Comprehensive Biochemistry for Dentistry Textbook for Dental Students

226 10 Hormones

Metabolic Functions
TSH promotes synthesis of thyroid hormones through the following activities
as:

• TSH stimulates iodide pump and promotes transport of iodide from circulation
to follicular cells.

• TSH activates oxidation of iodide into active iodine.
• TSH stimulates generation of NADPH through HMP pathway.
• TSH promotes cleavage of iodinated thyroglobulin to release thyroid hormones.

Overall, TSH stimulates all stages of thyroid hormone synthesis.

10.6.3  A drenocorticotropic Hormone

Secretion

• It is secreted by anterior pituitary gland.

Structure

• It is a polypeptide hormone. It is made up of 39 amino acid residues. At
N-terminal, initial 23 amino acid residues are biologically active.

• ACTH is secreted in the form of a precursor molecule called as proopiomelanocor-
tin peptide (POMC peptide). The precursor is made up of 260 amino acid residues.

• POMC peptide is proteolyzed into:
–– ACTH
–– β-Lipotropin
–– γ-Lipotropin
–– Endorphin

Normal Serum Value
In males, its value is 1–10 pmol/L.
In females, it is 1–6 pmol/L.

Metabolic Functions

• ACTH stimulates conversion of cholesterol into pregnenolone and synthesis of
corticosteroids.

• ACTH enhances release of insulin from pancreas.
• ACTH enhances release of melanin from melanocytes.
• It stimulates mobilization of fats in adipose tissues.

10.6  Hormones from Pituitary Gland 227

Gonadotropins
Gonadotropins regulate functioning of ovaries and testes. Gonadotropins are of two
types as:

• Follicle-stimulating hormone (FSH)
• Luteinizing hormone (LH)

10.6.4  F ollicle-Stimulating Hormone (FSH)
Structure
• It is a glycoprotein. Protein component is made up of α- and β-subunits.
• α-Subunit is made up of 92 amino acid residues. Beta-chain is made up of 118

amino acid residues.

Normal Serum Value
In adult males, it is 2–15 mIU/L.
In adult females:

• Follicular stage, 3–9 mIU/L
• Ovulation stage, 3–18 mIU/L
• Luteal stage, 1–5 mIU/L

Metabolic Functions
In females

• FSH promotes growth of ovarian follicles.
• It stimulates maturation of graafian follicles.
• FSH promotes synthesis of estrogens.

In males

• FSH stimulates growth of testes.
• It increases growth of seminiferous tubules.
• It increases secretion of testosterone.
• FSH promotes proliferation of spermatocytes during spermatogenesis.
• FSH along with testosterone favors the maturation of spermatozoa (transfor-

mation of primary spermatocytes into secondary spermatocytes).

FSH and LH are essential for spermatogenesis in males.

228 10 Hormones

10.6.5  L uteinizing Hormone (LH)

Structure

• It is also called as interstitial cell-stimulating hormone (ICSH). It is a glyco-
protein. Protein component is made up of α- and β-subunits.

• α-Subunit is made up of 92 amino acid residues. Beta-chain is made up of 112
amino acid residues.

Normal Serum Value
In Males

• In adolescence, its value is up to 5 mIU/mL.
• In adult males, its value is 2–12 mIU/L.

In Females

• In puberty, its value is 2–30 mIU/mL.
• In menstrual phase

–– Follicular phase, up to 18 mIU/dL
–– Luteal phase up to 20 mIU/mL

Metabolic Functions
In females

• LH promotes final maturation of graafian follicles and release of ovum
(ovulation).

• LH induces release of estrogens from theca interna cells and granulose cells in
ovaries.

• LH promotes development of corpus luteum and release of progesterone.

In males

• LH stimulates interstitial cells in testes to release testosterone.

10.6.6  Growth Hormone

Growth hormone is also called as somatotropin or human growth hormone. It is a
peptide hormone. It regulates growth of cells and cell proliferation in human body.

Secretion
Growth hormone is synthesized by acidophilic cells in anterior pituitary gland.
These are specialized cells called as somatotropes.

10.6  Hormones from Pituitary Gland 229

Structure

• Growth hormone is made up of a single polypeptide chain. It is made up of 191
amino acid residues.

• Structurally, growth hormone is homologous to prolactin.

Normal Serum Value
Adult males, its value is <3 ng/mL.
Adult females, it is <8 ng/mL.
Children, it is <5 ng/mL.

Regulation of Growth Hormone
Secretion of GH is controlled by hypothalamic, anterior pituitary gland, liver, and
growth hormone as described below.

Hypothalamus

• It secretes growth hormone-releasing hormone (GHRH) and growth hormone-
inhibiting hormone (GHIH) to control secretion of GH.

Anterior Pituitary
It is under the control of the hypothalamus, liver, and serum growth hormone level.
Liver

• Growth hormone acts on hepatocytes and induces synthesis of somatomedin
C. This peptide hormone acts as:
–– Somatomedin C inhibits hypothalamus to release GHRH.
–– It stimulates release of GHIH from hypothalamus.
–– It inhibits pituitary gland to release GH.

Serum GH Level
Serum growth hormone level has feedback regulation on secretion of GH from ante-
rior pituitary. Increase in serum GH level activates release of GHIH from hypothala-
mus, and the mechanism is called as negative feedback mechanism.

In decreased serum GH level, it stimulates secretion of GHRH, and blood level
of GH is normalized.

Metabolic Functions
Effect on Protein Metabolism

• Growth hormone exerts protein anabolic effect through the following activities as:
–– It activates transcription of mRNA.
–– It stimulates uptake of amino acids by cells.
–– It activates polyribosome formation and promotes protein synthesis.
–– GH promotes positive nitrogen balance.

230 10 Hormones

GH and insulin have a similar anabolic effect on protein metabolism.
Effect on Carbohydrate Metabolism

• Growth hormone increases blood glucose level (hyperglycemia) through the
following activities as:
–– GH decreases glucose uptake by peripheral tissues.
–– GH reduces utilization of glucose by peripheral tissues.
–– GH promotes gluconeogenesis.
–– Increased secretion of GH leads to rise in blood glucose level. As a result,
secretion of insulin is increased from pancreas to control blood glucose level.
Growth hormone also stimulates beta-cells to release insulin. Continuous
secretion of GH exhausts beta-cells in the pancreas, and it causes deficiency
of insulin in blood. This stage is characterized by hyperglycemia, and this
effect of GH is called as diabetogenic effect.

GH and Insulin have an antagonistic effect on carbohydrate metabolism.
Effect on Lipid Metabolism

• Growth hormone induces lipolysis in adipose tissues through the following
activities as:
–– GH activates tissue lipase for breakdown of triglycerides in adipose tissues.
–– GH promotes mobilization of fatty acids in circulation and increases plasma-
free fatty acid concentration.
–– GH increases oxidation of fatty acids and promotes formation of ketone bodies.

Effect on Mineral Metabolism

• Growth hormone favors deposition of calcium and phosphate in the bone. It pro-
motes bone mineralization in growing children.

10.7 H ormone from Posterior Pituitary Gland

10.7.1 A ntidiuretic Hormone (ADH)

It is a peptide hormone. It is also called as vasopressin or arginine vasopressin.

Secretory of ADH

• ADH hormone is synthesized by neurosecretory neurons in supraoptic nucleus of the
hypothalamus. Trace amount of ADH is synthesized by paraventricular nucleus of
the hypothalamus. These nuclei are located in anterior portion of the hypothalamus.

• The hypothalamus transports ADH in association with neurophysin II (carrier
protein) to posterior pituitary gland.

• ADH is stored along with neurophysin II in Herring bodies (terminal part of
axons from the hypothalamus) located in posterior pituitary.

• ADH is released into blood circulation through exocytosis.

10.7  Hormone from Posterior Pituitary Gland 231

Chemical Structure (Arginine Vasopressin)

• ADH is made up of nine amino acid residues.
• Its amino acid sequence is as follows:

–– Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2
• There is intrachain disulfide bridge (-S-S-) between the first and sixth cysteine

residues.
• At C-terminal of ADH:

–– Glycine amino acid is converted into primary amide, called as glycinamide.

–– It determines biological activity of ADH hormone as in Fig. 10.6.

Fig. 10.6  Antidiuretic hormone CYS

1

TYR 2

ILE 3

GLN 4

ASN 5

CYS 6

PRO 7

ARG 8

GLY 9

232 10 Hormones

Normal Serum Value
It is 1–4 pg/mL.

Regulation of ADH Secretion
Angiotensin II

• It is a potent vasoconstrictor. It stimulates secretion of ADH.

Atrial Natriuretic Peptide

• It is a peptide hormone secreted by cardiac muscle fibers in the wall of auricles.
It inhibits secretion of ADH.

Cortisol

• It is a corticosteroid. It inhibits ADH secretion.

Extracellular Fluid Volume

• ↑ In ECV inhibits secretion of ADH.
• ↓ In ECV and blood volume (hypovolemia) stimulates secretion of ADH.

Replacement of arginine with lysine at eighth position will change nomenclature
of ADH as lysine vasopressin.

It is found in pigs, marsupials, and hippos.

Natriuresis
It is increase in excretion of sodium ions in urine. It leads to decrease in ECV.

Diuresis
It is increase in excretion of urine.

Natriuresis and diuresis result into excretion of large amount of urine except
that in natriuresis, urine has high amount of sodium ions.

Metabolic Functions
Antidiuretic Effect (Primary Function)

• ADH brings about reabsorption of water by distal convoluted tubules and col-
lecting ducts.

• It acts on V2 receptors located on cells of collecting ducts. It stimulates genera-
tion of cAMP (second messenger). Thereby, ADH increases water permeability
of cell membranes of cells of collecting ducts. Therefore, it brings about reab-
sorption of water from glomerular filtrate (antidiuresis).

10.7  Hormone from Posterior Pituitary Gland 233

• Urine becomes hypertonic with rise in concentration of sodium and chloride
ions. Volume of urine is decreased.

• ADH helps to regulate ECF volume.

Vasoconstrictor Effect (Subsidiary Function)

• ADH acts on V1 receptors located on smooth muscle fibers of blood vessels. It
acts through inositol triphosphate (IP3) pathway of signal transduction. It
increases calcium ions concentration in vascular smooth muscles.

• ADH causes vasoconstriction of blood vessels.

Urea-Retaining Effect

• ADH acts on collecting ducts in inner medulla of kidneys. It raises urea perme-
ability of cell membranes of collecting duct cells.

• ADH is responsible for retention of urea from filtrate. Urine becomes
hypertonic.

Applied Biochemistry
Diabetes Insipidus

• It is an endocrine disorder characterized by excretion of large quantity of urine
per day. It may go up to 20 L a day. Urine becomes hypotonic.

• Condition is attributed to diminished secretion of ADH (primary) or insensitivity
of renal tubules to ADH (secondary).

10.7.2  Oxytocin

It is a peptide hormone.

Secretion of Oxytocin

• Oxytocin is mainly synthesized by neurosecretory neurons in paraventricular
nucleus of the hypothalamus. Trace amount of oxytocin is synthesized in
s­ upraoptic nucleus of the hypothalamus. These nuclei are located in anterior por-
tion of the hypothalamus.

• Oxytocin is released from the hypothalamus in association with neurophysin I
(carrier protein). Oxytocin and neurophysin I are transported via the hypothal-
amo-neurohypophyseal tract.

• Oxytocin and neurophysin I are stored in Herring bodies in posterior pituitary.
• Oxytocin is released into blood circulation.

234 10 Hormones

Chemical Structure (Oxytocin)

• Oxytocin is made up of nine amino acids residues.
• Its amino acid sequence is as follows:

–– Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2
• There is intrachain disulfide bridge (-S-S-) between the first and sixth cysteine

residues.
• At C-terminal of ADH:

–– Glycine amino acid is converted into primary amide, called as glycinamide.
–– It determines biological activity of ADH hormone as in Fig. 10.7.

Fig. 10.7  Oxytocin hormone CYS

1

TYR 2

ILE 3

GLN ASN CYS PRO LEU GLY 4

5

6

7

8

9

10.8  Parathormone (Parathyroid Hormone) 235

Normal Serum Value
It is between 3 and 5.5 pg/mL.

Metabolic Functions of Oxytocin
Milk Ejection Reflex

• It is a neuroendocrinal reflex that brings about release of milk from the mam-

mary glands into the nipples.
• Oxytocin hormone induces milk ejection reflex through the following

steps as:

–– Suckling of the nipple by the baby stimulates tactile receptors located in areo-

lar area of the breast.

–– Sensory impulses travel to the hypothalamus through the spinothalamic

tract.
–– Oxytocin is released from Herring bodies. It causes contraction of myoepi-

thelial cells located around mammary alveoli. The intra-alveolar pressure

rises. Milk is forced into milk ducts and is released in the nipples.

Effect on Uterus
In Pregnancy

• During pregnancy, activity of oxytocin is inhibited by estrogen and
progesterone.

• Toward the end of pregnancy, oxytocin is secreted in large amount. It acts on
the smooth muscle fibers. It causes contraction of the uterus.

• At the onset of labor, the cervix is dilated, and fetus moves down through the
cervix. The receptors in the cervix send impulses to the hypothalamus to release
oxytocin. It causes powerful and prolonged uterine contraction. Therefore, oxy-
tocin helps in child birth.

In Nonpregnancy Condition

• During coitus, vaginal tactile receptors send sensory impulses to hypothalamus
to secrete oxytocin.

• Oxytocin promotes contraction of the uterus. It brings about transport of sperms
to the fallopian tube.

10.8 P arathormone (Parathyroid Hormone)

Parathormone is a peptide hormone. It is essential for calcium homeostasis. It
is a hypercalcemic hormone.

236 10 Hormones

Secretion of Parathormone

• Parathormone is secreted by parathyroid glands. There are two pairs of parathy-
roid glands in the neck region. Each pair is located behind right and left lobes of
thyroid gland.

• Histologically, the parathyroid gland is made up of chief cells and oxyphil cells.
Parathormone is secreted by chief cells.

Chemical Structure

• Parathormone is a linear polypeptide which is composed of 84 amino acids.
• Alanine occupies N-terminal, and glutamine is present at C-terminal in poly-

peptide chain. From N-terminal, sequence of 1st to 34th amino acid is meta-
bolically active and is essential for action of parathormone on the kidneys and
bones.
• Biosynthesis of parathormone:
–– Pre-proparathormone (115 AA)

It is a large peptide molecule and called as precursor hormone. It is synthe-
sized within polyribosomes which are attached to rough endoplasmic reticu-
lum (RER) of chief cells.
Pre-proparathormone is made of 115 amino acid residues. It is translocated
into lumen of rough endoplasmic reticulum (RER). It undergoes successively
two proteolytic cleavages.
–– Proparathormone (90 AA)
Within lumen of RER, an enzyme named as signal peptidase splits a short
peptide of 25 amino acids from N-terminal of pre-proparathormone. Pre-
proparathormone is converted into proparathormone. It is made up of 90
amino acids. It is translocated into cisternae of Golgi bodies.
–– Parathormone (84 AA)
Within cisternae of Golgi bodies, an enzyme named as lipase B (trypsin
resembling enzyme) removes a peptide of six amino acids from N-terminal.
Proparathormone is converted into parathormone.
Parathormone (PTH) is stored in the secretory vesicle of Golgi bodies.

Regulation of Parathormone
Plasma calcium concentration is the key regulatory factor in secretion of
parathormone.

• ↓ Plasma calcium ion concentration stimulates release of PTH.
• ↑ Plasma calcium ion concentration inhibits release of PTH.

10.8  Parathormone (Parathyroid Hormone) 237

Signal Peptidase
It is an enzyme in endoplasmic reticulum that splits a signal peptide from the
N-terminal of a newly formed protein in ER.

Signal Peptide
It is also called as leader peptide or transit peptide.

It is a short peptide of 15–30 amino acid residues. It is located at N-terminal
of newly synthesized protein.

Signal peptide helps to translocate protein from one organelle (site of syn-
thesis) to another organelle for storage. Example: secretory proteins (hor-
mones, enzymes) and membrane proteins are translocated by co-translational
translocation.

Normal Serum Value
Its value is between 10 and 60 pg/mL.

Metabolic Functions
Parathormone ↑ plasma calcium ion concentration through its direct actions on
kidneys and bones and indirect action on intestinal mucosa.

Effect on Kidneys
PTH binds on receptors located on cell membranes of proximal convoluted tubules
and distal convoluted tubules. PTH is the first messenger and induces rise in concen-
tration of cAMP (2nd messenger). It regulates cellular actions. It has the following
effects on kidneys.

Calcium Ions

• PTH increases reabsorption of Ca++ ions from glomerular filtrate in DCT of renal

tubules. It decreases excretion of calcium ions.
• PTH results in hypercalcemia.

Phosphate Ions

• PTH decreases reabsorption of inorganic phosphates from glomerular filtrate in
PCT and DCT portions of renal tubules. It increases excretion of inorganic
phosphates.

• PTH results in hypophosphatemia.
• Hypophosphatemia in turn induces mobilization of inorganic phosphates from

the bones into plasma along with calcium ions.

Alpha-1-Hydroxylase Enzyme

• Enzyme is present in mitochondria of cells of PCT. Enzyme brings about hydrox-
ylation of 25-hydroxycholecalciferol into calcitriol. It stimulates absorption of
calcium ions in intestinal mucosa.

238 10 Hormones

Effect on Bones
PTH binds with specific receptors on membranes of osteoblasts, osteocytes, and
osteoclasts. It induces its action via ↑ cAMP.  PTH has the following actions on
bones as:

• PTH increases calcium permeability of the membranes of osteoblasts and osteo-
clasts. It results into calcium mobilization from bones into blood circulation
(hypercalcemia).

• PTH activates osteoclasts in bones. These cells release proteolytic enzymes from
lysosomes which bring about dissolution of bone organic matrix. Calcium ions
diffuse into blood circulation (hypercalcemia).

Action on Intestinal Mucosa

• PTH has no direct action on intestinal mucosa owing to absence of receptors. It
stimulates hydroxylation of 25-hydroxycholecalciferol into calcitriol in kidneys.
Therefore, PTH acts through calcitriol on intestinal mucosa to enhance absorp-
tion of calcium ions (hypercalcemia).

10.9 I nsulin

It is a peptide hormone and is a heterodimer. It is a key regulatory hormone for
blood glucose homeostasis and carbohydrate metabolism.

Secretion of Insulin

• Insulin is secreted by β-cells of islets of Langerhans in the pancreas.

Chemical Structure

• Insulin is made up of 51 amino acids. They are assembled into two polypeptide
chains.

• Chain A is made up of 21 amino acids, and chain B is composed of 30 amino
acids. Both chains are linked together by two disulfide bridges as:
–– First interchain disulfide bridge is present between seventh cysteine residue of
chain A and seventh cysteine residue of chain B.
–– Second interchain disulfide bridge is present between 20th cysteine residue of
chain A and 19th cysteine residue of chain B.

• One intrachain disulfide bridge is present in chain A.  It links the 6th cysteine
residue to 11th cysteine residue in chain A as in Fig. 3.5.

10.9  Insulin 239

Insulin can never be administered orally. Low pH of stomach denatures
insulin by disruption of disulfide bridges. It is administered subcutaneously.

Biosynthesis of Insulin
Insulin is synthesized in the form of a large precursor molecule (single chain) in
beta-cells of islets of Langerhans. It undergoes proteolytic cleavages to form insulin.
It is described in the following steps.

Formation of Preproinsulin (109 AA)

• Synthesis of preproinsulin occurs in polyribosomes in beta-cells. Polyribosomes
are attached to the membrane of rough endoplasmic reticulum. It is made up of
109 amino acids.

• Preproinsulin contains a short peptide of 23 amino acid residues located at
N-terminal. It is called signal peptide.

• Signal peptide directs the translocation of preproinsulin from polyribosomes into

the lumen of rough endoplasmic reticulum.

Cleavage of Preproinsulin into Proinsulin (86 AA)

• Signal peptide in preproinsulin is cleavaged by signal peptidase enzyme (located
in membrane of RER).

• This cleavage results in conversion of preproinsulin into proinsulin. It is made up
of 86 amino acid residues.

• Proinsulin is translocated to cisternae of Golgi complex.

Conversion of Proinsulin into Insulin (51 AA)

• Proinsulin is composed of 86 amino acid residues which are arranged in three
domains in a single peptide chain as follows:

–– N-terminal domain of proinsulin (chain B).

–– C-terminal domain of proinsulin (chain A).

–– Connecting peptide: It is a short peptide (30–35 amino acid residues) that
connects two domains. It is called C-peptide. It contains dibasic amino acid
residues on both ends (31stArg-Arg32nd and 62ndLys-Arg63rd).

• Proinsulin is converted into insulin through hydrolytic action of two types of

protease enzymes as:
–– Action of endopeptidase on proinsulin It occurs inside golgi complex.

trypsin-like enzyme (endopeptidase) hydrolyses proinsulin at two points after

each dibasic amino acid pair. This results into release of connecting C-peptide

from proinsulin.
–– Action of exopeptidase on proinsulin

Carboxypeptidase B-like enzyme (exopeptidase) brings about cleavage of
amino acids from C-terminal in chain A and B as follows:
–– Two amino acids (62ndLys-Arg63rd) are cleavaged from C-terminal of chain A.
–– Two amino acids (31stArg-Arg32nd) are cleavaged from C-terminal of chain B.

240 10 Hormones

• Insulin and C-peptide are packed in equimolar concentration in vacuoles of
Golgi complex.

• Insulin undergoes dimerization by formation of hydrogen bond. It is formed
between hydrogen atom of amide group in phenylalanine of B25 and oxygen
atom of carbonyl group in tyrosine of A19.

• As concentration of insulin increases in vacuoles, three dimmers of insulin form
coordinative bond with two Zn++ ions. It results in crystallization of insulin and
is called as zinc insulin hexamer. Vacuoles are converted into secretory vesi-
cles containing zinc insulin crystals and C-peptide.

• Insulin is released by exocytosis.

Normal Serum Value
Its value is 30–180 pmol/L.

Metabolic Functions of Insulin

• Effect on Carbohydrate Metabolism
• Insulin decreases blood glucose level. It exerts hypoglycemic effect through

the following activities.
• ↑ Glucose Uptake by Peripheral Tissues

–– Glucose is actively transported across the peripheral tissues (adipose tissues,
mammary glands, kidneys, skeletal muscles). Insulin brings about prolifera-
tion of glucose transporters in cell membrane of peripheral tissues (extrahe-
patic tissues).

–– Glucose is permeable to hepatocytes. However, insulin can further enhance
glucose transport across hepatocytes.

↑ Glucose Utilization (Glycolysis)
–– Insulin stimulates formation of phosphofructokinase enzyme in peripheral tis-

sues. It is a rate-limiting enzyme in glycolysis. Therefore, insulin stimulates
utilization of glucose by peripheral tissues and enhances production of energy.
↑ Glycogenesis
–– Insulin activates glycogen synthase enzyme in hepatocytes and muscles. This
enzyme regulates glycogenesis. Therefore, insulin promotes glycogenesis in
the liver and skeletal muscles.
↓ Gluconeogenesis
Insulin decreases gluconeogenesis through the following activities as:
–– Insulin suppresses translation of PEP carboxykinase enzyme.
–– Insulin mediates through allosteric inhibition of fructose-1,6, bisphosphate
enzyme.
↓ Glycogenolysis
–– Insulin decreases glycogenolysis through the following activities as:
–– Insulin deactivates glycogen phosphorylase enzyme in the liver and muscles.
It is a rate-limiting enzyme in glycogenolysis.
• Effect on Lipid Metabolism

10.10  Glucagon 241

Insulin promotes synthesis of triglycerides in adipose tissues. It exerts lipo-
genesis effect through the following activities as:
↓ Lipolysis in Adipose Tissues
Insulin lowers lipolysis in adipose tissues through the following activities as:
–– Insulin deactivates tissue lipase.
–– Insulin stimulates phosphodiesterase enzyme. It decomposes cAMP in cyto-

sol and decrease activation of tissue lipase.
↑ Triglyceride Synthesis in Adipose Tissues
Insulin stimulates synthesis of triglycerides in adipose tissues through the
following activities as:
–– Insulin stimulates glucose uptake by adipose tissues. Surplus glucose is

diverted into synthesis of triglycerides in tissues.
–– Insulin induces synthesis of fatty acids in the liver which enter circulation as

free fatty acids. They are utilized by adipose tissues for triglyceride
formation.
↑ De Novo Synthesis of Fatty Acids in the Liver
Insulin promotes de novo synthesis of fatty acids in the liver. It mediates its
action through the following activities as:
–– Insulin activates pyruvate dehydrogenase complex and enhances oxidative
decarboxylation of pyruvate into acetyl CoA. It is necessary for de novo syn-
thesis of fatty acids in the liver.
–– Insulin promotes availability of NADPH through HMP shunt. It is necessary
for synthesis of fatty acids.
• Effect on Protein Metabolism
Insulin increases synthesis of proteins. Its protein anabolic effect is medi-
ated through the following activities as:
–– Insulin promotes transcription of mRNAs.
–– It increases polyribosomes formation by increasing availability of rRNA in
cytosol.
–– Insulin activates uptake of amino acids by body tissues. Conclusively, insulin
promotes translation of proteins on polyribosomes.

10.10 Glucagon

Glucagon is a peptide hormone. It is antagonistic to action of insulin. Glucagon
causes hyperglycemia.

Secretion of Glucagon
Glucagon is secreted by α-cells of islets of Langerhans in the pancreas.

Chemistry
Glucagon is a linear polypeptide hormone. It is composed of 29 amino acids. Its
molecular weight is 3485 daltons. Histidine is located at N-terminal and threonine
and is present at C-terminal in glucagon molecule as in Fig. 10.8. Glucagon does not
need zinc ion in crystallization.

242 10 Hormones

N– 1 2 3 4 5 6 7 8 9 10
Terminal HIS SER GLN GLY THR PHE THR SER ASP TYR

GLN ALA ARG ARG SER ASP LEU TYR LYS SER
20 19 18 17 16 15 14 13 12 11

ASP PHE VAL GLN TRP LEU MET ASN THR C–
21 22 23 24 25 26 27 28 29 Terminal

Fig. 10.8  Glucagon hormone

NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-­
Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-COOH

Biosynthesis of Glucagon
Proglucagon is synthesized in polyribosomes of alpha-cells. It is cleavaged by pro-
protein convertase-2 (endopeptidase) and carboxypeptidase (exopeptidase) and is
transformed into its active form, called as glucagon as in Fig. 10.8.

Normal Serum Value
Its value is 15–100 pg/mL in fasting condition.

Metabolic Functions
Glucagon is antagonistic to insulin in effects on protein, carbohydrate, and
lipid metabolism.

• Effect on Carbohydrate Metabolism
Glucagon increases blood glucose level (hyperglycemia). Its action is mediated
through the following activities.
–– ↑ Glycogenolysis
In the liver, glucagon activates phosphorylase b into phosphorylase a which
is responsible for glycogenolysis. It stimulates breakdown of glycogen.
Glucagon increases formation of glucose-6-phosphatase enzyme in liver.
Therefore, glucagon enhances liberation of free glucose molecules in liver.
In the skeletal muscles, glucagon has no effect on the glycogen in skeletal
muscles. It is due to the absence of glucagon receptors in muscle fibers.
–– ↑ Gluconeogenesis
In the liver, glucagon stimulates synthesis of PEP carboxykinase enzyme and
pyruvate carboxylase enzyme. Glucagon increases concentration of gluco-
genic amino acids in liver cells.
Overall, glucagon promotes gluconeogenesis from glucogenic amino acids
and lactic acid.

• Effect on Lipid Metabolism

10.11  Thyroid Hormones 243

Glucagon exerts lipolytic effect on lipid metabolism through the following

activities.
–– ↑ Lipolysis of Tissue Triglycerides

Glucagon activates tissue lipase. It stimulates lipolysis of triglycerides in adi-

pose tissues. Its action is synergistic to thyroxine and antagonistic to insulin.

It increases production of fatty acids and glycerol.
–– ↑ Plasma FFA Concentration

Glucagon mobilizes fatty acids from tissues to blood circulation.
–– ↑ Ketogenesis

Glucagon promotes synthesis of ketone bodies in the liver from surplus fatty

acids.
• Effect on Protein Metabolism

Glucagon has a protein catabolic effect through the following activities.
–– ↑ Catabolism of Protein

Glucagon promotes breakdown of proteins in the liver. It increases concentra-

tion of amino acids in the liver. These are diverted into gluconeogenesis.
–– ↓ Protein Synthesis

Glucagon decreases synthesis of proteins.
• Effect on BMR

Glucagon enhances production of calories in association of thyroxine and corti-

costeroid hormones. It is called as calorigenic effect. It increases basal metabolic

rate by enhancing consumption of oxygen.

10.11 T hyroid Hormones

Thyroid hormones are catecholamines. They are derived from tyrosine amino acid.
Important catecholamine hormones derived from thyroid gland are as follows:

• Thyroxine (3′,5′,3,5-Tetra-iodothyronine), represented as T4
• 3′,3,5-Tri-iodothyronine, represented as T3
• 3′,5′,3-Tri-iodothyronine, represented as reverse T3

T4 T3
It constitutes 90% of total thyroid secretion It constitutes 9% of total thyroid secretion
It has moderate affinity to TBG
It has high affinity to TBG and TBPA Its biological activity is 4 times higher than T4
Its biological activity is 1/4 to that of T3
hormone It has rapid onset of action and short
duration of action
It has slow onset of action and longer
duration of action

In blood circulation, 0.05% of total T4 is in unbound form. Remaining
amount of hormone is in bound form with carrier molecule.

In extrathyroidal tissues (liver, peripheral tissues, kidneys, and muscles), more

than 80% of circulation T4 is deionized by deiodinase enzyme into T3 hormone.
Thus T4 hormone acts as prohormone.
Under normal iodine intake,
Ratio of T4: T3 is 9:1.

244 10 Hormones

Secretion of Thyroid Hormones

• Thyroid hormones are secreted by follicular cells of thyroid follicles.
• Thyroid follicle is a spherical in shape. It is lined by cuboidal epithelial cells

called as follicular cells. They are endocrinal in nature.
• Thyroid follicles contain a central cavity (thyroid lumen). It is filled with a vis-

cous fluid called as colloid. It is enriched with thyroglobulin.

Chemistry

• T4 and T3 hormones are derived from iodinated tyrosine. Two tyrosine residues
are linked through oxygen atom (ether bonding) and form thyronine (C15H15NO4).

• Thyronine contains iodine atoms at C3 and C5 positions on inner aromatic ring.
• It contains iodine atoms at C′3 and C′5 positions on outer aromatic ring.
• The number of iodine atoms determines the nature of thyroid hormone as:

–– Iodination at all four positions (C′3, C′5, C3, C5) forms T4.
–– Iodination at three positions (3′,3,5) forms T3.One iodine atom is missing in

the outer aromatic ring.
–– Iodination at three positions (3′,5′,3) forms Reverse T3. One iodine atom is

missing in inner aromatic ring as in Fig. 10.9.

10.11.1  Biosynthesis

T4 and T3 hormones are synthesized by iodination of tyrosine residues in thyro-
globulin molecule. Biosynthesis of T4 and T3 hormones can be summarized in
the following two steps.

1 . Synthesis of Thyroglobulin
2. Iodination of Tyrosine Residues

• Active uptake of Iodide
• Oxidation of Iodide
• Tyrosine Iodination
• Oxidative Coupling of Iodotyrosines

S ynthesis of Thyroglobulin
• Thyroglobulin acts as prohormone.
• Chemically, thyroglobulin is a glycosylated protein (glycoprotein). It is a mac-

romolecule with molecular weight of 660,000 daltons.
• Thyroglobulin is composed of two units as:

–– A dimeric protein which is made up of two identical subunits. Each subunit
has a molecular weight of 330,000 daltons. Thyroglobulin molecule contains
about 140 tyrosine residues.

10.11  Thyroid Hormones 245
3′ I
3I

O

HO O CH2 CH C OH
5I I5
HN

H
3,5,3′,5′ – Tetraiodothyronine

[Thyroxine (T4)]

3′ I 3I HO
HO O
C CH C OH
I
5 H NH

H
3,5,3′ – Triiodothyronine

[T3]

3′ I 3I HO
HO O
C CH C OH
I
5′ H NH

H
3,3′,5′ – Triiodothyronine

[Reverse T3]

Fig. 10.9  Structure of thyroid hormones

–– A carbohydrate moiety which is made up of N-acetyl glucosamine, glucose,
galactose, and sialic acid. Carbohydrates constitute about 8% of the total
weight of thyroglobulin.

• Iodide weighs about 1% of total weight of thyroglobulin. About 70% of total
iodide in thyroglobulin is present in the form of iodinated tyrosyl residues as
monoiodotyrosine (MIT) and diiodotyrosine (DIT). Another 30% of total iodide
is present in the form of iodinated thyronyl residues as triiodothyronine and
tetraiodothyronine as in Figs. 10.10 and 10.11.

246 10 Hormones

Fig. 10.10  Oxidation of NADPH2 O2
iodide

NADP+ H2O2 IODIDE
I′

H2O ACTIVE
IODINE

I+

FOOD Food intake Endothelium Thyroid Colloid
(Contains Iodine) follicular cell Nucleus
Basolateral
I2 membrane

I2 Iodine Follicular Apical
Capillary cell membrane
Oesophagus
cytoplasm Pendrin Tyrobine
Thyro peroxidase residues
Stomach Na+ Na+
Iodide pump
I2 Iodide trapping

HCL I– I–

I– Iodide I– Cytosolic
movement
Thyroglobulin
Duodenum I– I– I– Active
Blood circulation I– iodine
Thyroid Oxidation
Blood Vacuole hormone Iodination
circulation

Iodide absorption

Endo- Thyroglobulin
cytosis

Decomposition of
thyroglobulin

Iodinated
tyrosine

Fig. 10.11  Biosynthesis of thyroid hormone

Steps in Synthesis of Thyroglobulin

• It is synthesized on polyribosomes present in cytoplasm of thyroid follicular cells.
Polyribosomes are attached to the membrane of rough endoplasmic reticulum. After
synthesis of protein component, it is translocated into cisternae of Golgi complex.

10.11  Thyroid Hormones 247

• Within Golgi complex, glycosylation of protein component is completed.
Glycoprotein is packed in secretory vesicles, and they are budded off from cister-
nae of Golgi complex.

• Secretory vesicles translocate toward the cell membrane of follicular cells and
release glycoprotein into colloid by exocytosis.

Synthesis of T4 and T3 hormones is largely dependent on exogenous
supply of iodine which in turn is determined by hormone synthesis and
level of TSH.

I odination of Tyrosine Residues
Iodine is the most essential trace element in the human body. Normal iodine require-
ment for a healthy adult is 150 μg/day. Its requirement increases during early child-
hood period, puberty, and pregnancy. The human body contains about 20  mg of
iodine, and 80% of total iodine is concentrated in thyroid gland.

Dietary sources like vegetables and seaweeds are rich in iodine. Dietary iodine is
reduced into iodide in alimentary canal. Iodides are absorbed from intestinal mucosa
and are transported into blood circulation. In plasma, it exists as inorganic iodide
and is distributed in association with albumin.

Active Uptake of Iodide

• Thyroid follicles are supplied with blood capillaries. Normal plasma iodide con-

centration varies between 40 and 90 μg/L; however, thyroid iodide concentration
(T) is much higher than serum iodide concentration (S). It may vary between T/S

(10:1) and (100:10).
• Iodide is actively transported from plasma to the follicular cells. This influx of

iodide occurs against concentration gradient. It is called as iodide trapping.
• Active uptake of iodide is mediated by sodium-iodide symporter (NIS):

–– Sodium-iodide symporter is located in the basolateral membrane of follicu-

lar cell.

–– It is a transmembrane protein with molecular weight of 87,000 daltons. It is

involved in active cotransport of two Na+ ions with every iodide ion.

–– Sodium-iodide symporter is energy dependent. It relies on Na+-K+-ATPase

enzyme for its energy demand. ATP provides energy for NIS.
• Inhibitors of sodium-iodide symporter:

–– Thiocyanates and perchlorates are competitive inhibitors of NIS.

–– Cyanide inhibits NIS.

–– Cardiac glycosides (ouabain) inhibit NIS.
• Accelerator of sodium-iodide symporter (NIS):

–– Thyroid-stimulating hormone activates sodium-iodide pump.
• Iodide enters the follicular cells.

248 10 Hormones

Oxidation of Iodide

• Intracellular iodide moves toward the apical membrane of follicular cell.
• This transport of iodide across the cell is mediated by sodium-independent

chloride-iodide exchanger. It is called as pendrin. It brings about efflux of
iodide ions through the apical membrane of follicular cell as in Fig. 10.10.
• Activity of thyroperoxidase enzyme:
–– Thyroperoxidase is a metalloprotein. It located at the apical membrane of fol-

licular cell. It contains heme as a prosthetic group.
–– It is synthesized in RER of follicular cells.
–– Thyroperoxidase requires H2O2 for its activity. H2O2 is toxic in body tissues.

However, it is essential for oxidation of iodide and iodination of tyrosine
in follicular cells. Intracellular hydrogen peroxide is synthesized by a dual
oxidase enzyme (DUOX1 and DUOX2) which is located in the apical mem-
brane. Thyroperoxidase acts on hydrogen peroxide and reduces it into water
and oxygen.
–– At apical membrane-colloid interface, iodide and thyroglobulin are attached
at separate domains of thyroperoxidase enzyme. Released oxygen brings
about oxidation of iodide into active iodine as in Fig. 10.10.

Tyrosine Iodination
Tyrosine iodination occurs in colloid within thyroid lumen.

• At iodide-binding site of thyroperoxidase, active iodine is transported to tyro-
sine residue of thyroglobulin under the influence of thyroperoxidase enzyme.

• Iodination of tyrosine takes place at the third position of aromatic ring. It results
in the formation of monoiodotyrosine (MIT). Next iodination occurs at fifth
position of aromatic ring of tyrosine residue and forms diiodotyrosine (DIT).

• Under normal condition, MIT and DIT exist in equal concentration. However, in
deficiency of iodine intake, concentration of MIT exceeds concentration of DIT
in thyroid gland. The process of iodination of thyroglobulin is called as orga-
nization of thyroglobulin as in Fig. 10.10.

Oxidative Coupling of Iodotyrosines

• Two diiodotyrosine (DIT) molecules undergo oxidative coupling to form thy-
roxine. Reaction is catalyzed by thyroperoxidase enzyme. A molecule of alanine
amino acid is released in the coupling reaction. Alanine further undergoes deam-
ination to form ammonia and pyruvate.

• One molecule MIT undergoes coupling with one molecule of DIT to form
triiodothyronine with a release of alanine amino acid.

• One molecule of DIT undergoes coupling with one molecule of MIT to form
reverse triiodothyronine with release of alanine amino acid as in Fig. 10.10.

10.11  Thyroid Hormones 249

Internalization and Proteolysis of Thyroglobulin

• Pits are located on the apical membrane of follicular cells. Colloid containing
iodinated thyroglobulin enters into pits. These pits in turn invaginate to form
intracellular vesicles, and the process is called internalization or endocytosis.

• Endocytosis can be either receptor-mediated endocytosis or non-specific endo-
cytosis. Megalin is a surface protein located on apical membrane. It helps in
internalization of colloid as in Fig. 10.10.

• Vesicles are coated with megalin proteins. Vesicles contain iodinated thyroglobu-
lin (iodinated thyroglobulin; MIT, DIT, and T3 and T4 hormones).

• These vesicles shed their protein coat and are transformed into endosomes.
• Endosomes fuse with lysosomes. They contain hydrolytic enzymes which digest

thyroglobulin and liberate T4 and T3 hormones. These hormones pass through the
basal membrane of follicular cell and enter blood circulation.
• MIT and DIT are deiodinated in follicular cells. Iodine is reused in cells.

Transport

• Within blood circulation, T4 and T3 hormones bind with carrier proteins called
as thyroxine-binding proteins, which follow the two types as:
–– Thyroxine-binding prealbumin (TBPA)
–– Thyroxine-binding globulin (TBG)

• Hormones are transported in bound form to tissues.

Storage
• Thyroid hormones are stored in colloid in association with thyroglobulin.

Normal Serum Value
Free T4 is 10–25 pmol/L.
Total T4 is 60–160 mmol/L.
T3 is 1.5–3.5 mmol/L.

Metabolic Functions of Thyroid Hormones
Effect on Protein Metabolism

Thyroid hormones are protein anabolic hormones. They promote synthesis of
proteins in cells through the following activities as:

• These hormones stimulate mRNA synthesis.
• These hormones activate polyribosome formation and enhance synthesis of

proteins.

250 10 Hormones

In pathological condition, thyroid hormones are protein catabolic hormones:

• In hyperthyroidism, ↑catabolic activity results into muscle breakdown, wast-
ing, and muscle weakness. There is excessive formation of creatinine, and it
causes ↑ excretion of creatinine in urine (creatinuria).

• These manifestations are called as hyperthyroid myopathy.

Effect on Lipid Metabolism

• In adipose tissues:
–– Thyroxine activates tissue lipase enzyme. This hormone stimulates lipolysis
of tissue triglycerides. It increases plasma-free fatty acid concentration.
Thyroid lipolytic action is antagonistic to insulin.

• In the liver:
–– Thyroxine enhances biosynthesis cholesterol and phospholipids in the liver.
–– It promotes deposition of fats in the liver (fatty liver).

• In blood circulation:
Thyroxine decreases concentration of cholesterol in plasma. Its action is medi-
ated through the following activities as:
–– ↑ Synthesis of cholic acid and deoxycholic acid from cholesterol in the liver
–– ↑ Excretion of cholesterol through bile

Effect on Carbohydrate Metabolism
Thyroid hormones stimulate all activities associated with carbohydrate metabo-
lism as follows:

• In the small intestine, these hormones increase intestinal absorption of
glucose.

• They increase blood glucose level (hyperglycemia).
• In peripheral tissues, these hormones decrease insulin tolerance. Therefore,

they promote uptake and utilization of glucose by peripheral tissues. These hor-
mones stimulate glycolysis and TCA cycle and generate energy.
• In the liver:
–– Thyroid hormones increase glycogenolysis through activation of glucose-

6-phosphatase enzyme.
–– Thyroid hormones increase gluconeogenesis by activation of pyruvate car-

boxylase and PEP carboxykinase enzymes.
–– Thyroxine proliferates β-adrenergic receptors located on hepatocytes.

Therefore, it enhances glycogenolysis effect of adrenaline.

Effect on Basal Metabolic Rate

• Thyroid hormones have calorigenic effect. They stimulate consumption of oxy-
gen by tissues (except the brain, spleen, testes, and uterus) and increase the pro-
duction of energy. In thyroid hypersecretion, BMR can be increased to 50% of
the normal value.

10.12 Calcitonin 251

Effect on Vitamins
• Thyroxine is helpful in conversion of carotene into retinol.

10.12 C alcitonin

It is a peptide hormone. It is essential in calcium metabolism. It is a hypocalce-
mic hormone.

Secretion of Calcitonin

• Calcitonin is secreted by C cells found in thyroid gland. The C cells are also
called as parafollicular cells. These are specialized endocrinal cells.

Chemical Structure

• Calcitonin is a linear polypeptide. It is made up of 32 amino acids.
• At N-terminal, cysteine amino acid is present, while proline amino acid occu-

pies C-terminal of calcitonin. Proline is converted into primary amide and is
called as prolinamide.
• Interchain disulfide bridge links first cysteine residue with seventh cysteine resi-
due in the molecule as in Fig. 10.12.

Cysteine

I SS

2 3 4 5 6 7 8 9 10

N– CYS GLY ASN LEU SER THR CYS MET LEU GLY
Terminal

20 HIS PHE LYS ASN PHE ASP GLN THR TYR THR 11

21 THR PHE PRO GLN THR ALA ILE GLY VAL GLY 30

H2N PRO ALA
32

C – Terminal

Prolinamide

Fig. 10.12  Structure of calcitonin

252 10 Hormones

Regulation of Calcitonin
Calcitonin is regulated by plasma calcium concentration.

• ↓ Plasma calcium ion concentration inhibits release of calcitonin.
• ↑ Plasma calcium ion concentration stimulates release of calcitonin.

Normal Serum Value
It is < 8 pg/L.

Metabolic Functions
Calcitonin ↓ plasma calcium ion concentration through its actions on the kidneys,
bones, and intestinal mucosa.

Calcitonin is antagonistic to parathormone.
Calcitonin binds to receptors on the cell membranes of bones cells and cells of renal
tubules. It induces rise in concentration of cAMP which in turn control cell activities.
Effect on the Kidneys

• Calcitonin acts on distal convoluted tubule and ascending limb of loop of Henle.
It decreases reabsorption of calcium ions and phosphate ions.

• Calcitonin results into hypocalcemia and hypophosphatemia.

Effect on Bones

• Calcitonin inhibits activity of osteoclasts and suppresses bone resorption. It
inhibits mobilization of calcium and phosphate ions from bone matrix into blood
circulation.

• Calcitonin promotes mineralization of bones.

Effect on Intestinal Mucosa

• Calcitonin inhibits hydroxylation of 25-hydroxycholecalciferol in kidneys and
synthesis of calcitriol. It indirectly decreases absorption of calcium from the
intestine.

10.13 S omatostatin

Somatostatin is a peptide hormone. It is a growth hormone-inhibitory hor-
mone or growth hormone-release inhibitory hormone.

Secretion of Somatostatin
Somatostatin is secreted by three organs in the body as:

• Hypothalamic Somatostatin
It is secreted by secretory neurons in ventromedial nucleus of hypothalamus. It
enters hypothalamo-hypophyseal tract and reaches anterior pituitary gland from
where it is released.

10.14  Adrenal Cortical Hormones (Corticosteroids) 253

• Pancreatic Somatostatin
It is secreted by delta (δ)-cells in the pancreas.

• Gastrointestinal Somatostatin
It is secreted by delta (δ)-cells in pyloric antrum in the stomach and duodenum.

Chemistry
It is a linear peptide. It is made up of 14 amino acids. Alanine amino acid is located
at N-terminal, and cysteine amino acid is present at C-terminal of somatostatin mol-
ecule. There exists an intrachain S-S bridge between the 3rd cysteine residue and
14th cysteine residue in the peptide chain.

Normal Serum Value
It is 8–20 pg/mL.

Metabolic Functions of Somatostatin

• Hypothalamic Somatostatin
It functions as regulator of release of growth hormone. It inhibits release of
growth hormone from anterior pituitary gland.

• Pancreatic Somatostatin
Somatostatin acts through paracrine signaling (communication between cells).

• It inhibits the following secretions as:
Insulin, glucagon, and pancreatic juice

• Gastrointestinal Somatostatin
Somatostatin inhibits secretory activity of parietal cells in the stomach through
paracrine signaling. It inhibits release of gastric secretion. Somatostatin from
duodenum enters hepatic portal vein and reaches systemic circulation. It acts on
target cells.
It inhibits the following secretions as:
Gastrin, secretin, cholecystokinin-pancreozymin, gastric inhibitory peptide, and
vasoactive intestinal peptide
Gastrointestinal somatostatin delays gastric emptying. It decreases gut motility.

10.14 Adrenal Cortical Hormones (Corticosteroids)

Corticosteroids are steroidal hormones which are secreted by adrenal cortex. They
are derived from cholesterol.

Corticosteroid hormones are characterized by the presence of cyclopentano-
perhydro-phenanthrene nucleus or also called as sterane nucleus.

Classification of Adrenocorticosteroids
They are classified into two categories based upon carbon skeleton and func-
tional activity.

254 10 Hormones

1 . Depending Upon Carbon Skeleton

The two types of corticosteroids are as follows:

• C 21 corticosteroids
These hormones contain a total of 21 carbon atoms. The 17 carbon atoms in ring

“D” contain a side chain of 2 carbon atoms.

Examples:

Mineralocorticoids and glucocorticoids

• C19 corticosteroids
These hormones contain a total of 19 carbon atoms. These hormones contain

a keto group (C〓O) at position C17 and are called as 17-ketocorticosteroids

or 17-oxosteroids.

These hormones have androgenic functional activity.

Examples:

Androstenedione and dehydroepiandrosterone (DHEA)

2. Depending upon Functional Activity

The two types of corticosteroids are as follows:

• Glucocorticoids

These hormones are primarily involved in regulation of carbohydrates, addi-

tionally control metabolism of proteins and lipids, and have minor effect on

minerals metabolism and total body water (TBW).

Example:

Cortisol

It is C-21 corticosteroid. It contains three OH groups at C-11, C-17, and C-21

atoms. It is also called as 11-17-21-trihydroxycorticosterone as in Fig. 10.13.

Cortisol is the primary and most potent glucocorticoid hormone.

11-Deoxycortisol

It is a weak glucocorticoid. It is derived from cortisol.

Cortisone

It is a C-21 corticosteroid. It contains OH group at C-17 atom. There is dehy-

drogenation at C-11 atom. It is also called as

17-hydroxy-11-dehydrocorticosterone.

Corticosterone

It is a C-21 steroid. It contains OH groups at C-11 and C-21 atoms. It is also

called as 17-deoxycorticosterol. It has minor glucocorticoid activity.

• Mineralocorticoids

These hormones are mainly involved in regulation of mineral metabolism and

total body water (TBW).

Examples: Aldosterone, 11-Deoxycorticosterone (DOC),

11-Dehydrocorticosterone as in Fig. 10.13

Adrenocortical Sex Steroids

• These hormones are primarily involved in regulation of secondary sexual

characteristics.
Examples:
Androstenedione and dehydroepiandrosterone (DHEA)

10.14  Adrenal Cortical Hormones (Corticosteroids) 255

H

HCH

C17 oxygenator H 20 C = O C20,C3 ketone
C3 OH Group H CH H groups

H3C O H HCH C4,C5 Double
HCH Bond
17
CD
CD

AB AB
HO 4 5 O = C3 4 5

C19 Steroid C21 Steroid

H H

HCH H C OH

C11 Dehydrogenator 202 C = O 20 C = O

O H3C OH HO H3C OH
17 H3C 11C 17D
H3C 11C D

3A B CA B
O O

Cortisone 17 – hydroxy – 11 – dehydro Cortisol 11,17,21 – Trihydroxy
corticosterone corticosterone

HH

HCH C11 Dehydrogenase H C OH

21 21

20 C = O 20 C = O

OH H3C OH O H3C OH
H3C 11C 17D H3C 11C 17D

3A B 3A B
O O

Corticosterone 11 – Dehydro corticosterone

Fig. 10.13  Hormones of adrenal cortex

Cortisol is the most essential and chief corticosteroid (glucocorticoid) hor-
mone which exists in free state in blood circulation. It is vitally important for
the functioning of the cardiovascular system, homeostasis, and immunological
response of body.

256 10 Hormones

10.14.1  Glucocorticoids

Biosynthesis
Corticosteroids are synthesized in adrenal cortex. It has three zones which are
specific for synthesis of individual group of corticosteroids as described below:

• Zona Fasciculata
It is the middle zone of adrenal cortex. Cells are arranged into bundles, also
called as zona fasciculata. This zone synthesizes chiefly cortisol (glucocorti-
coid) which controls glucose metabolism in adverse conditions like stress, fear,
fight, or flight.
This zone synthesizes small amount of androgens.

• Zona Glomerulosa
It is the uppermost zone of adrenal cortex which lies underneath renal capsule.
Ovoid cells are arranged into clusters.
This zone synthesizes aldosterone (mineralocorticoid) and is involved in reg-
ulation of mineral metabolism.

• Zona Reticularis
This is the innermost zone of adrenal cortex. It lies above the adrenal medulla.
Cells are arranged into a network-like pattern. This zone mainly synthesizes
cortical sex steroids. Small amount of cortisol is also produced.

Steps in Biosynthesis of Glucocorticoids
In Zona Fasciculata

• Intracellular Transport of Cholesterol
Cholesterol is the precursor for synthesis of corticosteroid hormones in adrenal
cortex. Cholesterol is present in cytosol of cells of adrenal cortex. Cholesterol
transport from outer mitochondrial membrane to inner mitochondrial membrane
is the rate-limiting step in synthesis of hormones.
Intracellular transport of cholesterol is mediated by a transport protein located in
adrenal cortex cells. It is called as steroidogenic acute regulatory protein
(StAR). This transport protein transfers cholesterol to inner mitochondrial
membrane.

• Conversion of Cholesterol into Pregnenolone
Inner mitochondrial membrane contains cytochrome P450 side-chain cleavage
enzyme (Cytochrome P450 SCC).
Cytochrome P450 SCC brings about two hydroxylations of cholesterol side chain at
C22 andC20 positions. First hydroxylation forms 22R-hydroxycholesterol. It
undergoes second hydroxylation to form 20-alpha-22R-dihydroxycholesterol.
Cytochrome P450 SCC requires molecular oxygen and reducing equivalents
(NADPH) for its activity. There is transfer of electrons from NADPH to cyto-
chrome P450 SCC through adrenodoxin and adrenodoxin reductase proteins.

10.14  Adrenal Cortical Hormones (Corticosteroids) 257

• Cytochrome P450 SCC enzyme splits linkage between C20 and C22 in side chain
of cholesterol to form pregnenolone and isocaproic aldehyde.

• Conversion of Pregnenolone into 17-Hydroxypregnenolone

Pregnenolone is translocated to smooth endoplasmic reticulum. It undergoes
hydroxylation at C17 position to form 17-hydroxypregnenolone as in Fig. 10.14.
Reaction is catalyzed by 17alpha-hydroxylase. [It is also called as cytochrome
P450 17A1 or 17,20-desmolase. Enzyme has 17alpha-hydroxylase and 17,20-

lyase enzymatic activities. It is a key enzyme in the adrenal steroidogenic

pathway.]
• Conversion of 17-Hydroxypregnenolone into 17-Hydroxyprogesterone

Cytochrome Cholesterol
p450- NADP+
O2
side chain clevge NADPH2
FAD
Pregnenolone
17– Hydroxy 17– alpha–hydroxylase Isocaproic
pregnenolone aldehyde
O2
Isomerase NADPH2 NADP+ Isomerase
+ +
NADP+ O2 NADPH2
dehydrogenase dehydrogenase
NAD+ NAD+

17– Hydroxy Progesterone
pregnenolone
17– alpha–hydroxylase

NADPH2 21–Hydroxylase
O2

NADPH+

11– Deoxycorticosterol

NADPH2 11– β – Hydroxylase
O2

NADPH+

Cortisol

Fig. 10.14  Biosynthesis of glucocorticoids

258 10 Hormones

17-Hydroxypregnenolone is converted into 17-hydroxyprogesterone by 3-beta-
hydroxysteroid dehydrogenase enzyme. It requires NAD+ as coenzyme to
accept hydrogen atoms.
• 3-Beta-hydroxysteroid dehydrogenase belongs to lass of oxidoreductase
enzymes. It is the single enzyme in adrenal cortical steroidogenic pathway
that does not belong to the family of cytochrome P450 enzymes.
• Conversion of 17-Hydroxyprogesterone into 11-Deoxycortisol
17-Hydroxyprogesterone undergoes hydroxylation to form 11-deoxycortisol.
Reaction is catalyzed by 21-hydroxylase enzyme located in the smooth endo-
plasmic reticulum. Enzyme requires molecular oxygen and NADPH for its
activity.
• Formation of Cortisol
11-Deoxycortisol is translocated to the inner mitochondrial membrane.
11-Deoxycortisol is converted into cortisol.
Reaction is catalyzed by 11-beta-hydroxylase enzyme. It requires molecular
oxygen and NADPH for its activity.
–– 17-Alpha-hydroxylase, 21-hydroxylase, and 11-beta-hydroxylase are

monooxygenase enzymes.
–– They belong to the family of cytochrome P450 enzymes. They require

molecular oxygen and NADPH and adrenodoxin protein.

Regulation by Adrenocorticotropic Hormone (ACTH)
ACTH regulates synthesis of glucocorticoid hormones through the following activi-
ties as:

• ACTH activates enzyme cholesterol esterase in cytoplasm. This enzyme pro-
vides cholesterol molecules for adrenal glucocorticoidogenesis.

• ACTH activates phosphogluconate dehydrogenase enzyme to provide ample
supply of NADPH.

Metabolic Functions of Glucocorticoids

• Effect on Carbohydrate Metabolism
• Glucocorticoids are antagonistic to insulin in carbohydrate metabolism.

They increase blood glucose concentration (hyperglycemia) through the follow-
ing activities as:
–– ↓ Uptake of glucose by peripheral tissues

Glucocorticoids inhibit activity of glucose transporters. It decreases transport
of glucose into muscles, adipose tissues. Concentration of glucose is increased
in plasma.
–– ↓ Utilization of glucose by peripheral tissues
Glucocorticoids decrease utilization of glucose in peripheral tissues. It dimin-
ishes glycolysis.

10.14  Adrenal Cortical Hormones (Corticosteroids) 259

Therefore, glucocorticoids exhibit carbohydrate catabolic effect in
peripheral tissues.
–– ↑ Gluconeogenesis in the liver
It promotes formation of pyruvate carboxylase and fructose-1,6-bisphosphate

enzymes in the liver. It increases availability of glucogenic amino acids in the

liver.
Overall, glucocorticoids enhance gluconeogenesis in the liver.
Glucocorticoids stimulate formation of glycogen synthase enzyme. So it pro-
motes glycogen synthesis in the liver.
Therefore, glucocorticoids exhibit carbohydrate anabolic effect in liver.
• Effect on Lipid Metabolism
Glucocorticoids Have Lipolytic Effect
Glucocorticoids activates tissue lipase enzyme. They stimulate lipolysis of tri-
glycerides in adipose tissues. Glucocorticoids promote mobilization of lipids
and increase free fatty acid concentration in plasma.
• Effect on Protein Metabolism

Glucocorticoids have both protein anabolic and catabolic effects.
–– Protein Catabolic Effect

In peripheral tissues, glucocorticoids increase breakdown of proteins and

diminish protein synthesis. They increase concentration of amino acids in

plasma.
–– Protein Anabolic Effect

In the liver, glucocorticoids promote synthesis of proteins by the following

activities as:

↑ Transcription of mRNA in hepatocytes
↑ Uptake of amino acids by hepatocytes
Promotes protein synthesis

Conclusively, glucocorticoids induce negative nitrogen balance on protein
metabolism.

Peripheral tissues Liver
Glucocorticoids induce catabolism Glucocorticoids induce anabolism
• ↑ Gluconeogenesis
• ↓ Glucose uptake and utilization • ↑ Glycogenesis
• ↑ Protein synthesis
• ↑ Proteolysis
• ↓ Protein synthesis
• ↑ Free amino acids in plasma
• ↑ Lipolysis of triglycerides
• ↑ Free fatty acids in plasma

• Anti-inflammatory Effect

Endogenous cortisol in blood circulation does not have anti-inflammatory effect.
Therapeutic dose of cortisol induces potent anti-inflammatory effect through

the following activities as:
–– ↓ Release of pro-inflammatory cytokines

260 10 Hormones

Glucocorticoids suppress express of genes which are responsible for synthe-
sis of pro-inflammatory cytokines and key enzymes implicated in initiation
and continuation of inflammatory response in the body of host.
Glucocorticoids inhibit release of pro-inflammatory cytokines like TNF-α and
IL-1.
–– ↓ Capillary oermeability
Glucocorticoids reduce capillary permeability. Therefore, emigration of leu-
cocytes, especially neutrophils, is inhibited at the site of injury.
–– ↓ Activity of kallikrein
Kallikrein is a proteolytic enzyme for formation of bradykinin from kinino-
gen. Bradykinin mediates inflammation. Glucocorticoids inhibit synthesis of
bradykinin.
–– ↓ Proliferation of leukocytes at site ofiInjury
Glucocorticoids reduce proliferation of leukocytes like eosinophils, mono-
cytes, and neutrophils at site of injury.
–– ↓ Proliferation of fibroblasts
Glucocorticoids reduce proliferation of fibroblasts at site of injury. They
inhibit formation of collagen fibers.
–– ↓ Activity of phospholipase A2
Glucocorticoids inhibit lipolytic activity of phospholipase A2. They reduced
synthesis of prostacyclin, prostaglandin, thromboxane, and leukotrienes.
These endogenous substances are involved in mediation and maintenance of
inflammation.
Therapeutic cortisol is widely utilized in management of chronic inflammatory
disorders like multiple sclerosis, inflammatory bowel disease, rheumatoid
arthritis, and psoriasis.
• Anti-allergic Effect
Therapeutic glucocorticoids have anti-allergic effect through the following activ-
ities as:
–– Glucocorticoids inhibit proliferation of mast cells. They stabilize mast cells
and reduce degranulation of mast cells.
–– They prevent vasodilation by inhibiting release of histamine and bradykinin
from granules of mast cells.
–– They reduce capillary permeability.
Therapeutic cortisol and hydrocortisone that are used in treatment of anaphylaxis
(immediate hypersensitivity reaction, life-threatening) have profound anti-allergy
effect.
• Immunosuppressive Effect
Therapeutic glucocorticoids have immune-suppressive effect in viral, bacterial,
protozoan, and fungal diseases. They are widely used after organ transplantation
to minimize graft failure.
Glucocorticoids suppress proliferation of lymphocytes in the thymus, spleen,
and lymphoid tissues. They reduce the number of circulating lymphocytes.
• Effect on Gastrointestinal Secretions

10.14  Adrenal Cortical Hormones (Corticosteroids) 261

Therapeutic glucocorticoids induce hypersecretion of gastric glands and pancre-
atic glands. The synthesis of HCl and pepsin is increased in the stomach. The
secretion of trypsin is enhanced in pancreatic juice.
Prolonged administration of glucocorticoids is associated with high predis-
position to peptic ulcer.
• Effect on the Bone
Therapeutic glucocorticoids suppress protein synthesis and organic bone matrix
formation. They prompt demineralization in bones. Prolonged use of glucocorti-
coids result into osteoporosis.

10.14.2  M ineralocorticoids

Mineralocorticoids are steroidal hormones which are chiefly concerned with
regulation of mineral metabolism and water balance.

Types of Mineralocorticoids

• Aldosterone
It is the principal mineralocorticoid hormone. It is a C21 steroid. It contains a
hydroxyl group at C11 position and an aldehyde group at C18 position as in
Fig. 10.13.

• 11-Deoxycorticosterone (DOC)
This is a weak mineralocorticoid. It produces effects similar to the effects of
aldosterone. It is synthesized in minute quantity.

• Corticosterone
• 11-Deoxycortisol

Biosynthesis of Mineralocorticoids
Mineralocorticoids are synthesized by cells of zona glomerulosa in adrenal cor-
tex. This zone has 18-hydroxylase enzyme and 18-hydroxysteroid dehydrogenase
enzyme which are essential for synthesis of mineralocorticoids. These enzymes are
absent in other two zones of adrenal cortex. Biosynthesis is described in follwoing
steps as:

• Intracellular Transport of Cholesterol
Cholesterol is the precursor for synthesis of corticosteroid hormones in adrenal
cortex. Cholesterol is present in cytosol of cells of adrenal cortex. Cholesterol
transports from outer mitochondrial membrane to inner mitochondrial mem-
brane and is the rate-limiting step in synthesis of hormones.
Intracellular transport of cholesterol is mediated by a transport protein located in
adrenal cortex cells. It is called as steroidogenic acute regulatory protein
(StAR). This transport protein transfers cholesterol to inner mitochondrial mem-
brane as in Fig. 10.16.

262 10 Hormones

• Conversion of Cholesterol into Pregnenolone
Inner mitochondrial membrane contains cytochrome-P 450 side-chain cleavage
enzyme (cytochrome P450 SCC).
Cytochrome P450 SCC brings about two hydroxylations of cholesterol side chain
at C22 and C20 positions. First hydroxylation forms 22R-hydroxycholesterol. It
undergoes second hydroxylation to form 20-alpha-22R-dihydroxycholesterol.
Cytochrome P450 SCC requires molecular oxygen and reducing equivalents
(NADPH) for its activity. There is transfer of electrons from NADPH to cyto-
chrome P450 SCC through adrenodoxin and adrenodoxin reductase proteins.
Cytochrome P450 SCC enzyme splits linkage between C20 and C22 in side chain of
cholesterol to form pregnenolone and isocaproic aldehyde.

• Conversion of Pregnenolone into Progesterone
Pregnenolone is translocated to smooth endoplasmic reticulum. It is converted
into progesterone by 3-beta-hydroxysteroid dehydrogenase enzyme.

• Hydroxylation of Progesterone into 11-Deoxycorticosterone
Progesterone is hydroxylated to form 11-deoxycorticosterone. Reaction is cata-
lyzed by 21-hydroxylase.

• Conversion of 11-Deoxycorticosterone into Corticosterone
The 11-deoxycorticosterone is transported to inner mitochondrial membrane. It
is converted into corticosterone by 11-beta-hydroxylase.

• Hydroxylation of Corticosterone into 18-Hydroxycorticosterone
Corticosterone undergoes hydroxylation to form 18-hydroxycorticosterone.
Reaction is catalyzed by 18-hydroxylase enzyme.

• Formation of Aldosterone
The 18-hydroxycorticosterone undergoes oxidation to form aldosterone.
Reaction is catalyzed by 18-hydroxysteroid dehydrogenase.

• Forms of Aldosterone
It exists in blood circulation in two forms as:
–– Aldehyde form of aldosterone
Aldosterone contains an aldehyde group at C18 position in D ring as in Fig. 10.15.
–– Hemiacetal form of aldosterone
Aldosterone contains hemiacetal group at C11 position in C ring.

Metabolic Functions of Aldosterone

• Renal Reabsorption of Sodium Ions
Aldosterone acts on distal convoluted tubules and collecting tubules and induces
reabsorption of sodium ions from glomerular filtrate.
Aldosterone is highly important hormone for the regulation of sodium ions in
plasma and extracellular fluid (Fig. 10.16).

• Renal Reabsorption of Chloride Ions
Aldosterone also brings about reabsorption of chloride ions from filtrate. This
function of aldosterone is secondary to sodium reabsorption.

• Renal Excretion of Potassium Ions
Aldosterone induces excretion of potassium ions in urine. Every potassium ion is
exchanged with sodium ion.

10.14  Adrenal Cortical Hormones (Corticosteroids) 263

Fig. 10.15  ■ H CH2– OH
OH O C C O

11 18
H3C

C11 Hydroxyl Group (OH)
C18 Aldehyde Group (CHO)
O
Aldosterone

Cholesterol

Precursor to
aldosterone

Pregnenolone

O2 11 – Deoxycorticosterone

NAD+ Dehydrogenase NADPH2 NADP+
+
NADPH2
Isomerase O2 11 – Beta –
Hydroxylase
NADP+
Progesterone

21 – Hydroxylase

18 – Hydroxy 18 – Hydroxylase Corticosterone
corticosterone NADPH2 O2 NADP+

Dehydrogenase

Aldosterone
Fig. 10.16  Biosynthesis of aldosterone

264 10 Hormones

• Regulation of Acid-Base Balance
Aldosterone promotes reabsorption of sodium ions from glomerular filtrate.
Reabsorption of each sodium ion is exchanged with tubular secretion of H+ ion
in filtrate. This function helps to maintain pH (hydrogen ion) of plasma and body
fluid.
Within the renal tubule, each reabsorbed sodium ion is exported to plasma in
association with one HCO3_ion. Therefore, NaHCO3 enters plasma, and it repre-
sents alkali reserve of the body.
These functions help to maintain acid-base balance of the body. The ↑ in secre-
tion of aldosterone is manifested as ↑ in plasma bicarbonate level. It is termed
as alkalosis, whereas ↓ in secretion of aldosterone, it is characterized as
↓plasma bicarbonate level and is termed as acidosis.

• Regulation of Blood Volume
Aldosterone promotes reabsorption of sodium ions, chloride ions, and bicarbon-
ate ions. It results in increased plasma osmolarity.
It is followed by increase in secretion of ADH from posterior pituitary gland. It
induces proportionate increase in reabsorption of water by renal tubules from
glomerular filtrate.
Overall, aldosterone maintains normal blood volume.

• Regulation of Extracellular Fluid Volume
Aldosterone also results into rise in osmolarity of extracellular fluid. It is due to
reabsorption of sodium and chloride ions.
The ↑ in electrolyte concentration of ECF is associated with increase in renal
reabsorption of water.
Hyperosmolarity of ECF stimulates the thirst center. Intake of water increases.
Overall, volume of extracellular fluid is increased.

• Effect on Exocrine Secretions
Aldosterone limits excretion of electrolytes in exocrine secretions. It helps to
conserve electrolytes in salivary, gastric, and intestinal glands.

Normal Serum Value
Cortisol
It is 15–70 μmol/L.
Aldosterone
It is 2–10 ng/dl.

10.14.3  A drenal Medulla Hormones

Adrenal medullary hormones are called as catecholamines. They contain a cate-
chol ring (a benzene ring to which one hydroxyl group at C1 and other hydroxyl
group at C2 positions are linked) and amino group containing side chain.

Therefore, catecholamines are monoamines.

10.14  Adrenal Cortical Hormones (Corticosteroids) 265

Types of Hormones

• Adrenaline (epinephrine)
• Noradrenaline (norepinephrine)

Biosynthesis
Catecholamines are synthesized in adrenal medulla and sympathetic neurons in cen-
tral nervous system.

Steps in Biosynthesis

• Conversion of Tyrosine into Dihydroxyphenylalanine (DOPA)
Tyrosine is precursor amino acid in synthesis of catecholamines. Tyrosine under-
goes hydroxylation to form 3,4-dihydroxyphenylalanine. Reaction is catalyzed
by tyrosine hydroxylase enzyme.
Reaction requires molecular oxygen. Biopterin (chemically related to folate) acts
as coenzyme in the reaction. Its biologically active form is called tetrahydrobi-
opterin that takes part in the reaction. It is oxidized into dihydrobiopterin during
hydroxylation reaction. Dihydrobiopterin reductase enzyme again reduces dihy-
drobiopterin into tetrahydrobiopterin utilizing NADPH as reducing equivalents.

• Formation of Dopamine
3,4-Dihydroxyphenylalanine undergoes decarboxylation to form dopamine.
Reaction is catalyzed by aromatic amino acid decarboxylase enzyme.

• Formation of Norepinephrine
Dopamine undergoes hydroxylation to form norepinephrine. Reaction is cata-
lyzed by dopamine beta-hydroxylase enzyme. Ascorbate acts as cofactor, and it
is oxidized into dehydroascorbate in hydroxylation reaction.

• Formation of Epinephrine
Norepinephrine is methylated to form epinephrine. Reaction is catalyzed by
phenylethanolamine N-methyltransferase enzyme. S-adenosyl methionine acts
as a methyl group donor, and it is converted into S-adenosyl homocysteine in
methylation reaction.

Storage
Epinephrine and norepinephrine are stored in chromaffin granules in the adrenal
medulla. These catecholamines are present in form of granules with size of 0.5 μ.
These hormones are released into blood circulation.

Normal Serum Value
Epinephrine
It is < 50 nmol/L.
Norepinephrine
It is < 2 nm/L.

266 10 Hormones

Metabolic Functions

• Effect on Carbohydrate Metabolism
Adrenaline and noradrenaline promote hydrolysis of glycogen and favor increase
in blood glucose concentration (hyperglycemia). These hormones produce
hyperglycemic effect through the following activities:
In the liver, adrenaline attaches with beta-adrenergic receptors located on cell
membrane of hepatic cells. It enhances concentration of cAMP in cytosol of
hepatocytes. Adrenaline activates phosphorylase b into phosphorylase a. This
enzyme is responsible for glycogenolysis in the liver. These hormones also stim-
ulate gluconeogenesis in the liver.
Overall, adrenaline and noradrenaline increase release of glucose from the liver
into blood circulation.
In skeletal muscles, adrenaline stimulates glycogenolysis through beta-receptor-­
induced cAMP concentration.
The glycogenolytic effect of adrenaline is almost similar to that of glucagon in
the liver.
Adrenaline activates glycolysis in muscle fibers. It increases plasma lactate level.

• Effect on Lipid Metabolism
Adrenaline and noradrenaline activate tissue lipase enzyme and promote lipoly-
sis of triglycerides in adipose tissues. These hormones increase transport of free
fatty acids into blood circulation. They increase plasma fatty acid
concentration.

• Effect on BMR
Adrenaline and noradrenaline increase consumption of oxygen and heat produc-
tion in the body. They increase BMR.

10.15 H ormones of Gonads

Gonadal hormones are steroidal in nature. They are derived from cholesterol.
They are characterized by the presence of sterane nucleus.

Gonadal hormones or sex hormones are secreted by the testes, ovary, corpus
luteum, placenta, and adrenal cortex.

Types of Sex Hormones
The three types of sex hormones are as follows:

• Androgens
Androgens are male sex hormones. They are C19 steroids. They contain methyl
groups at C10 and C13 positions.
Examples:
Testosterone, dihydrotestosterone, androstenediol, androstenedione, and
dehydroepiandrosterone (DHEA)

• Estrogens
Estrogens are female sex hormones. They are C18 steroids.

10.15  Hormones of Gonads 267

Examples:
Estrone, estriol, estetrol, and estradiol
• Progestogens
Progestogens are progestational hormones. They are C21 steroids.
Example:
Progesterone

10.15.1  A ndrogens

They are male sex hormones. They are highly important in the development of sec-
ondary sex characters in males. Androgens are secreted by testes.

A small fraction of androgens is found in females. They are present in circu-
lation. They are produced by conversion of androstenedione into testosterone
in peripheral tissues.

Biosynthesis
Androgens are synthesized by Leydig cells and zona reticularis in the adrenal cortex.

Steps in Biosynthesis of Androgens

• Conversion of Cholesterol into Pregnenolone
Intracellular Transport of Cholesterol
–– Cholesterol is the precursor for synthesis of androgens. Cholesterol is present
in cytosol of Leydig cells in testes. Transport of cholesterol from outer mito-
chondrial membrane to inner mitochondrial membrane is the rate-limiting
step in synthesis of androgens.
–– Intracellular transport of cholesterol is mediated by a transport protein located
in Leydig cells. It is called as steroidogenic acute regulatory protein (StAR).
This transport protein transfers cholesterol to inner mitochondrial membrane.
Formation of Pregnenolone
–– Inner mitochondrial membrane contains cytochrome-P 450 side-chain cleav-
age enzyme (cytochrome P450 SCC).
–– Cytochrome P450 SCC brings about two hydroxylations of cholesterol side chain at
C22 andC20 positions. First hydroxylation forms 22R-hydroxycholesterol. It
undergoes second hydroxylation to form 20-alpha-22R-dihydroxycholesterol.
–– Cytochrome P450 SCC requires molecular oxygen and reducing equivalents
(NADPH) for its activity. There is transfer of electrons from NADPH to cyto-
chrome P450 SCC through adrenodoxin and adrenodoxin reductase proteins.
–– Cytochrome P450 SCC enzyme splits linkage between C20 and C22 in side
chain of cholesterol to form pregnenolone and isocaproic aldehyde.
–– Pregnenolone is translocated to smooth endoplasmic reticulum (SER).

• Conversion of Pregnenolone into Testosterone
It follows two pathways as shown below:
–– ∆4 Pathway or progesterone pathway
–– ∆5 Pathway or 17-alpha-hyroxypregnenolone pathway

268 10 Hormones

Steps in ∆4 Pathway or Progesterone Pathway

• Conversion of Pregnenolone into Progesterone
In SER, pregnenolone is changed into progesterone. Reaction is catalyzed by
3-beta-hydroxysteroid dehydrogenase enzyme.

• Hydroxylation of Progesterone
Progesterone undergoes hydroxylation to form 17-alpha-hydroxyprogesterone.
Reaction is catalyzed by 17-alpha-hydroxylase enzyme. The enzyme lyase splits
side chain of 17-alpha-hydroxyprogesterone to form androstenedione.

• Reduction of Androstenedione
Androstenedione undergoes reduction to form testosterone. Reaction is cata-
lyzed by 17-beta-hydroxysteroid dehydrogenase enzyme.

Steps in ∆5 Pathway or 17-alpha-Hyroxypregnenolone Pathway

• Conversion of Pregnenolone into 17-alpha-Hydroxyprogesterone
In SER, pregnenolone undergoes hydroxylation to form 17-alpha-hydroxypro-
gesterone. Reaction is catalyzed by 17-alpha-hydroxylase enzyme.

• Conversion of 17-alpha-Hydroxyprogesterone into Dehydroepiandrosterone
(DHEA)
Side chain of 17-alpha-hydroxyprogesterone is cleavaged by enzyme lyase to
form dehydroepiandrosterone.

• Reduction of Dehydroepiandrosterone
Dehydroepiandrosterone undergoes reduction to form androstenediol by enzyme
17-beta-hydroxysteroid dehydrogenase enzyme (Fig. 10.17).
Androstenediol undergoes isomerization to form testosterone as in Figs. 10.11
and 10.18.

• Dihydrotestosterone (DHT) is a biologically active form of testosterone.
• It is produced in peripheral tissues by reduction of testosterone catalyzed by

5-alpha-reductase enzyme.
–– Testosterone may be considered as prohormone; however, both hormones

exert metabolic effects on the human body.

Fig. 10.17 Testosterone H3C18 OH
17

H3C19 13

10 Methyl groups at C10,C13
O C19 – Carbon skeleton

10.15  Hormones of Gonads 269
Cholesterol

Pregnenolone

Dehydrogenase
+

Isomerase

Progesterone n – ∝ – Hydroxylase 17 – ∝– OH – Progesterone
Lyase
enzyme

Androstenedione

Dihydro testosterone Reductase Dehydrogenase
Testosterone

Fig. 10.18  Biosynthesis of andrgens

Transport of Androgens
Testosterone and DHT bind to sex hormone-binding globulin in plasma. They are
distributed to target tissues.

Metabolic Functions
Testosterone and dihydrotestosterone (DHT) are metabolically active hormones.
They have the following effects on metabolism.

• Effect on Protein Metabolism
Testosterone and DHT are prominently protein anabolic hormones.
These hormones increase mRNA transcription and protein synthesis in accessory
glands (seminal vesicle, prostate gland) of males, bones, and skeletal muscles.
These hormones are involved in the growth of musculoskeletal system in males
during puberty.
These hormones reduce urinary excretion of nonprotein nitrogen. They exert
positive nitrogen balance. These hormones increase muscle mass and body
weight.

• Effect on Lipid Metabolism
Androgens promote rise in low-density lipoproteins in plasma and decrease in
high-density lipoproteins in plasma. These hormones are implicated in high pre-
disposition to coronary artery disease in males than females. After menopause,
plasma level of estrogen is reduced, and women are equally inclined to heart
diseases.

• Effect on Carbohydrate Metabolism

270 10 Hormones

Androgens activate conversion of D-glucose into D-fructose in seminal vesicles.
These hormones activate synthesis of aldolase enzyme and promote glycolysis
and TCA cycle in seminal vesicle.
• Effect on Mineral Metabolism
Androgens reduce urinary excretion of nonprotein nitrogen (NPN). These hor-
mones limit urinary excretion of sodium ion, chloride ion, sulfate ion, phosphate,
and potassium. These hormones promote retention of NPN and other ions in
body tissues. This function prevents elevation of plasma NPN concentration.
• Effect on Bone Growth
Androgens promote mineralization of bones. These hormones increase forma-
tion of organic bone matrix and deposition of calcium and phosphate in bones
before closure of epiphyseal plates in long bones.

10.15.2  F emale Sex Hormones

These hormones are steroidal in nature. They are synthesized from cholesterol.
Female sex hormones belong to two categories as:

Estrogens

• Estrogens are synthesized from ovarian follicles.

Progestogen

• Progesterone is synthesized by corpus luteum.

Estrogens
Estrogens are the predominant female sex hormones secreted by ovaries. These hor-
mones are involved in growth of female reproductive organs. They are responsible
for appearance of secondary sex characters in females.

Chemistry and Forms of Estrogens
Estrogens are found in the following three forms as in Fig. 10.19:

• Estriol
• β-estradiol
• Estrone

Metabolically active form of estrogen is β-estradiol. It is found in blood circula-
tion. β-estradiol and estrone are interconvertible.

β-estradiol is ten times more biologically active than estrone.
Estriol is an important metabolite of estrone. It is found in urine during
pregnancy.

10.15  Hormones of Gonads 271

H3C18 OH OH

3 Estriol
HO

OH

H3C O

HO 3
Estradiol HO

Estrogens Estrone

CHO
CO

O
Progesterone

Fig. 10.19  Structure of female sex hormones

Structurally

• Estrogens are C18 steroids. They have sterane nucleus (nonlinear arrangement
A, B, C, and D rings).

• Ring A has aromatic character. These hormones contain –OH group at C3
position.

Biosynthesis
Estrogens are synthesized in graafian follicles and corpus luteum in the ovaries.

272 10 Hormones

Steps in Biosynthesis

• Conversion of Cholesterol into Pregnenolone
Intracellular Transport of Cholesterol
–– Cholesterol is the precursor for synthesis of androgens. Cholesterol is present
in cytosol of theca interna and granulose cells in ovaries. Transport of choles-
terol from outer mitochondrial membrane to inner mitochondrial membrane
is the rate-limiting step in the synthesis of estrogens.
–– Intracellular transport of cholesterol is mediated by a transport protein located in
theca interna cells. It is called as steroidogenic acute regulatory protein (StAR).
This transport protein transfers cholesterol to inner mitochondrial membrane.
Formation of Pregnenolone
–– The inner mitochondrial membrane contains cytochrome-P 450 side-chain
cleavage enzyme (cytochrome P450 SCC).
–– Cytochrome P450 SCC brings about two hydroxylations of cholesterol side
chain at C22 andC20 positions. First hydroxylation forms
22R-hydroxycholesterol. It undergoes second hydroxylation to form
20-alpha-22R-dihydroxycholesterol.
–– Cytochrome P450 SCC requires molecular oxygen and reducing equivalents
(NADPH) for its activity. There is transfer of electrons from NADPH to cyto-
chrome P450 SCC through adrenodoxin and adrenodoxin reductase proteins.
–– Cytochrome P450 SCC enzyme splits linkage between C20 and C22 in side
chain of cholesterol to form pregnenolone and isocaproic aldehyde.
–– Pregnenolone is translocated to smooth endoplasmic reticulum (SER of
theca interna cells).

• Conversion of Pregnenolone into Progesterone
–– In SER, pregnenolone is changed into progesterone. Reaction is catalyzed by
3-beta-hydroxysteroid dehydrogenase enzyme.
–– Hydroxylation of Progesterone
–– Progesterone undergoes hydroxylation to form 17-alpha-hydroxyprogesterone.
Reaction is catalyzed by 17-alpha-hydroxylase enzyme. The enzyme lyase
splits side chain of 17-alpha-hydroxyprogesterone to form
androstenedione.
–– Androstenedione is converted into testosterone by aromatic acid dehydroge-
nase enzyme.
–– Androstenedione and testosterone are precursor molecules for biosyn-
thesis of estrogens.

• Conversion of Androstenedione into Estrone
–– Androstenedione undergoes three successive hydroxylations at C19 posi-
tion, and hydroxylations are accompanied by elimination of C18 methyl group
to form estrone.
–– Reaction is catalyzed by aromatase enzyme. It belongs to the family of cyto-
chrome P450 enzymes (monooxygenase enzymes inducing hydroxylation dur-
ing steroidogenesis). Enzyme requires molecular oxygen and NADPH.
–– Estrone undergoes further hydroxylation to form 16-alpha-OH estrone cata-
lyzed by 16-alpha-hydroxylase enzyme.

10.15  Hormones of Gonads 273

–– 16-Alpha-OH estrone is reduced into estriol by reductase enzyme.
• Conversion of Testosterone into beta-Estradiol

Cholesterol

Pregnenolone

Progesterone

Androstenedione Aromatase Testosterone
+
NADPH2
O2 Dehydrogenase

NADP+ NADPH2 Aromatase
O2

NADP+

Estrone Dehydrogenase Estradiol

NADPH2 16 – ∝ – Hydroxylase
O2

NADP+

16 – ∝ – Hydroxy estrons Reductase Estriol

Fig. 10.20  Biosynthesis of estrogens

274 10 Hormones

–– Testosterone undergoes three successive hydroxylations at C19 position, and
hydroxylations are accompanied by elimination of C18 methyl group to form
beta-estradiol as in Fig. 10.20.

–– Extra-graafian follicular tissues like the liver, skeletal muscles, and adi-
pose tissues can synthesize beta-estradiol and estrone utilizing circulat-
ing testosterone and androstenedione.

–– β-Estradiol is a predominant circualting estrogen.

Metabolic Functions

• Effect on Protein Metabolism
Estrogens exert protein anabolic effect.
These hormones activate mRNA transcription and protein synthesis in the bones,
uterus, and vaginal epithelium. Protein synthesis helps to prepare the uterus for
pregnancy.

• Effect on Lipid Metabolism
Estrogens promote synthesis of triglycerides in adipose tissues (lipogenesis).
Estrogens are responsible for higher proportion of body fat.
Estrogens increase concentration of high-density lipoprotein in plasma. These
hormones decrease low-density lipoprotein fraction in plasma. Estrogens
decrease plasma total cholesterol level. Total cholesterol-lowering effect of
estrogens is antagonistic to testosterone. As a result, women have lower preva-
lence of coronary artery disease than men.

• Effect on Carbohydrate Metabolism
Estrogens stimulate synthesis of glycogen in cells of endometrium and vaginal
epithelium. These hormones promote glycolysis and generation of lactic acid in
the vaginal epithelium. Rise in lactate content of vagina helps to maintain low pH
(4.0) in vagina.

• Effect on Transhydrogenase Enzyme
Transhydrogenase enzyme catalyzes the following reaction as:
NADPH2 + NAD+ ⇔ NADP+ + NADH2
Estrogens activate transhydrogenase activity. It is necessary for oxidation of
NADPH2 and generation of NADH, which passes through electron transport sys-
tem to produce ATP.
After menopause, estrogen level is decreased. Transhydrogenase activity is
reduced. It results into utilization of NADPH in synthesis of triglycerides in
adipose tissues. It manifests as postmenopausal obesity in women.

• Effect on Bones
Estrogens promote protein synthesis in bones. These hormones activate organic
osteoid formation. Estrogens increase retention of calcium and phosphate ions in
the bone and favor mineralization of bones. Estrogens promote growth of bones
in females during puberty before closure of epiphyseal plates.
After menopause, plasma level of estrogens is reduced. It prompts demineralization
of bones. Menopause is associated with higher chances of osteoporosis in women.

• Estrogens Priming Effect

10.15  Hormones of Gonads 275

Estrogens activate gene expression for progesterone receptors on mammary
glands and the uterus. These hormones increase proliferation of progesterone
receptors. It is called priming effect of estrogen. Receptors are essential for effect
of progesterone on target tissues.
• Effect on Mineral Metabolism
Estradiol has a retentive effect on mineral metabolism. It retains sodium, chlo-
ride, calcium, and phosphate ions in body tissues. It exerts water retention effect.

P rogesterone
Progesterone is a progestogen (steroidal hormone) which is synthesized by corpus
luteum in the ovary and placenta. It is also called as luteinizing hormone or gestagen.

Progesterone is additionally synthesized by adrenal cortex and testes.

Chemistry

Progesterone is a C21 steroid hormone. It contains methyl group at C10 and C13
positions.

Biosynthesis
Progesterone is synthesized as an intermediate metabolite in the steroidogene-
sis pathway of adrenal cortical hormones, androgens, and estrogens.

Cholesterol is a precursor molecule for biosynthesis of progesterone.

• Conversion of Cholesterol into Pregnenolone
• Intracellular Transport of Cholesterol

–– Cholesterol is the precursor for synthesis of progesterone. Cholesterol is pres-

ent in cytosol of cells. Transport of cholesterol from outer mitochondrial

membrane to inner mitochondrial membrane is the rate-limiting step in syn-

thesis of progesterone.

–– Intracellular transport of cholesterol is mediated by a transport protein located
in cells. It is called as steroidogenic acute regulatory protein (StAR). This

transport protein transfers cholesterol to inner mitochondrial membrane.
Formation of Pregnenolone

–– Inner mitochondrial membrane contains cytochrome-P 450 side-chain cleav-

age enzyme (cytochrome P450 SCC).
–– Cytochrome P450 SCC brings about two hydroxylations of cholesterol side chain at

C22 andC20 positions. First hydroxylation forms 22R-hydroxycholesterol. It
undergoes second hydroxylation to form 20-alpha-22R-dihydroxycholesterol.

–– Cytochrome P450 SCC requires molecular oxygen and reducing equivalents
(NADPH) for its activity. There is transfer of electrons from NADPH to cyto-

chrome P450 SCC through adrenodoxin and adrenodoxin reductase proteins.
–– Cytochrome P450 SCC enzyme splits linkage between C20 and C22 in side

chain of cholesterol to form pregnenolone and isocaproic aldehyde.
–– Pregnenolone is translocated to smooth endoplasmic reticulum (SER).
• Conversion of Pregnenolone into Progesterone
In SER, pregnenolone is changed into progesterone. Reaction is catalyzed by

3-beta-hydroxysteroid dehydrogenase enzyme.