ENDOCRINE CONTROL MECHANISMS:

~ General concepts of endocrine control

The endocrine system is a regulatory system. It
functions to maintain the internal environment (the body
fluids) at a relatively constant level with respect to
volume and concentration, and within the limits of life in
the face of changes in the activity of the body. It
transmits information by means of chemical messengers,
the hormones. These are dispersed without direction
throughout the body via the circulatory system, from
which they move to act upon genetically conditioned and
differentiated cells of the body, the target cells. The
effects of the hormones are much more diffuse and
relatively slower than are those of the nervous system,
which transmits its information rapidly, with point-to-point
precision via the neurons. {The endocrine system is
comparable to the postal system. A hormone is like a
letter posted by an endocrine gland. It is addressed to a
target organ or organs. On the other hand, the nervous
system is comparable to the telegraphic system. It is
faster than the postal system, and employs a code
(frequency/pattern of nerve impulses) to convey a
message. However, there is no watertight boundary
between the endocrine and the nervous system. On the
contrary, they influence each other, and at some points,
there is an organic and functional link between them.}
The fundamental microscopic anatomy of the glandular
elements of the endocrine glands is similar to that of the
exocrine glands, with two exceptions. The endocrine
gland does not possess a duct system, and each
glandular cell of the endocrine system has a surface
which abuts a venous sinusoid or a capillary. Thus, the
morphology of the system is such that the secretions can
be released directly into the circulation.
The word hormone is derived from the Greek
“hormaein”, which means “to excite” or “to arouse”.
Hormones are generally considered to be substances
secreted into the blood in very small amounts by
specialized cells or glands and carried by the bloodstream
to other parts of the body, where they interact with
specific receptors in target tissue cells to produce a
particular biological response.

~ Functions of hormones:
The effects of hormones fall into three general
groups.
(1) They influence reactions that aid in the
maintenance of a constant internal environment.
Thus they regulate the rates at which
carbohydrates, fats, proteins, electrolytes, and
water are deposited in or removed from the tissues
of the body. For example, insulin participates in
regulating the chemical and/or physical factors
which ensure an adequate supply of glucose to
 most extrahepatic tissues by increasing the
permeability of the cell membrane to glucose.
(2) Thehormones have a morphogenic actions; this
includes the effects on growth, differentiation,
development, maturation, trophic actions, and
aging processes. For example, effects of the
ovarian or testicular hormones during the growth
and development of the accessory sex organs and
secondary sex characteristics at puberty.
(3) The hormones regulate autonomic activity, as
well as certain CNS activities and behavioral
patterns. For instance, maternal behavioral
patterns are linked to the presence of various
hormones.

@ Feedback regulation is an important feature of

endocrine communication~
One of the hallmark features of the endocrine system
is feedback regulation. Endocrine cells have the
ability to manufacture and secrete a particular
hormone; in most instances, they are also equipped to
detect or monitor the magnitude of the biological effect
of that hormone. Feedback regulation permits the
endocrine cell to adjust the rate of hormone secretion
in an appropriate manner to achieve the desired effect,
which is the maintenance of a steady state.
In most instances, feedback regulation involves
negative feedback, although some cases of positive
feedback are also known.
An example of negative feedback regulation is the
control of blood glucose concentration by the hormone
insulin, which is produced by specialized endocrine
cells within the pancreas. These cells are triggered to
secrete insulin when the amount of glucose in the
blood exceeds the normal concentration of about 100
mg%. Therefore, when blood glucose levels are
increased above normal, such as might occur soon
after a meal, the insulin-secreting cells sense this
increase and respond by increasing the secretion of
insulin. Insulin in turn stimulates the uptake of glucose
from the blood by such tissues as muscle and adipose
(fat). The overall response to insulin therefore is a
reduction in the amount of glucose circulating in the
blood. The stimulus for insulin secretion is then
(therefore) lessened, and the secretion rate decreases.
(Diagram: negative feedback control of hormone
secretion)

# Hormones regulate or influence a variety of

processes in the body:
The specific effect of individual hormones can
generally be categorized as relating to the regulation of
one of four physiological processes: (1) the digestion
and storage of nutrients and their metabolism and use
for metabolic energy, (2) salt and water balance, (3)
growth and development, and (4) reproductive
function.
Most hormones have several different target tissues. In
addition, many hormones produce multiple individual
effects within their specific target cells. These multiple
effects, when added together, produce the overall
response characteristic of that particular hormone.
• Hormones may be peptides, metabolites of
single amino acids, or metabolites of
cholesterol-
Most mammalian hormones are divided into three
groups based on their chemical structure and how
they are made in the body.
(a) Peptide hormones: insulin, glucagon, and
somatostatin (all from pancreas); GH, ACTH, FSH &
LH, TSH, and prolactin (all from pituitary); PTH
(from parathyroid gland); calcitonin (from thyroid)
(b) Derivatives of a single amino acid:
catecholamines and thyroid hormone are derived
from the amino acid tyrosine.
(c) Steroids/metabolites of cholesterol: synthesis
of steroid hormones (from cholesterol)
necessitates a number of enzymatic steps. Only
very specialized tissues are capable of the series
of enzymatic conversions that are necessary to
make active hormone from the starting materials.
~ Hormone synthesis: general principles
(a) Peptide hormones- Within the cell of the endocrine
gland the peptide molecule prepared first is
usually a larger precursor called “preprohormone”;
it is cleaved (some portion removed from it) to
form “prohormone”; the further cleavage of this
peptide forms the final mature hormone. (e.g.
preproinsulin – to – proinsulin – to – insulin). The
hormone may not be released immediately into
the circulation; it is stored
(b) Steroid hormones- are synthesized form
cholesterol; once formed they are immediately
released into the circulation (not stored).
~ Hormones can circulate either free or bound to carrier
proteins-
Once secreted, many hormones circulate freely in
the blood until they reach their target tissue. Others form
complexes with circulating binding proteins (e.g. in
case of thyroid hormones, steroid hormones)
Most peptide hormone exist free in the circulation.
Steroid and thyroid hormones circulate bound to plasma
proteins. {IGF-I and IGF-II are an exception to this rule: at
least six plasma proteins bind these peptide growth
factors.}
Forming a complex with a circulating binding protein
serves several functions: (i) it provides the blood with a
reservoir or pool of the hormone, thus minimizing minute-
to-minute fluctuations in hormone concentration. (ii) it
extends the half-life of the hormone in the circulation.
(The hormones bound to plasma-binding proteins appear
to be those whose actions are chronic – in particular,
those involving induction of the synthesis of new protein
in target tissues. Hormones that play a major acute role
in the regulation of body metabolism circulate freely
without associated binding proteins.)
• Mechanisms of hormone action- (short note)
Mechanism Examples
Open or close ion channels Acetylcholine on nicotinic
in cell membrane cholinergic receptor;
norepinephrine on K+
channel in the heart
Act via cytoplasmic or Thyroid hormones, retinoic
nuclear receptors to acid, steroid hormones
increase transcription of
selected mRNAs
Activate phospholipase C Angiotensin II,
with intracellular production norepinephrine via α 1-
of DAG, IP3, and other adrenergic receptor,
inositol phosphates vasopressin via V1 receptor
Activate or inhibit adenylyl NE via β 1-adrenergic
cyclase, causing increased receptor (increased cAMP);
or decreased intracellular NE via α 2-adrenergic
production of cAMP receptor (decreased cAMP)
Increase cGMP in cell ANP; NO (EDRF)
Increase tyrosine kinase Insulin, EGF, PDGF, M-CSF
activity of cytoplasmic
portions of transmembrane
receptors
Increase serine or threonine TGFβ , MAPKs
kinase activity

~ Two important general mechanisms by which many of

the hormones function are: (1) activation of the second
messenger system of cells, or (2) activation of the genes
of the cells which causes the formation of intracellular
proteins that initiate specific cellular functions
(1) Action of peptide hormones: For the peptide
hormones, the receptor is in the membrane. (thus
they would exert their effects without entering the
cell; this is probably because they are not lipid-
soluble). Once these hormones combine with their
receptors, there is activation of “second messenger”
in the cells; (the hormone may be termed “first
messenger”).
Cyclic AMP – the second messenger ~
- The combination of hormone and receptor
activates the enzyme adenyl cyclase in the
membrane.
- The portion of the adenyl cyclase that is exposed to
the cytoplasm causes immediate conversion of
cytoplasmic ATP into cyclic AMP (cAMP).
- The cAMP then initiates any number of cellular
functions before it itself is destroyed – functions such
as activating enzymes in the cell, altering the cell
permeability, initiating synthesis of specific
intracellular proteins, causing muscle contraction or
relaxation, initiating secretion, and many other
possible effects.

Hormone combines with receptor

On the cell membrane

Activation of adenyl cyclase enzyme

Conversion of cellular ATP into cAMP

cAMP (the “second messenger”) stimulates

protein kinase A

Protein kinase A in turn phosphorylates

enzyme proteins; the enzymes are
either stimulated or inhibited
 altered metabolism / biological effect

~ Other intracellular second mediators are cyclic GMP,

inositol triphosphate (IP3), diacyl glycerol (DAG)
(2) Action of steroid hormones: {action on genes to
cause protein synthesis}
- The steroid hormone enters the cytoplasm of the cell,
where it binds with a specific receptor protein.
- The receptor + hormone complex then diffuses into
or is transported into the nucleus
- It then activates specific genes to form mRNA
- The mRNA diffuses into the cytoplasm where it
promotes the translation process at the ribosomes to
form new proteins; these proteins then function as
enzymes or carrier proteins that in turn activate
other functions of the cells.
(Estrogen, though a steroid, has intranuclear
receptor. Thyroid hormone though not a
steroid, does enter cells and has intranuclear
receptor.)
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THE PITUITARY GLAND AND ITS RELATIONSHIP
TO THE HYPOTHALAMUS~
The pituitary gland, also called the hypophysis,
is a small gland; it lies in the sella tucica at the base
of the brain. It is connected with the hypothalamus
by the pituitary stalk.
Physiologically, the pituitary gland is divisible into
two distinct portions: the anterior pituitary, also
known as the adenohypophysis, and the posterior
pituitary, also known as the neurohypophysis.
~ Hormones secreted by the anterior pituitary:
I. Growth hormone: promotes growth
II. Prolactin: promotes mammary gland
development and milk production
III. Adrenocorticotropic hormone (ACTH):
controls the secretion of some of the
hormones of adrenal cortex gland
IV. Thyroid stimulating hormone (TSH): controls
the rate of secretion of thyroxine by the
thyroid gland
V. Follicle-stimulating hormone (FSH) and
VI. Leutinizing hormone (LH): FSH and LH are
gonadotropins; control growth of the gonads
as well as their reproductive activities
 ~ Hormones secreted by the posterior pituitary:
I. Antidiuretic hormone (ADH): also called
vasopressin; controls the rate of water excretion
into the urine
II. Oxytocin: helps in milk ejection during breast
feeding and probably helps in the delivery of the
baby at the end of gestation
• Control of pituitary secretion by the
hypothalamus-
Secretion from the posterior pituitary is controlled by
nerve fibers originating in the hypothalamus and
terminating in the posterior pituitary. This is called
neuroendocrine control.
In contrast, secretion by the anterior pituitary is
controlled by hormones called hypothalamic
releasing and inhibitory hormones (or factors)
secreted within the hypothalamus and then
conducted to the anterior pituitary through minute
blood vessels called hypothalamic-hypophysial portal
vessels. This is typical endocrine control.
Note that: Posterior pituitary hormones are
actually synthesized in the nerve cell bodies of
neurons in the hypothalamus. Then, via the
axons of those hypothalamic neurons, they
reach the posterior pituitary gland and from
there, they are released into the circulation.
Hormones of the anterior pituitary are
 synthesized in the anterior pituitary itself, and
are released into the circulation.
Cell types of the anterior pituitary:
Two main types of cells: (i) chromophobe cells;
which do not have stainable granules, and (ii)
chromophil cells; contain cytoplasmic granules
which take up stain readily.
Chromophil cells are further divided into:
(a) Acidophil or alpha cells - which stain strongly
with acidic dyes, and
(b)Basophil or beta cells - which stain strongly
with basic dyes.
The acidophils produce growth hormone (GH) and
prolactin; the basophils produce FSH, LH, ACTH, and
TSH.
Usually, there is one cell type for each major hormone
formed in the anterior pituitary gland.
1. Somatotropes – human growth hormone (hGH or GH)
2. Corticotropes – adrenocorticotropic hormone (ACTH)
3. Thyrotropes – thyroid-stimulating hormone (TSH)
4. Gonadotropes – gonadotropins FSH & LH
5. Lactotropes – prolactin (PRL)
About 30 to 40 % of the anterior pituitary cells are
somatotropes, about 20% cells are corticotropes, and
remaining cells 3 to 5 % each.
The hypothalamic-hypophysial portal system-
Most of the anterior pituitary hormones are
controlled by hypothalamic hormones. The hypothalamic
hormones control the release, and in some cases also the
production, of the anterior pituitary hormones. Special
neurons in the hypothalamus synthesize and secrete
hormones called hypothalamic releasing and inhibitory
hormones (or releasing and inhibitory factors). The
hormones/factors are first released into the median
eminence (lowermost portion of the hypothalamus) by
the hypothalamic neurons. From there, they diffuse into
the hypothalamic capillaries, which join to form the
hypothalamo-hypophysial portal venous system. The
portal veins carry these hypothalamic factors towards the
anterior pituitary. In the anterior pituitary, the portal
vessels break into another set of capillaries. The factors
diffuse out of these capillaries into the anterior pituitary
and influence the release of its hormones.

Hormones of the posterior pituitary-

~ Anti-diuretic hormone (ADH): (also called
“vasopressin”) – (short note)
{Diuresis means increase urine flow or increase water
output in the urine. Anti-diuresis would mean opposite;
that is, water will be reabsorbed from renal tubules.}
Synthesis:
It is synthesized in the supraoptic nucleus of the
hypothalamus.
And it is secreted by the posterior pituitary gland.
Functions/actions:
(1) The primary effect of ADH is to increase water
retention by the kidney. ADH released by posterior
pituitary, via circulation, reaches kidneys. It acts on
renal tubules, to increase the water reabsorption
from the tubular fluid into the blood. Thus, the blood
volume will increase.
(2) ADH acts on the blood vessels; it causes
vasoconstriction. For this effect, it is also called
“vasopressin.”
- Mechanism of ADH action:
There are two types of ADH/vasopressin receptors:
V1 and V2.
V1 receptors are present in the blood vessel walls
and they mediate vasoconstriction.
V2 receptors are present in the renal tubules. When
ADH acts on these receptors, there is insertion of
channel proteins called “aquaporins”. Aquaporin II
 channels allow water reabsorption from distal
collecting tubules and the collecting ducts of
renal nephron.
Physiological stimulus for the release of ADH:
Since ADH causes water to be absorbed from kidneys into
the blood, most important stimulus for ADH release is
when water content of the plasma is decreased. That is,
when the osmolality of the plasma is increased.

Increased osmolality of plasma

Sensed by the osmoreceptors in hypothalamus

Release of ADH in the circulation; it reaches

kidneys

Increased water reabsorption from renal tubules

into blood

Water content of plasma increases; osmolality

normalized
Another stimulus for ADH release is: large decrease in
blood volume. When there is more than 10% decrease in
the total circulating blood volume, ADH will be released. It
will cause water reabsorption from kidneys into the blood,
thus increasing the blood volume.
Alcohol is known to inhibit ADH release. This is why, urine
volume increases after alcohol consumption.

• Applied physiology-
(i) Diabetes insipidus:
This is ADH deficiency; it results in excess urine
output.
(ii) SIADH (syndrome of inappropriate ADH
secretion):
In certain kinds of stress (e.g. surgery), there is
an excessive release of ADH.

~ Oxytocin – (short note)

- It is a small peptide hormone. It is synthesized by the
paraventricular nucleus of the hypothalamus.
And is released from the posterior pituitary gland.
- The principal action site of oxytocin is the female
breast. In the breast, oxytocin stimulates contraction
of specialized smooth muscle cells. This results in
transfer of milk from the alveoli of breast glands into
the ducts.
 - Milk ejection reflex / milk let down reflex:
When the baby starts suckling at the nipple, it sets
up a reflex. This is also a neuroendocrine reflex,
because the afferent signals are sent to the pituitary
via nerves, and the efferent signals to the breast are
by oxytocin hormone.
Baby suckling at the nipple

Signals are sent to the brain

Neurons on paraventricular nucleus of hypothalamus are

stimulated; release of oxytocin from posterior pituitary

Oxytocin reaches the breasts, it causes contraction of

myoepithelial cells of the breast;

milk ejected out from glands into the ducts

- Oxytocin has another action. It can also stimulate

contraction of smooth muscle in the uterus. A non-
pregnant uterus does not respond to the oxytocin.
However, near the end of pregnancy, the delivery of
the baby may be initiated by oxytocin action on the
 uterus. The process of parturition/delivery occurs by
positive feedback mechanism.

~ Hormones of the anterior pituitary-

Prolactin:
- It is synthesized by the acidophil cells called
lactotrophs in the anterior pituitary gland.
- It has the function of milk synthesis in breast glands
in females.
- Prolactin secretion is under the control of some
factors. (For other hormones of the anterior pituitary,
there are releasing factors and inhibitory factors
released from the hypothalamus, which control
secretion of the anterior pituitary hormones.) For
prolactin, there is a prolactin inhibiting factor (PIF).
However, there is no established prolactin releasing
factor (PRF) from hypothalamus. Instead, TRH
(thyrotropin releasing hormone) is known to act as
PRF.
- Prolactin secretion is also inhibited by dopamine.
 - Prolactin release also increases in response to
stimulation of the mother’s nipple by a suckling
infant.
Adrenocorticotropic hormone: (corticotrophin)
- It is synthesized by the basophil cells of the anterior
pituitary gland; the cells are corticotropes.
- The primary effect of ACTH is to promote the
synthesis and secretion of the steroid hormone
cortisol from the adrenal cortex gland.
- The secretion of ACTH is controlled by corticotrophin-
releasing hormone (CRH) from hypothalamus. It is
released mainly in response to body stress.
- ACTH is actually synthesized from a large precursor
protein – called pro opio melanocortin [POMC]. This
protein is cleaved into two products: ACTH and β -
LPH. From ACTH, melanocyte stimulating hormone
[MSH] is cleaved. And, from LPH, β -endorphin is
formed.

TSH / Thyroid stimulating hormone: (thyrotropin)

- It is synthesized by the basophil cells, called
thyroptropes, of the anterior pituitary gland.
- The action of TSH is to cause synthesis and secretion
of thyroid hormones from the thyroid gland. Thyroid
hormones control the body’s basal metabolic rate
(BMR).
 - TSH and thyroid hormones are secreted in response
to cold. They would then increase the metabolic rate
and also the heat production.
- TSH secretion is under the control of hypothalamic
hormones – TRH (thyrotropin releasing hormone) and
TIH.
- Levels of circulating TSH form an important part of
investigation of thyroid disorders. When the thyroid
hormone levels increase in disorders, they suppress
TSH levels by negative feedback mechanism.

Gonadotropins: FSH and LH-

- Follicle stimulating hormone [FSH] and Luteinizing
hormone [LH] are known as gonadotropins because
they act on gonads.
- They are synthesized by the basophil cells, called
gonadotropes, of the anterior pituitary gland.
- In general, they have two primary effects: (i) to
promote the development and maturation of sperm
and ovum; and (ii) to stimulate production of sex
steroid hormones by the gonads. The principal sex
steroids are: testosterone (males), and
estrogen/estradiol (females).
[Please note that: The language used in the explanation
of hormone actions is deliberately made simple, for easy
understanding of the actions of hormones.
Also note that: Actions of all hormones are divided into (i)
metabolic effects, and (ii) non-metabolic effects.

~ Growth hormone (GH): {also called somatotropin}

It is also called human growth hormone (hGH); it is
synthesized by the acidophil cells, called somatotropes,
of the anterior pituitary gland.
The main theme of the actions of growth
hormone is the “somatic growth” of the body. {Thus,
all its actions or effects can be explained on the basis of
this theme.}
~ Actions/functions/effects of growth hormone:
A. METABOLIC ACTIONS:
(1) On carbohydrate metabolism- {high blood
glucose is required for growth}
 It decreases the peripheral utilization of
glucose. If the glucose does not enter the
cells from blood, glucose levels in blood will
increase. This is called hyperglycemia,
caused by GH. (High blood glucose is
necessary so that it can be supplied to a
tissue for its GROWTH.)

 High blood glucose will cause insulin release

from the pancreas {insulin has the function
of pushing glucose into cells}.
  Excessive GH action will cause excess blood
sugar, which will cause excess insulin
secretion. Eventually, insulin will be
exhausted. This leads to diabetes mellitus. It
can be called “pituitary diabetes”, as the
reason is excess GH secretion by the
pituitary. Thus, GH is a diabetogenic
hormone.
(2) Onprotein metabolism- {proteins form the
framework of tissues; they are required for
growth}
 Since proteins are required for growth, they
are not broken down by the GH (for energy).
GH stimulates synthesis of proteins. All
aspects of protein synthesis are increased
by the GH.

 Thus, GH promotes amino acid transport into

cells, increased DNA transcription and mRNA
translation. All these effects will increase
protein synthesis.
 Proteins are “spared”, that is, not utilized for
energy. Their breakdown is prevented. This is
called “protein sparing effect” of GH.
(3) On fat metabolism- {proteins spared,
carbohydrates not utilized, so fats are used
for energy}
  GH causes increased breakdown/mobilization
of fats for the use of energy. Triglycerides are
broken down, forming free fatty acids [FFA].
Thus, GH increases the FFA levels in
plasma.
 Since the carbohydrates are not available in
the cells, it alters the fat oxidation, forming
ketone bodies. This is called “ketogenic
effect” of GH. {Carbohydrates are necessary
in the cell, for complete oxidation of fats. GH
does not allow glucose to enter cells normally.
Less glucose in cells will cause incomplete
burning of fat, resulting in ketone body
formation.}
B. OTHER PHYSIOLOGIC (NON-METABOLIC)
ACTIONS:
Somatic growth: growth of bone, cartilage, and
connective tissue
- Growth hormone stimulates increased
deposition of protein and increased
growth in almost all tissues of the body.
The most obvious effect is to increase
growth of the skeletal frame.
- Long bones grow in length at the
epiphyseal cartilages. New cartilage is
first deposited, due to proliferation of
chondrocytes. Then the cartilage is
converted into new bone.
 - Growth hormone strongly stimulates
osteoblasts. These are bone forming
cells. After a certain age (puberty),
epiphyses fuse with the shaft and bones
cannot increase in length thereafter.
However, bones can increase in
thickness throughout life, under the
influence of GH. This is due to periosteal
growth.
Increased tissue growth and increased organ size also
occurs under the influence of GH. This is because of
increased protein synthesis.
~ Mechanism of action:
The effects of GH on skeletal growth are mediated by
a family of polypeptides called somatomedins.
(Mediators of somatotropic hormones, hence
somatomedins.)
Somatomedins are produced by the liver. They are
also called insulin-like growth factors (IGFs). There
are two types of somatomedins: IGF-I and IGF-II.
{They are called insulin-like growth factors because they
are structurally similar to proinsulin – the insulin
precursor. And, they have growth effects similar to
insulin.}
The linear growth of the skeleton, caused by the GH, is
actually effected by the IGF – I.
{GH is released by the pituitary; it has a very short half-
life in circulation. GH goes to the liver and causes release
of somatomedins. Somatomedins have a very long half-
life in circulation; and they exert the growth action of the
GH.}
~ Regulation of secretion of GH:
(I) Stimulators of GH release-
- Exercise, emotional stress
- Sleep (especially first 2 hours of sleep)
- Hypoglycemia
- Increased plasma amino acids (especially
arginine)
- GH-RH (released by hypothalamus)
(II) Inhibitors of GH release-
- Growth hormone itself; inhibits GH release
by negative feedback loop
- GH-IH or somatostatin released by
hypothalamus
- Glucocorticoids
~ Disorders of GH secretion:
{Note that: for all the hormones, disorders are of two
types – excess secretion and deficient secretion.}
Deficiency of GH:
 - In childhood: dwarfism
- In adults: acromicria
Excess GH secretion:
- Before puberty: gigantism or giantism
- After puberty: acromegaly
~ Gigantism or giantism:
- It is the disorder of excess GH secretion before
puberty.
- Before a person attains puberty, epiphyses of the
long bones are yet not fused with the bones. The
bones have the scope to increase further in length.
Excess GH causes new bone deposition, so much so,
that length of the bones goes on increasing
disproportionately.
- Hence, the person may attain a body height of up to
7 to 8 feet. (looks giant).
~ Acromegaly:
- It is the disorder of excess GH secretion after
puberty.
- Around the time of puberty, epiphyses of the long
bones are united with the bones. Now the bones
cannot increase further in length. Thus, after puberty
excess GH secretion cannot increase the height of
the individual.
 - However, bone deposition will continue to occur due
to excess GH action. Hence, the bones increase in
thickness.
- Enlargement of the hands and feet (acral parts). The
hands are broadened with thickening of the fingers.
The terminal phalanges are tufted.
- Enlargement of facial bones. Protrusion of the lower
jaw – called “prognathism”; enlargement of nasal
bones and supraorbital ridges.
- The subcutaneous tissues of the hands, feet, scalp,
nose, lips, and forehead are thickened. This causes
appearance of deep furrows over the scalp,
resembling “bulldog scalp”. The tongue is
thickened.
- Kyphosis of the spine causes bowing of the person,
looking “gorilla type”.
- The viscera, heart, lungs, liver, spleen, and tongue
are all enlarged. This enlargement is collectively
called “splanchnomegaly.”

~ Dwarfism: (short-statured individual)

- It is due to the lack of secretion of the GH; due to
hypoactivity of the acidophil cells.
- It occurs in childhood, when the bone growth is
expected to occur under the influence of GH. Lack of
GH secretion does not cause new bone deposition;
 long bones do not increase in length. Thus, the
person remains short statured.
- Stunted but proportionate growth; 3 to 4 ft
height due to arrest of skeletal growth.
- Intelligence may be normal and proportionate to age
in some types of dwarfism (Lorain type).
- The gonads are underdeveloped and secondary
sexual characters do not develop. The sexual
functions are depressed.
- Several types of dwarfism have been described –
 Levy-Lorain dwarfism (infantilism): This is the
usual type; due to GH deficiency
 Laron type dwarfism: GH hormone secretion is
NORMAL, but there is somatomedin deficiency.
Somatomedin C is deficient. Hence GH cannot
exert its effects of growth. Another type is seen
in African pygmies. GH and somatomedins are
normal, but tissues fail to respond to circulating
somatomedins.
 Brissaud type: (“fat boy of Dickens”) Excessive
deposition of fat and chubby face and sluggish
nature; low intelligence, lack of initiative and
dynamism.

~ Acromicria:
 - Hypopituitarism in adults; hypo functioning of the
acidophil cells of the anterior pituitary. Deficiency of
GH in adults.
- Retarded development of bones, hands, feet, and
face.
Other conditions of the hyposecretion of GH:
- Simmond’s disease
- Sheehan’s syndrome
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THYROID GLAND
(THE THYROID HORMONES)
{The central theme: BODY’S METABOLIC RATE}

Introduction:
Thyroid gland is situated in the neck, just below the
larynx.
It secretes two hormones: T3 and T4.
The thyroid hormones control body’s basal metabolic rate
(BMR). However, these hormones are not absolutely
essential for life.
STRUCTURE:
The thyroid gland is made up of acini or follicles.
Each follicle contains a viscid, homogenous mass called
thyroglobulin. It is commonly called colloid.
Thyroglobulin is the storage protein of the thyroid gland.
Thyroid hormones are bound to it. Thyroid hormones are
synthesized in the colloid.
• Synthesis of the thyroid hormones: (from
IODINE)
- Thyroid hormones are synthesized from the iodine in
the diet.
- Steps in the thyroid hormone synthesis are as
follows:
(1) Iodine in the diet –
The iodine of food is converted into iodides in the
digestive tract and in this form it is absorbed into
the blood. Via, circulation, it reaches the thyroid
gland.
(2) Trapping of iodides by the thyroid gland –
Circulating iodides are trapped by the thyroid
gland. Inorganic iodide is transported into the
 thyroid gland by the so-called “iodide pump”; it is
an active transport mechanism.
(3) Oxidation of inorganic iodide to free iodine –
Once the inorganic iodide is transported within the
gland, within a few seconds it is converted to free
iodine. This oxidation is catalyzed by the enzyme
PEROXIDASE.
(4) Iodination of the tyrosin residue –
Active iodine now reacts with tyrosine residue of
protein chain of the thyroglobulin. This forms
mono-iodo-tyrosine (MIT).
(5) Further iodination of MIT –
One more iodine combines with MIT, to form di-
iodo-tyrosine (DIT).
(6) Coupling and condensation: formation of
thyroid hormones –
1 MIT + 1 DIT = tri-iodo-thyronine (called T3)
1 DIT + 1 DIT = tetra-iodo-thyronine (called T4
or thyroxine)

Thus, two thyroid hormones are synthesized: T3 and T4

(thyroxine).
They are stored in the colloid material, attached to the
thyroglobulin. Thus, thyroid hormones are the only
hormones in the body that are stored extracellularly.
~ Release of the thyroid hormones:
The thyroid gland releases thyroid hormones in the
following ratio:
93% secretion is T4; 7% secretion is T3.
~ Transport of thyroid hormones in blood:
Thyroid hormones are bound with 3 plasma proteins and
then transported in blood.
- Thyroxine binding globulin (TBG): It has high
affinity for thyroid hormones. Hence, they will bind
this protein first. However, it has low capacity to bind
thyroid hormones, hence it gets saturated quickly.
- Thyroxine binding prealbumin (TBPA): Once TBG
is saturated with thyroxine then thyroxine starts
binding with TBPA. This also will get saturated.
- Albumin: Albumin has low affinity for thyroxine.
Hence it is last to be binding with it. But it has a high
capacity for thyroxine binding.

99.15 % of T3 is loosely bound with plasma proteins.

99.5% of thyroxine is bound to plasma proteins. The
remaining hormone is the free hormone in plasma. It is
the free hormone which is physiologically active.
That is, it regulates the tissue level of the hormones; and
it regulates the secretion of TSH by negative feedback.
The protein bound hormone represents the storage pool
of the hormone. It is a pool of hormone; gland, bound
hormone, free hormone, and tissues.
Thyroid hormones act on all cells of the body. T4 enters
the cells, and is converted into T3.

T4 de-iodination in tissues T3
This conversion occurs due to the action of enzyme
“deiodinase” present in all tissues. The effects of the
thyroid hormones are exerted by the T3 (and not
T4).
Note that: majority of secretion of the thyroid gland is T4.
The gland can synthesize T3. But it does so in small
amounts. And, then T4 is peripherally converted into T3
and then T3 exerts the effects. If it is the T3 that is going
to exert the actions, and thyroid gland can synthesize it
also, then why the gland first secretes T4 and then in
tissues it is converted into T3?
- T4 is bound more extensively with the plasma
protein carriers.
- T4 has a long half-life (7-8 days) compared to T3 (1
day).
- Daily turnover rate of T3 is 70%, whereas that of T4
is 10%.
It indicates that T4 gives a stable thyroid storage pool.

~ Functions of the thyroid hormones:

(A) METABOLIC FUNCTIONS
(B) OTHER SYSTEMIC ACTIONS (NON-
METABOLIC)

(A) Metabolic functions:

(1) General
metabolism; O2 consumption, heat
production –
o The outstanding action of thyroxine is
to stimulate metabolism in the tissues
generally. It will have two effects: (i)
increased oxygen consumption, and (ii)
increased heat production.
o The basal metabolic rate (B.M.R.) is the
basal energy output of the individual at
complete rest, 12 to 14 hours after a
meal. The rate of this basal energy
expenditure is controlled by the
thyroxine. More the levels or activity of
thyroid hormone more will be the
B.M.R.
o As the metabolism increases, there is
increased oxygen consumption. A
 correlate of this is an increase in the
size and number of mitochondria, and
increase in the enzymes that regulate
oxidative phosphorylation.
o The increase in B.M.R. is also
associated with an increase in Na+ -
K+ ATPase (pump) activity. It is an
active transport process; it is estimated
to spend about 40% of the total energy
expenditure by the cells.
o As the metabolism increases, heat
production also increases in the body.
- Hypothyroid individuals are obese and are intolerant
to cold.
- Hyperthyroid individuals are lean/thin and are
intolerant to hot weather.

Explanation: Decreased thyroid activity

(hypothyroidism)
 Decreased metabolism in the body

Decreased energy expenditure decreased heat

production

Energy is conserved, cold weather cannot

be
Obesity results tolerated

(2) Effect on carbohydrate metabolism –

 Since the metabolic rate is increased by
thyroxine, metabolisms of all nutrients are
increased.
 Increased carbohydrate metabolism will mainly
result in hyperglycemia. It will result from
increased breakdown of glycogen
(glycogenolysis), and gluconeogenesis (new
glucose formation - from non-carbohydrate
source – protein and fat. Thus, it will also
increase breakdown of protein and fat.
(3) Effect on protein metabolism –
  All aspects of protein metabolism will
increase.

 Protein breakdown will provide source for

glucose formation (gluconeogenesis)
(4) Effect on fat metabolism –

 Fat metabolism increased by thyroxine

 Cholesterol metabolism is increased by

thyroxine.
{Hypothyroid persons will suffer from atherosclerosis.
Low thyroid – cholesterol not metabolized – cholesterol
deposited in blood vessels – atherosclerosis.}
(5) Vitamin metabolism –
As thyroxine increases the metabolic rate, it will
also cause increased consumption of vitamins.
This is because many vitamins are actually co-
factors in various metabolic processes,
particularly B-complex vitamins (mainly
thiamine).
(B) Other systemic actions: (non-metabolic)
(1) On cardiovascular system –

 Since the thyroxine increases metabolic rate,

oxygen requirement of the tissues is
increased. Hence, all aspects of CVS
functioning will be stimulated.
  Increased heart rate, increased cardiac
output, and increased blood pressure
(2) On the nervous system –
 Neurons of the CNS start functioning – sending
action potentials – only when there
myelination is complete.
 The process of myelin sheath formation of
neurons begins early in the intrauterine life,
and continues after birth for upto 6 years. The
process requires normal levels of thyroid
hormones.
 Lack of thyroid hormones during this period
will cause lack of CNS development. It will
manifest in the form of mental retardation
(a key feature of cretinism).
(3) On G.I.T. –

 Appetite is increased due to increased activity

of thyroid; and weight loss occurs due to
increased metabolism. Thus, weight loss even
in the presence of voracious appetite is a
hallmark of hyperthyroidism.
(4) On reproductive system –
Gonads function normally only when the thyroid
secretion is normal.
In hypothyroid, gonadal growth is impaired;
secondary sexual characters do not develop.
~ Disorders of the thyroid hormones or thyroid
gland:
- Goiter:
Generalized enlargement of the thyroid gland is
called “goiter”.
It may be due to any cause: a thyroid tumor,
hypothyroidism or hyperthyroidism.
(A) HYPOTHYROIDISM –
Less thyroid secretion is hypothyroidism.
In infants and children, this disorder is called
“cretinism”; in adults, it leads to “myxedema”.
1. Cretinism:

 Deficiency of thyroid hormones

(hypothyroidism) in infants and children

 Deficiency of thyroid hormone in pregnant

woman may also cause deficiency of thyroid in
fetus and cretinism.
 The most common cause: iodine deficiency
in the diet.
 The child’s milestones of growth are
delayed: (i) The child fails to grow in height
and weight; (ii) dentition is delayed; (iii)
holding up of head, sitting, standing, walking,
and speech – all these milestones are delayed.
  The child is dwarfish – short statured
 Due to lack of CNS development, mental
retardation is the hallmark of cretins.
(Thyroid hormones are required for
myelinogenesis in CNS which occurs during
intrauterine life and upto 6 years after birth.)

 Under-development of gonads, absence of

sexual functions and secondary sexual
characters.
2. Myxedema:

 Thyroid deficiency in adults; usually it occurs in

adult females below the age of 35 years.
 There is edema over the shin (over the tibia
bone) – called “pretibial edema”.
 It is a non-pitting type of edema. (Edema is
accumulation of fluid in the interstitial space.
When watery fluid accumulates in a tissue, it will
form a pit when pressure is applied over that
part.) Carbohydrate breakdown is less in
hyperthyroidism; hence mucopolysaccharides,
chondroitin sulfate, and hyaluronic acid
accumulate in the tissues. They adsord water,
and this combination forms a semisolid gel-like
material. Hence, it will not form a pit as in
watery edema.
 Other features: swollen, puffy face.
  Yellowish appearance of the skin. (carotene - to -
vitamin A conversion requires thyroxine. In
hypothyroidism, carotene does not get
converted. Carotene is a yellow pigment, hence
the yellow skin.)

 Since the BMR is less: the person will be

lethargic; lack of initiative

 Due to slowed metabolism, person will be obese

and intolerant to cold

(B) HYPERTHYROIDISM –
Excess thyroid secretion is hyperthyroidism. It
may be known as thyrotoxicosis or Grave’s
disease.
1. Thyrotoxicosis / Grave’s disease:
o Excess thyroid secretion is the basic cause.

o There is generalized moderate enlargement of

the thyroid gland. Hyperthyroidism with toxic
symptoms is thyrotoxicosis.
o Grave’s disease is thought to be due to an
autoimmune process. An autoantibody, called
Long Acting Thyroid Stimulator (LATS), is formed
from lymphocytes. It causes stimulation of the
thyroid, to secrete excess thyroid hormones.
 o Exophthalmos: A diagnostic sign of this
disease. It means protrusion of the eyeball.
Reason: deposition of fat behind the eyeball,
pushes the eyeball outward. Also, there is
degeneration of the extraocular muscles.
o Other features: BMR will be high. Hence, the
person will be thin, and intolerant to heat.
o Sleeping heart rate > 90 beats/min. is the toxic
symptom.

~ Regulation of secretion of thyroid hormones:

Two main factors determine the amount of hormones
secreted by the thyroid gland:
1. The thyrotropin/thyroid stimulating hormone (TSH)
2. The availability of iodine to the thyroid gland.

1. There are two main factors which influence the

secretion of TSH: (I) the release of TRH from the
hypothalamus, and (II) the blood level of thyroid
hormones.
Thyroid hormones then, by negative feedback loops,
inhibit the secretion of TSH (from pituitary) and TRH (from
hypothalamus).
If the circulating T4 is increased, it decreases TSH
secretion. If T4 levels have decreased, it will stimulate the
TSH secretion. TSH will then act on the thyroid gland.
- Other regulators of thyroid hormone release:
1. Temperature:
Thyroid activity is rapidly enhanced when the body
is exposed to a cold environment. The increased
 metabolism and heat production stimulated by
thyroxine will help to maintain body temperature.

2. Stress: it increases thyroid activity.

3. High concentrations of iodides: although iodine
is necessary for the synthesis of thyroid hormones,
high concentrations of organic iodide lead to
decrease in iodide uptake. Thyroid synthesis and
release will decrease.
4. Dietary goitrogens: certain foods can produce
goiter. For example, cabbage is known to be anti-
thyroid.

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--------------
Adrenal gland (suprarenal gland)
(cortex and medulla)

~ Above each kidney, there is an endocrine gland called

adrenal gland or suprarenal gland.
cortex
medulla
~ The adrenal gland has two parts:
(1) Outer part is called cortex.
(2) Inner part is called medulla.

ADRENAL MEDULLA GLAND

(It secretes catecholamines: NE and
Epi.)
- The adrenal medulla consists of chromaffin cells
(pheochromocytes); these cells are the functional
analogs of the sympathetic postganglionic fibers of
the autonomic nervous system. {That is, these cells
and the sympathetic postganglionic fibers
secrete the same chemicals and perform the
same functions.}
- The adrenal medulla represents essentially an
enlarged and specialized sympathetic ganglion. It is
called a neuroendocrine transducer because a
neural signal to this organ evokes a hormonal
 secretion. Sympathetic preganglionic nerves
synapse with the chromaffin cells.
Sympathetic preganglionic nerve

Ganglion = adrenal
medulla
chromaffin
Post ganglionic nerve = cells

Secretes catecholamines secrete

catechlamines
The diagram shows that: adrenal medulla gland is an
equivalent of sympathetic ganglion, because sympathetic
preganglionic nerve ends at both these places. And,
chromaffin cells in the adrenal medulla are equivalents of
the postganglionic sympathetic nerve. Both the
chromaffin cells and the postganglionic nerve release
catecholamines. Thus, catecholamines – epinephrine &
norepinephrine – are neurotransmitters as well as
hormones; neurotransmitters because released by
sympathetic nerves, and hormones because released by
the adrenal medulla gland. As hormones secreted by the
medulla, they circulate throughout the body. However:
Adrenal medulla: > 80% secretion is epinephrine
 < 20% secretion is norepinephrine.
Sympathetic nerves: majority secretion is
norepinephrine, and very less epinephrine.
Thus, most of the circulating epinephrine in blood
comes from the adrenal medulla.
The adrenal medulla synthesizes and secretes
catecholamines: epinephrine (or adrenaline) and nor-
epinephrine (or nor-adrenaline).
They are synthesized from the amino acid tyrosine.

Tyrosine in the diet

Tyrosin hydroxylase
Forms L-DOPA
decarboxylase
Converted to dopamine

Dopamine-β -hydroxylase
Forms nor-epinephrine/nor-adrenaline
 Epinephrine/adrenaline

~ Sympathetic alarm reaction: (OR stress reaction)

- Adrenal medulla releases the adrenaline during the
states of emergency. This response to stress is called
fight-or-flight reaction. (As if the person is readied
for either to face/fight the stressful situation or to
flee from the situation.)
- In the stressful situations, there is widespread
stimulation of the sympathetic nervous system.
Sympathetic nerves to the adrenal medulla will also
cause release of adrenaline (and nor-adrenaline)
from the gland. Thus, there would be a sympathetic
mass discharge.
- Mental or physical stress can thus excite the
sympathetic nervous system. States of anxiety,
anger, active aggressive states are particularly
responsible for such stimulation.
- It will have the following effects:

 Dilatation of the pupils

 Increased heart rate, cardiac output, and blood

pressure

 Vasodilatation in skeletal muscle (to increase its

blood flow)

 Bronchodilatation
  Glycogenolysis; increase in blood glucose (so
that the fuel is ready for the muscles or organs)

 Increased cerebration/mental activity

Thus, the body is prepared for a vigorous muscular
activity, so as to face the stressful situation.
~ Applied physiology:
- Pheochromocytoma is the tumor of the chromaffin
cells in adrenal medulla.
- There is hypersecretion of catecholamines.
- Patients have sustained hypertension; also other
clinical manifestations.

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--------------
ADRENAL CORTEX GLAND
(Secretion of steroids)
{Adrenal cortex gland is the gland that is larger in fetus
and newborn, compared to adults. The fetal adrenal
cortex has an outer “neocortex”, about 15% of the total
volume of the gland, and inner “fetal zone” which is
about 85%. After birth, in about 3 to 12 months, the “fetal
zone” undergoes involution and it disappears completely.
Only the “neocortex” remains, and functions as the
adult adrenal cortex gland. The other gland that is larger
in infants than in adults is: pineal gland}
ADRENAL CORTEX GLAND SECRETES HORMONES
WHICH ARE STEROIDS IN STRUCTURE. Those structures
which have CPPP nucleus are called steroids.
The (adult) adrenal cortex gland has 3 zones:
1. Zona glomerulosa: It synthesizes and secretes
aldosterone. Aldosterone is a mineralocorticoid; it
is a steroid that affects the mineral levels in the
body/blood.
2. Zona fasciculata: It synthesizes and secretes
glucocorticoids. Cortisol is the prototype example of
the glucocorticoids. They are called glucocorticoids
as they increase the blood glucose levels, apart from
the other effects exerted by them.
3. Zona reticularis: It secretes sex steroids.
{Many authors argue that the inner two zones – zona
glomerulosa and reticularis – should be considered single
functional unit. This unit secretes glucocorticoids and sex
steroids (androgens and very small amounts of
estrogen.)}
Adrenal cortex gland secretes steroids. All these
adrenocortical steroids are synthesized by a common
biosynthetic pathway.
All the steroids of the adrenal cortex are synthesized from
a common precursor: CHOLESTEROL.
 Cholesterol

Pregnenolone

Progesterone17-(OH) pregnenolone Androgens

Corticosterone 17-(OH) progesterone

Estrogens

Aldosterone cortisol

~ Aldosterone: (short note)

- It is the mineralocorticoid; the steroid that affects
the mineral levels in the body.
- It is synthesized by the zona glomerulosa, of the
adrenal cortex gland.
- It is synthesized from the cholesterol.
- Principal action of aldosterone is: increase in Na+
retention into the blood.
- Stimulus for the aldosterone secretion: decreased
blood volume
 Decreased blood volume
And/or
Decreased blood pressure

It causes release of renin by the JG complex of kidneys

Renin

Angiotensinogen (in blood) angiotensin I

Angiotensin II

Causes secretion of aldosterone from adrenal

cortex

Aldosterone causes Na+ and water retention from the

renal tubules into the blood. This is by its action on Na+ -
K+ pumps.
 Increase in blood volume and blood
pressure

~ Applied physiology –
- Hypokalemia: Excess aldosterone secretion will lead
to excess retention of sodium into the blood. And,
potassium moves in the opposite direction (action of
Na+ - K+ pump). That is, from the blood into the
tubules, and excreted into urine. Potassium levels of
blood will fall – hypokalemia.
- Acidosis : Potassium and hydrogen ions move in
opposite direction in renal tubules, due to the
presence of the transporter pump in tubules. If
potassium is lost in the urine, equivalent amount of
H+ will be reabsorbed from tubules into the blood.
This will lead to acidosis.

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--------------
GLUCOCORTICOIDS/CORTISOL
(Raise blood glucose; suppress inflammation, fight
stress)
~ Introduction:
- They are the steroids that raise blood glucose
 - They are synthesized by the zona fasciculata of the
adrenal cortex gland
- They are synthesized from the cholesterol
- Cortisol is the principal/prototype glucocorticoid
Physiologic effects of cortisol:
(A) Metabolic effects
(B) Non-metabolic effects

A. Metabolic effects –
1. On carbohydrate metabolism:
GLUCONEOGENESIS
 Cortisol is an anti-insulin hormone. It causes
hyperglycemia and insulin-resistance.
 The principal hyperglycemic action of cortisol is
by gluconeogenesis (new glucose synthesis –
from non carbohydrate sources - proteins). This
occurs by protein catabolism/breakdown. This
will result in mobilization of amino acids – to
form glucose.

 It also causes glucose intolerance; blocking

glucose transport in muscle and adipose tissue.
It causes insulin exhaustion and eventual
“steroid/adrenal diabetes”.
 2. On protein metabolism: (breakdown, for
gluconeogenesis)
 For gluconeogenesis, proteins are broken
down from skeletal muscle. Amino acids are
released into the blood. Most important
glucogenic amino acid is alanine.
 Also, protein synthesis is inhibited –
antianabolic effect.
3. On fat metabolism: (lipolysis, mobilization of fats)

 Gluconeogenesis from fats; fats are broken

down and glycerol provides substrate for
glucose formation.
 Mobilization of fats from adipose tissue. This
leads to characteristic distribution of fat in
the central axis of the body – “centripetal
redistribution of fat”.
o Deposition of fat on the face – “moon
face”
o In the suprascapular region – “buffalo
hump”
o Protuberant belly

B. Non-metabolic effects –
Cortisol is ANTI-INFLAMMATORY, ANTI-
ALLERGIC, IMMUNOSUPPRESSIVE, AND ANTI-
STRESS.
1. Anti-inflammatory effects:
{Inflammation literally means burning. It is the
tissues reaction to any type of injury – physical,
chemical, etc. Five cardinal signs of inflammation
are: rubor (redness), calor (heat), tumor (swelling),
dolor (pain), and functio laesa (temporary loss of
function). There is vasodilatation, leakage of fluid
out of capillaries, release of proteolytic enzymes
from lysosomes.}

 Cortisol stabilizes lysosomal membranes,

thereby inhibiting the release of proteolytic
enzymes

 Prevents migration of fluid and WBCs out of

capillaries.
[Inflammation interferes healing of the injured
tissue. Sportspersons are known to take steroids
after an injury, limit the effects of inflammation.]
2. Anti-allergic action:

 Histamine release in allergy, by the basophils

and mast cells, produces manifestations of
allergy.
  Cortisol reduces circulating basophils and
circulating histamine, thus decreasing the
effects of allergy. It suppresses eosinophils.
[Many allergic conditions are treated with steroids.
For example, steroid based creams for skin rash of
allergy.]
3. Immunosuppressive action:
 Cortisol reduces the actions of lymphocytes, and
decreases the number of circulating
lymphocytes.
[After a kidney transplant, the patient is kept on
steroids. Thus, the immune mechanisms do not
attack/reject the implanted kidney.]
4. Stress adaptation:
Cortisol allows the human to adapt to various
types of stress. It is known to stimulate
sympathetic activity. It enhances catecholamine
synthesis.
5. Cardiovascular effects:
Cortisol increases the blood pressure. It enhances
the vasopressor effect of norepinephrine.
6. CNS effects:
Cortisol may cause euphoria, restlessness, and
psychosis.
7. Gastric effects:
 Cortisol increases the acid flow in the stomach,
and it decreases the mucosal cell proliferation.
This may result in peptic ulcers in stomach.

~ Regulation of secretion of
cortisol/glucocorticoids:
- The most important regulator of the cortisol
secretion is the ACTH (or corticotrophin). ACTH is
released from the anterior pituitary gland.
- Most important action of ACTH is to stimulate
conversion of cholesterol to pregnenolone.
- ACTH secretion is controlled by the corticotrophin
releasing hormone (CRH) from the hypothalamus.
- ACTH secretion is increased when body faces stress.
- ACTH secretion shows circadian rhythm; highest
levels in blood at 6 A.M. and lowest levels at 6 P.M.
Hence, even the cortisol levels are highest in the
early morning and lowest in the evening.
- Negative feedback inhibition: Circulating cortisol
inhibits further secretion of ACTH and CRF.
HYPOTHALAMO-PITUITARY-ADRENAL AXIS
Negative feedback
inhibition

Negative feedback
inhibition

~ Disorders of the cortisol secretion:

(1) Hypersecretion – Cushing’s syndrome
(2) Hyposecretion – Addison’s disease

1. Cushing’s syndrome:
 Prolonged excessive production of cortisol; may
result from an adrenal tumor or adrenal
hyperplasia.

 Features are mainly those of protein breakdown

and fat mobilization and deposition

 Features from head-to-toe are as follows:

 Acne and hirsuitism (excessive hairiness of the

face). Acne are due to increased activity of the
sebaceous glands

 Centripetal redistribution of fat leads to –

“Moon face” (face becomes rounded due to fat
deposition)
“Buffalo hump” (fat deposition in the
suprascapular region)
Protuberant belly (fat over the abdomen)

 Protein breakdown leads to –

- Thin limbs (due to breakdown of muscle
protein)
- Purple striae (striations) over the abdomen,
thighs; due to tendency to bruising (easy
breakdown of protein matrix).
- Thinning of bones

 The patient will have hyperglycemia and

eventual diabetes.
  The patient will be hypertensive

2. Addison’s disease:
- It is chronic adrenal cortex insufficiency;
there is hyposecretion of the cortisol.
- It may result from bilateral destruction of
the adrenal cortex, or failure of the anterior
pituitary
- The outstanding clinical features are:
muscular weakness and easy fatiguability;
pigmentation of the skin and buccal
mucosa
- Loss of weight, dehydration
- Hypotension
- Hypoglycemia
- Anorexia, nausea, and vomiting
- Decreased ability to withstand trauma,
infections, hemorrhage, and other
“stresses”.
{Reason of pigmentation: Cortisol secretion is abolished
in Addison’s disease. Then, by negative feedback, ACTH
secretion by pituitary is increased. Since ACTH and MSH
(melanocyte stimulating hormone) are derived from the
common precursor, sharing same amino acid sequence,
ACTH has MSH-like activity. It stimulates melanin
production, resulting in pigmentation.}
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--------------

CALCIUM HOMEOSTASIS
Regulation of Ca++ in the body
{Parathyroid hormone, calcitonin, and vitamin D}
~ Role of Ca++ in physiologic processes:
1. Blood clotting – Calcium is necessary for the
activation of clotting enzymes in plasma.
2. Neurotransmitter release – At synapses, release of
neurotransmitter by the nerve endings depends on
calcium influx into the nerve terminal.
3. Muscle contraction – Calcium is the agent of
excitation-contraction coupling. Thus, it initiates
contraction of muscle.
4. Excitation-secretion processes – Calcium is essential
for the release of hormone by endocrine cells.
 5. Membrane excitation – Ca++ controls membrane
excitation, especially that of the nerve. In the heart,
excitation of the pacemaker cells is brought about by
the influx of calcium.
6. Ca++ is necessary for the production of milk and the
formation of bone and teeth.
There are many other roles played by the calcium, at
various places in the body.
~ Ca++ distribution:
- More than 99% of the total body Ca++ is
stored in the skeleton. The skeleton of a 70-
kg adult contains about 1000 gm of Ca++;
and about 1 gm in the extracellular pool.
- Plasma Ca++ = about 10 mg%
- Ca++ in plasma:
1. Ionized or free (45%)
2. Non-ionized or bound (55%): {Of this
bound form – 45% is bound to protein
(mainly albumin), and 10% is complexed
with ions (citrates, HPO4--, etc)
- The sum of the free/ionized and complexed
Ca++ (55%) forms the diffusible fraction of
calcium; the protein-bound form (45%)
caonstitutes the non-diffusible fraction.
 - PTH, calcitonin, and vitamin D regulate
the ionized Ca++ in the serum.
~ About 1% of the body’s calcium pool consists of young
(labile) bone. It is readily exchangeable. That is, it
provides an immediate reserve for calcium, in case there
is a sudden decrease in blood Ca++. Remaining 99%
calcium of the Ca++ pool is not readily exchangeable. It
is stable (mature) bone.
~ Bone Ca++ is found in the form of hydroxyapatite
crystals.
A large surface area is provided by the microcrystalline
structure of bone.
Calcium: phosphorus ratio in bone is about 1.7 : 1.

Calcium regulation in blood

It involves three tissues: bone, kidney, and
intestine.
It involves three hormones: PTH, calcitonin, and
Vitamin D.
It involves three cell types: osteoblasts, osteoclasts,
and osteocytes.
Osteoblasts: cause deposition of new bone, thus they
are bone forming cells
Osteoclasts: cause resorption of bone, thus they remove
bone constituents (Ca++)
Hormonal control of Ca++ metabolism:
(There is no major role played by the pituitary gland.)
1. Parathyroid hormone (PTH): (increases blood
calcium)
 There are four parathyroid glands (2 superior and 2
inferior); located on the posterior aspect of the
thyroid gland. They secrete the parathyroid hormone
(PTH) or parathormone.
 The PTH is released by the gland when the blood
calcium falls. It then increases the blood calcium.

 PTH exerts its effects on the bone, kidneys, and

intestine.
a. On the bone:
PTH causes increased mobilization of Ca++ from
the bone. This is bone resorption or bone
dissolution. Calcium from the bone will be released
into the blood, thus increasing blood calcium.
Mechanism:
- PTH stimulates osteoclastic and osteocytic
activity.
 - It also stimulates formation of new
osteoclasts.
- Osteoclasts cause bone resorption; thus Ca+
+
from the bone is removed, and is released
into blood.
- cAMP is the mediator of bone resorption.
b. On the kidney: (calcium reabsorbed from tubules
into blood)
- PTH acts on renal tubules, to cause
reabsorption of Ca++ from the tubules
into the blood. This occurs from the distal
nephron. Mechanism: It is by active
transport. PTH increases tubular maximum
[Tm] for calcium.
- PTH also inhibits phosphate reabsorption
from the proximal tubules. This leads to
phosphate excretion in the urine –
phosphaturia.
c. On the intestine: (Ca++ absorption from the gut)
- Calcium and phosphate absorption from
the intestine is increased by the PTH. This
occurs mainly by facilitated diffusion.
- Ca++ absorption increased by PTH is an
indirect effect. PTH promotes synthesis of
vitamin D, which in turn increases Ca++
absorption from the gut.
~ Applied physiology: (Hypoparathyroidism)
• Tetany: (decreased serum calcium)
- It is the condition of sustained spasmodic
contraction of the muscles, failure of muscle
relaxation.
- It is due to decrease in serum Ca++ level.
- It results from hypoparathyroidism. PTH
secretion is decreased/abolished. It may
occur due to damage to PTH glands. For
example, during thyroid gland surgery,
parathyroids may be damaged.
- The early manifestation of tetany is
“carpopedal spasm”. The flexion at the
wrist, fingers are extended, thumb is drawn
on to the palm. (“obstetrician’s hand”)
- Trousseau’s sign: When a BP cuff is
applied to the arm, and pressure is raised,
the capopedal spasm is manifested. (this is
due to stimulation of the nerves entering
the arm, by the pressure)
- Chvostek’s sign: Even a faint tap over the
angle of mandible causes facial muscles to
go into spasm. (facial nerve emerging from
the parotid, at the angle of mandible. It is
stimulated excessively, even with such a
faint stimulus.)
Mechanism of spasm of muscles:
Ca++ of the blood is said to the “stabilizer” of the
sodium channels, particularly the Na+ channels in the
nerve membrane. Serum Ca++ controls the Na+ channel
activity and their gating behavior.
Decrease in serum Ca++

Na+ channels become unstable

Threshold for action potential is decreased

Nerve becomes “hyperirritable", sends continuous

impulses to the
muscle, muscle is excited continuously
- Symptoms of tetany may begin to appear
when the serum Ca++ falls upto 7 mg%
(Normal = 10 mg%)
- Death may occur when the serum Ca++
falls below 6 mg%.
- Reason of death in tetany: It causes
spasm of lartyngeal muscles, and spasm of
thoracic/respiratory muscles.
~ Apart from parathyroid deficiency, the other cause of
clinical tetany is ALKALOSIS. For instance,
hyperventilation washes out CO2 and H+ from blood. It
results in alkalosis. Increased alkalis then increase
plasma protein ionization, which in turn reduced the free
Ca++ in plasma.

2. Calcitonin: (decreases blood calcium)

 In the thyroid gland, out of the follicles, there are
parafollicular (C) cells. These “C” cells secrete
calcitonin or thyrocalcitonin.
 It causes hypocalcemia; that is, reduces blood
calcium. Thus, calcitonin secretion will be
increased when the blood calcium is
increased, and then, it will reduce the
calcium level of blood.

 Calcitonin exerts its effect on 3 tissues: bone,

intestine, and kidney.
a. On the bone –
- Calcitonin inhibits osteoclastic activity; this
will inhibit bone resorption.
- It may also increase the activity of
osteoblasts. Thus, calcium will be
removed from blood and will be
deposited on the bone.
b. On the intestine –
 - Calcitonin inhibits the intestinal (jejuna)
absorption of dietary Ca++ (and also
phosphate).
c. On the kidney –
- Calcitonin promotes urinary excretion of
Ca++, phosphate, and sodium.
- It also decreases the enzyme which forms
vitamin D at the final step in the kidney.
(less vitamin D, less intestinal absorption of
calcium)

3. Vitamin D: {although it is called vitamin, it is a

steroid hormone as it shows all the properties of a
hormone}
- Steroid with 27 carbon atoms; it is the
largest steroid hormone.
- The active metabolites of vitamin D are
calcidiol and calcitriol; they exert the effects
of vitamin D.
• Synthesis of active vitamin D3: (calcitriol)

 In the epidermis (skin), there is a previtamin: “7

– dehydrocholesterol”. When sun’s u.v. rays fall
on the skin, this 7 – dehydrocholesterol is
converted into “cholecalciferol”.
  Cholecalciferol goes to liver. Here, a hydroxyl
(OH) group is attached to 25th position (carbon
atom). This forms 25-(OH) cholecalciferol.

 25-(OH) CCF then goes to kidney. Here, one

more hydroxyl group is attached to 1st carbon
atom. Now, it is 1,25- di- hydroxyl-
cholecalciferol. This is the most active form.
Note that: Last step in the vitamin D
formation is under the influence of PTH.

~ Actions of vitamin D: (increases blood calcium, but

also causes bone deposition)
- Vitamin D acts together with the PTH. Thus,
their actions are mostly synergistic. It is to
increase the blood calcium.
- On the bone: along with PTH, it causes
mobilization of Calcium from bone into the
blood. However, this action also fosters
bone deposition (paradoxically).
- On the intestine: increased calcium
absorption from the intestine. PTH
enhances this action; and this is the
principal action of vitamin D.
- On the kidney: It causes reabsorption of
Ca++ from the distal tubules. But unlike PTH,
 it does not cause phospahturia. It causes
phosphates also to be reabsorbed.
~ Applied physiology:
Vitamin deficiency in childhood causes rickets, and in
adults its deficiency causes osteomalacia.
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