thyroxine (T4) and - Oxytocin.
triiodothyronine (T3) ii. Long-chain polypeptides include:
- Insulin,
3. Steroid hormones: These - Glucagon,
include:
- Parathormone and
• Glucocorticoids,
- Other anterior pituitary hormones.
• Mineralocorticoids,
• Sex steroids
• Vitamin D.
 B. Depending upon the mechanism of action

• Group I hormones. These act by binding to

intracellular receptor and mediate their actions via
formation of a hormone receptor complex. These
include steroid, retinoid and thyroid hormones.
• Group II hormones. These involve second
messenger to mediate their effect. Depending upon
the chemical nature of the second messengers,
group II hormones are further divided into four
subgroups A, B, C and D
TABLE 1. Types of Group II Hormones Based on the Chemical Nature of
Second Messenger Involved in their Mechanism of Action
Group Second messenger Hormones
Group II-A Cyclic AMP (cAMP) Adrenocorticotropic hormone (ACTH) 
Antidiuretic hormone (ADH) 
Angiotensin II 
Calcitonin 
Corticotropic hormones (CRH) 
Catecholamine (α2 adrenergic) 
Follicle-stimulating hormone (FSH) 
Glucagon 
Luteinizing hormone (LH) 
Parathormone (PTH) 
Somatostatin 
Thyroid-stimulating hormone (TSH)

Group II-B Cyclic GMP (cGMP) Atrial natriuretic factor (ANF) and nitric oxide
Group II-C Calcium/or Acetylcholine (ACh), catecholamines (α 1 adrenergic), gastrin,
phosphatidyl oxytocin, thyrotropin releasing hormone (TRH), gonadotropin-
inositol or both releasing hormone (GnRH), platelet-derived growth factor
(PDGF) and substances
Group II-D Kinase or Human chorionic somatotropin (HCS), erythropoietin, growth
phosphatase hormone, insulin and insulin-like growth factors (IGF-I and IGF-
cascade II), nerve growth factor (NGF), prolactin and other growth
factors
 Hormone chemistry, synthesis, storage and release

1. Amines or amino acid derivatives

• Synthesis: include catecholamines, thyroid hormone and calciferol,
which are derived from the amino acid tyrosine.
• Thyroid hormones are derived from two iodinated tyrosine
residues. Thyroid hormones are the only substances in the body
that contain iodine. These are synthesized in the cell cytoplasm.
Storage and release
• Catecholamines are stored in secretory granules inside the
cytoplasm of chromaffin cells. Secretion occurs when the
membrane of granule fuses with the plasma membrane, causing
the granular contents to be extruded into the circulation.
• Thyroid hormones are stored outside the follicular cells in the form
of thyroglobulin. Following endocytosis and proteolysis of
thyroglobulin, thyroid hormones are secreted into the bloodstream
by simple diffusion.
• Calciferol (1,25-dihydroxy-vitamin D3) is stored as a precursor in the
form of 7-dehydrocholesterol or cholecalciferol (vitamin D 3) in the
skin.
 2. Protein and polypeptide hormones

Synthesis: Are composed of chains of amino acids linked by

peptide bonds. Are synthesized in the granular endoplasmic
reticulum of glandular cells in the same manner as other
proteins:
• The amino acid sequence is determined by specific DNA
molecules through the mRNA.
• First the precursor hormone (prohormone, or preprohormone)
is synthesized in the rough endoplasmic reticulum.
• Then the precursor hormone is converted into proper hormone
within the Golgi complex by post-translational cleavage.
Storage and release: Are stored exclusively in subcellular
membrane-bound secretory granules within the cytoplasm of
endocrine cell until a release signal is received. On receiving
the release signal, these hormones are released into the blood
by exocytosis.
 3. Steroid hormones
Synthesis: Steroids are hydrophobic lipid-soluble
substances. These are synthesized from cholesterol.
Storage and release: There is little storage of steroids.
• Different precursors of cholesterol and intermediate
compounds are present in the cells.
• These serve as precursors and when the necessity
of hormone arises, the enzymatic action converts
them into steroids which are released in the
circulation by simple diffusion.
 Hormone transport 

• After secretion into bloodstream, the hormones may

circulate in two forms:
Unbound form: Circulate as free molecule, e.g.
catecholamines and most peptide and protein hormones
circulate unbound.
Bound form: Steroids, thyroid hormones and vitamin D,
circulate bound to specific globulins that are synthesized in
the liver. The binding of hormones to proteins is
advantageous as it:
• Protects the hormone against clearance by the kidney,
• Slows down the rate of degradation by the liver
• Provides circulating reserve of the hormone.
• Some hormones are carried in the blood as inactive forms
with proteins. They become active at the target site only.
Only unbound hormones pass through capillaries to
produce their effects or to degrade.
 Plasma concentration 
• Hormones are usually secreted into the circulation
in extremely low concentrations:
• Peptide hormone concentration is between 10−12 and
10−10 mol/L.
• Epinephrine and norepinephrine concentrations
are 2 × 10−10 and 13 × 10−10 mol/L, respectively.
• Steroid and thyroid hormone concentrations are
10−9 and 10−6 mol/L, respectively.
Half-life: Most hormones are metabolized rapidly
after secretion. In general: Peptide hormones have
short half-life. Steroids and thyroid hormones have
significantly longer half-life because they are bound
to plasma proteins. 
TABLE: 2. Half-Life of Some of the Important Hormones
Class of Hormone Half-life
hormone
Protein and ADH  <1 min 
peptide Oxytocin  <1 min 
hormones Insulin  5 min 
Prolactin  12 s 
Growth hormone  <30 min 
ACTH  15–25 s 
LH  15–45 min 
FSH 180 min

Amines Epinephrine  10 s 
Norepinephrine  15 s 
Thyroxine (T4)  5–7 days 
Triiodothyronine (T3) 1–3 days

Steroid Aldosterone  30 min 

hormones Cortisol  90–100 min 
1,25-Dihydroxycholecalciferol  15 h 
25-Hydroxycholecalciferol 15 days
 Functions of hormones

• Hormones regulate existing fundamental processes but do not

initiate reactions de novo.
1. Regulation of biochemical reactions: Hormones regulate the
metabolic functions in a variety of ways:
• They stimulate or inhibit the rate and magnitude of biochemical
reactions by controlling enzymes and thereby cause morphologic,
biochemical and functional changes in target tissues.
• They modulate energy-producing processes and regulate the
circulating levels of energy-yielding substances (e.g. glucose, fatty
acids). However, they are not used as energy sources in biochemical
reactions.
2. Regulation of bodily processes
• Hormones regulate different bodily processes such as growth,
maturation, differentiation, regeneration, reproduction and
behaviour. Thus, the main function of endocrine glands is to
maintain homeostasis in an internal environment. For these
functions, the hormones do not act directly on the intracellular
machinery.
Mechanisms of hormone disposal
H orm one di s po s a l

The circulating hormones are disposed off by the

following mechanisms:
• Target cell uptake and intracellular degradation,
• Metabolic degradation/inactivation
• Urinary or biliary secretion.
1. Target cell uptake and intracellular degradation.
• The interaction of hormones with their target cells is
followed by intracellular degradation.
• Degradation of protein and amine hormones occurs
after binding to membrane receptors, and then
internalization of hormone receptor complex.
• Degradation of thyroid and steroid hormones occurs
after binding the hormone-receptor complex to the
 Hormone disposal cont’
2. Metabolic degradation/inactivation.
• Only a small fraction of the circulating hormone is
removed by target tissue cells; most of the hormone
extraction and degradation occurs in the liver and
kidneys.
• Metabolic degradation occurs by enzymatic processes
that include proteolysis, oxidation, reduction,
hydroxylation, decarboxylation and methylation.
• Virtually all the hormones are extracted from the
plasma and degraded to some extent by the liver.
• In addition, glucuronization and sulfaction of hormones
or their metabolites may be carried out, and the
conjugates are subsequently excreted in the bile or
urine.
 3. Urinary and biliary excretion

• Renal clearance of hormones is reduced greatly by

protein binding in the plasma, e.g. less than 10% of
secreted cortisol appears unchanged in the urine,
because only the small, free fraction of plasma cortisol
is filtered by the glomerulus.
• On the other hand, about 30% of cortisol metabolites
are excreted in urine, because they are generally
unbound or only loosely bound to protein.
• Peptide and smaller protein hormones are filtered to
some degree by the glomerulus. However, they may
subsequently undergo tubular reabsorption and
degradation within the kidney, so that only a small
fraction appears in the final urine.
• Further, the conjugated hormones are excreted in the
bile or urine.
 Metabolic clearance rate (MCR)

• Refers to the sum of all the removal processes, i.e. target

cell uptake and degradation, metabolic degradation and
urinary or biliary excretion. In a steady rate, MCR is
defined as the volume of plasma cleared/unit time,
which equals mass removed/unit time divided by
circulating mass/unit volume, that is,
• MCR is inversely correlated with plasma half-life.

• Functional turnover rate (k). 

• Functional turnover rate (k) refers to the ratio of MCR to
the volume of distribution of a hormone. The plasma
half-life, which is inversely related to k, is a wider but
more conveniently determined index of hormone
disappearance.
• General mechanisms that govern the secretion of hormone include:
Regulation of hormone secretion

Feedback control, Neural control and Chronotropic control.

1. Feedback control: ​Regulation of a hormone in terms of
requirement is best accomplished through feedback from the blood
concentration of the hormone concerned (hormone–hormone) or
some result of action of the hormone (substrate–hormone).
Feedback control is of two types: Negative feedback control and
Positive feedback control.
Negative feedback control: Generally, the influence of blood
concentration of the hormone concerned or its effect is to inhibit
further secretion of the hormone and is called negative feedback
control
Positive feedback control: This is less common and acts to amplify
the initial biological effects of the hormone. Depending upon the
product involved, the feedback mechanism may be:
• Hormone–hormone feedback,
• Substrate–hormone feedback and
• Mineral–hormone feedback.
FIGURE: 2Hormonal regulation by feedback control
mechanism: A, negative feedback; and B, positive feedback.
 i. Hormone–hormone feedback control 

• The best example of hormone–hormone negative feedback

control is regulation of hormone secretions by hypothalamus
and pituitary, which involves three loops (Fig. 3):
• Long-loop feedback (Fig.3A). The peripheral gland hormone
(e.g. thyroid, adrenocortical and gonads) can exert long-loop
negative feedback control on both the hypothalamus and the
anterior lobe of pituitary.
• Short-loop feedback (Fig. 3B). The pituitary trophic hormones
decrease the secretion of hypophysiotrophic hormone (e.g.
GHRH, GHIH, TRH, GnRH, etc.) by short-loop feedback.
• Ultrashort-loop feedback (Fig.3C). The hypophysiotrophic
hormones may inhibit their own synthesis and secretion via
an ultrashort-loop feedback mechanism.
FIGURE:
3Hormone–
hormone negative
feedback control by
hypothalamus and
pituitary: A, long
loop feedback; B,
short loop
feedback; and C,
ultrashort loop
feedback.
 ii. Substrate–hormone feedback control 

• The best example of substrate–hormone feedback

control is regulation of insulin secretion from
pancreatic beta cells of islets of Langerhans and
glucagon secretion from alpha cells by blood
glucose levels.
• A rise in blood glucose level promotes the secretion
of insulin, while a fall in blood glucose promotes
secretion of glucagon.
• These responses keep the blood glucose level
within narrow limits in spite of variation in
carbohydrate intake in diet.
 iii. Mineral–hormone feedback

2. Neural control: Acts to evoke or suppress hormone

secretion in response to both external and internal stimuli.
External stimuli which can modulate hormone release
through neural mechanisms may be visual, auditory,
olfactory, gustatory and tactile.
Internal stimuli which influence hormonal release through
neural mechanism include pain, emotion, sexual
excitement, fright, stress and changes in blood volume.
Neural control depending upon the type of nerve fibres
involved may be: Adrenergic, Cholinergic, Dopaminergic,
Serotoninergic and Gabaergic.
 iii. Mineral–hormone feedback cont’

E.g., of neural control of hormones: Release of

oxytocin, which fills the milk ducts in response to the
stimulus of suckling, Release of aldosterone, which
augments the circulatory volume in response to upright
posture and Release of melatonin in response to darkness.
3. Chronotropic control: of hormone secretion accounts for:
Oscillating and pulsatile release of certain hormones,
Diurnal variation in hormonal levels, Menstrual rhythm,
Seasonal rhythm and Developmental rhythm. The source
of regular oscillatory cycles is a pulse generator(s) located
in the suprachiasmatic nucleus (SCN) of the hypothalamus
The intrinsic
circadian clock is
also located in
the SCN, which is
responsible for
endocrinal,
metabolic and
behavioural co-
ordinated
rhythms.

FIGURE 4: The origin of circadian rhythms in endocrine gland secretion,

metabolic process and behavioural activity.
Hormone: Receptors and mechanism of action
• Hormone receptors: All hormones act through specific receptors. Almost all
hormone receptors are large proteins present in hormone-sensitive target
cells.
Characteristics of hormone receptors
• Receptor specificity: There are specific receptors for each hormone. This is the
reason that all hormones circulate to all parts of the body, yet each hormone
has a specific target tissue for its action
• Receptor location: Depending upon the location, receptors are of two types:
i. Internal receptors are located inside the cells, e.g. receptors for steroid
hormones and thyroid hormones are localized within the nucleus of target cells.
ii. External receptors are located on the plasma membrane of target cells, e.g.
peptide and protein hormones, amines and prostaglandins are interspersed
within the phospholipid bilayer of the plasma membranes.
• Receptor affinity refers to the degree of attraction between the hormone and
receptor and is measured from the speed of hormone binding by the receptor.
• Receptor capacity refers to the quantity of hormone binding.
 Hormone: Receptors and mechanism of action cont’

• Receptor density: Approximately 104–105 receptors exist on the surface

of a polypeptide hormone target cell, and about 3 × 103–3 ×
104 intracellular receptors exist per steroid target cell.
• Change in receptor number: vary depending upon the situation. It is
regulated by two mechanisms: downregulation and upregulation.
i. Downregulation refers to decrease in the number of active receptors. It
occurs to regulate the hormone sensitivity when it is present in excess.
For example, elevated ambient insulin concentration causes a loss or
inactivation of insulin receptors in liver cells, fat cells and WBCs.
ii. Upregulation refers to increase in the number of active receptors on a
cell. It occurs to regulate the hormone action when its concentration is
less. This phenomenon tends to reduce the effect of hormone deficiency.
Spare receptors. A maximum physiologic response of a target cell is
observed even when the concentration of a hormone is lower than
required to occupy all of the receptors on that cell. Therefore, most of
the receptors (∼97%) are referred to as spare (reserve) receptors.
FIGURE 5: Specificity of hormone action is because of specific
receptors.
 Classification of membrane receptors

FIGURE 6: Schematic general structure of four major classes of membrane

receptors.
 Horm one: Receptors and m echanism of action cont’

1. Receptor kinases.These include membrane receptors that

contain enzyme activity. For example, receptors for insulin
hormone contain tyrosine or serine kinase as an intrinsic
part of structure.
2. Receptor-linked kinases. These have no intrinsic enzyme
activity, e.g. receptors for growth hormone, prolactin and
cytokines.
3. G-protein-coupled receptors. Examples are: receptors for
pituitary tropic hormones, glucagon, epinephrine
norepinephrine, parathyroid hormone and prostaglandins.
4. Ligand-gated ion channels. These act as receptors for
neurotransmitters such as acetylcholine (ACh), γ-
aminobutyric acid (GABA) and glycine.
 Structure of a receptor
• The receptors in general have two parts or domains: a
recognition domain (R), and a coupling domain (C)
• Recognition domain (R). It is that part of the receptor
where the hormone binds. It is formed by extracellular N-
terminus portion of the receptor (extracellularly projected
NH2 group).
• Coupling domain (C). It is that part of receptor which
initiates signals for intracellular activities after the
recognition. It is formed by the intracellular C-terminus
tail of the receptor (intracellularly projected carboxyl, i.e.
COOH). The membrane receptors wind in and out  of the
plasma membrane by means of seven transmembrane
segments.
FIGURE 7: General structure of a hormonal receptor.
 Mechanism of action of hormones

• all hormones act through specific receptors, and depending upon the
mechanism of action hormones they have been divided into group I
and group II.
• Group I hormones act by affecting gene expression at cellular level, and
• Group II hormones act through intermediary molecules called second
messenger, and depending upon the chemical nature of second
messenger, the group II hormones have been further divided into
subgroups A, B, C and D.
The main mechanisms of hormone actions are:
• Action through change in membrane permeability,
• Action through effect on gene expression by binding of hormones with
intracellular receptors,
• Action through secondary messengers which activate intracellular
enzymes when hormones combine with membrane receptors and
• Action through tyrosine kinase activation.
 Action through change in membrane permeability

• Certain hormones bind with the receptors present in the cell

membrane (external receptors) and cause conformational change in
the protein of the receptors, this results into either opening or closing
of the ions channels (such as Na+ channels, K+ channels and
Ca2+channels). The movement of ions through Ca2+ channels causes
the subsequent effect, e.g. adrenaline, noradrenaline act by this
mechanism.
• Group I hormones act by their effect on gene expression which
include steroid hormones, retinoids and thyroid hormones. These
hormones are lipophilic in nature and can easily pass across the cell
membrane. They act through intracellular receptors located either in
the cytosol or in the nucleus. The sequence of events involved is:
1. Transport. After secretion, the hormone is carried to the target tissue
on serum-binding protein.
2. Internalization. Being lipophilic, the hormone easily diffuses through
the plasma membrane.
 Action through change in mem brane permeability

3. Receptor–hormone complex is formed by binding of hormone to

the specific receptor inside the cell. There are three distinct
pathways by which primary messenger alter transcription and
gene expression as under:
• Primary messenger (in case of steroid and thyroid hormone)
directly binds to nuclear receptor and directly interacts with DNA
to alter gene expression.
• By activation of cytoplasmic receptor protein (kinase) that moves
into the nucleus and activates latent transcription factor causing
phosphorylation, e.g. mitogen-activated protein kinase (MAP).
• The third pathway is the activation of latent transcription factor
present in the cytosol. This pathway is shared by nuclear factor
kappa B (NFKB) and signal transducers of activated transcription
(STATs).
 Action through change in membrane permeability cont’

4. Conformational change occurs in receptor proteins leading to

activation of receptors.
5. The activated receptor–hormone complex then diffuses into
the nucleus and binds on the specific region on the DNA
known as hormone responsive element (HRE), which initiates
gene transcription.
6. Binding of the receptor–hormone complex to DNA alters the
rate of transcription of messenger RNA (mRNA).
7. The mRNA diffuses in the cytoplasm, where it promotes the
translation process at the ribosomes. In this way, new proteins
are formed which result in specific responses. Some of the
new proteins synthesized are enzymes.
FIGURE 8: Action
of hormones
through their
effect of gene
expression. Note
1–7 represent the
steps involved in
the process 
 Note

• The hormonal action mediated through intracellular

receptors is comparatively slower due to the time
(45 min to several hours) involved in the processes
described above. Therefore, glucocorticoids may
take hours to few days to achieve the therapeutic
effect.
 Action through second messengers

• The peptides and biogenic amines are two principal classes of hormones
which act through second messengers and are classified as group II
hormones. Such hormones are also called first messengers. The release of
second messenger is mediated by GTP-binding proteins also called G-
proteins.
Coupling by G-proteins 
• ​The G-proteins involved in cell signalling are divided into two groups: small
G-proteins and heterotrimeric G-proteins.
(i) The small G-proteins further belong to six different families or small
GTPases and act as follows:
• The GTPases cause hydrolysis of GTP to GDP and tend to inactivate small G-
proteins.
• Guanine exchange factors (GEFs), present on the active site, activate G-
protein by encouraging exchange of GDP for GTP.
• Some small G-proteins lead to lipid modification and thus help to anchor
them to the membrane.
• Some small G-proteins are free to diffuse into the cytosol.
 Functions:

• The Rab family members of small G-proteins

regulate vesicular movement between endoplasmic
reticulum, the Golgi apparatus, lysosomes and cell
membrane.
• The Rho/Rac family small G-proteins mediate
interaction between cytoskeleton and cell
membrane.
• Ras family small G-proteins are responsible for
regulation of growth by transmission of signals from
the cell membrane to the nucleus.
 Action through second messengers cont’

(ii) Heterotrimeric G-proteins are large G-proteins that couple the

receptors to catalytic units on the cell surface and catalyse the
formation of intracellular second messenger. The heterotrimeric G-
proteins are made up of three subunits (α, β and γ). The α and γ
subunits help in anchoring of G-protein to the cell surface. The α
subunit is bound to GDP. When hormone or ligand binds to G-
protein-coupled receptor the GDP is exchanged with GTP and α
subunit separates from the β and γ subunits and is responsible for
various biological activities. The intrinsic GTPase activity of
separated α subunit converts GTP into GDP and leads to
reassociation of α subunit with β and γ subunits.
• The regulators of G-protein signalling (RGS) accelerate α subunit
GTPase activity.
• The heterotrimeric G-protein involved in relaying signals for more
than 1000 G-protein receptors
 Action through second messengers cont’

G-protein-coupled receptors structurally (GPCRs) are

barrel like.
• The GPCR are seven helix or serpentine receptors and
span the cell membrane seven times.
• Mechanism of action: When a ligand binds the GPCR,
a conformational change occurs, which activates
heterotrimeteric G-protein-associated cytoplasm, i.e.
leaf of plasma membrane which in turn activates
many G-proteins, thus leading to amplification of the
effect. A large number of ligands act through G-
protein-coupled proteins. These include: (Table 3).
 A ctio n thro ug h s e co nd me s s eng ers co nt’

• Events involved in coupling by G-protein which lead onto changes

in the cellular concentration of the second messengers are
summarized
- Group II hormones are water soluble and bind to the plasma
membrane of the target cell via cell surface receptors.
- The hormone-bearing receptor then interacts with a G-protein and
activates it by binding GTP. There are two classes of G-proteins:
stimulatory G-protein (Gs) and inhibitory G-protein (Gi).
- In its activated (“on”) state, the G-protein interacts with one or
more of the effector protein (most of which are enzymes or ion
channels such as adenylyl cyclase, Ca2+ or K+ channels or
phospholipase C, A2 or D) to activate or inhibit them.
- The changed effector molecules in turn generate second
messenger that mediates the hormone’s intracellular action.
FIGURE 9:
Schematic
mechanism of
coupling by G-
protein leading
to increase in
second
messenger
which
mediates
hormone’s
physiological
response.
 TABLE 3. ​The Ligands Act via G-Protein-Coupled Receptors.
Type of ligands Examples
Neurotransmitters Epinephrine, norepinephrine,
dopamine, 5-HT, acetylcholine, opiods
and adenosine
Tachykinins Substance P, neuropeptide-K and
neurokinin
Hormones Vasopressin, angiotensin II, oxytocin,
VIP, GRP, parathyroid, TRH, TSH, FSH,
LH, HCG
Arachidonic acid Thromboxane A2
derivatives
Other Endothelins, odorants and tastants,
platelet-activating factor, cannabinoid
and light
 Second messenger systems 

• The second messenger systems that are activated through

coupling of hormone receptor complexes by G-protein include:
Adenylyl cyclase–cAMP system, Guanylyl cyclase–cGMP system,
Membrane phospholipase–phospholipid system and Calcium–
calmodulin system.
1. Adenylyl cyclase–cAMP system. 
• The hormones which act through adenylyl cyclase–cAMP
system constitute the group IIA hormones (Table 1). The steps
involved in the hormone action via adenylyl cyclase–cAMP
system are summarized below:
i. Binding of hormone (Step 1) to a specific receptor in the cell
membrane.
ii. Activation of G-protein (Step 2). After formation of hormone–
receptor complex, the GDP is released from the G-protein and is
replaced by GTP, i.e. G-protein is activated.
iii. Activation of enzyme adenylyl cyclase (Step 3). The
hormone–receptor complex via activated G-protein (stimulatory
or inhibitory) either stimulates or inhibits the enzyme adenylyl
 1. Adenylyl cyclase–cAMP system 

• iv. Formation of cAMP (Step 4). A part of the enzyme adenylyl cyclase

protrudes through the inner surface of the cell membrane and when
activated it catalyses the formation of cAMP from cytoplasmic ATP with
Mg2+ as cofactor. A stimulatory G-protein (Gs) therefore increases
intracellular cAMP levels, whereas an inhibitory G-protein (Gi) decreases
cAMP levels.
• v. Action of cAMP. The cAMP once formed stimulates a cascade of enzyme
activation. One molecule of cAMP may stimulate many enzymes. Therefore,
even the slightest amount of hormone acting on the cell surface can initiate
a very powerful response. The cyclic AMP so formed initiates response by
different mechanisms in eukaryotic and prokaryotic cells.
• In eukaryotic cells, the cAMP activates protein kinase A (Step 5) which
phosphorylates the specific proteins, producing highly specific physiological
actions (Step 6):
• Increase in cell permeability (e.g. ion transport and secretion),
• Increase in synthesis of enzyme system (enzyme induction),
• Activation of enzymes present in the cell.
• Release of hormones from storage pack cells and steroidogenesis,
• Gene regulation and so on.
 1. Adenylyl cyclase–cAMP system cont’ 
• In prokaryotic cells, in contrast to eukaryotic cells, the
cAMP acts directly at the gene level. It binds to a
specific protein called catabolic regulatory protein
(CRP). In association with CRP, it binds to DNA and
influences gene expression or transcription. Therefore,
cAMP in prokaryotic cells acts just like steroid
hormones.
• vi. Inactivation of cAMP. The cAMP is degraded to 5’-
AMP (inactive form) by enzyme phosphodiesterase.
Hence, the effect of cAMP is short lived if the hormone
stimulating adenylyl cyclase is removed.
Phosphodiesterase inhibitors such as caffeine and
theophylline would be expected to augment the
physiologic action of cAMP.
FIGURE 10:
Mechanism of
action of hormone
through adenylyl
cyclase (cAMP)
system as second
messenger.
 Note

• The bacterial toxins (cholera and pertussis) exert an

important effect on adenylyl cyclase.
• Cholera toxin catalyses the transfer of ADP ribose
on arginine residue of α subunit of Gs protein, which
inhibits its GTPase activity thus resulting in
prolongation of its stimulation activity.
• Pertussis toxin inhibits G-protein activity. This toxin
acts by catalysing ADP ribosylation of cystein
residue near the carboxyl terminal of α subunit of
Gi, thus inhibit its function.
 2. Guanylate cyclase–cGMP system

• Group II-B hormones which act via second messenger

cGMP include atrial natriuretic factor (ANF) and nitric
oxide (NO).
i. Synthesis of cyclic GMP is analogous to the formation of
cAMP. Enzyme guanylate cyclase produces cGMP from
GTP.
ii. cGMP exerts its biochemical response through an
enzyme protein kinase G, which when activated initiates
a cascade of subsequent enzyme activations that is
characteristic of this signalling system.
Note: Cyclic GMP is important in vision. Both rod and
cone cells contain ion channels which are regulated by
cGMP.
FIGURE11:
Mechanism of
action of
hormone via
membrane
phospholipase–
phospholipid
system or
IP3 mechanism.
3. Membrane phospholipase–phospholipid system or inositol triphosphate (IP3)mechanism. 

• Hormones which exert their response through this system constitute

the so-called group II-C hormones. Steps involved in this system are:
• Hormone binds to a receptor in the plasma membrane.
• The hormone–receptor complex via a G-protein activates the
membrane enzyme phospholipase C present on the inner surface of
the membrane.
• Activated phospholipase C (PLC) then releases diacylglycerol and
inositol triphosphate (IP3) from membrane phospholipid.
• IP3 then mobilizes Ca2+ from the endoplasmic reticulum.
• Ca2+ and diacylglycerol together activate protein kinase C.
• Activated protein kinase C phosphorylates proteins and causes
specific physiological action.
• Diacylglycerol also yields arachidonic acid which serves as a substrate
for rapid synthesis of prostaglandins that modulate cell response.
 4. Calcium–calmodulin system 

• Hormones that act through this system as second

messenger are also included in the so-called group-II C
hormones. Steps involved in this system are:
• Hormone binds to a specific receptor in the plasma
membrane.
• Then the hormone–receptor complex, via G-protein opens
the Ca2+ channels on the cell membrane and also activates
mobilization of Ca2+ bound to the endoplasmic reticulum.
• Ca2+ binds to a specific binding protein, calmodulin, in
various proportions.
• The different calcium–calmodulin complexes activate or
deactivate various calcium-dependent enzymes producing
different physiologic actions.
FIGURE 8.1-
12Mechanism of
action of hormone
via calcium–
calmodulin
system.
 Mechanism of action of hormone via tyrosine kinase activation
• Certain hormones act by activating tyrosine kinase system and have
been classified as group-II D hormones. This mechanism of signal
generation from plasma membrane receptors does not require G-
protein intermediaries. These receptors have an extracellular hormone-
binding portion, a single transmembrane portion and an
intracytoplasmic C-terminal portion.
• The activation of tyrosine kinase occurs by two mechanisms:
1. Hormone receptors possessing intrinsic tyrosine activity, e.g. those for
insulin and epidermal growth factor (EGF) involve the following steps:
• Binding of hormone to the receptor changes its conformation and
exposes sites on its intracellular portion that are capable of receptor
autophosphorylation at specific tyrosine sites.
• As a result, the receptor itself becomes a tyrosine kinase that
phosphorylates tyrosine residue on intracellular protein substrates.
• This latter activity sets into motion a cascade of events leading to
Mechanism of action of hormone via tyrosine kinase
activation cont’
2. Hormone receptors that do not possess intrinsic tyrosine activity, e.g. those
for growth hormone, prolactin-releasing hormones, cytokines etc. act by
activation of JAK2–STAT pathway. JAK2 belongs to Janus family of tyrosine
kinases. The phosphorylation of tyrosine kinases causes activation of STATs
(signal transducer and activators of transcription) which are cytoplasmic
transcription factors. On activation, STATs migrate into the nucleus and causes
transcription of various genes as follows:
• Hormone binding to extracellular portion of the receptor changes its
intracytoplasmic tail.
• The changes produced in intracytoplasmic tail of receptor expose sites which
attract and dock the intracytoplasmic tyrosine kinases (such as JAK kinases and
STAT kinases) and then activates them.
• The activated intracytoplasmic tyrosine kinases phosphorylate cytoplasmic
substrates such as transcription factor proteins and ultimately modulate gene
expression.
FIGURE 13:
Mechanism of
action of hormone
via tyrosine kinase
activity: A, by
receptors that
possess intrinsic
tyrosine activity;
and B, by receptors
that act by
activation of JAK2–
STATs pathway.
 Me asure ment of hormone s

• Measurement of blood level of hormones is essential to confirm the

endocrinal disorders associated with either deficiency or excess of a
hormone. Since hormones exist in the blood at very low
concentrations, they are measured by hormone assays and some
special techniques which include: Bioassay, Immunoassay,
Cytochemical assay and Dynamic tests.
Bioassay: Biological assay that was frequently used earlier to measure
the level of a hormone in the plasma is now an obsolete technique.
In this method, hormone levels were assessed by injecting the
unknown sample of plasma in experimental animals and observing
quantitatively the specific biological effect. The effect chosen was a
characteristic action of the hormone for which a clear dose–
response relationship existed. For example, one unit of insulin was
defined as one third of the amount of insulin that will lower the
blood sugar of a rabbit weighing 2 kg to conclusive levels in 3 h.
 Immunoassay

• The immunoassay methods, frequently employed for estimation of

hormone levels, include: Radio immunoassay (RIA) and Enzyme-
linked immunosorbent assay (ELISA).
1. Radioimmunoassay 
• ​RIA was developed by Bershon and Yalow in 1960s, for which they
were awarded the Nobel Prize in late 1970s. This test is performed
as:
• An unknown sample of plasma in which the concentration of a
particular hormone (H) to be estimated is mixed with commercially
available purified specific antibody (anti-H) and an appropriate
amount of the purified hormone tagged with radioactive isotope
(H+). The mixture is incubated in cold.
• The antibodies have high affinity for the hormone. There occurs a
competition between the free hormone (H) present in the unknown
sample of plasma and the tagged hormone (H+) for binding to the
specific antibody (anti-H).
2. Enzyme-linked immunosorbent method (ELISA)  
• m
​ ethod is principally similar to RIA, i.e. it is also
based on the principle of antigen–antibody reaction.
• Any antigen that is protein can be measured by this
technique. In this method, radioactivity is not
measured; instead specific antibody hormone
(antigen) complex is stained with suitable dye, e.g.
di-ammonium 2-2’ azinobis (3-ethylbenzothiazolene
6 sulphate), also called ABTS, and the intensity of
colour is measured by spectrophotometer.
• This technique is useful in estimating peptide and
steroid hormones.
 2. Enzyme-linked immunosorbent method (ELISA) cont’
Cytochemical assay
• This test is much more sensitive than the immunoassay, but is
cumbersome and time consuming and so rarely used. In this technique,
genesis of hormone can be detected in slices cut out of the endocrine
gland by incubating them in an ascorbate-enriched culture medium. This
test is very useful in measuring the minute basal levels of hormone
secretion.
Dynamic tests
• Dynamic tests are needed in certain situations when simple blood
hormone level estimation is not enough. Two types of dynamic tests are:
• Suppression type of dynamic tests are useful in certain conditions, e.g. to
know whether a lung cancer is secreting ACTH.
• Stimulation type of dynamic tests are useful in certain other conditions,
e.g. metyrapone test is performed to know whether the corticotrophs of
the pituitary (which secrete ACTH) are normally functioning or not.