REGULATION OF HORMONE SECRETION

Hormones secretion is strictly under control of several mechanisms.

a. Neuroendocrinal Control Mechanism

Nerve impulses control some endocrine secretion. Cholinergic sympathetic fibers stimulate
cathecholamine secretion from adrenal medulla. Centres in the midbrain, brainstem,
hippocampus, etc can send nerve impulses which react with the hypothalamus through
cholinergic and bioaminergic neurons. At the terminations of these neurons they release
acetylcholine and biogenic amines to regulate the secretions of hypophysiotropic peptide
hormones from hypothalamic peptidergic neurons. Some of the endocrine releases are controlled
by either stimulatory or inhibitory hormones from a controlling gland, e.g corticosteroids are
controlled by coticotropins and thyroid hormonrs are controlled by thyroptropin from anterior
pituitary. The tropins are further regulation by hypothalamic releasing hormones.

b. Feedback Control Mechanism

It is due mainly to negative feedback that such control is brought about. When there is a high
blood level of a target gland hormone. It may inhibit the secretion of the tropic hormone
stimulating that gland. Adrenal cortex secretes a hormone called cortisol which brings about the
inhibition of secretion of corticotrophin from anterior pituitary and corticotropin releasing
hormones from the hypothalamus by a long-loop feedback. This leads to reduction in cortisol
secretion.

c. Endocrine Rhythms

There are certain cyclic rhythmic associated with the secretion of hormone over a period of time.
When there is a cyclic periodicity of 24 hrs, it is called as circadian rhythm. However, if it is
more than 24hrs, it is named as infradian rhythm and when it is less than 24 hrs it is called as
ultradian rhythm. Due to rhythm the highest and lowest concentration of corticotrophin is
normally found in the morning and around midnight. Growth hormone and prolactin rise in the
early hours of deep sleep. Cortisol peak is found between 4am and 8am. Endocrine rhythms
results from cyclic activities of a biological clock in the limbic system supplemented by the
diurnal light-dark and sleep activity cycles and mediated by the hypothalamus.

Pituitary Hormones

Control of secretion

Secretion of hormones from anterior pituitary are controlled by

  Nervous mechanism: by release of regulatory factors from hypothalamus
 Hormonal mechanism by feedback inhibition

Hypothaciamic Releasing Factors

Control of hormone secretion from pituitary is in part modulated by regulating factors or

hormone from the hypothalamus. The median eminence of hypothalamus is connected directly to
the pituitary stalk. Within this stalk is a portal system of blood vessels required to maintain
normal secretary activity of the pituitary gland. The activities of the cells of the anterior lobe are
controlled by the nerve cells of the hypothalamus which send axons to the capillary beds. The
nerve endings liberate chemical substances, hypothalamic releasing factors or hormones. At
present 10 discrete regulatory factors have been described that may affect the synthesis as well as
secretion of specific pituitary hormone. They are:

Hypothalamic Hormone or factor Abbreviation

* Corticotropin (ACTH) releasing hormone CRH or CRF

* Thyrotropin (TSH) releasing hormone TRH or TRE

* Follicle stimulating hormone (FSH) FSH-RH or FSH-RF

* Luteinizing hormone (LH) releasing hormone LH-RH or LH-RF

* Growth Hormone (GH) GH-RH or GH-RF

releasing hormone GH-RF

* Growth hormone release inhibiting GH-RH or GIF

* Prolaction (PL) release PL-RIH or PL-RIF

* Melanocyte stimulating hormones mSH-RIH or

* (MSH) release inhibiting hormone MSH-RIF

* Melanocyte stimulating hormone MSH-RH or

* (MSH) releasing hormone MSH- RF

Hormones of the Anterior Pituitary

The hormones secreted by the anterior lobe of the pituitary gland are:
  Growth hormone and
 Pituitary tropic hormones such as protactin, gonadotropins (FSH and LH), thyrotropic
hormones (TSH) and adrenocorticotropic hormones (ACTH)
Growth Hormone.(GH)

Growth Hormone (GH) or somatotropin (STH) was first isolated in sufficient quantity from
cattle, now it has been prepared in crystalline form several species including man.

Chemistry

Growth hormone from all mammalian species consists of a single polypeptide with a molecular
weight of about 21500. It consists of 191 amino acids. There are two disulfide bridges between
the adjacent cysteine residue (52 and 165 and 183 189). Although there is a high degree of
similarity in the amino acid sequences of human, bovine and porcine GH, only human GH or that
of other primates is active in man. GH can bring about some of the actions of prolactin and
human placental lactogen (HPL) due to amino acid homology.

Metabolic Role

Growth hormone has a variety of effects on different tissues. The hormones act slowly requiring
from 1-2 hours to several days before it biological effects are detectable. This slow action and its
stimulatory effects on RNA synthesis suggest that it is involved in protein synthesis. The
hormone acts by binding to specific membrane receptors on its target cells. But its exact
mechanism of action and second messenger are not yet known.

1. Protein Synthesis

Growth hormone brings about positive nitrogen balance by retaining nitrogen. It stimulates
overall protein synthesis with an associated retention of phosphorus probably by increasing
tubular reabsorption. Blood amino acid and urea level are decreased. It facilitates the entry of
amino acids into the cell. In addition, growth hormone facilitates protein synthesis in muscle
tissue by a mechanism independent of its ability to provide amino acids. This protein synthesis
carries on even if the amino acid transport is blocked.

 Growth hormones increases DNA and RNA synthesis

 It increases the synthesis of collagen
2. Lipid Metabolism
Growth hormone brings about lipolysis in a mild way by mobilizing fatty acids from adipose
tissue by activating the hormone sensitive triacylglycerol lipase. Thus it increases circulating
fatty acids.

3. Carbohydrate Metabolism

Growth hormone is a diabetogenic hormone, antagonizes the effect of insulin. Hypersecretion of

GH can result in hyperglycemia, poor sugar tolerance and glycosuria. Growth hormone
produces.

 Hyperglycaemia by increasing gluconeogenesis

 It reduces insulin sensitivity and thereby decreases the hypoglycaemic effect of
insulin
 It brings about glycostatic effect, i.e increases liver glycogen it can also increase
muscle and cardiac glycogen level probably by reducing glycolysis.

4. Effect on Growth of Bones and Cartilages

Growth hormone when secreted in abnormally high concentration prolongs the growth of
epiphyseal cartilages to cause over growth of long bones. Acromegaly is found in adults.
Hyposecretion causes stunted stature due to premature cessation of growth of the epiphyseal
cartilages and consequently of long bones.

 The effect of growth hormone partly depends upon its calcium anabolic action. It
promotes the retention of calcium and phosphate which helps in ossification and
osteogenesis.
 It enhances the incorporation and hydroxylation of proline in the matrix collagen,
incorporation of amines into glycosaminoglycans of cartilage, incorporation of
sulphate into matric proteoglycans like chondroitin sulphates, the synthesis of DNA
and RNA in chondrocytes.
 The growth effects are mediated by a peptide called insulin-like growth factor I (IGF-
I) or somatomedin – C)

5. Prolactin Action

Growth hormone has a sequence homology with prolactin. Growth hormone binds to membrane
receptors for prolactin and stimulates the growth and enlargement of mammary gland.

6. Ion or Minerial metabolism

It is observed that the intestinal absorption of calcium is increased by GH, since the bone growth
and development is stimulated by growth hormone. Growth hormone retains Na, Ca, K, Mg, and
PO43-

PITUITARY TROPIC HORMONES

In addition to GH, anterior pituitary gland secretes some tropic hormones usually called as
pituitary tropins.

A tropin or tropic hormones is the one which influences the activities of other endocrine gland,
principally those involved in stress and reproduction. These are carried by the blood to other
target gland. The pituitary tropins are under the positive and negative control of peptide factors
from hypothalamus. Further the tropic hormones are usually subject to feedback inhibition at the
pituitary or hypothalamic level by hormone product of the final target gland. Prolactin
(mammotropin), TSH (thyrotropin), FSH and LH (Gonadotropins), ACTH (Corticotropin) are
the tropic hormones secreted by the pituitary gland.

A. Prolaction: PRL or Leuteotropic Hormone (LTH)

This is a monomeric simple protein (Mw23, 000). It contains 199 amino acids with three –s-s-
linkages. It is secreted by lactotroph -cells of anterior pituitary and has sequence homology
with growth hormone.

Metabolic Role

 The main function of PRL is to stimulate mammary growth and the secretion of milk.
By acting through specific glycoprotein receptors on plasma membrane of mammary
gland cells, it stimulates mRNA synthesis. This ultimately leads to enlargement of
breast (udder) during pregnancy. This is called mammotropic action.
 The synthesis of milk proteins such as lactalbumin, and casein takes place after
parturition such an effect is called lactogenic action.
 Estrogen, thyroid hormones and glucocorticoids increases the number of prolactin
receptors on the mammary cell membrane.
 Progesterone has the opposite effect.

B. Thyrotrophic Hormone or Thyroid Stimulating Hormone (TSH)

 This is produced by basophil cells of anterior pituitary and is glycoprotein in nature. Its
molecular weight is approximately 30,000. This consists of  and β submits.

 The  - subunit of TSH, LH and HCG and FSH are nearly identical
 The biological specificity of thyrotropin must therefore be in β -subunit. The -
subunit consist of 92 amino acids while β-subunit has 112 amino acids. Both  and β
have several disulfide bridges. It carbohydrate content is 21% and it and β chains
bears two and one oligosaccharide chains linked by N-glycosidic linkages to specific
asparagine residues. The chains are synthesized separately by separate structural
genes and later undergo post-translation modification and glycosylation separately.
Metabolic Role

There are glycoprotein receptors on the thyroid cells membrane which binds to the receptor
binding site on β-subunit of TSH. The complex then activates adenylate cyclase which catalyzes
the formation of c-AMP which acts as the second messenger for most TSH actions an follows:

 TSH stimulates the synthesis of thyroid hormones at all stages such as Iodine uptake,
organification and coupling.
 It enhances the release of stored thyroid hormones.
 It increases DNA content, RNA and translation of proteins, cell size.
 It stimulates glycolysis, TCA Cycle, HMP and phospholipids synthesis. Stimulation
of last two does not involve c-AMP.
 It activates adipose tissue lipase to enhance the release of fatty acids (lipolysis)

C. ADRENOCORTICOTROPIC HORMONE (ACTH) OR CORTICOTROPIN: It is a

single polypeptide containing 39 amino acids in its structure with a molecular weight of 4500
two forms have been isolated, -corticotropin and β-corticotropin. Biological activity of ACTH
resides in the first 23 amino acids from N-terminal end. The sequence of these 23 amino acids in
the peptide chain is the same in all species tested. The remaining biologically inactive 16 amino
acid residue varies accordingly to sources. ACTH is synthesized as a part of precursor peptide of
[Link] of 31500 with 260 amino acids. ACTH contains sequence of amino acids common for
LPH, MSH and the endorphins. The precursor molecule is synthesized as a glycoprotein called
pro-opiomelanocortin peptide (POMC). Various proteolytic enzymes hydrolyze POMC to give
different peptides. Thus POMC is broken down into

 ACTH
 β-lipotropin (LPH). β-LPH is further cleaved into γ-LPH and endophins.

METABOLIC ROLE
The principal actions of corticotrophin are exerted on the adrenal cortex and extra adrenal tissue.
ACTH increases the synthesis of corticosteroids by the adrenal cortex and also stimulates their
release form the gland. Profound changes in the adrenal structure, chemical composition and
enzymatic activity are observed as a response to ACTH. Total protein synthesis is found to be
increased. Thus, ACTH produces both a tropic effect on steroid production and tropic effect an
adrenal tissue. It is observed that ACTH has specific receptors on cells of fasciculata which
increases c-AMP levels in the cell. This activation is calcium dependent. This result in DNA
content aid RNA is transcribed. This leads to proliferation of fasciculata cells and growth of
adrenal cortex.

 ACTH also stimulates the synthesis and secretion of glucocorticoids.

 ACTH is found to increase the transfer of cholesterol from plasma lipoproteins into
the fasciculata cells.
 The ACTH induces rise in c-AMP, bring about phosphorylation and activation of
cholesterol esterase. The enzyme action ultimately makes a large pool of free
cholesterol.
 It activates the rate limiting enzyme for conversion of cholesterol to pregnenolone.
 It activates dehydrogenases of HMP to increase the concentration of NADPH
required for hydroxylation.
 By activating adenylate cyclase of adipose tissue, it increases intracellular c-AMP
which in turn activates hormone sensitive lipase. This enzyme is involved in lipolysis
which increases the level of free fatty acids.
 It leads to increase ketogenesis.
 Direct effects on carbohydrate metabolism include :
 Lowering of blood glucose
 Increase in glucose tolerance
 Deposition of glycogen in adipose tissue is increased, regarded as due to stimulation
of insulin secretion.
 It has MSH activity due to homology in amino acid sequence.

D. PITUITARY GONADOTROPINS

These tropic hormones influence the function and maturation of the testes and ovary, and are
of two types.

 Follicle stimulating hormone (FSH)

 Luteinizing hormone (LH)
Both of them are glycoproteins with sialic acid, hexose and hexosamine as the carbohydrate
moiety. Molecular weight of FSH is 25000 and that of LH is 40000. FSH, LH are dimers of
 and β-chains linked non covalently. The -chain is identical for TSH, FSH and LH of the
 same species. The β-chain of human FSH and LH has respectively 118 and 112 amino acid
residues. Each chain has several disulfide bridges. A large precursor protein molecule for 
and β chains is synthesized separately in gonadotroph β-cells.

METABOLIC ROLE OF FSH

It brings about it action by specific receptor binding and c-AMP

In females:

 It promotes follicular growth

 Prepares the Graafian follicle for the action of LH
 Enhances the release of estrogen induced by LH
In males:

 It stimulates seminal tubule and testicular growth

 Plays an important role in maturation of spermatozoa.

Role of FSH in Spermatogenosis

The conversion of primary spermatocytes into secondary spermatocytes in the seminiferous

tubules is stimulated by FSH. In absence of FSH spermatogenesis cannot proceed. However,
FSH by itself cannot cause complete formation of spermatozoa. For its completion testosterone is
also required. Thus, FSH seems to initiate the proliferation process of spermatogenesis, and
testosterone is apparently necessary for final maturation of spermatozoa. Since the testosterone is
secreted under the influence of LH, both FSH and LH must be secreted for normal
spermatogenesis.

Metabolic Role of LH

This hormone is also known as interstitial cells stimulating hormone (ICSH)

In females

 It causes the final maturation of Graafian follicle and stimulates ovulation

 Stimulates secretion of oestrogen by theca and granulosa cells.
 It helps in the formation and development of corpus luteum for luteinization of cells.
 In conjunction with luteotropic hormone (LTH) it is concerned with the production of
estrogen and progesterone by the corpus luteum.
 In the ovary it can stimulate the non-germinal elements, which contain the interstitial
cells to produce the androgens, androstenedione, dihydroepiandronstenedione
(DHEA) and testosterone.

ACTION OF LH IN OVULATION (Ovulatory surge for LH): It is necessary for final

follicular growth and ovulation. Without this hormone, even though large quantities of FSH
are available the follicle will not progress to the stage of ovulation. LH acts synergistically
with FSH to course rapid swelling of follicles shortly before ovulation. It is worth noting that
especially large amount of LH called ovulatory surge is secreted by the pituitary during the
day immediately preceding ovulation.

REGULATION OF TESTOSTERONE SECRETION BY LH: Testosterone is produced

by the interstitial cells of leydig only when the testes are stimulated by LH from the pituitary
gland, and the quantity of testosterone secreted varies approximately in proportion to the
amount of LH available. Thus in males LH stimulate the development and functional activity
of leydig cells (interstitial) and consequently testicular androgen.

ENDORPHINS AND ENCEPHALINS

Endorphins are a group of polypeptides which influence the transmission of nerve impulse.
They are also known an opioides, because they bind to those receptors which bind opiates
like morphine and play a role in pain perception. The opiodes first discovered were two
penta-peptides in the brain and were named encephalin. They are of two types:

* Methionine - encephalin

* Leucine - encephalin

FORMATION OF ENDORPHINS

β – lipoprotein ( β-LPH) is the precursor for endorphin, all the three type α, β and γ and also
for β-MSH.

β- lipotprotein (β-LPH) is derived from the precursor molecule “Pro-opiomelanocortin

peptide (POMC). It is a single chain polypeptide containing 93 amino acids.

γ-LPH containing 60 amino acids is a part of β-LPH

POMC β-LPH

(93 a.a.) (β -lipoprotein)

 Endorphins β -MSH

(, β, Y)

TYPES OF ENDORPHINS

There are three types of endorphins, β.y

 The sequence of 31 amino acids at the C-terminal of β-LPH, (Obtained from POMC)
i.e amino acid 104 to 134 gives β endorphin
 - endorphin (104 to 117 amino acid) containing 17 amino acids less than the β from
the C terminal end.
 γ-endorphin (104 to 118) containing 16 amino acid less than the β from the C-
terminal end.

FUNCTION

Endorphins bind to the same CNS receptors like the morphine opiates and they play a role in
the endogenous control of pain perception. They have highs analgesic potency than
morphine.