Endocrine System

Endocrine Greek word “I separate within”

The endocrine are Ductless glands
• Secrete physiologically active substances /
chemical messengers (Hormones) directly into
the bloodstream.
• Exocrine gland secretions delivered to the
outside of the body or into the lumen of
Gut ,respiratory tract
• Hormone Greek word I Excite or Arouse was
introduced by Starling in 1905 in reference to
Secretin & Gastrin
• Endocrines together with CNS &ANS
forms the great coordinating systems
which regulate all the body functions
• How ??
They receive information, interpret &
integrate it and initiate responses via
bloodstream & nerves, to arouse the
bodily activities most appropriate to the
needs of the body while preserving the
Homeostasis
Endocrines plays a important role in
1. Metabolism
2. Water & Electrolyte balance
3. Growth & Development
(Skeletal, Neural, Reproductive)
4. Endocrine mechanisms are concerned
with the ability of humans to reproduce,
and the sexual maturation required for
this function
5. BEHAVIOR
 Chemical Structure & Synthesis of
Hormones
1. Polypeptides & Proteins Hormones
of Pituitary gland, PTH, Pancreas
etc.
2. Steroids Sex hormones , Adrenal
cortex hormones
3. Derivatives of tyrosine Amino acid
derivatives
, Ad & Nor adrenaline
• Polypeptide & Protein Hormones are
synthesized as Pre-pro-hormone
• In E R cleaved to form Pro-hormone
• In Golgi Apparatus are packed into
secretory vesicles
• In vesicles pro-hormone cleaved into
hormone & are Stored in cytoplasm
• Released by exocytosis into circulation
for transport to target tissue
• Steroid Hormones
Are not stored
Are synthesized from Cholesterol
Are lipid soluble & are highly
diffusible
Are transported in bound form in
circulation
Tyrosine AA derivatives
 are synthesizes & incorporated
with thyroglobulin in the thyroid
follicle
 Are transported in bound form

 Ad & Nor adrenaline are stored in

vesicle in adrenal medulla neurones
& released by exocytosis
 Coordination of Body Functions by
Chemical Messengers
• Neurotransmitters Act locally
• Endocrine/ Classical Hormones
• Neuroendocrine Hormones
( Hypophysiotropic Hormones )
• Paracrine
• Autocrine Poured into ECF
• Cytokines
 Transport &Clearance of Hormones from
the Blood
2 factors can increase or decrease the
hormone in the blood
a. Rate of secretion of hormone
b. Rate of removal of hormone from the
blood
Metabolic Clearance Rate
= Rate of disappearance of H from plasma /
Conc. Of H in plasma
 Feedback Control Hormone Secretion
Levels of control within Endocrine System
Long loop feedback
Short loop feedback
Ultra short loop feedback
 Hypothalamus
Anterior Pituitary
Gland ( Hypo-Pit- gland Axis)
Negative feedback
Positive feedback When the
biological action of the hormone
causes additional secretion of the
hormone
In addition control by :
a. Stress
b. Biological rhythm
Circadian (DAY) rhythm
Circhoral (HOUR) rhythm
c. Neural ( Neuroendocrine reflex)
d. Sleep
e. Exercise
f. Metabolites e.g. Glucose, AA,
 Most important Endocrine glands
• Hypothalamus
• Pituitary Gland
Anterior Pituitary
Posterior Pituitary
• Thyroid gland
• Parathyroid Gland
• Adrenal Gland
Adrenal Cortex
Adrenal Medulla
• Pancreas
• Gonads
• Testis in males
• Ovaries in females
• Placenta during pregnancy
• Heart
• Kidney
• GIT
• Adipocytes
Hypothalamus controls Pituitary Gland
• Anterior Pituitary by Hypophysitropic
hormones via Hypothalamic-
Hypophysial portal circulation
• Posterior Pituitary is connected to
hypothalamus via Hypothalamic -
Hypophysial tract neurons are
present in supraoptic &
paraventricular nuclei
 Hypophysiotropic Hormones
There are six established hypothalamic releasing and
inhibiting hormones :
• Corticotropin-releasing hormone (CRH) 41AA
• Thyrotropin-releasing hormone (TRH) 3AA
• Growth hormone- releasing hormone (GRH)44AA
• Growth hormone-inhibiting hormone
(GIH/ somatostatin) 14AA
• Gonadotropin-releasing hormone (GnRH) 10AA
luteinizing hormone-releasing hormone (LHRH)
• Prolactin-inhibiting hormone (PIH)
 Hypophysiotropic Hormones
• In addition, a prolactin-releasing
hormone (PRH) has been postulated to
exist.
• TRH, VIP, and several other polypeptides
found in the hypothalamus stimulate
prolactin secretion, but it is uncertain
whether one or more of these peptides is
the physiologic PRH
• The TRH-secreting and CRH-secreting
neurons are in the medial parts of the
paraventricular nuclei
• The GRH-secreting and Prolactin
secreting neurons are in the arcuate
nuclei
• The GnRH-secreting neurons are
primarily in the medial preoptic area
• The somatostatin-secreting neurons
are in the periventricular nuclei
The hypophysiotropic hormones affect the
secretion of more than one APH
• GnRH FSH & LH.
• TRH Prolactin & TSH
• Somatostatin inhibits TSH & GH. It
inhibits the abnormally elevated
secretion of ACTH in patients with
Nelson's syndrome.
• CRH stimulates the secretion of ACTH
and β-LPH.
 Hypothalamus dysfunctions
• Related to Endocrine
• Neurological
Obesity
Diabetes insipidus
Hypogonadism
Anoraxia
Precocious puberity
Kallman’s sundrome
 Anterior Pituitary /Adenohypophysis

The anterior pituitary secretes 6 hormones:

• Growth hormone, 191 AA
• Thyroid-stimulating hormone (thyrotropin, TSH)
α 89 AA β subunit 112 AA
• Adrenocorticotropic hormone (corticotropin,
ACTH) 39AA
• Follicle-stimulating hormone (FSH),
• Luteinizing hormone (LH)
• Prolactin (PRL) 198 AA
• An additional polypeptide, β-lipotropin (β-LPH),
is secreted with ACTH,
• In women, FSH and LH act in
sequence on the ovary to produce
growth of the ovarian follicle,
ovulation, and formation and
maintenance of the corpus luteum.
• In men, FSH and LH control the
functions of the testes
• Prolactin stimulates lactation in
women
• ACTH, prolactin, and growth hormone
are simple polypeptides or proteins
• TSH, LH, and FSH are glycoproteins
have 2 subunit αβ
Other glycoprotein H. is hCG
• Prolactin acts on the breast
• The remaining five are tropic hormones;
ie, they stimulate secretion of
hormonally active substances by other
endocrine glands or, in the case of
growth hormone, the liver and other
tissues
• The anterior lobe of the pituitary also
secretes β-lipotropin ( β-LPH)
 PITUITARY HYPERFUNCTION IN HUMANS

Tumors of the somatotropes /

Acidophilic cells 30-40% cells of the
anterior pituitary secrete large
amounts of growth hormone,
leading
In children to gigantism
In adults to acromegaly
• Proganthism
• Abnormal growth of viscera/internal
organs may prove fatal
• 20-40% patients may have increase
Prolactin
• 25% may develop abnormal glucose
tolerance
• 4% may develop Lactation
• Tmt. Somatostatin analogues
GH receptor’s antagonist
Surgical removal of tumour
 DWARFISM
• GRH deficiency,
• GH deficiency,
• Deficient secretion of IGF-I
• Laron dwarfism: Receptors are
nonresponsive to GH GH Normal
but Plasma IGF-I is markedly reduced,
along with IGFBP 3
• Africans pygmies IGF-1 level fails to
rise at puberty
 Other causes of Dwarfism
• Cretinism Idiotic look
• Turner's syndrome/gonadal dysgenesis seen
in patients who have an XO chromosomal
pattern
• Chronic abuse and neglect can also cause
dwarfism in children. This condition is
known as psychosocial dwarfism or the
Kaspar Hauser syndrome, named for the
patient with the first reported case
ACHONDROPLASIA: Most common form
of dwarfism in humans
• Characterized by short limbs with a
normal trunk
• It is an autosomal dominant condition
caused by a mutation in the gene that
codes for fibroblast growth factor
receptor 3 (FGFR3).
• This member of the fibroblast growth
receptor family is normally expressed in
cartilage and the brain.
Panhypopituitarism
• In women who have an episode of shock
due to PPH, the pituitary may become
infarcted, with the subsequent
development of PP necrosis (Sheehan's
syndrome). The blood supply to the
anterior lobe is vulnerable because it
descends on the pituitary stalk through
the rigid diaphragma sellae, and during
pregnancy the pituitary is enlarged.
• Simmond’s disease
POSTERIOR PITUITARY SECRETION
• Vasopressin
• Oxytocin
They are nonapeptides with a
disulfide ring at one end
• Diabetes insipidus is the syndrome that
results when there is a vasopressin
deficiency
• Nephrogenic diabetes insipidus : when
the kidneys fail to respond to the
hormone
 The Intermediate lobe
• The intermediate lobe is rudimentary in human
• Intermediate-lobe cells and corticotropes of the anterior lobe both
synthesize a large precursor protein that is cleaved to form a family of
hormones.
• After removal of the signal peptide, this prohormone is known as
proopiomelanocortin (POMC).
• This molecule is also synthesized in the hypothalamus, the lungs, the
gastrointestinal tract, and the placenta.
• In the corticotropes, it is hydrolyzed to ACTH and β-LPH plus a small amount
of β -endorphin, and these substances are secreted.
• In the intermediate lobe cells, POMC is further hydrolyzed to corticotropin-
like intermediate-lobe peptide (CLIP),β -LPH, and appreciable quantities of
β-endorphin. The functions, if any, of CLIP andβ -LPH are unknown, whereas
-endorphin is an opioid peptide that has the five amino acid residues of
metenkephalin at its amino terminal end. The melanotropins - andα -MSH
are also formed.
• neither α-MSH norβ -MSH is secreted in adults
 Pigment Abnormalities in Humans
• The pigmentary changes in several endocrine diseases are due to changes
in circulating ACTH. For example, abnormal pallor is a hallmark of
hypopituitarism. Hyperpigmentation occurs in patients with adrenal
insufficiency due to primary adrenal disease. Indeed, the presence of
hyperpigmentation in association with adrenal insufficiency rules out the
possibility that the insufficiency is secondary to pituitary or hypothalamic
disease because in these conditions, plasma ACTH is not increased (see
Chapter 20: The Adrenal Medulla & Adrenal Cortex).
• Albinos have a congenital inability to synthesize melanin. Albinism occurs
in humans and many other mammalian species. It can be due to a variety
of different genetic defects in the pathways for melanin synthesis.
Piebaldism is characterized by patches of skin that lack melanin as a result
of congenital defects in the migration of pigment cell precursors from the
neural crest during embryonic development. Not only the condition but
also the precise pattern of the loss is passed from one generation to the
next. Vitiligo is due to a similar patchy loss of melanin, but the loss
develops after birth and is progressive.
 Pigment Abnormalities in Humans
• Albinos have a congenital inability to
synthesize melanin. Albinism occurs in humans
and many other mammalian species. It can be
due to a variety of different genetic defects in
the pathways for melanin synthesis.
• Piebaldism is characterized by patches of skin
that lack melanin as a result of congenital
defects in the migration of pigment cell
precursors from the neural crest during
embryonic development Vitiligo is due to a
similar patchy loss of melanin, but the loss
Thyroid Gland
Follicular cells secretes
Tetra iodothyronine (Thyroxine )
Tri iodothyronine
Parafollicular Cells
Thyrocalcitonin
• Hypothyroidism non pitting oedema
• Myxedema ( adult hypothyroidism )
• Cretinism Children who are hypothyroid
from birth or before are called cretins.
They are dwarfed and mentally retarded
and have potbellies and enlarged,
protruding tongues
Worldwide, congenital
hypothyroidism is one of the most
common causes of preventable mental
retardation
• Hyperthyroidism
Grave’s Disease
Autoimmune Disease TS Igs +++
( Exophthalmos)
 Parathyroid glands
• Parathyroid hormone (PTH)
• In humans, few are seen before puberty, and
there number increases with age
• PTH is essential for life.
• In humans, tetany is most often due to
inadvertent parathyroidectomy during thyroid
surgery.
• The signs of tetany include Chvostek's sign
• Trousseau's sign, a spasm of the muscles of the
upper extremity that causes flexion of the wrist
and thumb with extension of the fingers
 Parathyroid Hormone Excess
• Hyperparathyroidism in humans
hypercalcemia and hypophosphatemia
++
• Usually asymptomatic
• However, there may be minor changes
in personality, and calcium-containing
kidney stones occasionally form
ADRENAL CORTEX
Essential endocrine gland
• The mineralocorticoid Aldosterone
• The glucocorticoids Cortisol
Corticosterone
• The androgens
Dehydroepiandrosterone (DHEA)
Androstenedione
• Excess androgen secretion causes
masculinization (adrenogenital
syndrome) and precocious
pseudopuberty or female
pseudohermaphroditism.
• Excess glucocorticoid secretion
produce Cushing's syndrome
• Excess mineralocorticoid secretion
primary hyperaldosteronism; Conn's
syndrome.
 Primary adrenal insufficiency
 Addison's disease The condition
used to be a relatively common
complication of tuberculosis, and now
it is usually due to autoimmune
inflammation of the adrenal
• Primary adrenal insufficiency Addison's disease. The
condition used to be a relatively common complication of
tuberculosis, and now it is usually due to autoimmune
inflammation of the adrenal. Patients lose weight, are tired,
and become chronically hypotensive. They have small hearts,
probably because the hypotension decreases the work of the
heart. Eventually they develop severe hypotension and shock
(addisonian crisis). This is due not only to mineralocorticoid
deficiency but to glucocorticoid deficiency as well. Fasting
causes fatal hypoglycemia, and any stress causes collapse.
Water is retained, and there is always the danger of water
intoxication. Circulating ACTH levels are elevated. The diffuse
tanning of the skin and the spotty pigmentation characteristic
of chronic glucocorticoid deficiency. Minor menstrual
abnormalities occur in women, but the deficiency of adrenal
sex hormones usually has little effect in the presence of normal
testes or ovaries.
 Adrenal medulla
• Nor Adrenaline
• Adrenaline
• Dopamine
• Pheochromocytomas AM Tumour secrete
norepinephrine, or epinephrine, or both &
produce sustained hypertension
• 15% of epinephrine-secreting tumors secrete
this catecholamine episodically, producing
intermittent bouts of palpitations, headache,
glycosuria, and extreme systolic hypertension
 Pancreas

• Insulin β / B cells
• Glucagon α / A cells
• Somatostatin δ / D cells
• Pancreatic polypeptide F cells

• Type 1 & Type II Diabetes mellitus

• Hyperinsulinism
Mechanism of Action of Hormones
Hormone Act as first messenger
• Receptors are specific
• Agonist & Antagonist
Nor adrenaline
β blockers
• Classification of receptors
Cytosol/ Nuclear receptors
Membrane bound receptors
 Mechanism of Action of Hormones
• The receptors for Hs have now been
isolated and characterized
• These proteins are not static
components of the cell, but their
numbers increase and decrease in
response to various stimuli
• Their properties change with
changes in physiologic conditions
• When a hormone or neurotransmitter is
present in excess, the number of active
receptors generally decreases
(Down-regulation)
• In the presence of a deficiency of the
chemical messenger, there is an increase in
the number of active receptors
(Up-regulation)
• Angiotensin II in its actions on the adrenal
cortex is an exception; it increases rather than
decreases the number of its receptors in the
• In the case of receptors in the membrane,
receptor-mediated endocytosis is
responsible for down-regulation
(internalization)
• Some receptors are recycled after
internalization, whereas others are
replaced by de novo synthesis in the cell
• Another type of down-regulation is
desensitization, in which receptors are
chemically modified in ways that make
them less responsive
Mechanism Examples
Open or close ion Ach on N cholinergic R;
channels in cell Nor Ad on K+
Membrane channel in the heart

Act via
cytoplasmic Thyroid hormones,
or retinoic acid, &
nuclear receptors all steroid hormones
to increase
transcription
of selected mRNAs
 Angiotensin II,
Activate PLC with
intracellular nor ad
via α1-adrenergic
production of DAG,
vasopressin via V1
IP3, and other
receptor
inositol
phosphates
 Nor ad via α1-
Activate or inhibit
adrenergic receptor
Adenyl Cyclase
(increased cAMP);
causing increased
or
decreased
intracellular adrenergic receptor
production of cAMP (decreased cAMP)

Increase cGMP in ANP; NO (EDRF)

cell
Increase Tyrosine
Insulin, EGF, PDGF,
Kinase activity of
M-CSF
cytoplasmic
portions of
transmembrane
receptors

Increase serine or TGF , MAPKs

threonine
kinase activity
 Stimulation of Transcription
• The estrogen and the T3 receptors bind
hormones in the nucleus
• The glucocorticoid, estrogen, and
progesterone receptors, the receptor is
bound to the heat shock protein Hsp90
• Hsps are a group of intracellular proteins
whose amounts increase when cells are
exposed to heat and other stresses, and
they help the cells survive a variety of
stresses are called stress proteins.
 G Proteins
• G proteins ( Nucleotide regulatory
proteins that bind GTP )
• A common way to translate a signal to
a biologic effect inside cells is via G prs
• When the signal reaches a G protein,
the protein exchanges GDP for GTP. The
GTP–protein complex brings about the
effect
 G Proteins
• GTPase activity of the protein then
converts GTP to GDP, restoring the
resting state.
• The GTPase activity is accelerated
by a family of RGS (regulators of G
protein signaling) proteins that
accelerate the formation of GDP.
 G Proteins
The larger heterotrimeric G proteins,
couple cell surface receptors to
catalytic units that catalyze the
intracellular formation of second
messengers or couple the receptors
directly to ion channels
GPCRs
Small G proteins are involved in many
cellular functions & are put in 3 families:

1. Rab family of these proteins regulate

the rate of vesicle traffic between the
endoplasmic reticulum, the Golgi
apparatus, lysosomes, endosomes, and the
cell membrane.
 2. Family of small GTP-binding proteins, the
Rho/Rac family, mediates interactions
between the cytoskeleton and cell membrane
3. The Ras family, regulates growth by
transmitting signals from the cell membrane
to the nucleus.
• The members of these three families are
related to the product of the ras proto-
oncogene.
Inositol Triphosphate & Diacylglycerol as
Second Messengers
 Cyclic AMP
• Activation of Adenylyl Cyclase
 Guanylyl Cyclase
Cyclic Guanosine Monophosphate
( cGMP).
 Is important in vision in both rods and
cones.
 There are cGMP-regulated ion channels,
 cGMP activates cGMP-dependent
kinase ( producing a number of
physiologic effects
 Growth Factors
Growth factors have become increasingly
important in many different aspects of
physiology. They are polypeptides and proteins &
are divided into three groups.
• First group is made up of agents that foster the
multiplication or development of various types
of cells;
• Nerve growth factor
• Insulin-like growth factor
• Activins and Inhibins
• Epidermal growth factor (EGF)
• The Second group are the cytokines
• These factors are produced by
macrophages and lymphocytes and
are important in regulation of the
immune system
• The third group is made up of the
colony-stimulating factors that
regulate proliferation and maturation
of red and white blood cells.
• One of the direct pathways by which
growth factors alter gene activity.
• TK, tyrosine kinase domain
• Grb2, Ras activator controller
• Sos, Ras activator; Ras, product of the
ras gene
• MAP K, mitogen-activated protein kinase
• MAP KK, MAP kinase kinase
• TF, transcription factors
Most of Growth factors do not have
tyrosine kinase domains in their
cytoplasmic portions and some have
little or no cytoplasmic tail
However, they initiate tyrosine kinase
activity in the cytoplasm & act via JAK
–STAT mechanism
 Pituitary Gland/ Hypophysis
• 0.5-1Gm wt.
• 1cm in diameter Sella turcica of Sphenoid bone
• Histology
• In the posterior lobe, the endings of the supraoptic and
paraventricular axons can be observed in close relation to blood
vessels. Pituicytes, stellate cells that are modified astrocytes, are
also present.
• As noted above, the intermediate lobe is rudimentary in humans
and a few other mammalian species. In these species, most of its
cells are incorporated in the anterior lobe. Along the residual
cleft are small thyroid-like follicles, some containing a little
colloid. The function of the colloid, if any, is unknown.
• The anterior pituitary is made up of interlacing cell cords and an
extensive network of sinusoidal capillaries. The endothelium of
the capillaries is fenestrated, like that in other endocrine organs.
The cells contain granules of stored hormone that are extruded
from the cells by exocytosis. The granules presumably break
down in the pericapillary space, and their contents enter the
capillaries.
Cell Type Hormones % of Total Stain Affinity Diameter
Secreted Secretory of
Cells Secretor
Granules
(nm)

Somatotrope Growth 50 AcidophilIc 300–40

Hormone
Lactotrope Prolactin 10–30 AcidophilIc 200

Corticotrope ACTH 10 BasophiliC 400–55

Thyrotrope TSH 5 Basophilic 120–20

Gonadotrope FSH, LH 20 Basophilic 250–40

 GROWTH HORMONE NOT REQUIRED FOR
FOETAL G

Biosynthesis & Chemistry

The long arm of human chromosome
17 contains the GH-hCS cluster that
contains five genes:
1.HGH-N (for normal), codes for GH
2. hGH-V (for variant), codes for
the variant form of GHs
3.Two code for hCS
4. is probably an hCS pseudogene
• Normal" human growth hormone, the product of
hGH-N, accounts for 75% of the circulating hGH.
• MW 22,000, it is also known as 22 K hGH.
• 191 amino acid residues with 2disulfide bridge
• hGH-N gene undergoes alternative splicing to
produce a growth hormone identical to 22 K hGH
except that amino acid residues 32–46 are
deleted. This smaller form, 20 K hGH, is also
biologically active and makes up about 10% of the
circulating growth hormone. The physiologic
significance of having the two principal forms, 22
K and 20 K, is unknown
• GH are species specific
• HGH prepared by DNA recombinant
technique is commercially available
 Plasma level, transport & Metabolism
• The basal plasma GH level measured by
radioimmunoassay in adult humans is
normally less than 3 ng/mL.
• GH is bound to a protein in plasma that is a
large fragment of the extracellular domain
of GH receptor
• It appears to be produced by cleavage of
receptors in humans, and its concentration is
an index of the number of GH receptors in
the tissues.
 Plasma level, transport & Metabolism
• About half the GH activity is bound,
providing a reservoir of the hormone to
compensate for the wide fluctuations that
occur in secretion.
• GH is metabolized rapidly, probably at least
in part in the liver.
• The half-life of circulating GH in humans is
6–20 minutes
• The daily growth hormone output has been
calculated to be 0.2–1.0 mg/d in adults.
• Hypothalamic and Peripheral Control of Growth Hormone
Secretion
• The secretion of growth hormone undergoes marked and rapid
spontaneous fluctuation in children and young adults before it
declines in old age. Therefore, it is not surprising that it is
under hypothalamic control. One factor is growth hormone-
releasing hormone (GRH); a second is somatostatin, the
growth hormone release-inhibiting factor A third is ghrelin.
The main site of ghrelin synthesis and secretion is the stomach,
but it is also produced in the hypothalamus and has marked
growth hormone-stimulating activity. In addition, it appears to
be involved in the regulation of food .
• Growth hormone secretion is under feedback control, like the
secretion of other anterior pituitary hormones. Growth
hormone increases circulating IGF-I, and IGF-I in turn exerts a
direct inhibitory action on growth hormone secretion from the
pituitary. It also stimulates somatostatin secretion