1

HORMONES
Different mechanisms involved in hormone action. (MGR U)
Hormones are classified into two broad groups based on the mechanism of action:
Group I hormones:
These hormones bind to intracellular receptors to form receptor hormone complexes (the
intracellular messengers) e.g. estrogens, androgens, glucocorticoids, calcitriol.
Group ll hormones :
These hormones bind to cell surface (plasmam embrane) receptors and stimulate the release of
certain molecules, namely the second messengers which, in turn, perform the biochemical
functions. The hormones themselves are the first messengers. Croup ll hormones are subdivided
into three categories based on the chemical nature of the second messengers.
(a) cAMP e.g. ACTH, FSH, LH, PTH, glucagon, calcitonin.
(b) Phosphatidyl inositol / calcium e.g. TRH, GnRH, gastrin, CCK.
(c) Unknown e.g. growth hormone, insulin, oxytocin, prolactin.
Group I hormones:
1. These hormones are lipophilic in nature and can easily pass across the plasma membrane. Eg.
steroid hormones and thyroid
hormones
2. They diffuse through the
plasma
membrane and bind to the
receptors
in the cytoplasm and lead to
the
hormone
receptor
(HR)
complex in
the cytoplasm.
3. The
complex
is
then
translocated to the nucleus. In
the
nucleus, the HR binds to the
specific
regions on the DNA called
hormone
response elements (HRE) and
causes
increased
expression
of
specific
genes
4. Hormone receptor complex
with
HRE
promotes
initiation
and
elongation
and
termination
of
RNA
synthesis
(transcription).
5. The ultimate outcome is the
production
of
specific
proteins
(translation) in response to
hormonal
action.
6. Examples of the effect of
hormones
on genes are:
a. The induction of synthesis of amino transferases by glucocorticoids.
b. Synthesis of calcium binding protein by calcitriol
Group II hormones:

2
1. Many hormones are water-soluble, have no transport proteins (and therefore have a short plasma
half-life), and initiate a response by binding to a receptor located in the plasma membrane.
2. The mechanism of action of this group of hormones are mediated by the intracellular signals
generated by cAMP, cGMP, Ca2+ , and phosphatidylinositides. These are called second messengers
and act by affecting gene transcription. cAMP is a nucleotide derived from ATP through the action
of adenylyl cyclase; cGMP, a nucleotide formed by guanylyl cyclase; cAMP acts as a second
messenger for a majority of polypeptide hormones.
3. The hormone is not passed through the membrane; but only the signal is passed; hence this
mechanism is called signal transduction
4. Group II hormones act first by binding to a receptor located in the plasma membrane. Receptors,
which have guanine nucleotide, are known as G proteincoupled receptors, or GPCRs. They
represent the largest family of cell surface receptors in humans. Different types of G proteins are
present in the cells that are coupled with different receptors. The G-protein is a membrane protein
consisting of alpha, beta and gamma subunits.
Steps in the action of Gr. II hormones:
1. First, the hormone combines with the specific receptor on the plasma membrane. These receptors
have extracellular hormone-binding regions as well as intracellular portions that interact with the G
protein
2. The Hormone -Receptor complex activates the G-protein which in turn releases GDP and binds to
GTP.
3. The GTP-bound subunit of G protein activates adenylate cyclase. The active G-alphaGTP is
immediately inactivated by GTPase.
4. Adenyl cyclase converts ATP to cAMP (3',5'-cyclic AMP), and phosphodiesterase hydrolyses cAMP to
5' AMP
5. Cyclic AMP, being the second messenger, in turn, activates the enzyme, PKA (Cyclic AMP dependent
protein kinase). Cyclic AMP binds to the regulatory subunits of PKA so that the catalytic subunits
having kinase activity can phosphorylate proteins (the transfer of the phosphate of ATP to a serine
or threonine residue in a variety of proteins). For eg.
a. Serinethreonine protein kinase phosphorylates a large number of enzymes, providing a
rapid response to hormones such as glucagon and epinephrine.
b. PKA phosphorylates hormone sensitive lipase thus activating it.
c. Phosphorylase Kinase that phosphorylates glycogen phosphorylase.
d. PKA induces phosphorylation of cAMP regulated gene regulatory proteins or CREBs. These
proteins will bind to cAMP sensitive regulatory elements (CRE) on genes, and control their
expression.
6. Degradation of cAMP : cAMP undergoes rapid hydrolysis, catalysed by the enzyme
phosphodiesterasteo 5' AMP which is the inactive form.
Cyclic GMP:
7. It is made from GTP by the enzyme guanylyl cyclase. A family of peptides produced in cardiac atrial
tissues, called atrial natriuretic pepdides, bind and activate the membrane-bound form of guanylyl
cyclase. This causes natriuresis, diuresis, and inhibition of aldosterone secretion.
8. The increased cGMP activates cGMP-dependent protein kinase (PKG), which in turn phosphorylates
a number of smooth muscle proteins leading to relaxation of smooth muscle and vasodilation.

1.

Calcium:
Calcium is
also an

intracellular messenger of
hormone
action. Calcium is an important intracellular regulator of cell function like contraction of muscles,
secretion of hormones and neurotransmitters, cell division and regulation of gene regulation.
2. The calcium-dependent regulatory protein is called calmodulin which has four Ca2+ binding sites,
and full occupancy of these sites leads to a marked conformational change, which allows calmodulin
to activate enzymes and ion channels. The interaction of Ca2+ with calmodulin is similar to the
binding of cAMP to PKA and the subsequent activation of this molecule.
3. Steps:
a. Group II hormones like antidiuretic hormone, and a-1 -type catecholamines act by binding
to membrane surface receptors and activate phospholipase C.
b. Phospholipase C catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol
trisphosphate (IP3 ) and 1,2-diacylglycerol.
c. Diacylglycerol activates protein kinase C (PKC), and releases of Ca2+ from the endoplasmic
reticulum.
d. Increase in intracellular calcium concentration favors formation of the calmodulin-calcium
complex.
e. The calmodulin-calcium complex binds to inactive enzymes and results in their conversion to
active enzymes. Eg. Adenyl cyclase, calcium-dependent protein kinases, calciummagnesium-ATPase, cyclic nucleotide phosphodiesterase, nitric oxide synthase and
phosphorylase kinase.
Phosphatidylinositol phosphates:
a. The binding of some Group II hormones to cell surface receptor triggers the activation of the
enzyme phospholipase-C which hydrolyses the phosphatidyl inositol to Inositol triphosphate (ITP)
and diacylglycerol (DAG). These act as second messengers. This is found in case of vasopressin,
TRH, GnRH, etc.
a. IP3 can release Ca++ from intracellular stores, such as from endoplasmic reticulum and from
sarcoplasmic reticulum. The elevated intracellular calcium then triggers processes like smooth
muscle contraction, glycogen breakdown and exocytosis. Diacylglycerol is capable of activating
protein kinase C that release Ca2 from endoplasmic reticulum.
G-PROTEINS (Short notes)
1. G proteins are intracellular signaling proteins. They are so named because of their ability to bind to
guanosine triphosphate (GTP ).
2. G proteins are regulated based on their binding to GTP.

4
3. They also possess GTPase activity, the ability to hydrolyze GTP to GDP.
4. Two categories of G proteins are known:
a. Heterotrimeric G proteins (heteromeric= containing different types of sub units)
b. The Ras superfamily of monomeric G proteins
Heterotrimeric G proteins

Ras superfamily G proteins

Three subunits, , ,

Monomers

Use G-protein linked receptors

Use catalytic receptors

Regulate second messengers

1. Ras superfamily (RAS= abbreviation of 'Rat sarcoma') members are called small G proteins since
they are monomers that resemble just one subunit of the heterotrimeric G proteins. The Ras signaling
involves induction of cell proliferation, cell differentiation, or vesicle transport.
2. Heterotrimeric G proteins:
Structure:
1. Many hormones and neurotransmitters have receptors on their target cells that are linked to G
proteins. G proteinlinked receptors are the most common form of cell surface receptor.
2. G protein consist of three subunits, , , and . G subunit has different isoforms denoted by
subscripts s, i, and q etc.
3. When a G protein is bound to GDP molecule it
is in an off
state, or inactive. When a GTP molecule
replaces
the GDP, it renders the G protein fully active.
This activity
allows the G protein to transmit a signal by
binding to
enzymes like adenylyl cyclase for further
signaling.
4. GDP is bound to the , subunit of the G
protein
when all three subunits are joined together in
the inactive
form.
5. G proteins regulate the activity of adenylyl
cyclase.
This enzyme uses ATP as a substrate to produce the second messenger cAMP.
6. Gs refers to subunits stimulate adenylyl cyclase
(hence
the s).
7. G-subunits that inhibit adenylyl cyclase are called
Gi .
Function:
1. There are receptors on the cell surface for the
hormones to act. Group II hormones act through
receptor
sites which are linked to G protein. G proteinlinked
receptors are transmembrane proteins with seven
membrane-spanning regions. These receptors have
extracellular hormone-binding regions as well as
intracellular portions that interact with the G protein
to send
the message from the hormone into the cell.
2. A ligand is a molecule that binds specifically to a particular receptor. Hormones and
neurotransmitters are ligands of G proteinlinked receptors.
3. Hormone, after binding to receptor form the Hormone - Receptor complex which induces G-protein
to releases GDP and instead bind to GTP, which is the active form.

5
4. The GTP-bound subunit of G protein, dissociates from the and subunits and activates
adenylate cyclase. The active G-alphaGTP is immediately inactivated by GTPase and restored to
original form.
5. Adenyl cyclase converts ATP to cAMP (3',5'-cyclic AMP), and phosphodiesterase hydrolyses cAMP to
5' AMP
6. Cyclic AMP, being the second messenger, in turn, activates the enzyme, PKA (Cyclic AMP dependent
protein kinase).
7. PKA phosphorylates serine or threonine residues in a variety of proteins. Phosphorylation regulates
the activity of proteins and enzymes and can lead to desired intracellular effects.
CYCLIC AMP (S.N)
Structure:
1. These are phosphate esters of nucleosides. Base plus pentose
sugar plus
phosphoric
acid
is
a
nucleotide
like
adenosine
monophosphate.
2. In AMP, a phosphodiester linkage may be formed between the
3' and 5'
positions of ribose group. Such compounds are called cyclic
nucleotides
namely 3, 5-cyclic AMP or cAMP
Biosynthesis:
1. Cyclic AMP (cAMP) is formed from ATP by adenylyl cyclase in
response
to hormones such as epinephrine, norepinephrine and glucagon.
2. First, the hormone combines with the specific receptor on the plasma membrane. These receptors
have extracellular hormone-binding regions as well as intracellular portions that interact with the G
protein. The Hormone -Receptor complex activates the G-protein which in turn releases GDP and
binds to GTP.
3. The GTP-bound subunit of G protein activates adenylate cyclase. The active G-alphaGTP is
immediately inactivated by GTPase. Adenyl cyclase converts ATP to cAMP (3',5'-cyclic AMP).
Functions:
1. cAMP is the intracellular second messenger for several hormones that regulate fuel metabolism.
Cyclic AMP activates the enzyme, PKA (Cyclic AMP dependent protein kinase).
2. Cyclic AMP binds to protein kinase A, which then catalyzes the transfer of phosphate from ATP to
serine, threonine residues of effector proteins.
3. Serinethreonine protein kinase phosphorylates a large number of enzymes, providing a rapid
response to hormones such as glucagon and epinephrine.
4. PKA phosphorylates hormone sensitive lipase thus activating it.
5. Phosphorylase Kinase that phosphorylates glycogen phosphorylase.
6. PKA induces phosphorylation of gene regulatory proteins which will bind on genes and initiate
transcription.
Degradation of cAMP: cAMP undergoes hydrolysis, catalysed by the enzyme phosphodiesterasteo 5'
AMP which is the inactive form. Caffeine and theophylline can inhibit phoshodiestrase and enhance the
level of cAMP
ADRENOCORTICL HORMONES
1. Classification of adrenocortical hormones:
a. Corticosteroids:

6
i. Glucocorticoids: example, cortisol from adrenal
cortex.
ii. Mineralocorticoids: example, aldosterone from
adrenal
cortex.
b. Sex hormones:
i. Androgens: ex. Testosterone from testes.
ii. Estrogens, and progestins: example estrogens and
progestins
from ovaries and placenta.
2. Synthesis of steroid hormones:
a. Cholesterol is the precursor of all classes of steroid
hormones.
b. Cholesterol is first acted upon by desmolase and a 6-carbon unit is cleaved off, forming the 21
carbon steroid, pregnenolone. It is a common precursor for all the steroid hormones.
c. ACTH stimulates this step. This is the rate limiting step for synthesis of all steroid hormones.
d. P
r
o
g
e
s
t
e
r
o
n
e
i
s
t
h
e

first steroid hormone formed from pregnenolone in two steps. The beta hydroxyl group is
converted to a keto group by a 3-beta-ol-dehydrogenase and the 5 double bond shifted to 4.
e. Progesterone is further converted into:
i. Glucocorticoids

7
ii. Mineralocorticoids
iii. Sex streroids
FUNCTIONS OF ADRENOCORTICAL HORMONES
1.
2.
3.
4.
5.

Role of adrenocortical hormones in protein metabolism Pon May 2009

Functions of adrenal cortical hormones. MGR U
Functions of Glucocorticoids. MGR U
What is the mechanism of action of steroid hormones? MGR U
Addisons disease.

BIOCHEMICAL FUNCTIONS OF ADRENOCORTICOSTEROIDS:

Glucocorticoid hormones:
1. The important glucocorticoids are-cortisol, cortisone and corticosterone.
2. Carbohydrate metabolism:
a. Increase blood glucose concentration and produce hyperglycemia
b. Mechanism of hyperglycaemia:
i. Decreases glucose uptake and utilisation in muscles, in adipocytes and lymphoid cells
by inhibiting the membrane transport of glucose into these cells.
ii. Enhancing gluconeogenesis in liver.
iii. Induces the synthesis of key gluconeogenic enzymes such as pyruvate carboxylase,
PEP carboxykinase, fructose 1-6-bi-phosphatase and also Glucose- 6-phosphatase.
iv. It makes available more of substrates required for gluconeogenesis. This is achieved
by:
a. Increasing protein catabolism in extrahepatic tissues.
b. Decreasing incorporation of amino acids in protein in peripheral tissues.
c. Also increasing synthesis of some key enzymes required for amino acid
catabolism like, alanine transaminase, tyrosine transaminase, tryptophan
pyrrolase, etc.
v. Decreases glycolysis in peripheral tissues:
c. In liver: Glucocorticoids are anabolic. It increases the glycogen store in liver. This is due to:
i. Increase in gluconeogenesis from amino acids and glycerol.
ii. Increase in the synthesis of phosphoenolpyruvate carboxykinase, the rate limiting
enzyme in gluconeogenesis.
d. The biological actions of glucocorticoids generally oppose that of insulin.
3. Lipid metabolism :
a. Increase the circulating free fatty acids by:
i. Increased breakdown of storage triacylglycerol ( ipolysis) in adipose tissue.
ii. Reduced utilization of plasma free fatty acids for the synthesis of triacylglycerols.
4. Effects on protein metabolism: (S.N)
a. Glucocortiocoids exhibit both catabolic and anabolic effects on protein and nucleic acid
metabolism.
b. Anabolic effects:

8
i. In liver: Cortisol is anabolic, it increases protein synthesis.They promote transcription
(RNA synthesis) and protein biosynthesis (translation) in liver.
ii. These anabolic effects are caused by the stimulation of specific genes.
iii. It increases hepatic uptake of amino acids.
iv. Incorporation of amino acids into ribosomal proteins.
v. Increased m-RNA formation and synthesis of proteins including plasma proteins.
vi. In liver, cortisol also enhances urea synthesis from amino acids. There is increased
synthesis of enzymes necessary for urea cycle, e.g. arginino succinate synthetase,
arginase, etc.
c. Catabolic effects:
i. Clucocorticoids (particularly at high concentration) cause catabolic effects in
extrahepatic tissues (e.g. muscle, adipose tissue, bone etc.). This results in enhanced
degradation of proteins.
ii. In peripheral extrahepatic tissues, cortisol increases protein breakdown, leading to
increased amino acids availability in plasma.
iii. Reasons of increased catabolism:
a. Enhances synthesis of key enzymes of amino acid catabolism like
transaminases, tyrosine transaminase, tryptophan pyrrolase, etc.
b. Also there is decreased incorporation of amino acids in protein molecule.
d. Over-all effect on protein metabolism by cortisol is Negative Nitrogen Balance.
5. Effects on water and electrolyte metabolism:
a. water metabolism is mediated through antidiuretic hormone (ADH).
b. Deficiency of glucocorticoids causes increased production of ADH. ADH decreases glomerular
filtration rate causing water retention in the body.
6. Effects on the immune system :
a. Cortisol suppress the host immune response. The steroid hormones act at different levelsdamaging lymphocytes, impairment of antibody synthesis, suppression of inflammatory
response etc.
7. Anti-inflammatory Action:
a. Normal cortisol level does not affect; but therapeutic doses exert an anti-inflammatory
effect.
b. Mechanism: Three basic mechanisms by which glucocorticoids exerts anti-inflammatory
effects are:
i. Action on Lysosomes: Stabilises cell membrane of lysosomes and thus block the
release of lysosomal hydrolases.
ii. Action on Kinin Formation: Prevents formation of bradykinin which is produced by
action of Kallikrein, a proteolytic enzyme on -globulin.
iii. Action on Capillaries: Decreases permeability of capillary walls and prevent protein
leakage.
iv. Decreases the formation of PGs, PG-I2, Tx and leukotrienes by inhibiting
phospholipase A2.
v. Prevents the release of histamine from mast cells.
vi. Reduces fibroblastic proliferation and collagen synthesis.
vii. Inhibits the release of interleukin-I from granulocytes.

8. Other
a.
b.
c.
d.

viii. Decreases the number of circulating lymphocytes (lymphopenia), eosinophils and

monocytes.
physiological effects of glucocorticoids:
Glucocorticoids are involved in several physiological functions.
Stimulate the fight and flight response (to face sudden emergencies) of catecholamine
Increase the production of gastric HCI and pepsinogen.
lnhibit the bone formation, hence the subjects are at a risk for osteoporosis.

Mechanism of action of glucocorticoids :

1. Steroid hormone diffuses across the
plasma
membrane of its target cell and binds to a
specific
cytosolic receptor
in
the
cells
of
liver,muscles, adipose tissue, lymphoid
tissue, skin,
bone, fibroblasts, etc.
2. Steroid receptor molecule has three
distinct
domains:
a. A steroid binding domain
b. A DNA binding domain
c. A transcription-activating domain.
3. A heat-shock protein, hap 90, binds to the receptor in the absence of hormone and prevents
activation of the receptor protein. Steroid binding causes dissociation of the hsp 90.
4. The steroid-receptor complex enters the nucleus, and bind by DNA-binding site called the Hormone
responsive element (HRE) through a zinc-finger motif and activate the gene promoter sequence of
DNA, causing transcription.
Mineralocorticoid hormones :
1. The most active and potent mineralocorticoid is aldosterone. lt promotes Na+ reabsorption at the
distal convoluted tubules of kidney. Na+ retention is accompanied by corresponding excretion of
K+, H+ and NHf ions.
2. Regulation of aldosterone synthesis : The production of aldosterone is regu.lated by different
mechanisms. These include reninangiotensin, potassium, sodium and ACTH.
3. Mechanism of aldosterone action : Aldosterone acts like other steroid hormones. Lt binds with
specificr eceptorso n the targett issue and promotes transcription and translation.
Metabolism of adrenocorticosteroids:
1. The steroid hormones are metabolized in the liver and excreted in urine as conjugates of
glucuronides or sulfates.
2. The urine contains mainly two steroids- 17 -hydroxysteroid s an d 17-ketosteroids-derived from the
metabolism of glucocorticoids and mineralocorticoids. Androgens synthesized by gonads also
contribute to the formation of 1 7-ketosteroids.
3. Urinary 17-ketosteroids estimated in the laboratory are expressed in terms of
dehydroepiandrosterone and their normal excretion is in the range of O.2-2.O mg/day.
Addison's disease :
1. lmpairment in adrenocortical function results in Addison's disease. This disorder is characterized by
decreased blood glucose level (hypoglycemia), loss of weight, loss of appetite, muscle weakness,

10
impaired cardiac function, low blood pressurel, decreased Na+ and increased K + level in serum,
increased susceptibility to stress etc.
Cushing's syndrome :
1. Hyperfunction of adrenal cortex may be due to long term pharmacological use of steroids or tumor
of adrenal cortex or tumor of pituitary.
2. Cushing's syndrome is characterized by hyperglycemia (due to increased gluconeogenesis), fatigue,
muscle wasting, edema, osteoporosis, negative nitrogen balance, hypertension, moon-face etc.
THYROID HORMONES
1.
2.
3.
4.
5.

Explain thyroid function tests and its importance Pon May 2009
Assessment of hypothyroidism
Thyroid function Tests
What is primary hyperthyroidism? Name the conditions causing It. Pon May 2010
Hypothyroidism presents with hypercholesterolemia. Why?

Mechanism of Action of Thyroid Hormone

1. The hormone attaches to specific nuclear receptors. Then the receptor-hormone complex binds to
the DNA. The T3 receptor complex binding sequence in the DNA or the thyroid responsive element
(TRE) has been identified.
2. The T3 binding results in increase in transcription rate.
Metabolic Effects of Thyroid Hormones
1. The hormone exerts action on every cell of the body. Calorigenic effect or thermogenesis is the
major effect of thyroid hormone. One mg of T4 will produce an excess of 1000 kcal. This
thermogenic effect is mediated by uncoupling of oxidative phosphorylation.
2. Basal metabolic rate (BMR) is increased. Thyroxine increases cellular metabolism.
3. Earliest effect of T4 is stimulation of RNA synthesis and consequent increase in protein synthesis.
Higher concentration of T3 causes protein catabolism and negative nitrogen balance. Loss of body
weight is a prominent feature of hyperthyroidism.
4. Gluconeogenesis and carbohydrate oxidation are increased. Glucose tolerance test shows rapid
absorption.
5. Fatty acid metabolism is increased. Cholesterol degradation is increased and hence
cholesterol level in blood is decreased, which is another hallmark of hyperthyroidism.
HYPERTHYROIDISM
1. Hyperthyroidsm may be due to:
a. increase in binding protein;
b. increased affinity of binding protein;
c. effects of autoantibodies;
d. TSH secreting tumors;
e. T4 toxicosis (T4 increase; T3 low).
2. Primary hyperthyroidism: It is due to diseases of thyroid gland. It is seen in:
a. Graves' disease.
b. Toxic multinodular goiter,

11
c. Toxic adenoma,
d. Functioning metastatic thyroid carcinoma,
e. Tsh receptor mutation,
f. Struma ovarii (teratomas of ovary),
g. Iodine excess.
3. Secondary hyperthyroidism is due to diseases of pituitary or hypothalamus). It is seen in:
a. TSH secreting pituitary adenoma,
b. Thyroid hormone resistance syndrome,
c. Chorionic gonadotropin secreting tumors
d. Gestational thyrotoxicosis.
HYPOTHYROIDISM:
1. Primary hypothyroidism is due to diseases of thyroid gland. It is seen in:
a. Auto immune hypothyroidism (e.g. Hashimotos thyroiditis),
b. Thyroidectomy and
c. Radiation therapy.
d. Drugs producing hypothyroidism are Lithium, antithyroid drugs and para aminosalicylic
acid.
e. Congenital hypothyroidism is seen in:
i. Iodine deficiency,
ii. Absent or ectopic thyroid gland,
iii. Dyshormonogenesis
iv. TSH receptor mutation.
2. Secondary hypothyroidism is due to diseases of Pituitary or Hypothalamus.
a. Hypopituitarism is caused by:
i. Pituitary tumors,
ii. Pituitary surgery or irradiation, infiltration,
iii. Sheehans syndrome and
iv. Isolated TSH deficiency.
b. Hypothalamic diseases causing secondary hypothyroidism are:
i. Tumors,
ii. Trauma and
iii. Malignant infiltration.
Thyroid Function Tests:
HYPOTHYROIDISM:
1. BMR: Measuremento f basal metabolic rate was once used to reflect thyroid activity. It is low in
hypothyroidism.
2. PBI: The estimation of serum protein bound iodine (PBl), representing the circulating thyroid
hormones, was employed for a long time to assess thyroid function. The normal serum PBI
concentration is 3-8 g/ 1OO ml. Hypothyroidism is associated with decreased PBI
3. Radioactive iodine uptake (RAIU) and scanning of thyroid gland are also used for diagnosis.
4. Hormone assay:
i. T4 is the main hormone produced by the thyroid. T3 is produced by peripheral conversion of
T4.

12
ii. T3 and T4 are largely protein bound in the plasma, mainly to thyroxine-binding globulin
(TBG). Only the unbound or 'free' portion (FT3, FT4) is active.
iii. In pregnancy and oral pills, estrogen causes the production of more TBG resulting in higher
levels of total T4 but the physiologically important free T4 levels remain normal. This is also
why total T4 levels tend to be higher in women and Free T4 estimation becomes necessary.
iv. The concentration of free T3 and T4, and TSH are measured (by RIA or ELISA) and their serum
normal concentrations are:
1. Free triiodothyronine (T3) : 80-220 ng/dl
2. Free thyroxine (T4): 0.8-2.4 ng/dl
3. Total thyroxine (T+): 5-12 ng/dl
4. Thyroid stimulating hormone (TSH): <10 U/ml
v. In Hypothyroidism:
i. T3 and T4 are reduced;
ii. TSH:
1. In primary hypothyroidism, TSH level is elevated due to lack of feedback.
2. But in secondary hypothyroidism, TSH, T3 and T4 levels are low; this could point
to a pituitary or hypothalamic cause.
5. TRH response test
iii. TRH stimulates anterior pituitary to release thyroidstimulating hormone (TSH or
thyrotropin) which, in turn, stimulates the release of thyroid hormones (T3 and T4).
iv. TRH administration will stimulate the production of TSH from pituitary. If the
hypothalamopituitary-thyroid axis is normal, the T3 and T4 secretions will be increased.
v. Hypopituitarism. The pituitary could not respond to TRH. In these cases the plasma
thyroid hormone levels are subnormal.
vi. An exaggerated response is observed in primary hypothyroidism since the negative
feedback effect of T4 is reduced.
6. Cholesterol:
vii. In hypothyroidism, cholesterol level in blood is increased. It is not diagnostic, because
hypercholesterolemia is seen not only in hypothyroidism, but also in diabetes mellitus,
hypertension, obstructive jaundice and nephrotic syndrome.
viii. However, cholesterol level is a useful index in monitoring the effectiveness of the therapy
in thyroid conditions. Cholesterol level is increased in hypothyroidism, because
cholesterol carrying lipoprotein degradation is decreased.
7. Radioactive iodine uptake (RAIU)
ix. Radioactive Iodine uptake by thyroid gland and thyroid scanning with Tc99 (radioactive
technicium) are of diagnostic value. These tests are contraindicated in pregnancy and
childhood.
x. Iodine uptake is reduces in primary hypothyroidism;
8. Detection of thyroid antibodies
xi. In Hashimoto's thyroiditis antimicrosomal antibodies, antithyroglobulin antibodies, and
antinuclear antibodies are detected in the circulation. They produce cell destruction and
eventual hypothyroidism.
HYPERTHYROIDISM:
1. Assay of hormones

13

2.

3.

4.

5.

6.

a. Measurement of T4 and T3 levels in blood by RIA (radio immuno assay) or by ELISA form the
basis of laboratory diagnosis of thyroid diseases.
b. In hyperthyroidism:
1. Both T3 and T4 levels are increased
2. TSH is reduced due to feedback inhibition.
3. Free T3 and T4: These are more sensitive tests since the values of free hormones
are not affected by the amount of carrier proteins (TBG) in the blood. Hence
useful during pregnancy.
Plasma TSH
a. Hyperthyroidism due to primary thyroid disease has high T3 and T4 levels, but suppressed TSH
levels.
b. Hyperthyroidism due to pituitary cause is indicated by high TSH, T3 and T4 levels.
TRH response test
1. TRH administration will stimulate the production of TSH. If the hypothalamopituitary-thyroid axis
is normal, the T3 and T4 secretions will be increased.
2. In hyperthyroidism. The negative feedback effect of high T4 overpowers the stimulant effect of
TRH. Here the thyroid hormone levels are elevated.
Cholesterol:
1. It is decreased in hyperthyroidism.
2. Cholesterol estimation will be of no value in the assessment of thyroid function since cholesterol
level is elevated in many other disorders
Radioactive iodine uptake (RAIU)
1. Radioactive Iodine uptake by thyroid gland and thyroid scanning with Tc99 (radioactive
technicium) are of diagnostic value. These tests are contraindicated in pregnancy and childhood.
2. It will indicate thyroid hyperfunction.
Detection of thyroid antibodies
1. In Grave's disease (Hyperthyroidism) , the presence of thyroid stimulating immunoglobulin
(TSIg), also known as long acting thyroid stimulator (LATS) is seen in circulation. The LATS can
bind to TSH receptors on thyroid gland and produce stimulation which is not under feedback
control. The TSIg is an antibody generated against the TSH receptor.
FUNCTIONS OF PARATHYROID HORMONE

1. Metabolic consequences of administration of PTH are:

i. Increase in serum Ca++ concentration.
ii. Decrease in serum inorganic PO4 concentration.
iii. Increased urinary Ca++ following an initial decrease.
iv. Increased urinary PO4 .
v. Removes Ca from bones, particularly if dietary intake of Ca is inadequate.
vi. Increase in citrate content of blood plasma, kidney and bones.
2. Vit.D: Iincrease the rate of conversion of 25-OH-cholecalciferol to 1,25-di-OH-cholecalciferol, by
stimulating -1- hydroxylase enzyme.
3. Mg metabolism: Incrase urinary excretion of Mg
4. Kidneys:

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i. PTH acts through by increasing c-AMP.
ii. PTH binds to specific receptors on plasma membrane of renal cortical cells of both proximal
and distal tubules and stimulates adenyl cyclase to produce c-AMP.
iii. c-AMP then is transported to apical/luminal part of the cell where it activates c-AMP dependent
protein kinase, which phosphorylates specific proteins of the apical membrane to affect the
several mineral transport, across the membrane.
iv. PTH decreases the transmembrane transport and reabsorption of filtered Pi in both proximal and
distal tubular cells and increases the urinary excretion of inorganic phosphate (phosphaturic
effect)
v. Fall in serum inorganic PO4 level leads to mobilisation of PO4 from bones, which also mobilises
Ca++ along with, resulting to hypercalcaemia.
vi. PTH stimulates -1-hydroxylase enzyme located in mitochondria of proximal convoluted tubule
cells, which converts 25-OHcholecalciferol, to 1-25, di-OH-cholecalciferol which in turn increases
the intestinal and renal absorption of Ca++ resulting to hypercalcaemia.
vii. PTH inhibits the transmembrane transport of K+ and HCO3 to decrease their reabsorption by
renal tubules.
viii. PTH increases the transmembrane transport and reabsorption of filtered Ca++ in the distal
tubules resulting initially to decrease urinary excretion of Ca++. But later on, PTH-induced
hypercalcaemia enhances the amount of filtered Ca++ which increases the renal excretion.
5. Action on Bones:
i. PTH binds to specific receptors present on membranes of osteoclasts, osteoblasts and
osteocytes and increases cyclic AMP level in these cells, which acts through c-AMP dependent
protein kinases. Following actions are seen:
ii. Osteoclastic activity: It stimulates the differentiation and maturation of precursors cells of
osteoclasts to mature osteoclasts.
iii. Osteoclastic osteolysis: PTH stimulates the osteoclasts through second messenger c-AMP to
increase the resorption of bones which enhances mobilisation of Ca and P from bones.
iv. Osteocytic osteolysis: PTH also stimulates osteocytes which increases bone resorption thus
mobilising Ca++ and Pi. There occurs enlargement of bone lacunae.
v. Action on alkaline phosphatase: Alkaline phosphatase activity varies as per PTH concentration.
At low concentrations, PTH stimulates the sulfation of cartilages and increases the number of
osteoblasts and alkaline phosphatase activity of bone osteoblasts. At higher levels of
physiological concentrations, PTH inhibits alkaline phosphatase activity and collagen synthesis
in osteoblasts and decreases the Ca++ retaining capacity of bones. PTH induced rise in
intracellular c-AMP in osteoclasts/and osteocytes leads to secretion of lysosomal hydrolases/and
collagenases which increase breakdown of collagen and MPS in bones matrices.
6. Action on Intestinal Mucosa:
i. PTH does not act directly on intestinal mucosal cells as the cells do not possess the specific
receptors for PTH. But it increases the absorption of Ca++ and PO4 through production, 1-25,
di-OH-cholecalciferol (calcitriol).
FUNCTIONS OF GLUCAGON.(S.N)

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1. It is a polypeptide hormone with 29 amino acids. It is secreted by the alpha cells of pancreas.
Glucagon is synthesized as a longer proglucagon precursor. Glucagon has a half-life in plasma at
about 5 minutes. It is inactivated in the liver. The major regulator of secretion of glucagon is
glucose. An increase in blood glucose level inhibits secretion of glucagon.
Physiological Actions of Glucagon
2. Glucagon is the most potent hyperglycemic hormone. It is anti-insulin in nature.
3. Glucagon is mainly glycogenolytic. The active form of glycogen phosphorylase is formed under the
influence of glucagon. Liver is the primary target for the glycogenolytic effect of glucagon.
4. It depresses glycogen synthesis.
5. Gluconeogenesis is favored by glucagon by inducing enzymes like PEPCK, glucose-6- phosphatase
and fructose-1,6-bisphosphatase.
6. Glucagon increases plasma free fatty acid level. In adipose tissue glucagon favors beta-oxidation,
as it activates carnitine acyl transferase. The mitochondrial acetyl CoA level increases
7. Ketogenesis is favored.
Mechanism of action
1. Glucagon combines with a membrane bound receptor. This activates the GDP-bound G-protein, by
converting it into GTP form.
2. The alpha subunit of the G protein dissociates from the beta and gamma subunits. The alpha
subunit binds to GTP. The GTP-G protein will in turn activate adenylate cyclase to convert ATP to
cAMP.
3. Cyclic AMP is the second messenger, which combines with the regulatory subunit of the protein
kinase so that the catalytic subunit is free to act.
4. The active protein kinase will phosphorylate enzyme proteins and alter their activity; covalent
modification and activation of glycogen phosphorylase, inactivation of glycogen synthase, etc.

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