ENDOCRINE SYSTEM

Hypothalamus
Hypophysis
Adrenal Glands
OBJECTIVES
❑ Describe the location and boundaries of the hypothalamus
❑ Discuss the subdivisions of the hypothalamus.
❑ Describe the different hypothalamic nuclei and their functions.
❑ Discuss the location and anatomy of the pituitary gland
❑ Discuss the two division of the hypophysis and their connections
❑ Give the parts of the adenohypophysis and their secretions
❑ Give the parts of the neurohypophysis and their secretions.
❑ Discuss the anatomic structure and location of the adrenals.
❑ Know the parts of the adrenals and their secretions.
 Hypothalamus

The hypothalamus is part of the diencephalon ( the

in between the brain).
 Hypothalamus

❖ Part of Diencephalon that extends from the region of the

optic chiasma to the caudal border of the mammillary
bodies.
❖ Lies below the hypothalamic sulcus on the lateral wall of
the third ventricle
❖ Microscopically, the hypothalamus is composed of small
nerve cells that are arranged in groups or nuclei.
ANATOMIC BOUNDARIES

A : lamina terminalis
P : subthalamus
I : structures in the floor of
the 3rd ventricle
- tuber cinereum,
- infundibulam
- mammillary bodies
S : thalamus
HYPOTHALAMIC NUCLEI
❖ Preoptic region
❖ Supra optic region
❖ Tuberal region
❖ Mammillary region
 Subdivision of Hypothalamus

• Divided into 2 lateral halves by the cavity of the 3rd

ventricle
• The anterior column of fornix divides the
hypothalamus into medial and lateral zones
• The medial zone again divided into thin
periventricular zone and thick intermediate zone
 HYPOTHALAMUS
MEDIAL ZONE LATERAL ZONE

PRE-OPTIC NUCLEUS PRE OPTIC NUCLEUS

ANTERIOR/ POSTERIOR NUCLEUS SUPRA OPTIC NUCLEUS

SUPRACHIASMATIC NUCLEUS SUPRACHIASMATIC NUCLEUS

PARAVENTRICULAR NUCLEUS TUBEROMAMMILLARY NUCLEUS

DORSOMEDIAL NUCLEUS LATERAL NUCLEUS

VENTROMEDIAL NUCLEUS LATERAL TUBERAL NUCLEUS

INFUNDIBULAR NUCLEUS
 Blood Supply of HYPOTHALAMUS

➢ All derived from the circle of Willis (lying at the

base of the brain)
➢ Anterior part: anterior cerebral
arteries/anterior communicating artery
➢ Middle part: 2 posterior communicating
arteries (bulk of the blood supply)
➢ Posterior part: bifurcation of basilar arteries
➢ Superior hypophyseal arteries
 Functions of the hypothalamus:

1. autonomic control
2. thermoregulation
3. regulation of food and water intake
4. emotion and behavior
5. control of circadian rhythms
6. endocrine control
 ENDOCRINE FUNCTION

Hormones secreted by the hypothalamus and the

pituitary gland play important roles in the
regulation of virtually all aspects of growth,
development, metabolism, and homeostasis.
 Hypothalamus connections with
the hypophysis cerebri

Two pathways:
1. hypothalamohypophyseal tract
2. hypophyseal portal system
Tubulo-Infundibular Tract
 PITUITARY GLAND

❑ It is referred to as the master of endocrine glands.

❑ It is a small oval structure 1 cm in diameter.
❑Endocrine gland about the size of a pea
weighing 0.5g (0.02 oz)
❑It is a protrusion off the bottom of the
hypothalamus at the base of the brain, and
rests in a small, bony cavity (sella turcica)
covered by a dural fold (diaphragm sellae).
❑secretes hormones regulating homeostasis,
including tropic hormones that stimulate other
endocrine glands.
 PITUITARY GLAND

❑Also called the hypophysis (meaning undergrowth)

because of its location below the brain
❑smallest endocrine gland, is an unpaired ovoid
gland located in the sella turcica (behind the
sphenoid simus)
❑Carvernous sinuses are located laterally
❑ SUPERIOR : Diaphragma sellae
❑ INFERIOR : Sphenoidal air sinuses
❑ LATERAL : Cavernous sinuses
A fold of dura mater (Diaphragma sellae) covers the pituitary
gland & has an opening for passage of infundibulum
(pituitary stalk) connecting the gland to hypothalamus.
Optic chiasma
Mamillary body

Body of sphenoid

❑ it lies between optic chiasma (anteriorly) &

mamillary bodies (posteriorly).
The gland is subdivided into:
1. Anterior lobe (Adenohypophysis): it is the true gland,
secretes hormones
2. Posterior lobe (Neurohypophysis): connected to
hypothalamus through hypothalamo-hypophyseal tract,
stores hormones secreted by hypothalamic nuclei
The pars distalis is the larger bulbar portion, and the
pars tuberalis forms a sheath around the infundibulum.
The neurohypophysis consists of a large part, the pars
nervosa, and the smaller infundibulum stalk attached
to the hypothalamus at the median eminence
 ANTERIOR LOBE

❑ Hormone-releasing &
inhibiting factors produced by
hypothalamus use
Hypophyseal Portal System
of vessels to reach the anterior
lobe of pituitary gland
 POSTERIOR LOBE

❑ The neurohypophysis is
composed of neural tissue,
containing some 100,000
unmyelinated axons of large
secretory neurons with cell
bodies in the supraoptic and
paraventricular nuclei of the
hypothalamus.
 PITUITARY GLAND (HYPOPHYSIS)
HORMONE TARGET ORGAN /TISSUE
Adrenocorticotropic Hormone (ACTH) Adrenal Glands
Antidiuretic Hormone Kidney
Beta-melanocyte-Stimulating Hormone Skin
Endorphins Brian and Immune System
Enkephalins Brain
Follicle-Stimulating Hormone Ovaries or Testes
Growth Hormone Muscles and Bones
Luteinizing Hormone Ovaries or Testes
Oxytocin Uterus and Mammary Glands
Prolactin Mammary Glands
Thyroid Stimulating Hormone Thyroid Gland
 ADRENAL GLANDS

ADRENAL PHYSIOLOGY

Dr. Ryan Raymond Y. Bautista

 ADRENAL MEDULLA

❑ Constitute 28% of the mass of the adrenal glands

❑ Secretes Catecholamines
❑ Stimulated by preganglionic via splanchnic nerves
❑ Help prepare to deal with emergencies
 ADRENAL CORTEX

❑ Secretes steroid hormones

❑ Glucocorticoids → steroids with widespread effects
on the metabolism of carbohydrate and protein
❑ Mineralocorticoids → essential to the maintenance
of sodium balance and ECF volume
❑ Sex Hormones → exert minor effects on
reproductive function
ADRENAL CORTEX
END OF LECTURE
 References
Clinically Oriented Anatomy by Keith L. Moore, Arthur F. Dalley, Anne M.R. Agur; 7th ed
2014

Clinical Anatomy by Richard S. Snell ; 2004

The Big Picture Gross anaotomy David Morton, Kurt Albertine , Bo Foreman ; 2011

High Yield Gross Anatomy 5th ed by Ronald W. Dudek, Thomas M. Louis ; 2015

http://depts.washington.edu
THYROID, PARATHYROID
PANCREAS
OBJECTIVES
❑ Describe the location and structure of the parathyroid gland
❑ Discuss the neurovasculature of the parathyroid gland
❑ Describe the location and anatomy of the thyroid gland
❑ Discuss important relations of the thyroid gland
❑ Discuss the anatomic location of the pancreas.
❑ Discuss the parts of the pancreas.
Thyroid Gland

❖lies deep to the sternothyroid and

sternohyoid muscles
❖located anteriorly in the neck at the
level of the C5–T1 vertebrae .
❖consists primarily of right and left
lobes, anterolateral to the larynx and
trachea.
❖ is surrounded by a thin fibrous capsule
Thyroid Gland

Isthmus:
unites the lobes over the trachea, usually
anterior to the second and third tracheal rings.
Blood Supply:
superior thyroid arteries
descend to the superior poles of the gland, pierce
the pretracheal layer of deep cervical fascia, and
divide into anterior and posterior branches
supplying mainly the anterosuperior aspect of
the gland.
Blood Supply:
inferior thyroid arteries
➢ the largest branches of the thyrocervical
trunks arising from the subclavian arteries
➢ run superomedially posterior to the carotid
sheaths to reach the posterior aspect of the
thyroid gland.
➢ divide into several branches that pierce the
pretracheal layer of the deep cervical fascia
and supply the posteroinferior aspect,
including the inferior poles of the gland.
❑approximately 10% of people, a small, unpaired thyroid
ima artery arises from the brachiocephalic trunk
❑When present, this small artery ascends on the anterior
surface of the trachea, supplying small branches to it.
❑The artery then continues to the isthmus of the thyroid
gland, where it divides and supplies it.
Venous Drainage.

1. superior thyroid veins accompany the

2. middle thyroid veins do
3. inferior thyroid veins

Form a thyroid plexus of veins on the anterior

surface of the thyroid gland and anterior to the
trachea

The superior and middle thyroid veins drain

into the IJV; the inferior thyroid veins drain into
the brachiocephalic veins posterior to the
manubrium.
Lymphatic Drainage
lymphatic vessels pass initially to the ff
lymph nodes:
prelaryngeal
pretracheal
paratracheal

prelaryngeal nodes drain in turn to the

superior deep cervical lymph nodes,
pretracheal and paratracheal lymph nodes
drain to the inferior deep cervical nodes
Parathyroid Gland

❑lie external to the thyroid capsule

on the medial half of the posterior
surface of each lobe of the thyroid
gland, inside its sheath
Parathyroid Gland

❑The superior parathyroid glands

usually lie slightly more than 1 cm
superior to the point of entry of
the inferior thyroid arteries into
the thyroid gland.
❑The inferior parathyroid glands
usually lie slightly more than 1 cm
inferior to the arterial entry point
Blood Supply
inferior thyroid arteries
superior thyroid arteries
thyroidea ima
laryngeal
tracheal
esophageal arteries

Parathyroid veins drain into the thyroid plexus of veins of

the thyroid gland and trachea.

Lymphatic vessels from the parathyroid glands drain with

those from the thyroid gland into deep cervical lymph
nodes and paratracheal lymph nodes
Nerves of Parathyroid Glands

❑ The nerve supply of the parathyroid glands is derived

from thyroid branches of the cervical (sympathetic)
ganglia
❑ They are vasomotor rather than secretomotor because
these glands are hormonally regulated.
 Pancreas

❑ The pancreas is an elongated, accessory digestive gland that lies

retroperitoneally, overlying and transversely crossing the bodies of the
L1 and L2 vertebra on the posterior abdominal wall.
❑ It lies posterior to the stomach between the duodenum on the right and
the spleen on the left.
 pancreas

The transverse mesocolon attaches to its anterior margin.

The pancreas produces:
1. pancreatic juice
- an exocrine secretion from the acinar cells
that enters the duodenum through the main
and accessory pancreatic ducts.
2. hormones (glucagon and insulin)
- endocrine secretions from the pancreatic
islets of Langerhans that enter the blood
The pancreas is divided into four parts:
1. Head
2. Neck
3. Body
4. tail
 Head of the Pancreas

❑ The head of the pancreas is the expanded part of the gland that is embraced by the
C-shaped curve of the duodenum to the right of the superior mesenteric vessels just
inferior to the transpyloric plane.
❑ It firmly attaches to the medial aspect of the descending and horizontal parts of the
duodenum.
 Head of the Pancreas

❑ The uncinate process, a projection from the inferior part of the pancreatic
head, extends medially to the left, posterior to the SMA.
❑ On the posterosuperior surface of the head, the bile duct lies in a groove or
is embedded in its substance.
 Neck of the Pancreas
❑ The neck of the pancreas is
short (1.5–2 cm) and overlies
the superior mesenteric
vessels, which form a groove in
its posterior aspect.
❑ The superior mesenteric vein neck

joins the splenic vein posterior

to the neck to form the hepatic
portal vein.
 Body of the Pancreas

The anterior surface of the body of the pancreas is covered

with peritoneum and forms part of the stomach bed.
The posterior surface of the body
is devoid of peritoneum and is in
contact with the
1. Aorta
2. Superior mesenteric artery
3. left suprarenal gland,
4. left kidney
5. renal vessels
 Tail of the Pancreas

The tail of the pancreas lies anterior to the left kidney, where it is closely
related to the splenic hilum and the left colic flexure. The tail is relatively
mobile and passes between the layers of the splenorenal ligament with
the splenic vessels.
 Tail of the Pancreas

❑ The main pancreatic duct begins in the tail of the pancreas and runs
through the parenchyma of the gland to the pancreatic head.
❑ The accessory pancreatic duct opens into the duodenum at the opening
of the minor duodenal papilla.
The main pancreatic duct and bile duct usually unite to form
the short, dilated hepatopancreatic ampulla (of Vater), which
opens into the descending part of the duodenum at the major
duodenal papilla.
The sphincter of the pancreatic duct, the sphincter of the bile duct, and the
hepatopancreatic sphincter (of Oddi) around the hepatopancreatic ampulla
are smooth muscle sphincters that control the flow of bile and pancreatic
juice into the ampulla and prevent reflux of duodenal content into the
ampulla.
Blood supply of the pancreas
1. branches of the splenic artery
2. pancreaticoduodenal
branches of the gastroduodenal
3. anterior and posterior inferior
pancreaticoduodenal arteries,
branches of the SMA
Venous drainage

pancreatic veins - tributaries of the

splenic and superior mesenteric parts of
the hepatic portal vein; most empty into
the splenic vein.
End of Lecture
References
Clinically Oriented Anatomy by Keith L. Moore, Arthur F. Dalley, Anne M.R. Agur; 7th
ed 2014

Clinical Anatomy by Richard S. Snell ; 2004

The Big Picture Gross anaotomy David Morton, Kurt Albertine , Bo Foreman ; 2011

High Yield Gross Anatomy 5th ed by Ronald W. Dudek, Thomas M. Louis ; 2015

http://depts.washington.edu
Endo I (Physio) - Introduction
to Endocrinology
Objectives
• Classify the hormones according to chemical structure
• Explain the synthesis, storage and secretion of hormones
• Explain the different mechanisms and physiologic actions of different
hormones
COORDINATION OF BODY FUNCTIONS BY
CHEMICAL MESSENGERS
• Neural, in which neurotransmitters are released at synaptic junctions
and act locally
• Endocrine, in which hormones released from specialized glands or
cells reach the circulating blood and influence the function of target
cells some distance away
COORDINATION OF BODY FUNCTIONS BY
CHEMICAL MESSENGERS
• Neuroendocrine (neurocrine), in which secretion products from
neurons (neurohormones) reach the circulating blood and influence
the function of target cells some distance away
• Paracrine, in which cell secretion products diffuse into the
extracellular fluid and affect neighboring target cells of a different
type
COORDINATION OF BODY FUNCTIONS BY
CHEMICAL MESSENGERS
• Autocrine, in which cell secretion products affect the function of the
same cell by binding to cell surface receptors
• Cytokine, in which cell proteins are secreted into the extracellular
fluid and function as autocrines, paracrines, or endocrines and often
act on a broad spectrum of target cells
MAINTENANCE OF HOMEOSTASIS AND
REGULATION OF BODY PROCESSES
• In many instances, neural and endocrine control of body processes is
achieved through interactions between these two systems, which are
linked by neuroendocrine cells located in the hypothalamus.
• The axons terminate in the posterior pituitary gland and median eminence.
• The neurohormones secreted from these neuroendocrine cells include
antidiuretic hormone, oxytocin, and hypophysiotropic hormones (which
control secretion of the anterior pituitary hormones).
• Hormones and neurohormones play a critical role in the regulation of
almost all aspects of body function, including metabolism, growth and
development, water and electrolyte balance, reproduction, and behavior.
Hormones Classified According to Chemical
Structure
• Chemically, three types of hormones and neurohormones exist:
• Proteins and peptides.
• Included in this group are peptides ranging from as small as three amino acids
(e.g., thyrotropin-releasing hormone) to proteins almost 200 amino acids long
(e.g., growth hormone and prolactin).
• Steroids.
• Steroids are derivatives of cholesterol and include the adrenocortical (cortisol,
aldosterone) and gonadal (testosterone, estrogen, progesterone) hormones.
• Derivatives of the amino acid tyrosine.
• Included in this group are hormones from the thyroid gland (thyroxine,
triiodothyronine) and adrenal medulla (epinephrine and norepinephrine).
Synthesis, Storage, and Secretion of
Hormones
• Protein/Peptide Hormones Are Synthesized Like Most Proteins.
• Protein/peptide hormones are synthesized on the rough endoplasmic reticulum in
the same fashion as most other proteins.
• Typically, the initial protein formed by the endoplasmic reticulum is larger than the
active hormone and is called a preprohormone.
• The signal sequence of this large protein is cleaved in the endoplasmic reticulum to
form a prohormone.
• Subsequently, in the Golgi apparatus the prohormone is packaged in secretion
granules along with proteolytic enzymes that cleave the prohormone into active
hormone and other fragments.
• When the endocrine cell is stimulated, the secretion granules migrate from
the cytoplasm to the cell membrane.
• Free hormone and co-peptides are then released into the extracellular fluid
by exocytosis.
Synthesis, Storage, and Secretion of
Hormones
• Steroid Hormones Are Synthesized From Cholesterol.
• In contrast to protein/peptide hormones, there is little hormone storage in
steroid-producing endocrine cells.
• Typically, large stores of cholesterol esters exist in cytoplasmic vacuoles and
can be rapidly mobilized for synthesis of steroid hormones after stimulation of
the steroid-producing cell.
• Once the steroid hormone appears in the cytoplasm, storage does not take
place, and the hormone diffuses through the cell membrane into the
extracellular fluid.
Synthesis, Storage, and Secretion of
Hormones
• Thyroid Hormones and Catecholamines Are Synthesized From
Tyrosine.
• As with steroid hormones, there is no storage of thyroid hormones in discrete
granules, and once thyroid hormones appear in the cytoplasm of the cell,
they leave the cell via diffusion through the cell membrane.
• In contrast to steroid hormones, large stores of thyroxine and tri-
iodothyronine exist as part of a large iodinated protein (thyroglobulin) that is
stored in the lumens of thyroid follicles.
Synthesis, Storage, and Secretion of
Hormones
• In comparison, the other group of hormones derived from tyrosine,
the adrenal medullary hormones epinephrine and norepinephrine, are
taken up into preformed vesicles and stored until they are secreted.
• As with protein hormones stored in secretion granules,
catecholamines are released from adrenal medullary cells through
exocytosis.
Control of Hormonal Secretion and Negative
Feedback
• In most instances, the rate of hormonal secretion is controlled by
negative feedback.
• In general, endocrine glands tend to oversecrete hormone, which in
turn drives target cell function.
• When the hormonal actions on the target cell are in excess, the
resultant conditions or products feed back to the endocrine gland and
cause a negative effect on the gland, decreasing its secretory rate.
MECHANISMS OF ACTION OF HORMONES
• Hormones control cellular processes by interacting with receptors on target
cells.
• These receptors are
• (1) either on or within the cell membrane, as in the case of peptide/protein and
catecholamine hormones
• (2) within the cell in either the cytoplasm or nucleus, as is the case for steroid and
thyroid hormones.
• Receptors are usually specific for a single hormone.
• The hormonereceptor interaction is coupled to a signal-generating
mechanism that then causes a change in intracellular processes by altering
the activity or concentration of enzymes, carrier proteins, and so forth.
Mediating Hormonal Responses
• Cell Responses to Protein/Peptide and Catecholamine Hormones Are
Mediated by Second Messengers
• Second-messenger mechanisms include the following:
• Adenylyl cyclase–cyclic adenosine monophosphate (cAMP).
• Hormone-receptor interaction may stimulate (or inhibit) the membrane-bound enzyme
adenylyl cyclase.
• Stimulation of this enzyme results in synthesis of the second-messenger cAMP.
• The cAMP activates protein kinase A, leading to phosphorylation that either activates or
inactivates target enzymes.
Mediating Hormonal Responses
• Cell Responses to Protein/Peptide and Catecholamine Hormones Are
Mediated by Second Messengers
• Second-messenger mechanisms include the following:
• Plasma membrane phospholipids.
• Hormone-receptor interaction activates the membrane-bound enzyme phospholipase C,
which in turn causes phospholipids in the cell membrane to split into the second
messengers diacylglycerol and inositol triphosphate.
• Inositol triphosphate mobilizes calcium from internal stores, such as the endoplasmic
reticulum, and the calcium in turn activates protein kinase C.
• Phosphorylation of enzymes by protein kinase C activates and deactivates enzymes
mediating the hormone responses.
Mediating Hormonal Responses
• Cell Responses to Protein/Peptide and Catecholamine Hormones Are
Mediated by Second Messengers
• Second-messenger mechanisms include the following:
• Calcium-calmodulin.
• Hormone-receptor interaction activates calcium channels in the plasma membrane,
permitting calcium to enter cells.
• Calcium may also be mobilized from intercellular stores such as the endoplasmic
reticulum.
• The calcium ions bind with the protein calmodulin; this complex alters the activity of
calcium-dependent enzymes and thus intercellular reactions.
Mediating Hormonal Responses
• Cell Responses to Steroid and Thyroid Hormones Are Mediated by Stimulating
Protein Synthesis
• In contrast to protein/peptide hormones and catecholamines, steroid and thyroid
hormones enter the cell and bind to intracellular receptors located in the
cytoplasm or nucleus of the cell.
• The hormone-receptor interaction results in a conformational change in the
receptor.
• This permits binding of the hormone-receptor complex to specific points on DNA
strands in the chromosomes, which results in activation of specific genes,
transcription, and translation of proteins that are essential for mediating the
hormonal response.
• Because the transcription mechanism is involved in mediating the hormonal
response, hours may be required for the biologic effects to become evident.
• END
References
• Berne, Robert M.,, Koeppen, Bruce M.Stanton, Bruce, A. (Eds.)
(2008) Berne & Levy physiology.Philadelphia : Mosby/Elsevier
• Guyton, Arthur C. Guyton And Hall Textbook Of Medical Physiology.
Philadelphia, PA : Saunders/Elsevier, 2011.
 Endocrine System I

Hypothalamus and Hypophysis

 Describe the relationship of the hypothalamus and pituitary

Learning gland.
Enumerate the hormones of the anterior and posterior pituitary

Objectives
gland.
Describe the function of the hormones of the anterior and
posterior pituitary gland.
 Guyton and Hall Textbook of Medical Physiology 13th
Edition, 2015

References Board Review Series, Physiology, 6th Edition 2015

Hypothalamus and Pituitary Physiology
https://www.youtube.com/watch?v=VkWmbeO8gqY
What is the • The anterior lobe of the pituitary gland is linked to the
hypothalamus by the hypothalamic– hypophysial portal system.

relationship of the • Blood from the hypothalamus that contains high concentrations of
hypothalamic hormones is delivered directly to the anterior

hypothalamus with •
pituitary.
Hypothalamic hormones then stimulate or inhibit the release of

the pituitary gland? anterior pituitary hormones

What is the • The posterior lobe of the pituitary gland is derived from neural

relationship of the •
tissue.
The nerve cell bodies are located in hypothalamic nuclei. Posterior

hypothalamus with
pituitary hormones are synthesized in the nerve cell bodies,
packaged in secretory granules, and transported down the axons

the pituitary gland?

to the posterior pituitary for release into the circulation.
What are the
hormones of the
Growth hormone, prolactin, thyroid-stimulating
hormone (TSH), LH, follicle-stimulating

anterior lobe of hormone (FSH), and adrenocorticotropic

hormone (ACTH).

the pituitary?
What are the TSH, LH, and FSH

hormones of the •
•
 Belong to the same glycoprotein family.
Each has an α subunit and a β subunit.

anterior lobe of •
•
The α subunits are identical.
The β subunits are different and are responsible for the

the pituitary?
unique biologic activity of each hormone.
What are the
hormones of the
• ACTH, melanocyte-stimulating hormone (MSH), b-
lipotropin, and b-endorphin   are derived from a single
precursor, proopiomelanocortin (POMC).

anterior lobe of • α-MSH and β-MSH are produced in the intermediary

lobe, which is rudimentary in adult humans.

the pituitary?
What is growth • Most important hormone for normal
growth to adult size.

hormone • A single-chain polypeptide that is

(somatotropin)?
homologous with prolactin and human
placental lactogen.
How is growth •
•
 Growth hormone is released in pulsatile fashion.
Secretion is increased by sleep, stress, hormones related

hormone secretion to puberty, starvation, exercise, and hypoglycemia.

Secretion is decreased by somatostatin, somatomedins,
regulated?
•
obesity, hyperglycemia, and pregnancy.
How is growth
hormone
Hypothalamic control—GHRH and somatostatin
•  GHRH stimulates the synthesis and secretion of growth
hormone.

secretion • Somatostatin inhibits secretion of growth hormone by

blocking the response of the anterior pituitary to GHRH.

regulated?
How is growth
hormone
Negative feedback control by somatomedins
•   Somatomedins are produced when growth hormone acts on target tissues.
• Somatomedins inhibit the secretion of growth hormone by acting directly on

secretion
the
• anterior pituitary and by stimulating the secretion of somatostatin from the
• hypothalamus.

regulated?
How is growth
hormone
Negative feedback control by GHRH and growth hormone
•   GHRH inhibits its own secretion from the hypothalamus.

secretion
•   Growth hormone also inhibits its own secretion by
stimulating the secretion of somatostatin from the
hypothalamus

regulated?
What are the •   In the liver, growth hormone generates the production of
somatomedins (insulin-like growth factors, which serve as

actions of growth •
the intermediaries of several physiologic actions.
 The IGF receptor has tyrosine kinase activity, similar to the

hormone? insulin receptor.

What are the Direct actions of growth hormone

actions of •
•
↓ glucose uptake into cells (diabetogenic)
↑ lipolysis

growth •
•
↑ protein synthesis in muscle and ↑ lean body mass
↑ production of IGF

hormone?
What are the Actions of growth hormone via IGF
• ↑ protein synthesis in chondrocytes and ↑ linear growth

actions of growth •
(pubertal growth spurt)
↑ protein synthesis in muscle and ↑ lean body mass
hormone? • ↑ protein synthesis in most organs and ↑ organ size
What is the Growth hormone deficiency

pathophysiology of
  in children causes failure to grow, short stature, mild obesity, and delayed puberty.
  Can be caused by:
• Lack of anterior pituitary growth hormone

growth hormone •
•
Hypothalamic dysfunction (↓ GHRH)
Failure to generate IGF in the liver

deficiency? • Growth hormone receptor deficiency

What is the Growth hormone excess
Can be treated with somatostatin analogs which inhibit growth hormone

pathophysiology of
•
secretion.
•  Hypersecretion of growth hormone causes acromegaly.

growth hormone
• Before puberty, excess growth hormone causes increased linear growth
(gigantism).

excess?
• After puberty, excess growth hormone causes increased periosteal bone
growth, increased organ size, and glucose intolerance (acromegaly).
What is
• Major hormone responsible for lactogenesis.
• Participates, with estrogen, in breast

prolactin?
development.
• Structurally homologous to growth hormone.
How is prolactin Hypothalamic control by dopamine and thyrotropin-releasing hormone
(TRH)

secretion
•   Prolactin secretion is tonically inhibited by dopamine (prolactin-
inhibiting factor [PIF]) secreted by the hypothalamus.
• Thus, interruption of the hypothalamic– pituitary tract causes

regulated?
increased secretion of prolactin and sustained lactation.
•   TRH increases prolactin secretion.
How is prolactin Negative feedback control

secretion •   Prolactin inhibits its own secretion

by stimulating the hypothalamic
regulated? release of dopamine.
What are the • Stimulates milk production in the breast (casein, lactalbumin)

actions of
• Stimulates breast development (in a supportive role with estrogen)
• Inhibits ovulation by decreasing synthesis and release of
gonadotropin-releasing hormone (GnRH)

prolactin? • Inhibits spermatogenesis (by decreasing GnRH)

What is the
pathophysiology of
prolactin deficiency • Results in the failure to lactate.
(destruction of anterior
pituitary)?
What is the •   Results from hypothalamic destruction (due to loss of the tonic “inhibitory”
control by dopamine) or from prolactin-secreting tumors (prolactinomas).

pathophysiology of
• Causes galactorrhea and decreased libido.
• Causes failure to ovulate and amenorrhea because it inhibits GnRH secretion.

prolactin excess?
• Can be treated with bromocriptine, which reduces prolactin secretion by acting
as a dopamine agonist.
What are the • Antidiuretic hormone (ADH) and oxytocin.

hormones of the
• Are homologous nonapeptides.
• Are synthesized in hypothalamic nuclei and are packaged

posterior lobe of the •

in secretory granules with their respective neurophysins.
Travel down the nerve axons for secretion by the
pituitary? posterior pituitary.
What is • Originates primarily in the supraoptic nuclei
of the hypothalamus.

antidiuretic • Regulates serum osmolarity by increasing

the H2O permeability of the late distal
hormone (ADH) tubules and collecting ducts.
How is ADH Factors that increase ADH secretion
Serum osmolarity

secretion
Volume contraction
Pain
Nausea

regulated?
Hypoglycemia
Nicotine, opiates, antineoplastic drugs
How is ADH Factors that decrease ADH secretion
Low serum osmolarity

secretion Ethanol

regulated?
α – Agonists
Atrial natriuretic peptide
What are the
• ↑ H2O permeability (aquaporin 2, AQP2) of the principal
cells of the late distal tubule and collecting duct (via a V2
receptor and an adenylate cyclase–cAMP mechanism)

actions of ADH? • Constriction of vascular smooth muscle (via a V1 receptor

and an IP3/Ca2+ mechanism)
What is
• Originates primarily in the paraventricular
nuclei of the hypothalamus.

oxytocin? • Causes ejection of milk from the breast

when stimulated by suckling.
How is oxytocin Suckling
•   Major stimulus for oxytocin secretion.

secretion
•   Afferent fibers carry impulses from the nipple to the spinal cord.
• Relays in the hypothalamus trigger the release of oxytocin from the posterior
pituitary.

regulated?
•  The sight or sound of the infant may stimulate the hypothalamic neurons to
secrete oxytocin, even in the absence of suckling.
Dilation of the cervix and orgasm
  Increases the secretion of oxytocin.
What are the Contraction of myoepithelial cells in the breast
•   Milk is forced from the mammary alveoli into the ducts and ejected.

actions of
Contraction of the uterus
•   During pregnancy, oxytocin receptors in the uterus are up-regulated as
parturition approaches, although the role of oxytocin in normal labor is

oxytocin?
uncertain.
• Oxytocin can be used to induce labor and reduce postpartum bleeding.
Endo I (Physio) - Thyroid
Objectives
• Classify the thyroid hormones according to chemical structure
• Explain the synthesis, storage and secretion of thyroid hormones
• Explain the different mechanisms and physiologic actions of different
adrenal hormones
• Explain the pathophysiology of common diseases involving the
hormones secreted by the adrenals
SYNTHESIS AND SECRETION OF THYROID
HORMONES
• The thyroid gland is composed of a large number of follicles.
• Each follicle is surrounded by a single layer of cells and filled with a
proteinaceous material called colloid.
• The primary constituent of colloid is the large glycoprotein
thyroglobulin, which contains the thyroid hormones in its molecule.
SYNTHESIS AND SECRETION OF THYROID
HORMONES
• The following steps are required for the synthesis and secretion of thyroid
hormones into the blood:
• Iodide trapping (iodide pump) or sodium-iodide symporter (NIS).
• Iodine is essential to thyroid hormone synthesis.
• Ingested iodine is converted to iodide and absorbed from the gut.
• Most circulating iodide is excreted by the kidneys; much of the remainder is taken up and
concentrated by the thyroid gland.
• Oxidation of iodide.
• Once in the thyroid gland, iodide is rapidly oxidized to iodine by thyroid peroxidase; this
occurs at the apical membrane of the follicular cells.
• Synthesis of thyroglobulin.
• Thyroglobulin is synthesized by the follicular cells and secreted into the colloid through
exocytosis of secretion granules that also contain thyroid peroxidase.
• Each thyroglobulin molecule contains many tyrosyl groups, but only a fraction become
iodinated.
SYNTHESIS AND SECRETION OF THYROID
HORMONES
• Iodination (organification) and coupling.
• Once iodide is oxidized to iodine, it is rapidly attached to the 3 position of tyrosine
molecules of thyroglobulin to generate monoiodotyrosine (MIT).
• MIT is next iodinated in the 5 position to give diiodotyrosine (DIT).
• Thereafter, two DIT molecules are coupled to form thyroxine (T4), the major product of
the coupling reaction, or one MIT and one DIT molecule are coupled to form
triiodothyronine (T).
3

• A small amount of reverse T3 (RT3) is formed by condensation of DIT with MIT. These
reactions are catalyzed by thyroid peroxidase and blocked by antithyroid drugs such as
propylthiouracil.
• Approximately two thirds of the iodinated compounds bound to thyroglobulin are MIT or
DIT; most of the remainder are the active hormones T3 and especially T4.
• Thyroglobulin is stored in the lumen of the follicle as colloid until the gland is stimulated
to secrete thyroid hormones.
SYNTHESIS AND SECRETION OF THYROID
HORMONES
• Proteolysis, deiodination, and secretion.
• The release of T3, T4, and RT3 into the blood requires proteolysis of the thyroglobulin.
• At the apical surface of the follicular cells, colloid is taken up from the lumen of the
follicles through endocytosis.
• Colloid vesicles then migrate from the apical to the basal cell membrane and fuse with
lysosomes.
• Lysosomal proteases release free RT3, T3, and T4, which then leave the cell.
• Free MIT and DIT are not secreted into the blood but instead are deiodinated within the
follicular cell by the enzyme deiodinase; the free iodine is reused in the gland for
hormone synthesis.
• More than 90 percent of the thyroid hormone released from the gland is T4. The
remaining secretion products are T3 and very small amounts of the inactive compound
RT3.
Transport and Metabolism of Thyroid
Hormones
• Thyroid Hormones Are Highly Bound to Plasma Proteins.
• On entering the blood, both T4 and T3 are highly bound to plasma proteins,
especially thyroxine-binding globulin (TBG), but also to other plasma proteins
such as albumin and thyroxine-binding prealbumin.
• Approximately 99.9 percent of T4 is bound to plasma proteins, and less than
0.1 percent is free hormone.
• The binding of T to plasma proteins is slightly less than that of T ; however,
3 4

less than 1 percent is free hormone.

• In the case of the thyroid hormones, it is the free hormone that is taken up by
tissues, in which it exerts biological effects and is metabolized.
• As a result of the high degree of binding to plasma proteins, the half-lives of T
4

and T are very long (7 days and 1 day, respectively).

3
Transport and Metabolism of Thyroid
Hormones
• Alterations in Plasma TBG Levels Do Not Influence Free Thyroid
Hormone Concentration.
• Reductions (e.g., during liver and kidney disease) and elevations (e.g.,
during estrogen administration and pregnancy) in plasma TBG levels
decrease and increase, respectively, the total amount of thyroid
hormones in the plasma but produce no more than a transient
change in the free hormone concentration because of the negative
feedback effect of free thyroid hormones on pituitary secretion of
thyroidstimulating hormone (TSH).
Transport and Metabolism of Thyroid
Hormones
• Most of the T4 Secreted by the Thyroid Gland Is Metabolized to T3.
• Although T4 is the dominant secreted and circulated thyroid
hormone, large amounts of the hormone are deiodinated in either
the 5ʹ or the 5 position in peripheral tissues to produce T3 and RT3.
• In fact, most of the T3 and RT3 in the plasma come from circulating
T4 that has been deiodinated in peripheral tissues rather than
secreted from the thyroid gland.
FUNCTIONS OF THYROID HORMONES IN THE
TISSUES
• Thyroid Hormones and Transcription of Many Genes
• After thyroid hormones enter the cell, they bind to nuclear receptors in the
DNA.
• This interaction either stimulates or inhibits transcription of a large number of
genes, which leads to alterations in numerous enzymes that alter cell
function.
• The actions of T3 occur more rapidly and are more potent than are those of
T4 because T3 is bound less tightly to plasma proteins and has a greater
affinity for nuclear receptors.
• Because thyroid hormones act in large part by influencing transcription, a
delay of several hours occurs before most hormonal effects are evident; these
effects may last several days.
FUNCTIONS OF THYROID HORMONES IN THE
TISSUES
• Physiological Effect of Thyroid Hormones— Cellular Metabolic Rate
• In most tissues of the body, thyroid hormones increase oxygen consumption
and heat production.
• Mitochondria increase in size and number, the membrane surface areas of
the mitochondria increase, and the activities of key respiratory enzymes
increase.
• A complete accounting of the cellular mechanisms responsible for the higher
oxygen consumption is not possible at present.
• Because thyroid hormones increase the activity of membrane-bound Na-K-
ATPase, the greater adenosine triphosphate consumption associated with the
greater sodium transport is believed to contribute to the greater metabolic
rate induced by thyroid hormone.
Specific Physiological Effects of Thyroid
Hormones
• Many of the Effects of Thyroid Hormones Are a Result of Increased
Metabolic Rate
• Increased thermogenesis and sweating.
• Skin blood flow increases because of the need for heat elimination.
• Increased rate and depth of respiration resulting from the need for oxygen.
• Increased cardiac output because increased metabolism and utilization of
oxygen in tissues cause local vasodilatation.
• Increased cardiac output is associated with elevations in both stroke volume and heart
rate, in part because thyroid hormones have direct and indirect effects on the heart to
increase the heart rate and force of contraction.
Specific Physiological Effects of Thyroid
Hormones
• Many of the Effects of Thyroid Hormones Are a Result of Increased
Metabolic Rate
• Increased pulse pressure but not mean arterial pressure.
• Because of the increased cardiac output (stroke volume) and reduced peripheral vascular
resistance, systolic arterial pressure is elevated and diastolic arterial pressure is reduced,
which results in an increase in pulse pressure but usually no change in mean arterial
pressure.
Specific Physiological Effects of Thyroid
Hormones
• Many of the Effects of Thyroid Hormones Are a Result of Increased
Metabolic Rate
• Increased utilization of substrates for energy.
• An increased metabolic rate is dependent on oxidation of metabolic substrates.
• Thyroid hormones increase the utilization of carbohydrates, fats, and proteins for energy.
• If food intake is not increased sufficiently, there is depletion of body fats and proteins, and
weight loss occurs.
• Although thyroid hormones promote lipolysis of triglycerides and increments in plasma levels
of free fatty acids, they also decrease the circulating levels of cholesterol.
• This action is due to increased formation of low-density lipoprotein receptors in the liver,
resulting in increased removal of cholesterol from the circulation, secretion in the bile, and
then excretion in the feces.
• Because thyroid hormones increase the rate of metabolic reactions, the need for vitamins is
greater, and excess thyroid hormone can lead to vitamin deficiency.
Specific Physiological Effects of Thyroid
Hormones
• Thyroid Hormones Are Essential for Normal Growth and
Development.
• Thyroid hormones are essential for many aspects of growth and
development; they play an important role in the development of the skeletal
system, teeth, epidermis, and central nervous system.
• In hypothyroid children, the rate of growth is greatly reduced.
• An important effect of thyroid hormone is to promote growth and
development of the central nervous system in utero and for the first few years
of postnatal life.
• If thyroid hormone is deficient at this time, irreversible brain damage occurs.
Specific Physiological Effects of Thyroid
Hormones
• Thyroid Hormones Have Excitatory Effects on the Nervous System.
• Thyroid hormones enhance wakefulness, alertness, and responsiveness to
various stimuli; they also increase the speed and amplitude of peripheral
nerve reflexes and improve memory and learning capacity.
REGULATION OF THYROID HORMONE
SECRETION
• Thyroid-Stimulating Hormone Is the Primary Controller of Thyroid
Hormone Secretion
• To maintain normal levels of metabolic activity in the body, the free plasma
levels of thyroid hormone must be regulated.
• Thyroid hormone secretion is primarily regulated by TSH (thyrotropin).
• TSH secretion from the pituitary gland is increased by the hypophysiotropic
hormone thyrotropin-releasing hormone (TRH) and is inhibited in a negative
feedback fashion by circulating T4 and T3.
REGULATION OF THYROID HORMONE
SECRETION
• Thyroid-Stimulating Hormone Promotes the Synthesis and Secretion
of Thyroid Hormones.
• Binding of TSH to its receptors on the cell membrane of the thyroid gland
activates adenylyl cyclase so that cyclic adenosine monophosphate mediates
at least some of the actions of TSH.
• An immediate effect of TSH is to promote endocytosis of colloid, proteolysis
of thyroglobulin, and release of T4 and T3 into the circulation
REGULATION OF THYROID HORMONE
SECRETION
• Thyroid-Stimulating Hormone Has Chronic Effects to Promote Growth
of the Thyroid Gland.
• The chronic effects of TSH include increased blood flow to the thyroid gland
and induction of hypertrophy and hyperplasia of the follicular cells.
• With prolonged TSH stimulation, the thyroid enlarges and a goiter occurs.
• In the absence of TSH, marked atrophy of the gland occurs.
DISEASES OF THE THYROID
• Graves’ Disease Is the Most Common Form of Hyperthyroidism.
• Graves’ disease is an autoimmune disease in which antibodies, thyroid-stimulating immunoglobulins, form
against the TSH receptor of the thyroid, bind to it, and mimic the actions of TSH.
• This phenomenon leads to goiter and the secretion of large amounts of thyroid hormones.
• As a result, several predictable changes occur:
• (1) increased metabolic rate,
• (2) heat intolerance and sweating,
• (3) increased appetite but weight loss,
• (4) palpitations and tachycardia,
• (5) nervousness and emotional lability,
• (6) muscle weakness, and
• (7) tiredness but the inability to sleep.
• Many patients with Graves’ disease have protrusion of the eyeballs, or exophthalmos.
• This is due to the degenerative changes in the extraocular muscles as a result of an autoimmune reaction.
• TSH secretion from the pituitary gland is depressed in Graves’ disease because of the feedback exerted by the
high plasma levels of thyroid hormones.
DISEASES OF THE THYROID
• Many of the Effects of Hypothyroidism Are Opposite to Those of Hyperthyroidism.
• Although hypothyroidism may have several causes, it often results from autoimmune destruction
of the thyroid gland (Hashimoto’s disease).
• In general, the symptoms are opposite to those of hyperthyroidism:
• (1) decreased metabolic rate;
• (2) cold intolerance and decreased sweating;
• (3) weight gain without increased caloric intake;
• (4) bradycardia;
• (5) slowness of movement, speech, and thought; and
• (6) lethargy and sleepiness.
• Mucopolysaccharides accumulate in interstitial spaces, giving rise to nonpitting edema.
• The puffiness of the skin is referred to as myxedema, a term used synonymously for adult
hypothyroidism.
• If severe hypothyroidism occurs in utero or during infancy, irreversible mental retardation results,
and growth is impaired; this condition is referred to as cretinism.
• If the hypothalamic-pituitary axis is normal, hypothyroidism is associated with increased plasma
levels of TSH resulting from feedback.
DISEASES OF THE THYROID
• Hypothyroidism can also be associated with goiter.
• In certain areas of the world, dietary iodine is deficient, so thyroid
hormone secretion is depressed.
• Many individuals in these regions have enlarged thyroids, or endemic
goiter, because high plasma levels of TSH stimulate the gland.
• The practice of adding iodine to table salt has decreased the
incidence of endemic goiter in many areas of the world.
• END
References
• Berne, Robert M.,, Koeppen, Bruce M.Stanton, Bruce, A. (Eds.)
(2008) Berne & Levy physiology.Philadelphia : Mosby/Elsevier
• Guyton, Arthur C. Guyton And Hall Textbook Of Medical Physiology.
Philadelphia, PA : Saunders/Elsevier, 2011.
 Endocrine System I

Parathyroid and Calcium Regulation

 Enumerate the hormones associated with
metabolism of bone.
Learning Describe the function of the hormones

Objectives Describe the relationship of the hormones with

each other.
 Guyton and Hall Textbook of Medical Physiology 13th
Edition, 2015

References Board Review Series, Physiology, 6th Edition 2015

Endocrinology - Calcium and Phosphate Regulation:
https://www.youtube.com/watch?v=EEM0iRJNhU8
How does calcium •
•
40% of the total Ca2+ in blood is bound to plasma proteins.
60% of the total Ca2+ in blood is not bound to proteins and is

homeostasis occur
ultrafilterable.
• Ultrafilterable Ca2+ includes Ca2+ that is complexed to anions

in the body?
such as phosphate and free, ionized Ca2+.
•  Free, ionized Ca2+ is biologically active.
How does calcium • Serum Ca2+ is determined by the interplay of intestinal
absorption, renal excretion, and bone remodeling (bone

homeostasis occur
resorption and formation).
• Each component is hormonally regulated.

in the body?
• To maintain Ca2+ balance, net intestinal absorption must
be balanced by urinary excretion.
 • Seen in growing children.
What is positive •  Intestinal Ca2+ absorption exceeds

calcium balance? urinary excretion, and the excess is

deposited in the growing bones.
 • Seen in women during pregnancy or

What is negative lactation.

Intestinal Ca2+ absorption is less than
calcium balance?
•
Ca2+ excretion, and the deficit comes from
the maternal bones.
What is • Major hormone for the regulation of
serum Ca2+.
parathyroid • Synthesized and secreted by the
hormone? chief cells of the parathyroid glands.
 • Controlled by the serum [Ca2+] binding to Ca2+-sensing

How is parathyroid •
receptors in the parathyroid cell membrane.
Decreased serum Ca2+ increases PTH secretion, whereas

hormone secreted?
increased serum Ca2+ decreases PTH secretion.
• Decreased serum Ca2+ causes decreased binding to the
Ca2+-sensing receptor, which stimulates PTH secretion.
 • Mild decreases in serum [Mg2+] stimulate PTH secretion.

How is parathyroid •  Severe decreases in serum [Mg2+] inhibit PTH secretion

and produce symptoms of hypoparathyroidism

hormone secreted?
(hypocalcemia).
•  The second messenger for PTH secretion by the
parathyroid gland is cAMP.
What are the • Coordinated to produce an increase in

actions of serum Ca2+ and a decrease in serum

phosphate.

parathyroid • The second messenger for PTH actions on

hormone?
its target tissues is cAMP.
What are the • PTH increases bone resorption, which brings both Ca2+

actions of •
and phosphate from bone mineral into the ECF.
Alone, this effect on bone would not increase the serum

parathyroid
ionized Ca2+ because phosphate complexes Ca2+.
•   Resorption of the organic matrix of bone is reflected in

hormone?
increased hydroxyproline excretion.
What are the PTH inhibits renal phosphate reabsorption in the proximal tubule

actions of
•
and, therefore, increases phosphate excretion (phosphaturic effect).
• As a result, the phosphate resorbed from bone is excreted in the

parathyroid
urine, allowing the serum ionized [Ca2+] to increase.
•   cAMP generated as a result of the action of PTH on the proximal
tubule is excreted in the urine (urinary cAMP).

hormone?
What are the
actions of
• PTH increases renal Ca2+ reabsorption in the distal
tubule, which also increases the serum Ca2+.
PTH increases intestinal Ca2+ absorption indirectly by

parathyroid
•
stimulating the production of 1,25-
dihydroxycholecalciferol in the kidney

hormone?
 Most commonly caused by parathyroid adenoma.
Characterized by the following:

What is primary
• ↑ serum [Ca2+] (hypercalcemia)
• ↓ serum [phosphate] (hypophosphatemia)

hyperparathyroidism?
• ↑ urinary phosphate excretion (phosphaturic effect of PTH)
• ↑ urinary Ca2+ excretion (caused by the increased filtered load of Ca2+)
• ↑ urinary cAMP
• ↑ bone resorption
What is humoral • Caused by PTH-related peptide (PTH-rp) secreted by
some malignant tumors (e.g., breast, lung).

hypercalcemia of • PTH-rp has all of the physiologic actions of PTH, including

increased bone resorption, increased renal Ca2+

malignancy?
reabsorption, and decreased renal phosphate
reabsorption.
What is humoral Characterized by the following:
• ↑ serum [Ca2+] (hypercalcemia)

hypercalcemia of •
•
↓ serum [phosphate] (hypophosphatemia)
↑ urinary phosphate excretion (phosphaturic effect of PTH-rp)

malignancy?
• ↓ serum PTH levels (due to feedback inhibition from the high
serum Ca2+)
 Most commonly a result of thyroid surgery, or it is congenital.

What is Characterized by the following:

• ↓ serum [Ca2+] (hypocalcemia) and tetany
hypoparathyroidism? • ↑ serum [phosphate] (hyperphosphatemia)
• ↓ urinary phosphate excretion
What is • Result of defective Gs protein in the kidney and bone, which causes
end-organ resistance to PTH.
pseudohypoparathyroidism •   Hypocalcemia and hyperphosphatemia occur (as in

type 1a (Albright hereditary hypoparathyroidism), which are not correctable by the

administration of exogenous PTH.

osteodystrophy? • Circulating PTH levels are elevated (stimulated by hypocalcemia).

What are the effects  Decreased glomerular filtration rate (GFR) leads to decreased filtration of

of chronic renal
•
phosphate, phosphate retention, and increased serum phosphate.
•   Increased serum phosphate complexes Ca2+ and leads to decreased ionized

failure in calcium
Ca2+.
• Decreased production of 1,25-dihydroxycholecalciferol by the diseased renal
tissue also contributes to the decreased ionized Ca2+

metabolism?
What are the
effects of chronic • Decreased Ca2+ causes secondary hyperparathyroidism.

renal failure in
• The combination of increased PTH levels and decreased
1,25-dihydroxycholecalciferol produces renal
osteodystrophy, in which there is increased bone

calcium resorption and osteomalacia.

metabolism?
What is familial •  Autosomal dominant disorder with decreased
urinary Ca2+ excretion and increased serum

hypocalciuric •
Ca2+
Caused by inactivating mutations of the Ca2+-
hypercalcemia? sensing receptors that regulate PTH secretion.
 • Provides Ca2+ and phosphate to ECF for bone

What is vitamin •
mineralization.
In children, vitamin D deficiency causes rickets.

D? •  In adults, vitamin D deficiency causes

osteomalacia.
How is vitamin D
•  Cholecalciferol, 25-hydroxycholecalciferol, and 24,25-
dihydroxycholecalciferol are inactive.
• The active form of vitamin D is 1,25-dihydroxycholecalciferol.

metabolized? • The production of 1,25-dihydroxycholecalciferol in the kidney

is catalyzed by the enzyme 1α-hydroxylase.
How is vitamin D
 1α-hydroxylase activity is increased by the following:
• ↓ serum Ca2+

metabolized? •
•
↑ PTH levels
↓ serum phosphate
What are the • Coordinated to increase both [Ca2+] and [phosphate] in ECF to mineralize new
bone.

actions of • Increases intestinal Ca2+ absorption. Vitamin D–dependent Ca2+-binding

protein (calbindin D-28K) is induced by 1,25-dihydroxycholecalciferol.
  PTH increases intestinal Ca2+ absorption indirectly by stimulating 1α-

vitamin D?
•
hydroxylase and increasing production of the active form of vitamin D.
What are the • Increases intestinal phosphate absorption.

actions of
• Increases renal reabsorption of Ca2+ and phosphate,
analogous to its actions on the intestine.
• Increases bone resorption, which provides Ca2+ and

vitamin D? phosphate from “old” bone to mineralize “new” bone.

 Hormone synthesized and secreted by the parafollicular

What is
•
cells of the thyroid.
•  Secretion is stimulated by an increase in serum Ca2+.

calcitonin? •
•
Acts primarily to inhibit bone resorption.
Can be used to treat hypercalcemia.
MODULE: ENDOCRINE I

TITLE: Classification and

Mechanism of Action of
Hormones
 Objectives

 At the end of the session, the student will be able to:

1. Define what is hormone.
2. Enumerate the different hormones and its specific
target glands
3. Understand the classification of hormones
4. Understand the mechanism of action of hormones.
 Hormone
 “chemicals that are synthesized in ductless
glands and is discharged into the circulatory
system to exert physiological effects to another
tissue”
 They are peptides/proteins, lipids or amino acid
derivatives which after their secretion act on
receptors to cause reactions within the
respective receptive cells.
 Each cell of the body is in one way or another
regulated by hormones.
 Hormones

 Simply biochemical messengers

 Provides intercellular communication
 Classified according to the
 chemical composition,
 organs where they work (eg reproductive hormones in
reproductive organs)
 if they act on the same cell producing them (eg
autocrine or paracrine)
 Releasing Hypothalamus Nervous
hormones

Anterior pituitary Posterior pituitary

Thyrotropin
Somatotropin FSH Vasopressin

LH Prolactin Oxytocin
ACTH

Adrenal Adrenal
Thyroid Cortex Pancreas Ovary Testis Medulla

T3 Cortisol Insulin, Estradiol Testosterone Epinephrine

aldosterone glucagon,
somatostatin

Muscles Liver, Reproductive Mammary

liver Tissues muscles organs glands
 Target Cell Concept

• Target Cell
• A cell with the ability to bind selectively a given
hormone via a receptor
• Factors that determine response of target cell to a
hormone
1. Factors that affect the concentration of the
hormone at the target cell
2. Factors that affect the actual response of the target
cell to a hormone
 Hormone Receptors
• Receptors
• Cell-associated recognition molecules that are protein in
nature exhibiting high degree of specificity and
discrimination for a hormone
• Target cell is defined by its ability to selectively bind a
given hormone to its cognate receptor
• Biologic features that are important for hormone-
receptor interactions to be physiologically relevant
a. Binding should be specific
b. Binding should be saturable
c. Binding should occur within the concentration range of
the expected biologic response
 Characteristics of Receptors

1. High affinity for a hormone

2. Reversible binding
• There must be an end to hormone action
3. Saturable
• Provided that all the receptors are occupied, there will
be no additive effect
• There is a certain Vmax
4. Specific
Functional Domains of Receptors
1. Recognition Domain
• Binds the hormone
2. Coupling Domain (Signal Transduction)
• Embedded to cell membrane
• When the hormone binds to the recognition domain, this will
cause the coupling domain to start a cascade of events
(signal transduction)
• Couples hormone recognition with some intracellular
function (receptor-effector coupling)
 Examples of Receptors

1. Insulin receptor
• A hetero dimer (α2β2)
• Alpha subunit is extracellular which binds insulin
• Beta subunit is membrane spanning which transduces signal
throug tyrosine kinase domain
2. Insulin-Like Growth Factor (IGF-1)
• Binding of ligand activates Jak-stat pathway (also type of
protein kinase) signal transducer
3. Polypeptide and Catecholamines
• Has 7 domains that span the plasma membrane
• G proteins after the production of cAMP
General Characteristics of Hormones

 Not secreted at a uniform rate

 Exert their effects in biocatalytic amounts
 Turnover is varied and usually rapid
 Exert multiple actions
 Exhibit high degree of specificity
 Different tissues may respond differently to a given
hormone
Diversity of Endocrine System
1. Hormones are synthesized in a variety of cellular
arrangements

 Hormones are synthesized in discrete organs designed solely for

this specific purpose
 Thyroid (triiodothyronine)
 Adrenal (glucocorticoids and mineralocorticoids)
 Pituitary ( TSH, FSH, LH, GH, prolactin, ACTH)
 Some organs are deigned to perform two distinct but closely
related functions
 Ovary – mature oocytes and reproductive hormones
 Testes – mature spermatozoa and testosterone
 They are also produced in specialized cells within other organs
 Small intestine (GLP); thyroid (calcitonin) and kidney (angiotensin)
 Synthesis of some hormones requires the parenchymal cells of
more than one organ
 Skin, liver and kidney are required for the production of active vitamin D
2. Hormones are Chemically Diverse

 Synthesized from a wide variety of chemical building

blocks
 Cholesterol – glucocorticoids, mineralocorticoids, estrogen,
progestins, and Vit D
 Steroid hormone – precursor molecule for another
hormone
 Testosterone- an obligatory intermediate in the biosynthesis of
estradiol and DHT
 Progesterone – a hormone but also a precursor in the formation of
glucocorticoids, mineralocorticoids, testosterone and estrogens
 Tyrosine – starting point in synthesis of catecholamines
and thyroid hormones (Thyroxine)
3. Hormones are synthesized & modified for full
activity in a variety of ways

 Some are synthesized in final form and secreted immediately

 Hormones derived from cholesterol
 Some are synthesized final form and stored in the producing
cells
 catecholamines
 Some are synthesized from precursor molecules in the
producing cells, then are processed and secreted upon a
physiologic cue
 insulin
 Some are converted to active forms from precursor
molecules in the periphery
 T3 and DHT
Biochemical Classification of
Hormones
 Basis of Classification

1. Chemical composition
2. Solubility Characteristics
3. Location of receptors
4. Nature of signal used to mediate hormone
action within the target cell
 1. Chemical Composition

A. Steroid - derived from cholesterol and are synthesized in

the adrenal cortex, gonads and placenta
B. Amino acid derivatives – synthesized from the amino acid
tyrosine;
• include catecholamine and dopamine as well as thyroid
hormones derived from the combination of 2 iodinated
tyrosine amino acid residues
C. Peptide – constitute the majority of hormones
• Synthesized as prohormone and undergo post-translational
processing
• Stored in secretory granules before being released by
exocytosis
 Polypeptides
Insulin FSH Oxytocin
glucagon LH thyrotropin
somatotropin vasopressin ACTH

Steroids
Estrogen Aldosterone
testosterone corticosterone Calcitriol
cortisol Progesterone

Amino acid derivatives

Epinephrine Thyroxine, T3 and T4

norepinephrine Melatonin
dopamine Serotonin
 2. Solubility Characteristics
A. Lipophilic Hormones
• Poorly soluble in water (lipid soluble)
• Associated with transport proteins
• Bind to plasma protein
• Free hormone readily traverses target cell membrane
• Receptors are located within the cytosol or nucleus of the
target cell
• Hormone-receptor complex itself is the intracellular
messenger ( no need for 2nd messenger)
• Binding to Hormone Response Elements (HREs) in DNA
affect gene transcription
• Ex. thyroid hormones, steroid hormones, vit D3
 2. Solubility Characteristics
B. Hydrophilic Hormone
• “lipophobic hormone”
• Does not require transport protein
• transported as simply dissolved in water
• Binds to plasma membrane receptors on the
target cell
• Hormone-receptor interaction results in the
activation of secondary messengers
• Ex. Glucagon, catecholamine
3. Location of receptors

 A. Cell membrane (surface

receptors)
 Hydrophilic hormones
 Peptide hormones
 Amino acid derived
hormones
Location of Receptors
B. Cytosol or nuclear
(intracellular) receptors
• Lipophilic
• Steroid hormones
Mechanism of Action
General Principles of Hormone Action

 Tropic Hormone – its primary function is regulation of

hormone secretion by another endocrine gland
 Trophic hormone – hormone that has growth effect
 eg TSH, thyrotropin – stimulates thyroid gland increasing the
size and number cells
 ACTH – stimulates adrenal cortex
 Synergism – when different hormones work together
and have a greater effect than individual hormone
action
General Principles of Hormone Action

 Permissiveness – a small amount of one hormone

allows a second hormone to have its full effect on a
target cell
 Ex. First hormone ‘permits’ the full action of the second
hormone
 Usually acts as precursors to active hormones
 Cortisol exerts a permissive effect on growth hormone
 Antagonism – one hormone produces the opposite
effect of the other
General Classification of Hormones by
Mechanism of Action

I. Hormones that bind to intracellular receptors:

Androgens
Calcitriol
Estrogens
Glucocorticoids
Mineralocorticoids
Progestins
Retinoic acid
Thyroid hormones
 General Classification of Hormones by
Mechanism of Action:
Hormones that bind to cell surface receptors
B. The 2nd messenger is cGMP
A. The 2nd messenger is cAMP
• α2 adrenergic catecholamines
• Β adrenergic catecholamines • Atrial natriuretic factor
• FSH • Nitric oxide
• LH
• ACTH
• PTH
• MSH
• TSH
• ADH
• Calcitonin
• CGH
• CRH
• Glucagon
 General Classification of Hormones by
Mechanism of Action:
Hormones that bind to cell surface receptors
C. The 2nd messenger is calcium or D. The 2nd messenger is a kinase or
phosphatidyl inositol (or both) phosphatase cascade:

• Acetylcholine • Chorionic somatomammotropin

• GRH • Epidermal growth factor
• Α1 adrenergic catecholamine
• Erythropoietin
• Angiotensin II
• Fibroblast growth factor
• Oxytocin
• ADH • Growth hormone
• platelet derived • Insulin
• Cholecystokinin • Insulin-like growth factors I and II
• growth factor • Nerve growth factor
• Gastrin • Platelet derived growth factor
• TRH
• prolactin
• Substance P
 Types of Receptor

 Internal
 Nuclear
 Cytoplasmic
 External
 Cell membrane
 Membrane receptor

 Receptors present in or on the surface of cell

membrane
 Types:
 Ion channel-linked receptor
 G-protein couple receptor
 Enzyme-linked receptor
 Ex. Proteins, peptides & catecholamine
 Cytoplasmic Receptor

 Receptors found in cell cytoplasm

 Ex. Steroid hormones
 Nuclear Receptor

 Receptors present in nucleus & there is direct

association with one or more chromosomes
 Ex. Thyroid hormones, retinoid hormones, vitamin D
 Hormone Transport
 Hormones released into the circulation can circulate either
freely or bound to carrier proteins known as binding
proteins
 The binding proteins serve as reservoir for the hormone
and prolong the hormone’s half-life
 Bound form cannot be metabolized
 The free or unbound is the active form of the hormone
 binds to specific hormone receptor
 Most carrier proteins are globulins and are synthesized in
the liver
 Specific Plasma Transport Proteins
 Thyroid –Binding Globulin
 Specific to thyroid hormone
 Glycoprotein with molecular mass of 50 kDA
 Binds T3 and T4 in plasma, with greater affinity to T4
 Corticosteroid Binding Globulin
 Also known as transcortin (α-globulin)
 Produced in the liver , its synthesis is increased by estrogen
 Binds most of the hormone when plasma cortisol level are
within the normal range
 Much smaller cortisol bind to albumin
Specific Plasma Transport Proteins

 Sex Hormone Binding Globulin

 Produced in liver
 Increased production by estrogen, liver disease and
hyperthyroidism
 Decreased by androgens, advancing age and
hypothyroidism
 Mode of Hormone Action

 Generally works in two ways:

1. Synthesis of new protein molecules
2. Changing cell permeability
 Mode of Hormone Action

 Lipid-soluble hormones
 Mobile receptor hypothesis
 Water-soluble hormones
 The second messenger mechanism
 Signal Transduction
Definition: The series events and components that
take part in transmitting a hormonal signal to a
the interior of the cell

Membrane or cytosolic Receptor

Signal Initiator

Signal mediator

Target molecule Action

Signal Generation
(bind to intracellular receptors:) (bind to cell surface receptors)
 How lipid soluble
hormones work?
Ligand-Receptor Complex is the signal for Group I
Hormones (lipophilic hormones)
 Group I Hormones
(lipophilic group)
 Hormones diffuse through the plasma membrane of all
cells but only encounter their specific, high-affinity
intracellular receptors in target cells
 These receptors are found in cytoplasm or in the nucleus
 Form hormone-receptor complex
 The receptor is eventually released for re-use
 Steroid activates a specific gene to produce mRNA
 mRNA pass out into the cytoplasm and initiates protein
(enzyme) synthesis
• mobile-receptor hypothesis
• Steroid hormone is not attached to the plasma membrane,
but seem to move freely in the nucleoplasm
How water soluble
hormones work?
Signal Amplification via 2nd
Messenger Pathways
 Group II Hormones
(water-based)

 Uses membrane receptors & use intracellular

messengers
 cAMP
 cGMP
 Calcium
 phosphatidylinositides
 Signal Amplification via 2nd
Messenger Pathways

 Initial signal is in the form of hormone

 Acts as a ligand
 Concentration is one/receptor
 Hormonal response has multiple steps and each step
multiplies the signal
 Cascading effect
 Finally leads to million fold amplification
 One hormone molecule mediate its effect through
million of molecules
 Uses the 2nd messenger mechanism
 Also known as fixed-membrane receptor
hypothesis
 The 1st messenger delivers to fixed receptors in
the target cells plasma membrane
 The message then is passed to the cell where 2nd
messenger triggers appropriate cellular changes
 G-Proteins
A family of membrane proteins that exist in an inactive
(GDP) and an active (GTP) state

So-named because they bind GTP, displacing GDP

Work with many receptors

Both Stimulate and inhibit hormone signals

GTP is a time-bomb slowly ticking

When GTP is hydrolyzed to GDP, stimulation is stopped

 GTP
GDP
AC
Resting
ATP

GTP AC
Active
cAMP

Inactive GDP
AC

PO4

Resting GDP
AC
 hormone
Inhibitor

RS Ri

 AC
GTP
GDP

 GDP

GTP 4 ATP

AT P
Inactive
Protein protein
4 cAMP kinase

Adenylate cyclase ADP

Active
Signaling System protein

Cell response
Summary of Mechanism of
Action
 1. Interaction with Nuclear Chromatin
(nuclear action)

 Steroid hormones act mostly by changing the

transcription rate of specific rate of specific genes in
the nuclear DNA
 The steroid hormones has a specific soluble, oligomeric
receptor protein (mobile receptor) – found in cytosol,
inside the nucleus
 The steroid-receptor complex is translocated to the
nuclear chromatic and binds to a steroid-recognizing
acceptor site called the hormone-responsive element
(HRE) of the DNA strand
 2. Membrane receptors

 Certain molecules cannot enter target cells through

the membrane lipid bilayer
 This is achieved by the specific receptor molecules
present on the surface of plasma membrane
 They specifically bind to the receptors on cell membrane
 Cause rapid secondary metabolic changes in the tissue
but have little effect on metabolic activity of
membrane-free preparations
 Most protein hormones and catecholamine activate
transport of membrane enzyme systems by direct
binding to specific receptors in the membrane
3. Stimulation of enzyme synthesis at the
ribosomal level

 Activity at the level of translation of information is

carried by the mRNA on the ribosomes
 Increased production of new ribosomes
 Create a new population of more active or more
selective ribosomes
4. Direct activation at the enzyme
level

 Rapid effect
 Requires cell membrane, the initiating hormonal
event is activation of membrane receptor
 5. c-AMP and hormone action

 3’-5’ c-AMP plays a unique role in the action of many

protein hormones
 Hormone binds to a specific membrane receptor
 Different types of these receptors remain associated
with either Gs and Gi type of GTP-dependent trimeric
nucleotide regulatory complexes of the membrane
 Formation of the receptor-hormone complex promotes
binding of GTP to the α subunit of either Gs or Gi
 When αδ-GTP is released, it binds to adenylate cyclase
located on the cytoplasmic surface of the membrane
and changes its conformation to activate it
 Adenylate cyclase catalyzes the conversion of ATP-cAMP
thus increasing the intracellular concentration of cAMP
 αi-GT inhibits adenylate cyclase by binding with it
 Lowers the intracellular cAMP
 6. Role of polyphosphoinositol and
diacylglycerol in hormone action
 These 2nd messengers are specially found in vasopressin, TRH,
GnRH
 These hormones activate the phospholipase C-polyphosphoinositol
sytem to produce ITP and DAG
 After binding, hormone activates a trimeric nucleotide regulatory
complex
 This in turn activates phospholipase C on the inner surface of the
membrane
 ITP enhances mobilization of calcium into the cytosol from
intracellular calcium pool from mitochondria, calcium ions then act
with tertiary messenger
 DAG activates the Ca++ phosphatidyl-serine-dependent protein
kinase C located on the inner surface of the membrane by lowering
its Km for Ca++
 This enzyme phosphorylates specific enzymes and other proteins in
the cytosol to modulate their activities
7. Role of calcium in hormone action

 The action of most protein hormones is inhibited in

absence of calcium even though ability to increase or
decrease c-Amp
 It is suggested that ionized calcium is the important
signal
8. Role of c-GMP in hormone action

 Insulin and growth hormone affect the guanylate

cyclase of c-GMP system
 This will increase the intracellular concentration of c-
GMP and activate c-GMP-dependent protein kinases.
 The active c-GMP-protein kinase would in turn bring
about phosphorylation of specific cellular proteins to
change their activities
 It is likely that Ca++ may act as a 2nd messenger to
activate guanylate cyclase, thereby increasing the
concentration of c-GMP inside the cell
 9. Role of phosphorylation of
tyrosine kinase

 second messenger for insulin, growth hormone, prolactin,

oxytocin, etc. has not been identified so far.
 However binding of them to their respective membrane
receptors activates a specific protein kinase called tyrosine
kinase which phosphorylates tyrosine residue of specific
proteins.
 This may bring about some metabolic changes.
 Control of Hormone Release

 3 General Mechanisms identified as common

regulators of hormone release
1. Neural Control
2. Hormone Control
3. Nutrients or Ion Control
Thank You…
 References:

1. Harper’s Illustrated Biochemistry, 28th

edition
2. Lippincott’s Biochemistry 5th edition
Hypothalamic and Pituitary
Hormones

Endocrine Module – Med 7524

(Biochemistry)
 Learning Competencies

1. Describe the anatomical relationship between

the hypothalamus and pituitary gland.
2. Discuss the hormones that are produced in
the hypothalamus and their functions.
3. Explain the different hormones secreted by
the anterior and posterior pituitary gland
and their functions.
4. Give an overview of the different hypothalamo-
pituitary-target organ axis and their regulation
 Hypothalamus-pituitary
Hypothalamus

Pituitary Stalk

Hypophyseal Portal Vessels Posterior Pituitary

(Neurohypophysis)

Anterior Pituitary
(Adenohypohysis)
(STUDY Figure 9-15)
 The hypothalamus as an endocrine gland

➢ located in the diencephalon of the brain

➢ receives input from the body and other brain
areas

➢ initiates endocrine responses to environmental

changes
➢ secretes regulatory hormones that control the
endocrine cells in the anterior pituitary gland

➢ synthesizes hormones and transports them

along axons to the posterior pituitary gland.
 Functions of the hypothalamus

➢ main role is to keep homeostasis in the body in

homeostasis

➢ plays a part in many essential functions of the

body such as: body temperature, sleep cycles,
sex drive, water-electrolyte balance, etc.

➢ different parts of the body send signals to the brain

alerting the hypothalamus of factors that
may disturb homeostasis

➢ together with the pituitary they respond by

releasing the right hormones to balance the body
Hypothalamo-Pituitary Axis (HPA)

STIMULUS

Hypothalamus
Releasing Hormone
(Release-Inhibiting Hormone)

Pituitary
Stimulating Hormone
(tropic)

Endocrine Gland Target organ

Hormone
 Hypothalamic hormones that act on cells
of the anterior pituitary gland
A. Release Inhibiting Hormones
1. Growth hormone inhibiting hormone (GHIH)
also called somatostatin
- peptide consisting of 14 amino acids
- inhibits secretion of growth hormones by
the somatotropes
2. Prolactin release inhibiting hormone (PIH) –
- it is dopamine derived from tyrosine
- inhibits synthesis and secretion of
prolactin by the lactotropes
B. Releasing Hormones
1.Thyrotropin-releasing hormone (TRH)
- a tripeptide (3 amino acids)
- stimulates secretion of thyroid stimulating
hormone by thyrotropes

2. Growth hormone-releasing hormone (GHRH)

- a peptide consisting of 44 amino acids
- stimulates secretion of growth hormone
by somatotropes
- exerts it effects on all tissues of the body
B. Releasing Hormones

3. Gonadotropin-releasing hormone (GnRH)

- a peptide with 10 amino acids
- stimulates secretion of follicle-stimulating
hormone (FSH) and luteinizing hormone (LH)

4. Corticotropin-releasing hormone (CRH)

- single chain of 41 amino acids
- stimulates secretion of adrenocorticotropic
hormone (ACTH) by corticotropes
Hypothalamo-hypophyseal portal system

• Carries hypothalamic hormones specifically

to the anterior pituitary without dilution in the
systemic blood.
1. Allows rapid response
2. Little dilution of peptide hormones
3. Peptides have short 1/2 life
• Specific hypothalamic nuclei secrete
releasing or release inhibiting hormones
Neurosecretory cells in the hypothalamus

• Posterior pituitary gland does NOT have cells

that produce hormones
• Neurosecretory cells of hypothalamus
release hormones
– directly into the posterior pituitary
– which is rapidly released into systemic
bloodstream
– producing rapid response on the target
organ or tissue
 Posterior Pituitary Hormones

• Manufactured in Hypothalamus, released

from Post. Pit.
• Oxytocin
– Target = smooth muscle of uterus and
breast
– Function = labor and delivery,
milk ejection, (pair bonding)

• ADH (Vasopressin )
– Target = kidneys
– Function = water reabsorption
Anterior Pituitary Cell Types and Hormones

• Corticotrophs
- Adrenalcorticotrophic hormone (ACTH)
• Gonadotrophs
– Release Leutinizing Hormone (LH) and
Follicle stimulating hormone (FSH)
• Thyrotrophs
– Thyroid Stimulating Hormone (TSH)
• Lactotrophs
– Release Prolactin (luteotropic hormone)
• Somatotrophs
– Release Growth Hormone (GH)
 Anterior Pituitary Hormones
HORMONE TARGET FUNCTION

Thyroid (TSH) Thyroid gland TH synthesis &

Stimulating release

Growth (GH) Many tissues growth

Adrenocortico- Adrenal cortex Cortisol release
tropin (ACTH) (androgens)

Prolactin (Prl) Breast Milk production

Follicle (FSH) Gonads Egg/sperm prod.
Luteinizing (LH) Gonads Sex hormones
 Growth Hormone
➢ protein hormone with 191 amino acids
➢ controls several complex physiologic processes,
including growth and metabolism
➢ promotes cell reproduction and regeneration

➢ stimulates synthesis of insulin-like growth

factor 1 (somatomedin)
➢ increases levels of glucose and fatty acids
➢ promotes specific differentiation of certain types
of cells such as bone growth cells and early
muscle cells.
 Metabolic effects of growth hormone

➢ increased amino acid uptake by tissues

➢ increased protein synthesis
➢ increased mobilization of fatty acids from
adipose tissue
➢ increased levels of fatty acids in the blood
➢ increased beta oxidation of fatty acids to
generate energy
➢ increased blood glucose levels due to
decreased uptake of glucose and possible
GH-induced insulin resistance.
 Effects of growth hormone on bones

➢ GH promotes growth of skeletal structures by

1. increased protein deposition on
chondrocytic and osteogenic cells
2. increased reproduction of above cells
3. increased conversion of chondrocytes to
osteogenic cells = deposition of new
bones
➢ GH causes the liver to synthesize somatomedin
which stimulates all aspects of bone growth
 Somatomedin (IGF-1)

Action of several hormones.

• GH primary job is to stimulate the liver
– To secrete IGF-1 (Insulin Growth Factor-1)
• IGF-1
– stimulates proliferation of
chondrocytes (cartilage cells),
resulting in bone growth.
– differentiation and proliferation
of myoblasts
– Stimulates amino acid uptake
and protein synthesis in
muscle and other tissues.
 Control of growth hormone secretion
Factors that stimulate GH
secretion
➢ decreased blood glucose and
fatty acids
➢ increased plasma amino acids
particularly arginine
➢ exercise, excitement, stress
➢ deep sleep (stages II & IV)
➢ testosterone and estrogen
➢ GHRH
➢ Ghrelin - hormone secreted by
the stomach before meals.
 Robert Wardlow 8’ 11”.

Acromegaly
- excessive GH
during adulthood

Giantism Pituitary
• Excessive GH during childhood dwarfism
• Growth plate stimulation
• Tumor of somatotrophs
 Hypothalamopituitary adrenal (HPA) axis
Immune
Stress system:
Circadian altered
rhythm Hypothalamus
Muscle:
CRH Net loss of amino
Posterior Acids (glucose)
Anterior Pituitary Gland
Pituitary Gland Liver:
(-) Deamination of
amino acids,
ACTH gluconeogenesis
(glucose)
Glucocorticoids,
Adrenals Catecholamines, etc.. Fat Cells:
Free fatty
acid
Kidney mobilization

Heart rate:
Increased

(Figure 9-40)
 ADRENAL GLAND
Adrenal cortex produces the following hormones:
❖ Aldosterone – a mineralocorticoid that regulates sodium
retention and potassium loss
❖ Cortisol – a glucocorticoid that regulates metabolism of
glucose, fatty acids and amino acids
❖ Androgens – regulates control over rapid growth spurts in
preadolescents
❖ Note: They are steroid hormones derived from cholesterol

Adrenal medulla secretes the following hormones:

❖ Epinephrine (adrenaline) – increases heart rate and
blood pressure.
❖ Norepinephrine (noradrenaline) – constricts arterioles.
 Adrenals
CORTEX
Zona Glomerulosa
Mineralocorticoids (Aldosterone)
Na+, K+ and water homeostasis
Zona Fasciculata
Glucocorticoids (Cortisol)
Glucose homeostasis and many
others
Zona Reticularis
Sex steroids (androgens)

Medulla: “Catecholamines”
Epinephrine, Norepinephrine, dopamine
 Testosterone
Hypothalamus Hypothalamic-Pituitary-
Gonadal Axis (HPG):
GnRH - Males
-
Anterior
Pituitary
Seminferous tubules:
FSH (Spermatogenisis)
LH
Inhibin
+

Sertoli cells
-

Leydig cells

Male characteristics Testosterone +

Growth
Behavior: Libido,
aggression + (Figure 9-46)
Estrogen
Hypothalamus
Hypothalamic-Pituitary-
GnRH Gonadal Axis (HPG):
Females
AP
FSH LH

Tonic LH
LH surge

PGF2a
+
Progesterone

Estrogens

(Figure 9-47)
 Hypothalamothyroid
axis
• Tissues become
sensitive to
epinephrine
• Increase cellular
respiration, O2 use and
metabolism
• Heat is generated
• Thermoregulation
• Growth and
developement
Neural Pathway
to Hypothalamus
Oxytocin
Hypothalamus

Spinal Posterior Pituitary

Cord

Capillaries

Oxytocin
Release
in Blood

Calf Stimulation
of Mammary Gland
• Oxytocin – role during labor
- stimulates powerful contractions that help
to thin and open (dilate) the cervix, move the
baby down and out of the birth canal, push out
the placenta, and limit bleeding at the site of
the placenta.

• Prolactin
- produced by lactotropes in the anterior pituitary
- also called luteotropic hormone
- promotes growth of mammary glands
- stimulates milk production
- when not pregnant or breastfeeding the level of
prolactin is low
 Antidiuretic Hormone (Vasopressin)

Decreased blood volume (5-10% decrease)

Hypothalamus increased plasma osmolality (1-2%)

Vasopressin from posterior pituitary; 9 amino acids

•Increased thirst
•increased water reabsorption in renal tubules (V2 receptors)
•vasoconstriction (V 1 receptors)
•Mechanism of action: increased cAMP
•Negative feedback regulation
 References

1. Harper’s Illustrated Biochemistry 30th Edition

by Rodwell, Bender, Botham, Kennelly and Weil
2. Lehninger Principles of Biochemistry 5th Edition
by Nelson and Cox
3. Textbook of Biochemistry With Clinical Correlation
6th Edition by Thomas M. Devlin
4. Lippincott’s Biochemistry 5th Edition
by Champe and Harvey
5. Textbook of Medical Physiology 13th Edition
by Guyton and Hall
HISTOLOGY AND EMBRYOLOGY
OF THE
ENDOCRINE SYSTEM
OBJECTIVES
❑ Understand the embryologic origin of the
different endocrine glands
❑ Describe the histologic features and the cells
in the different endocrine glands
❑ Know the hormones secreted by each organ
and the functions of these hormones.
The endocrine glands:
pituitary
thyroid
parathyroid
adrenal
pineal glands
Organ and tissues with endocrine
activities:
hypothalamus ,thymus
pancreas, ovaries
testes, kidneys, stomach, liver
small intestine, skin, heart
adipose tissue, placenta
 PITUITARY GLAND

❑ a protrusion off the bottom of the hypothalamus at the

base of the brain, and rests in a small, bony cavity
(sella turcica) covered by a dural fold (diaphragm sellae).
❑ secretes hormones regulating homeostasis, including
tropic hormones that stimulate other endocrine glands.
Embryology of the Pituitary Gland
The gland is subdivided into:
1. Anterior lobe (Adenohypophysis)
- it is the true gland, secretes hormones
2. Posterior lobe (Neurohypophysis): connected to
hypothalamus
- through hypothalamo-hypophyseal tract,
- stores hormones secreted by hypothalamic nuclei
ADENOHYPOPHYSIS

Has 3 parts:
pars distalis
pars tuberalis,
pars intermedia
The pars distalis is the larger bulbar portion,
and the pars tuberalis forms a sheath around
the infundibulum.
Pars Distalis
➢ 75% of the adenohypophysis and has a thin fibrous capsule.
➢ main components are cords of well-stained endocrine cells
interspersed with fenestrated capillaries and supporting
reticular connective tissue.
➢ Cells maybe acidophils, basophils and chromophobes.
Parenchymal cells of the pars distalis are
subdivided into acidophil cells (A), basophils (B),
and chromophobes (C) in which the cytoplasm is
poorly stained
Pars Tuberalis
❑ is a smaller funnel-shaped region surrounding the
infundibulum of the neurohypophysis
❑ Most of the cells of the pars tuberalis are
gonadotrophs.
Pars intermedia
❑ is a thin zone of basophilic cells
between the pars distalis and the
pars nervosa of the
neurohypophysis
❑ which is often invaded by basophils
❑ Remnants of the embryonic
hypophyseal pouch’s lumen are
usually present in this region as
colloid-filled cysts (C)
❑ Major hormone secreted:
Melanocyte Stimulating Hormone
(MSH)
 NEUROHYPOPHYSIS

The neurohypophysis consists of a large part, the pars

nervosa, and the smaller infundibulum stalk
attached to the hypothalamus at the median eminence
Par Nervosa
❑ composed of unmyelinated axons of large secretory neurons
with cell bodies in the supraoptic and paraventricular nuclei
of the hypothalamus
❑ consists also of highly branched glial cells called pituicytes
Neurosecretory (Herring)
bodies (NB)
swellings in the axons of neurons
from supraoptic and paraventricular
nuclei from which either oxytocin
or vasopressin is released upon
neural stimulation.
 Acidophils Basophils
Somatotrophs Thyrotrophs
Lactotrophs Gonadotrophs
Corticotrophs

Chromophobes
make up about 50 percent of anterior pituitary cells
and have little affinity for basic or acidic dyes.
 PITUITARY GLAND
HORMONE TARGET ORGAN
/TISSUE
Adrenocorticotropic Adrenal Glands
Hormone (ACTH)
Antidiuretic Hormone Kidney
Beta-melanocyte-Stimulating Skin
Hormone
Endorphins Brian and Immune System
Enkephalins Brain
Follicle-Stimulating Hormone Ovaries or Testes
Growth Hormone Muscles and Bones
Luteinizing Hormone Ovaries or Testes
Oxytocin Uterus and Mammary Glands
Prolactin Mammary Glands
Thyroid Stimulating Hormone Thyroid Gland
ADRENAL GLANDS

❑ are paired organs lying near the

superior poles of the kidneys,
embedded in the perirenal
adipose tissue
❑ each covered by a dense
connective tissue capsule that
sends thin trabeculae into the
gland’s parenchyma.
❑ Each gland has two concentric
regions: a yellowish adrenal
cortex and a reddish- brown
central adrenal medulla.
EMBRYOLOGY OF THE ADRENAL GLANDS
 Adrenal Cortex
The adrenal cortex has three concentric zones in which
the cords of epithelial steroid-producing cells are arranged
somewhat differently
- zona glomerulosa
- zona fasciculata,
- zona reticularis
Zona glomerulosa
❑ consists of closely packed, rounded or
arched cords of columnar or pyramidal
cells with many capillaries
❑ steroids made by these cells are called
mineralocorticoids
❑ principal product is aldosterone,
Zona fasciculata
❑ consists of long cords of large polyhedral
cells, one or two cells thick, separated by
fenestrated sinusoidal capillaries
❑ cells secrete glucocorticoids, especially
cortisol,
❑ Secretion is controlled by ACTH
Zona reticularis
❑ consists of smaller cells in a network of irregular cords
interspersed with wide capillaries
❑ cells are more heavily stained because they contain
fewer lipid droplets and more lipofuscin pigment.
❑ produce cortisol but primarily secrete the weak
androgens, including DHEA
❑ Secretion stimulated by ACTH
 Adrenal Medulla
❑composed of large, pale-staining polyhedral cells
arranged in cords or clumps and supported by a
reticular fiber network
❑parenchymal cells, known as chromaffin cells are
modified sympathetic postganglionic neurons
specialized as secretory cells.
❑ Chromaffin cells contain many electron-dense
granules for storage and secretion of catecholamines
❑ Both catecholamines, together with Ca2+ and ATP,
are bound in granular storage complexes with
chromogranins.
 PANCREATIC ISLETS

❑ The pancreatic islets (islets of Langerhans) are compact spherical or

ovoid masses of endocrine cells embedded within the acinar exocrine
tissue of the pancreas.
❑ A very thin reticular capsule surrounds each islet, separating it from the
adjacent acinar tissue.
❑ The cells of islets are polygonal or rounded, smaller, and more lightly
stained than the surrounding acinar cells, arranged in cords separated by
fenestrated capillaries
EMBRYOLOGY OF THE PANCREAS

❑ As a result of cephalocaudal and

lateral folding of the embryo, a
portion of the endoderm-lined
yolk sac cavity is incorporated
into the embryo to form the
primitive gut.
❑ With further development, the
primitive gut forms a blind-ending
tube, the foregut and hindgut,
respectively and the midgut
later on
❑With the establishment of the the 3 layers
endoderm, mesoderm and ectoderm on the third
week of development, note that the endoderm
forms the epithelial lining of the digestive tract
and gives rise to the parenchyma of glands
including the pancreas.
 The terminal part of the foregut and the
cephalic part of the midgut form the duodenu

❑ The terminal part of the foregut and the cephalic part of the
midgut form the duodenum and from the endodermal lining of
the duodenum would arise the dorsal pancreatic bud and the
ventral pancreatic bud.
❑ Progress of development would lead to fusion of the
parenchyma and the duct system of the two buds.
❑ The ventral bud forms the uncinate process.
❑ In the third month of fetal life, the pancreatic islets
of Langerhans develop from the parenchymatous
pancreatic tissue and scatter throughout the pancreas.
❑ Insulin secretion begins at approximately the fifth
month.
❑ Glucagon- and somatostatin-secreting cells also develop
from parenchymal cells.
❑ Splanchnic mesoderm surrounding the pancreatic buds
forms the pancreatic connective tissue.
Major islet cells :
A cells - secretes glucagon and are
(α) usually located peripherally.
B cells - secretes insulin, are the
(β) most numerous, located
centrally
D cells - somatostatin, are
(δ) scattered and much less
abundant.
THYROID GLAND

❑ located anterior and inferior to the

larynx, consists of two lobes united
by an isthmus
❑ synthesizes the thyroid hormones
thyroxine
tri- iodothyronine (T3),
calcitonin
❑ covered by a fibrous capsule from
which septa extend into the
parenchyma, dividing it into lobules
and carrying blood vessels, nerves,
and lymphatics.
 EMBRYOLOGY OF THE THYROID GLAND

❑ The thyroid gland appears as an epithelial proliferation in the floor of

the pharynx
❑ Subsequently the thyroid descends in front of the pharyngeal gut as a
bilobed diverticulum.
❑ During this migration, the thyroid remains connected to the tongue by
a narrow canal, the thyroglossal duct. This duct later disappears.
 EMBRYOLOGY OF THE THYROID GLAND

❑ With further development, the thyroid gland descends in front of the

hyoid bone and the laryngeal cartilages and reaches its final position in
front of the trachea in the seventh week.
❑ The thyroid begins to function at the end of the third month, at which
time the first follicles containing colloid become visible.
❑ Follicular cells produce the colloid that serves as a source of
thyroxine and triiodothyronine.
❑ Parafollicular, or C, cells derived from the ultimobranchial body
serve as a source of calcitonin
❑ The parenchyma of the thyroid is composed of millions of
thyroid follicles each with simple epithelium and a central
lumen (L) filled with gelatinous acidophilic colloid.
❑ Thyroid colloid contains the large glycoprotein thyroglobulin,
the precursor for the active thyroid hormones.
Cells of the Thyroid gland
1. follicular cells, or thyrocytes
2. Parafollicular (C) cells
Follicular cells (thyrocytes)
❑ range in shape from squamous to low columnar
❑ activity is controlled by thyroid-stimulating hormone
(TSH) from the anterior pituitary
❑ active glands have more follicles of low columnar
epithelium
Parafollicular cell (C cell)
❑ found inside the basal lamina of the follicular epithelium or
as isolated clusters between follicles
❑ somewhat larger than follicular cells and stain less
intensely.
❑ have a smaller amount of rough ER, large Golgi complexes,
and numerous small granules containing calcitonin
 PARATHYROID GLANDS

❑ four small ovoid masses located

on the back of the thyroid gland,
embedded in its capsule

❑ blood supply arises from the

inferior thyroid arteries.

❑ each gland is contained within a

thin capsule from which septa
extend into the gland.
 PARATHYROID GLANDS

❑ Embryologically, the parathyroid glands are derived

from the endoderm of the third and fourth pharyngeal
pouches.
❑ The third pharyngeal pouch gives rise to the inferior
parathyroid glands, while the superior parathyroids
arise from the fourth pharyngeal pouch.
❑ Due to their relatively long course of descent, the final
location of the inferior glands is more variable.
Cells of the parathyroid glands:
1. principal (chief) cells
2. oxyphil cells
Principal (chief) cells
❑ are small polygonal cells with
round nuclei and pale-staining,
slightly acidophilic cytoplasm.
❑ Irregularly shaped cytoplasmic
granules con- tain the
polypeptide parathyroid
hormone (PTH)
❑ Parathyroid hormone is an
important regulator of blood
calcium levels
Oxyphil cells
❑ often clustered and are much larger than the principal cells
❑ characterized by very acidophilic cytoplasm filled with
abnormally shaped mitochondria.
❑ Some oxyphil cells show low levels of PTH synthesis, suggesting
that these cells are transitional derivatives of principal cells.
 PINEAL GLAND

❑a small, pine cone-shaped organ also known as the

epiphysis cerebri
❑is covered by connective tissue of the pia mater,
from which septa containing small blood vessels
emerge and subdivide variously sized lobules.
Cells of the Pineal gland
1. pinealocytes (P)
2. astrocytes (modified) (A)
Pinealocytes
❑Secretory cells which have
slightly basophilic cytoplasm and
irregular euchromatic nuclei
❑Ultrastructurally are seen to
have secretory vesicles, many
mitochondria, and long
cytoplasmic processes
❑Produce melatonin, a low-
molecular-weight tryptophan
derivative.
Astrocytes
❑ interstitial glial cells that are
modified, staining positively for
glial fibrillary acidic protein
❑ represent about 5% of the cells
❑ have elongated nuclei more
heavily stained than those of
pinealocytes and are usually
found in perivascular areas and
between the groups of
pinealocytes.
A characteristic feature of
the pineal gland is the
presence of variously sized
concretions of calcium and
magnesium salts called
corpora arenacea (CA),
or brain sand, which form as
extracellular protein deposits
become mineralized.
END OF LECTURE
REFERENCES

Junqueira’s Basic Histology 13th Edition

Difiore’s Atlas of Histology with Functional correlation

11th Edition by Victor P. Eroschenko ; 2008

The Big Picture Histology John F. Ash David Morton, Sheryl A. Scott
2013

Langman’s Medical Embryology 9th edition

 Endocrine System I

Pancreas
 Enumerate the hormones of the pancreas

Learning Describe the function of the hormones of the

pancreas

Objectives Describe the relationship of insulin with glucagon

 Guyton and Hall Textbook of Medical Physiology 13th
Edition, 2015

References Board Review Series, Physiology, 6th Edition 2015

Pancreas – Structure & Function:
https://www.youtube.com/watch?v=S95FSQ6ACsI
How is the •  The islets of Langerhans contain three major cell types. (Alpha: glucagon, Beta:

endocrine
insulin, Delta: somatostatin and gastrin
• Other cells secrete pancreatic polypeptide.
• Gap junctions link beta cells to each other, alpha cells to each other, and beta

pancreas
cells to alpha cells for rapid communication.
• The portal blood supply of the islets allows blood from the beta cells
(containing insulin) to bathe the alpha and delta cells, again for rapid cell-to-cell

organized?
communication.
 • The major factor that regulates glucagon secretion is the

How is glucagon •
blood glucose concentration.
Decreased blood glucose stimulates glucagon secretion.

secreted? • Increased blood amino acids stimulate glucagon

secretion, which prevents hypoglycemia caused by
unopposed insulin in response to a high protein meal.
What are the Factors that increase glucagon secretion

factors affecting
• Decrease blood glucose
• Increase amino acid (arginine)

glucagon
• Cholecystokinin
• Norepinephrine, epinephrine

secretion?
• Acetylcholine
What are the Factors that decrease glucagon secretion

factors affecting •
•
Increase blood glucose
Insulin

glucagon • Somatostatin

secretion?
• Fatty acids, ketoacids
What are the • Glucagon acts on the liver and
adipose tissue.
actions of •  The second messenger for
glucagon? glucagon is CAMP.
What are the Glucagon increases the blood glucose concentration.
• It increases glycogenolysis and prevents the recycling of glucose

actions of
into glycogen.
• It increases gluconeogenesis. Glucagon decreases the production
of fructose 2,6-bisphosphate, decreasing phosphofructokinase

glucagon?
activity; in effect, substrate is directed toward glucose formation
rather than toward glucose breakdown.
What are the Glucagon increases blood fatty acid and ketoacid concentration.
•  Glucagon increases lipolysis. The inhibition of fatty acid synthesis in

actions of •
effect “shunts” substrates toward gluconeogenesis.
 Ketoacids (β-hydroxybutyrate and acetoacetate) are produced

glucagon?
from acetyl coenzyme A (CoA), which results from fatty acid
degradation.
What are the Glucagon increases urea production.

actions of • Amino acids are used for gluconeogenesis

(stimulated by glucagon), and the resulting

glucagon? amino groups are incorporated into urea.

 • Contains an A chain and a B chain, joined by two disulfide bridges.
•  Proinsulin is synthesized as a single-chain peptide.

What is insulin?
• Within storage granules, a connecting peptide (C peptide) is
removed by proteases to yield insulin.
• The C peptide is packaged and secreted along with insulin, and its
concentration is used to monitor beta cell function in diabetic
patients who are receiving exogenous insulin.
How is insulin Blood glucose concentration
Major factor that regulates insulin secretion.

secretion
•
•  Increased blood glucose stimulates insulin secretion.
An initial burst of insulin is followed by sustained

regulated?
•
secretion.
How is insulin Mechanism of insulin secretion
• Glucose, the stimulant for insulin secretion, binds to the Glut 2 receptor on the
beta cells.

secretion •   Inside the beta cells, glucose is oxidized to ATP, which closes K+ channels in
the cell membrane and leads to depolarization of the beta cells.
Similar to the action of ATP, sulfonylurea drugs stimulate insulin secretion by

regulated?
•
closing these K+ channels.
•  Depolarization opens Ca2+ channels, which leads to an increase in intracellular
[Ca2+] and then to secretion of insulin.
How is insulin Factors that increase insulin secretion
Increase blood glucose

secretion Increase amino acids (arginine, lysine, leucine)

Increase fatty acids

regulated?
Glucagon
Glucose-dependent insulinotropic peptide
ACh
How is insulin Factors that decrease insulin secretions?
Decrease blood glucose
secretion
•
• Somatostatin

regulated? • Norepinephrine, epinephrine

What is the • Found on target tissues for insulin.

significance of
• A tetramer, with two α subunits and two β subunits.
• The α subunits are located on the extracellular side of

the insulin
the cell membrane.
• The β subunits span the cell membrane and have

receptor? intrinsic tyrosine kinase activity.

What is the • When insulin binds to the receptor, tyrosine kinase is activated and
autophosphorylates the β subunits.

significance of • The phosphorylated receptor then phosphorylates intracellular

proteins.

the insulin
• The insulin–receptor complexes enter the target cells.
• Insulin down-regulates its own receptors in target tissues.

receptor?
•  The number of insulin receptors is increased in starvation and
decreased in obesity
What are the • The target organs of insulin
actions of include the liver, adipose tissue

insulin? and muscle.

What are the Insulin decreases blood glucose concentration by the following
mechanisms:

actions of • It increases uptake of glucose into target cells by directing the

insertion of glucose transporters into cell membranes.

insulin?
• As glucose enters the cells, the blood glucose concentration
decreases.
What are the
• It promotes formation of glycogen from glucose in muscle and
liver, and simultaneously inhibits glycogenolysis.

actions of
• It decreases gluconeogenesis.
• Insulin increases the production of fructose 2,6-bisphosphate,
increasing phosphofructokinase activity.

insulin?
• In effect, substrate is directed away from glucose formation.
What are the Insulin decreases blood fatty acid and ketoacid concentrations.
•   In adipose tissue, insulin stimulates fat deposition and

actions of •
inhibits lipolysis.
Insulin inhibits ketoacid formation in the liver because

insulin?
decreased fatty acid degradation provides less acetyl CoA
substrate for ketoacid formation.
What are the Insulin decreases blood amino acid concentration.

actions of
•   Insulin stimulates amino acid uptake into cells, increases protein
synthesis, and inhibits protein degradation (anabolic).
Insulin decreases blood K+ concentration.

insulin?  Insulin increases K+ uptake into cells, thereby decreasing blood K+.
What happens in Hyperglycemia

insulin
•  In the absence of insulin, glucose uptake into cells is decreased, as
is storage of glucose as glycogen→ elevated blood sugar
•   increased serum levels of both amino acids (because of increased

deficiency?
protein catabolism) and fatty acids (because of increased lipolysis)
What happens in Hypotension
• A result of ECF volume contraction.

insulin • The high blood glucose concentration results in a high filtered load
of glucose that exceeds the reabsorptive capacity of the kidney.

deficiency?
•  The unreabsorbed glucose acts as an osmotic diuretic in the urine
and causes ECF volume contraction.
What happens in
Metabolic acidosis
• Caused by overproduction of ketoacids (β-hydroxybutyrate and

insulin
acetoacetate).
•  The increased ventilation rate, or Kussmaul respiration, is the
respiratory compensation for metabolic acidosis.

deficiency?
Hyperkalemia
• Results from the lack of insulin; normally, insulin promotes K+
uptake into cells.
 • Secreted by the delta cells of the
What is pancreas.

somatostatin? • Inhibits the secretion of insulin,

glucagon, and gastrin.
Endo I (Physio) - Adrenal
Gland
Objectives
• Classify the adrenal hormonos according to chemical structure
• Explain the synthesis, storage and secretion of adrenal hormones
• Explain the different mechanisms and physiologic actions of different
adrenal hormones
• Explain the pathophysiology of common diseases involving the
hormones secreted by the adrenals
• The adrenal gland is composed of two distinct parts:
• (1) an inner adrenal medulla, which is functionally related to the sympathetic
nervous system and secretes mainly epinephrine but some norepinephrine,
• (2) an outer adrenal cortex, which forms the bulk of the gland and secretes
corticosteroids.
• The primary corticosteroids secreted by the adrenal cortex are as
follows:
• Mineralocorticoids—C21 steroids that have important effects on sodium and
potassium balance
• Glucocorticoids—C21 steroids that influence carbohydrate, fat, and protein
metabolism
• Sex hormones—C19 steroids that are mostly weak androgens and contribute
to secondary sex characteristics
• The secretion of mineralocorticoids and glucocorticoids is essential to
life.
• Only small amounts of sex hormones are normally secreted by the
adrenal cortex, and they have little effect on reproductive function.
CHEMISTRY OF ADRENOCORTICAL
SECRETION
• The Adrenal Cortex Is Composed of Three Distinct Layers or Cell
Types: Zona Glomerulosa, Zona Fasciculata, and Zona Reticularis.
• The zona glomerulosa, or outer zone, is relatively thin; it is the
exclusive site of the enzyme aldosterone synthase
• Its major secretion product is the principal mineralocorticoid aldosterone.
• The primary controllers of aldosterone secretion are angiotensin II and
potassium.
• Chronic increases in plasma angiotensin II concentration, such as occur during
sodium depletion, cause hypertrophy and hyperplasia of zona glomerulosa
cells only.
• Because the zona glomerulosa lacks the enzyme 17-hydroxylase it cannot
synthesize cortisol or sex hormones.
CHEMISTRY OF ADRENOCORTICAL
SECRETION
• The zona fasciculata, or middle zone, is the widest zone; it secretes
the glucocorticoids cortisol (the principal glucocorticoid) and
corticosterone.
• This zone also secretes small amounts of sex hormones.
• The major controller of cortisol secretion is adrenocorticotropic hormone
(corticotropin; ACTH).
CHEMISTRY OF ADRENOCORTICAL
SECRETION
• The zona reticularis, or inner zone, secretes sex hormones and some
glucocorticoids; like the zona fasciculata, it is stimulated by ACTH.
• Chronic excess of ACTH causes hypertrophy and hyperplasia of the inner two
zones of the adrenal cortex.
• The most prevalent adrenal androgens are dehydroepiandrosterone (DHEA)
and androstenedione.
CHEMISTRY OF ADRENOCORTICAL
SECRETION
• Adrenocortical Hormones Are Synthesized From Cholesterol.
• Most of the cholesterol in adrenocortical cells is taken up from the
circulation and then esterified and stored in lipid droplets.
• The rate-limiting step in the synthesis of adrenocortical hormones is the
side-chain cleavage of cholesterol to form pregnenolone.
• This step includes the delivery of cholesterol to the inner mitochondrial
membrane and the enzymatic cleavage (through cholesterol desmolase) of
a six-carbon unit from cholesterol to yield pregnenolone.
• In all three zones of the adrenal cortex, this initial step in steroid
biosynthesis is stimulated by the controllers of the major hormone
products (aldosterone and cortisol).
CHEMISTRY OF ADRENOCORTICAL
SECRETION
• Adrenocortical Hormones Are Bound to Plasma Proteins.
• Approximately 90 to 95 percent of the cortisol in the plasma is bound to
plasma proteins, especially transcortin or corticosteroid-binding globulin.
• As a result of this high degree of binding to plasma proteins, cortisol has a
long half-life (about 60 to 90 minutes).
• Corticosterone is bound to plasma proteins to a lesser degree than cortisol
and has a half-life of approximately 50 minutes.
• Even smaller amounts of aldosterone are bound to plasma proteins;
consequently, aldosterone has a half-life of only approximately 20 minutes.
CHEMISTRY OF ADRENOCORTICAL
SECRETION
• Adrenocortical Hormones Are Metabolized in the Liver.
• Cortisol and aldosterone are metabolized to various compounds in the liver
and then conjugated to glucuronic acid.
• These inactive conjugates are freely soluble in plasma and are not bound to
plasma proteins.
• Once released into the circulation, they are readily excreted in urine.
• The rate of inactivation of adrenocortical hormones is depressed in liver
disease.
FUNCTIONS OF THE MINERALOCORTICOIDS—
ALDOSTERONE
• Aldosterone accounts for approximately 90 percent of the
mineralocorticoid activity of adrenocortical hormones.
• Most of the remainder of the mineralocorticoid activity can be
attributed to:
• (1) deoxycorticosterone, which has approximately 3 percent of the
mineralocorticoid activity of aldosterone and is secreted at a comparable rate,
and
• (2) cortisol, a glucocorticoid with weak mineralocorticoid activity that is
normally present at plasma concentrations of more than 1000 times that of
aldosterone.
• In vitro studies have shown that cortisol binds with high affinity to
mineralocorticoid receptors.
FUNCTIONS OF THE MINERALOCORTICOIDS—
ALDOSTERONE
• 11β-hydroxysteroid dehydrogenase type 2, cortisol is converted to
cortisone, which does not avidly bind mineralocorticoid receptors.
• Consequently, cortisol does not normally exert significant
mineralocorticoid effects in vivo.
• Under conditions in which 11β-hydroxysteroid dehydrogenase is
either congenitally absent or inhibited (e.g., during excessive licorice
ingestion), cortisol may have substantial mineralocorticoid effects.
FUNCTIONS OF THE MINERALOCORTICOIDS—
ALDOSTERONE
• Aldosterone Increases Sodium Reabsorption and Potassium Secretion. Aldosterone and
other mineralocorticoids act on the distal nephron, especially the principal cells of the
collecting duct, to increase sodium reabsorption and potassium secretion.
• These effects occur after the binding of aldosterone to intracellular receptors and the
subsequent synthesis of proteins, including Na-K-ATPase in the basolateral membrane
and sodium and potassium channel proteins in the apical membrane.
• As a result of increased Na-K-ATPase activity, sodium is pumped out of the tubular cells into the
blood and exchanged for potassium.
• Potassium then diffuses into the tubular urine.
• As sodium is reabsorbed under the influence of aldosterone, tubular secretion of
potassium ions is enhanced.
• Aldosterone also causes secretion of hydrogen ions in exchange for sodium in the
intercalated cells of the cortical collecting tubules.
• Because protein synthesis is required to mediate the tubular actions of aldosterone, a lag time of
about 60 minutes occurs between exposure to aldosterone and its onset of action.
FUNCTIONS OF THE MINERALOCORTICOIDS—
ALDOSTERONE
• Angiotensin II Stimulates Aldosterone Secretion.
• Angiotensin II directly stimulates the cells of the zona glomerulosa to secrete
aldosterone.
• This effect of angiotensin II is mediated via increments in intracellular levels of
calcium and the phosphatidylinositol products diacylglycerol and inositol
triphosphate.
• These second messengers activate protein kinase C, which in turn stimulates
both early (cholesterol desmolase) and late (aldosterone synthase) steps in
the biosynthesis of aldosterone.
FUNCTIONS OF THE MINERALOCORTICOIDS—
ALDOSTERONE
• ACTH Plays a Permissive Role in the Regulation of Aldosterone
Secretion.
• As long as normal plasma levels of ACTH are present, the
responsiveness of the zona glomerulosa to its major controllers,
angiotensin II and potassium, is maintained.
• In contrast, if ACTH is chronically deficient, the aldosterone response
to angiotensin II and potassium is diminished.
• High plasma levels of ACTH, which occur acutely during stress,
stimulate aldosterone secretion, but in states of chronic ACTH excess
(e.g., with Cushing’s disease), hyperaldosteronism is not sustained.
FUNCTIONS OF GLUCOCORTICOIDS
• Cortisol decreases protein stores in extrahepatic tissues.
• In muscle and other extrahepatic tissues, cortisol decreases amino acid
uptake and inhibits protein synthesis; at the same time, it increases the
degradation of proteins.
• As a result of these catabolic and antianabolic effects of cortisol, amino acids
tend to increase in the blood and are taken up by the liver, where they are
converted to glucose and proteins, including gluconeogenic enzymes.
FUNCTIONS OF GLUCOCORTICOIDS
• Cortisol tends to increase the blood glucose concentration in two ways.
• First, cortisol increases hepatic production of glucose by increasing
gluconeogenesis.
• The proteins mobilized from peripheral tissues are converted to glucose and
glycogen in the liver.
• By maintaining glycogen reserves, cortisol allows other glycolytic hormones, such as
epinephrine and glucagon, to mobilize glucose in times of need, such as between
meals.
• A second way in which cortisol tends to increase the blood glucose
concentration is by impairing the utilization of glucose in peripheral tissues;
cortisol has an anti-insulin effect in tissues such as muscle and adipose
tissue and impairs the uptake and utilization of glucose for energy.
FUNCTIONS OF GLUCOCORTICOIDS
• Cortisol plays an important role in the mobilization of fatty acids from
adipose tissue.
• Although weakly lipolytic itself, normal levels of cortisol exert a
permissive effect on the mobilization of fatty acids during fasting.
• During fasting, cortisol allows other lipolytic hormones, such as
epinephrine and growth hormone, to mobilize fatty acids from lipid
stores.
FUNCTIONS OF GLUCOCORTICOIDS
• Increased Cortisol Secretion Is Important for Resistance to Stress.
• Physical or mental stress increases ACTH secretion, which in turn
stimulates the adrenal cortex to secrete cortisol.
• Although it is not clear how hypercortisolism mediates this response,
the large rise in cortisol secretion in response to many stressors is
essential to survival.
• Patients with adrenal dysfunction who receive maintenance doses of
steroids require extra glucocorticoid under stressful conditions.
FUNCTIONS OF GLUCOCORTICOIDS
• Pharmacological Doses of Glucocorticoids Have Anti- Inflammatory
and Antiallergic Effects and Suppress Immune Responses.
• Large doses of glucocorticoids decrease the inflammatory response to
tissue trauma, foreign proteins, or infections through several effects:
• Inhibition of phospholipase decreases the synthesis of arachidonic acid, which
is the precursor of leukotrienes, prostaglandins, and thromboxanes,
• Stabilization of lysosomal membranes decreases the release of proteolytic
enzymes by damaged cells.
• Suppression of the immune system is a result of decreased production of T
cells and antibodies that contribute to the inflammatory process.
• Inhibition of fibroblastic activity
Controller of Cortisol Secretion—ACTH
• The secretion of cortisol is under the control of the hypothalamicpituitary,
• corticotropin-releasing hormone (CRH)– ACTH axis.
• The release of ACTH (corticotropin) from the pituitary is dependent on the
hypophysiotropic hormone CRH.
• Once ACTH is secreted into the blood, it has a rapid effect on the inner two
zones of the adrenal cortex, especially the zona fasciculata, resulting in the
increase of the secretion of cortisol.
• This effect of ACTH is achieved by increasing the conversion of cholesterol
to pregnenolone and is mediated via the second messenger cyclic
adenosine monophosphate
Controller of Cortisol Secretion—ACTH
• Stress Increases ACTH Secretion.
• Several physical and mental stressors stimulate the neuroendocrine
cells of the hypothalamus to secrete CRH; as a result, ACTH secretion
increases, which stimulates release of cortisol.
• Under conditions of stress, the inhibitory effect of cortisol on ACTH
secretion is insufficient to counteract the extra neural input to the
neuroendocrine cells secreting CRH.
• Consequently, plasma levels of ACTH are increased.
ADRENAL ANDROGENS
• The adrenal androgens DHEA and androstenedione are secreted in
appreciable amounts but have only weak androgenic effects.
• Consequently, the normal plasma concentrations of these hormones
exert little effect on secondary sex characteristics, especially in males,
in whom large amounts of testosterone, the most potent androgen,
are secreted by the testes.
• In females, adrenal androgens are responsible for pubic and axillary
hair.
ADRENAL ANDROGENS
• Most of the androgenic activity of adrenal hormones may be due to
the conversion of adrenal androgens to testosterone in peripheral
tissues.
• In contrast to the normal state, when adrenal androgens are secreted
in excessive amounts, as with Cushing’s syndrome, appreciable
masculinization may be produced in both males and females.
• The secretion of adrenal androgens is stimulated by ACTH.
ABNORMALITIES OF ADRENOCORTICAL
SECRETION
• Increased Plasma Levels of Glucocorticoids (Cortisol) Cause Cushing’s
Syndrome.
• Excess cortisol secretion can be caused by an adrenal tumor, a
pituitary tumor that is secreting large amounts of ACTH and causing
bilateral adrenal hyperplasia (Cushing’s syndrome), or a tumor of the
lungs or other tissues (an ectopic tumor) that is secreting large
amounts of ACTH and causing bilateral adrenal hyperplasia.
• Cushing’s syndrome may also be produced by the administration of
large amounts of exogenous glucocorticoids.
ABNORMALITIES OF ADRENOCORTICAL
SECRETION
• Symptoms of Cushing’s syndrome include the following:
• Mobilization of fat from the extremities to the abdomen, face, and supraclavicular
areas
• Hypertension and hypokalemia resulting from high plasma levels of cortisol and 11-
deoxycorticosterone (when secreted in excess)
• Protein depletion resulting in muscle weakness, loss of connective tissue and
thinning of the skin (leading to purple striae), and impaired growth in children
• Osteoporosis and vertebral fractures resulting from their direct effect on bone,
decreased calcium absorption from the gut (anti–vitamin D action), and increased
glomerular filtration rate and renal excretion of calcium
• Impaired response to infections resulting from a suppressed immune system
• Impaired carbohydrate metabolism, hyperglycemia, and even insulin-resistant
diabetes mellitus
• Masculinizing effects when adrenal androgens are secreted in excess
ABNORMALITIES OF ADRENOCORTICAL
SECRETION
• Conn’s syndrome (primary aldosteronism) is caused by a tumor in the
zona glomerulosa.
• When a tumor is present in the zona glomerulosa that produces large
amounts of aldosterone, the most notable features are hypertension and
hypokalemia
ABNORMALITIES OF ADRENOCORTICAL
SECRETION
• Impaired secretion of adrenocortical hormones occurs in Addison’s
disease.
• Destruction of the adrenal cortex can result from autoimmune
disease, tuberculosis, or cancer.
• These processes usually are gradual, leading to a progressive
reduction in glucocorticoid and mineralocorticoid function.
• As a result of the decreased cortisol secretion, there is a
compensatory increase in ACTH secretion, which produces
hyperpigmentation.
ABNORMALITIES OF ADRENOCORTICAL
SECRETION
• Mineralocorticoid Deficiency
• Excessive loss of sodium, hypovolemia, hypotension, and increased plasma
renin activity
• Excessive potassium retention and hyperkalemia
• Mild acidosis
• Glucocorticoid Deficiency
• Abnormal carbohydrate, fat, and protein metabolism resulting in muscle
weakness, fasting hypoglycemia, and impaired utilization of fats for energy
• Loss of appetite and weight loss
• Poor tolerance to stress; the inability to secrete increased amounts of cortisol
during stress leads to an Addisonian crisis that may culminate in death if
supplemental doses of adrenocortical hormones are not administered
• END
References
• Berne, Robert M.,, Koeppen, Bruce M.Stanton, Bruce, A. (Eds.)
(2008) Berne & Levy physiology.Philadelphia : Mosby/Elsevier
• Guyton, Arthur C. Guyton And Hall Textbook Of Medical Physiology.
Philadelphia, PA : Saunders/Elsevier, 2011.
 ENDO I (PHYSIO)
Other Minor Hormones
Learning Objectives:

1. To enable the students to know the minor hormones that plays

an important role in homeostasis.
2. To know the organs and tissues that secrete these minor
hormones
3. To enable the students to understand the conditions which
triggers the release of these minor hormones in the body
4. To enable the students to explain the physiological effects of
these minor hormones
 Hormones

The process by which a substance is released in one organ and transferred

via the blood to its target organ is called an endocrine process: at one place
synthesis and release occur, then undirected transport in the blood occurs,
and finally reactivity occurs at a distant cell or organ.

Hormones can either be produced by an entire organ just like pituitary,

thyroid , parathyroid, adrenals, etc. or it can be produced by bits of tissue
interspersed within an organ like kidneys, intestines, placenta, stomach, etc.
 Hormones
Major hormones are critical to survival. These major hormones are usually
regulated by brain, within neurosecretory cells of the hypothalamus, signals
are integrated and processed, resulting in release of hormones into the
capillaries of the median eminence. From there, they reach the pituitary,
where other tropic hormones are released, which then induce the hormonal
(synthesis and) release in the thyroid gland, the adrenal glands, or the
gonads. These hierarchies have been named the hypothalamic–pituitary–
thyroid, hypothalamic–pituitary–adrenal, and hypothalamic–pituitary–gonadal
axes.
Major Endocrine Organs
 Minor Hormones

In addition to the major hormones, the body also has hundreds of ”minor”
hormones. Even though these minor hormones do not play as vital a role in
immediate survival, they are still critical to long-term health and wellbeing.
Indeed, survival is possible for many years after the loss or compromise of a
minor hormone. However, any minor hormone deficiency will undermine the
functioning of major hormones and progressively cause problems. As a
result, there will be faster aging, more rapid development of degenerative
disease, and possibly earlier death.

The emphasis of this lecture will be on the minor hormones of the human
body.
 Atrial Natriuretic Factor
This is also called atriopeptin. Atrial natriuretic factor is a 28-amino acid
peptide that is released from granule stores of the right and left atria in
response to volume overload with atrial distention or after an atrial
tachyarrhythmia.
The following effects of this hormone include:
1. Inhibits renin release and thus indirectly inhibits the production of
angiotensin II.
2. Inhibits aldosterone production regardless of the presence of
angiotensin II, high plasma K + , or elevated adrenocorticotropic
hormone.
3. Increases the glomerular filtration rate and thus increases the amount of
Na + available for excretion.
4. Directly inhibits the tubular reabsorption of Na + in the terminal collecting
duct.
 Vasoactive Intestinal Polypeptide

Vasoactive intestinal polypeptide is a neuropeptide with wide distribution in

the central and peripheral nervous systems, has a broad spectrum of
biologic actions. Usually acting as a neurotransmitter or neuromodulator but
sometimes also as a blood-borne hormone, it participates in the regulation of
a variety of major body functions and may be an important factor in the
pathogenesis of several diseases.

VIP is produced in many tissues of vertebrates including the gut, pancreas,

and suprachiasmatic nuclei of the hypothalamus in the brain.

VIP has an effect on several tissues: In the digestive system, VIP seems to
induce smooth muscle relaxation (lower esophageal sphincter, stomach,
gallbladder), stimulate secretion of water into pancreatic juice and bile, and
cause inhibition of gastric acid secretion and absorption from the intestinal
lumen. It also acts as a neurotransmitter in peripheral autonomic nervous
system.
 Vasoactive Intestinal Polypeptide

VIP is a neuromodulator that has broad significance in intestinal physiology.

VIP is a potent vasodilator that increases blood flow in the GI tract and
causes smooth muscle relaxation and epithelial cell secretion. As a chemical
messenger, VIP is released from nerve terminals and acts locally on cells
bearing VIP receptors. VIP belongs to a family of GI peptides, including
secretin and glucagon, that are structurally related. The VIP receptor is a
GPCR that stimulates intracellular cAMP generation.

VIP is an important neurotransmitter throughout the central and peripheral

nervous systems. Because of its wide distribution, VIP has effects on many
organ systems; most notably, in the GI tract, VIP stimulates fluid and
electrolyte secretion from intestinal epithelium and bile duct cholangiocytes.
 Vasoactive Intestinal Polypeptide

VIP, along with NO, is a primary component of nonadrenergic,

noncholinergic nerve transmission in the gut. GI smooth muscle exhibits a
basal tone, or sustained tension, caused by rhythmic depolarizations of the
smooth muscle membrane potential. VIP serves as an inhibitory transmitter
of this rhythmic activity, causing membrane hyperpolarization and
subsequent relaxation of GI smooth muscle. Accordingly, VIP is an important
neuromodulator of sphincters of the GI tract, including the lower esophageal
sphincter and sphincter of Oddi. In certain pathologic conditions, such as
achalasia and Hirschsprung's disease, the lack of VIP innervation is believed
to play a major role in defective esophageal relaxation and bowel dysmotility,
respectively.
 Cholecystokinin

CCK is a peptide transmitter produced primarily by enteroendocrine cells of

the proximal small intestine and is secreted into the blood following ingestion
of a meal. Circulating CCK binds to specific CCK-1 receptors on the
gallbladder, pancreas, smooth muscle of the stomach, and peripheral nerves
to stimulate gallbladder contraction and pancreatic secretion, regulate gastric
emptying and bowel motility, and induce satiety. These effects serve to
coordinate the ingestion, digestion, and absorption of dietary nutrients.
Ingested fat and protein are the major food components that stimulate CCK
release.

CCK also has been shown to delay gastric emptying. This action may be
important in coordinating the delivery of food from the stomach to the
intestine. CCK has been proposed as a major mediator of satiety and food
intake, an effect that is particularly noticeable when food is in the stomach or
intestine. CCK inhibits gastric acid secretion by binding to CCK-1 receptors
on somatostatin (D) cells in the antrum and oxyntic mucosa.
 Secretin

Secretin is a 27–amino acid peptide and, similar to many other GI peptides, is

amidated at the carboxyl terminus. It is the founding member of the secretin-
glucagon-VIP family of structurally related GI hormones. Secretin is selectively
expressed in specialized enteroendocrine cells of the small intestine called S
cells.
Secretin is released by acid in the duodenum and stimulates pancreatic fluid and
bicarbonate secretion, leading to neutralization of acidic chyme in the intestine.
Secretin also inhibits gastric acid secretion and intestinal motility.
One of the major physiologic actions of secretin is stimulation of pancreatic fluid
and bicarbonate secretion. Pancreatic bicarbonate, on reaching the duodenum,
neutralizes gastric acid and raises the duodenal pH, thereby “turning off”
secretin release (negative feedback).
Although the primary action of secretin is to produce pancreatic fluid and
bicarbonate secretion, it is also an enterogastrone, a substance that is released
when fat is present in the GI lumen and that inhibits gastric acid secretion. In
physiologic concentrations, secretin inhibits gastrin release, gastric acid
secretion, and gastric motility.
 Gastrin

Most gastrin is produced in endocrine cells of the gastric antrum. Much

smaller amounts of gastrin are produced in other regions of the GI tract,
including the proximal stomach, duodenum, jejunum, ileum, and pancreas.
Gastrin has also been found outside the GI tract, including in the brain,
adrenal gland, respiratory tract, and reproductive organs, although its
biological role in these sites is unknown.

Gastrin is released from specialized endocrine cells (G cells) into the

circulation in response to a meal. The specific components of a meal that
stimulate gastrin release include protein, peptides, and amino acids. Gastrin
release is profoundly influenced by the pH of the stomach. Fasting and
increased gastric acidity inhibit gastrin release, whereas a high gastric pH is
a strong stimulus for its secretion.

Gastrin is the major hormone that stimulates gastric acid secretion. Gastrin
was found to have growth-promoting effects on the gastric mucosa and
possibly some cancers.
 Substance P and the Tachykinins
Substance P belongs to the tachykinin family of peptides, which includes
neurokinin A and neurokinin B. The tachykinins are found throughout the
peripheral and central nervous systems and are important mediators of
neuropathic inflammation.

Substance P is a neurotransmitter of primary sensory afferent neurons and

binds to specific receptors in lamina of the spinal cord.

Substance P has been implicated as a primary mediator of neurogenic

inflammation. In the intestine, Clostridium difficile – initiated experimental
colitis results from toxin-induced release of substance P and consequent
activation of the NK-1 receptor. Substance P receptors are more abundant in
the intestine of patients with ulcerative colitis and Crohn's disease.
 Somatostatin
Somatostatin is a 14–amino acid cyclic peptide that was initially identified as an
inhibitor of growth hormone secretion. It is found in almost every organ in the
body and throughout the GI tract. In the gut, somatostatin is produced by D cells
in the gastric and intestinal mucosa and islets of the pancreas, as well as enteric
neurons. Somatostatin has a number of pharmacologic effects that are mostly
inhibitory.

In the stomach, somatostatin plays an important role in regulating gastric acid

secretion.

Somatostatin release is also influenced by mechanical stimulation, dietary

components of a meal, including protein, fat, and glucose, and other hormones
and neurotransmitters. Muscarinic stimulation appears to be the most important
neural stimulus to somatostatin secretion.
 Somatostatin

In the gut, somatostatin has broad inhibitory actions. In addition to effects on

gastric acid, somatostatin reduces pepsinogen secretion. Somatostatin
profoundly inhibits pancreatic enzyme, fluid, and bicarbonate secretion and
reduces bile flow. The effects of somatostatin on gut motility are largely
inhibitory, with the exception that it stimulates the migrating motor complex,
possibly through effects on motilin. Somatostatin also reduces intestinal
transport of nutrients and fluid, reduces splanchnic blood flow, and has
inhibitory effects on tissue growth and proliferation.
 Motilin

Motilin is a 22–amino acid peptide produced by endocrine cells of the

duodenal epithelium. It is not released by the stimulation of food but instead
is secreted into the blood under fasting conditions in a periodic and recurrent
pattern that is synchronized with the migrating motor complex (MMC).
Elevations in blood motilin levels regulate the phase III contractions that
initiate in the antroduodenal region and progress toward the distal gut.

Motilin binds to specific receptors on smooth muscle cells of the esophagus,

stomach, and small and large intestines through which it exerts propulsive
activity.
 Leptin
Leptin is a 167–amino acid protein that is secreted primarily from adipocytes.
Blood leptin levels reflect total body fat stores. Small amounts of leptin are
produced by the chief cells of the stomach and by the placenta and are
present in breast milk. Its primary action appears to be to reduce food intake.
Leptin is a member of the cytokine family of signaling molecules.
Leptin's ability to reduce food intake occurs within the brain by decreasing
NPY (a potent stimulant of food intake) and by increasing α-melanocyte-
stimulating hormone (α-MSH), an inhibitor of food intake. Peripherally, leptin
acts synergistically with CCK to reduce meal size.
Blood levels of leptin increase as obesity develops. At the cellular level, large
adipocytes produce more leptin than small adipocytes. Because of its effects
on food intake, it was initially thought that exogenous leptin could be used
therapeutically to treat obesity. However, only a very modest effect on weight
loss has been demonstrated in clinical trials. Leptin deficiency has been
reported as a cause of obesity in a few families, but this condition is
extremely rare.
 Ghrelin
Ghrelin is a 28–amino acid peptide produced by the stomach and is the
natural ligand for the growth hormone secretagogue (GHS) receptor. Ghrelin
stimulates growth hormone secretion, increases food intake, and produces
weight gain. Circulating ghrelin levels increase during periods of fasting or
under conditions associated with negative energy balance, such as
starvation or anorexia. In contrast, ghrelin levels are low after eating and in
obesity. Ghrelin appears to play a central role in the neurohormonal
regulation of food intake and energy homeostasis.

The gastric fundus is the most abundant source of ghrelin, although lower
amounts of ghrelin are found in the intestine, pancreas, pituitary, kidney, and
placenta.

Based on its structure, ghrelin is a member of the motilin family of peptides

and, like motilin, ghrelin stimulates gastric contraction and enhances
stomach emptying.
 Ghrelin

The observations that circulating ghrelin levels increase sharply before a

meal and fall abruptly after a meal suggest that it serves as a signal for
initiation of feeding. Circulating ghrelin levels are low in states of positive
energy balance such as obesity and are inversely correlated with body mass
index. Conversely, ghrelin levels are high in fasting, cachexia, and anorexia.
Importantly, weight loss increases circulating ghrelin levels.
 Inhibin
Inhibin, a heterodimeric glycoprotein product of the Sertoli cell of the testes
and the ovarian granulosa cell (as well as the placenta and other tissues),
exerts negative feedback action on the secretion of FSH from the pituitary.
Synthesis and secretion of gonadal inhibin are induced by FSH. Inhibin plays
a role in the feedback regulation of FSH secretion during puberty in males
and females. Inhibin may also be an inhibitor of LH release in the follicular
phase.
Inhibin is composed of an α-subunit and one of two β-subunits, β A or β B ,
which, respectively, form inhibin A or inhibin B, dimers with apparently
identical function.
During pregnancy, the placenta secretes inhibin A, and the fetal membranes
secrete inhibin A and inhibin B, but for at least the first 20 weeks of gestation,
only inhibin A is detected in maternal serum.
A low concentration of inhibin B in men and pubertal boys is an indicator of
impaired seminiferous tubule function.
 Inhibin

Early pubertal boys with testicular defects have higher FSH concentrations
and low inhibin levels. Inhibin B is the form most closely related to testicular
function, and it is absent in orchidectomized men. Inhibin B is related to
Sertoli cell function in prepuberty, but a developmental change occurs during
puberty so that later in life, inhibin B concentration is related to
spermatogenesis.

In prepuberty, the α and the β B inhibin subunits are expressed in Sertoli

cells, but during puberty and in men, fully differentiated Sertoli cells express
only the α-subunit; the β-subunit is expressed in germ cells. Inhibin B in the
adult appears to be a product of germ and Sertoli cells. In prepubertal boys,
basal plasma inhibin B concentrations have a high correlation with the
incremental testosterone response to administration of human chorionic
gonadotropin (hCG), and they provide a useful assessment of the presence
of testes and their function.
 Human Placental Lactogen

Also called chorionic somatomammotropin, hPL is a single-chain,

nonglycosylated polypeptide composed of 191 amino acid residues and two
disulfide bridges, with a molecular mass of 21,600 Da. hPL is synthesized
and secreted by the syncytiotrophoblast and is detected in maternal serum
between 20 and 40 days of gestation. The maternal serum levels rise rapidly
and peak at 34 weeks, followed by a plateau.

hPL has a number of biologic activities that are qualitatively similar to those
of hGH and prolactin and can bind to both the hGH and prolactin receptors.
It appears to be a major regulator of IGF1 production, and during pregnancy
hPL concentrations are correlated with those of IGF1.

HPL also affects the metabolism of maternal nutrients. It stimulates

pancreatic islet insulin secretion, both directly and after carbohydrate
administration, and is a diabetogenic factor during pregnancy through its
promotion of insulin resistance. It enhances lipolysis, leading to a rise in free
fatty acids, which may in part be responsible for the insulin resistance.
 Human Placental Lactogen

The various biologic activities of hPL have led to the hypothesis that the role
of hPL during pregnancy is to provide the fetus with a constant supply of
glucose and amino acids. The hPL-stimulated lipolysis allows the mother to
utilize free fatty acids for energy during fasting, allowing glucose, amino
acids, and ketone bodies to cross the placenta for use by the fetus. In
addition, hPL has actions in the fetus, promoting amino acid uptake by
muscle and stimulating protein production, IGF1 production, and glycogen
synthesis.
 Erythropoietin
EPO, the major regulatory hormone of erythrocyte production, is a 30.4-kDa
glycoprotein. Its production in the kidney is modulated by the delivery of
oxygen from the circulating erythrocytes. When the mass of the circulating
erythrocytes decreases because of decreased production, enhanced
destruction, or loss of erythrocytes, the reduction in oxygen delivery results
in increased production of this hormone.

It has also been shown that with the growing severity of anemia, the number
of EPO-producing peritubular cells increases. This recruitment was found
mostly in the inner cortex, but appeared also throughout the renal cortex
when the anemia was particularly severe. EPO production is regulated by a
specific hypoxia-sensing mechanism based on transcription factors
stabilized by hypoxia, called “hypoxia-inducible factors”.

EPO is produced primarily by the liver in the fetal period; after birth, the
kidneys become the major source of production.
 Melatonin
Melatonin is a derivative of tryptophan, with a molecular weight of 232 . The
most important physical characteristic of the molecule is that it is highly
hydrophobic, as indicated by high solubility in organic solvents.
Hydrophobicity is of physiologic importance because it facilitates rapid transit
across membranes. This explains why newly synthesized melatonin is
rapidly released and not stored to a significant degree. High solubility also
means that circulating melatonin has access to all compartments.
The pineal gland is a melatonin factory; trace amounts of melatonin have
been reported to be produced elsewhere, but it is clear that essentially all
melatonin in the circulation comes from the pineal gland, and that the daily
changes in circulating melatonin are due to changes in pineal melatonin
production.
Melatonin receptors are highly expressed in the suprachiasmatic nucleus,
and through these receptors melatonin plays an important role in control of
the internal clock. Hence, in this way, melatonin plays a broad role in
regulating circadian changes in all aspects of endocrinology.
 Melatonin
Melatonin plays a critical role in synchronizing seasonal reproductive cycles
to changes in the photic environment, as seen in studies on sheep and
hamsters. Melatonin acts on sites in the hypothalamus to time the
gonadotrophin/gonadal cycle and directly within the pituitary gland.

The SCN contains high levels of melatonin receptors. Melatonin acts on cells
in this tissue via electrophysiologic and second-messenger–mediated
mechanisms to reset the circadian clock. The effect of melatonin on the clock
mechanism in the suprachiasmatic nucleus represents the most important
physiologic function of the hormone at all stages of life.

Melatonin production increases at night in the dark as a result of neural

stimulation originating in the SCN.
 Renin
The primary source of renin in the circulation is the kidney, where its
expression and secretion are tightly regulated at the juxtaglomerular
apparatus.
Renin is produced within JG cells after processing and cleavage of prorenin,
which is produced in the liver. The primary stimuli for renin release from JG
cells include reduction of renal perfusion pressure and hyponatremia. Renin
release is also influenced by the sympathetic nervous system and by
endocrine influences, including angiotensin II (AII), ADH, endothelin, and
prostaglandins. Renin activates angiotensin II, which causes secretion of
aldosterone by the adrenal cortical zona glomerulosa. The net effect is
systemic vasoconstriction, intrarenal vasoconstriction, and increased
aldosterone release. The effect of aldosterone is predominantly on the distal
tubules, affecting an increase in sodium reabsorption in exchange for
potassium.
Renin release is suppressed by elevated perfusion pressure at the kidney
(e.g., hypertension) and a high-sodium diet. Renin release is increased
directly by hypokalemia and decreased by hyperkalemia.
 Angiotensin

Angiotensinogen, an α 2 -globulin synthesized in the liver, is the only known

substrate for renin and is broken down into the angiotensin peptides. The
action of renin on angiotensinogen produces angiotensin I. Angiotensin I
comprises the first 10–amino acid sequence after the presegment and does
not appear to have biologic activity. Angiotensin II, the main biologically
active angiotensin, is created by cleavage of the two carboxy-terminal
peptides of angiotensin I by angiotensin-converting enzyme (ACE).

Angiotensin II functions through the angiotensin receptor to maintain normal

extracellular volume and blood pressure by (1) increasing aldosterone
secretion from the zona glomerulosa via increased transcription of CYP11B2
; (2) constricting vascular smooth muscle, thereby increasing blood pressure
and reducing renal blood flow; (3) releasing norepinephrine and epinephrine
from the adrenal medulla; (4) enhancing the activity of the sympathetic
nervous system by increasing central sympathetic outflow, thereby
increasing norepinephrine discharge from sympathetic nerve terminals; and
(5) promoting the release of vasopressin.
 Endothelin
Endothelin-1 (ET1) is a 21–amino acid peptide secreted by vascular
endothelial cells in response to stimuli, including pulsatile stretch, sheer
stress, neurohormones, cytokines, growth factors, and thrombin. The
secretion of ET1 has been shown to be increased by hypoxemia in humans.
The effects of ET1 are mediated by both endothelin A (ET A ) and endothelin
B (ET B ) receptors. ET A is localized on vascular smooth muscle cells, and
ET B is expressed on vascular smooth muscle cells, endothelial cells, and
fibroblasts.

The effects of ET1 include vasoconstriction, hyperplasia, hypertrophy,

fibrosis, and increased vascular permeability.

Activation of ET B receptors on endothelial cells mediates release of

prostacyclin (prostaglandin I 2 ) and nitric oxide (NO), which exert
vasodilatory and antiproliferative effects while also inhibiting ET1 production
by endothelial cells. Furthermore, the pulmonary endothelial ET B receptors
are responsible for the pulmonary clearance of up to 50% of circulating ET1.
 Bradykinin

Bradykinin and lysyl-bradykinin ( kallidin ) are active peptides formed by

proteolytic cleavage of circulating proteins termed kininogens through a
protease cascade pathway. Bradykinin (BK) is a nonapeptide ‘clipped’ from a
plasma α-globulin, kininogen , by kallikrein . It is converted by kininase I to an
active octapeptide, BK 1–8 (des-Arg 9 -BK), and inactivated by the removal of
an additional amino acid by kininase II (angiotensin-converting enzyme) in the
lung.
Bradykinin causes vasodilatation and increased vascular permeability. Its
vasodilator action is partly a result of generation of prostaglandin-I 2 (PGI 2 )
and release of nitric oxide (NO). It causes pain by stimulating nociceptive nerve
terminals, and its action here is potentiated by prostaglandins, which are
released by bradykinin. Bradykinin also contracts intestinal, uterine and
bronchial smooth muscle in some species. The contraction is slow and
sustained in comparison with that produced by tachykinins such as substance P
( brady- means slow; tachy- means rapid). Physiologically, the release of
bradykinin by tissue kallikrein may regulate blood flow to certain exocrine
glands, and influence secretions. Bradykinin also stimulates ion transport and
fluid secretion by some epithelia, including intestine, airways and gall bladder.
 Bradykinin

Pharmacological actions:

1. Vasodilatation (largely dependent on endothelial cell nitric oxide and

PGI 2 )

2. Increased vascular permeability

3. Stimulation of pain nerve endings

4. Stimulation of epithelial ion transport and fluid secretion in airways and

gastrointestinal tract

5. contraction of intestinal and uterine smooth muscle.

 Histamine

Histamine is a basic amine formed from histidine by histidine decarboxylase.

It is found in most tissues but is present in high concentrations in tissues in
contact with the outside world (lungs, skin and gastrointestinal tract). At the
cellular level, it is found largely in mast cells (approximately 0.1–
0.2 pmol/cell) and basophils (0.01 pmol/cell), but non-mast cell histamine
also occurs in ‘histaminocytes’ in the stomach and in histaminergic neurons
in the brain.

Histamine is released from mast cells by exocytosis during inflammatory or

allergic reactions.
 Histamine
The main actions in humans are:
1. Stimulation of gastric secretion (H 2 )
2. Contraction of most smooth muscle, except blood vessels (H 1 )
3. Cardiac stimulation (H 2 )
4. Vasodilatation (H 1 )
5. Increased vascular permeability (H 1 )

The main pathophysiological roles of histamine are:

1. As a stimulant of gastric acid secretion (treated with H 2 -receptor
antagonists)
2. As a mediator of type I hypersensitivity reactions such as urticaria and
hay fever (treated with H 1 -receptor antagonists)
 Relaxin

Relaxin, a peptide hormone of approximately 6 kDa, belongs to the insulin

family. Relaxin is produced in a number of sites, including the corpus luteum
in pregnant and nonpregnant women, the decidua, the placenta, the
prostate, and the atria of the heart.

Relaxin first appears in the serum of pregnant women in the same time
frame as hCG. Relaxin concentrations are highest during the first trimester
and peak at approximately 1.2 ng/mL between the 8th and 12th weeks of
pregnancy and then gradually decrease to 1 ng/mL for the remainder of the
pregnancy. Available evidence suggests that all relaxin circulating in the
mother during pregnancy is of luteal origin.

Relaxin appears to have a broad range of biologic activities. These include

collagen remodeling and the resultant softening of the cervix and lower
reproductive tract and inhibition of uterine contractility. However, circulating
relaxin does not seem to be necessary for pregnancy maintenance or normal
delivery in women.
 Human Chorionic Gonadotrophin
HCG is one of the earliest products of the cells forming the embryo and
should be viewed as one of the first embryonic signals elaborated by the
embryo even before implantation. It is composed of a 92–amino acid α
subunit that is homologous to thyroid-stimulating hormone, luteinizing
hormone (LH), and follicle-stimulating hormone (FSH) and a 145–amino acid
β subunit that is similar to LH.
After implantation, hCG is produced principally by the syncytiotrophoblast
layer of the chorionic villus and is secreted into the intervillous space.
Cytotrophoblasts are also able to produce hCG.
Clinically, hCG can be detected in either the serum or urine 7 to 8 days
before expected menses and is the earliest biochemical marker for
pregnancy.
The major biologic role of hCG during early pregnancy is to rescue the
corpus luteum from premature demise while maintaining progesterone
production. Although the secretory pattern of hCG is not well characterized,
hCG is required for rescue and maintenance of the corpus luteum until the
luteal-placental shift in progesterone synthesis occurs.
 Anti-Müllerian Hormone

AMH (also called müllerian inhibiting substance [MIS] or factor [MIF]), a 14-
kDa homodimeric glycoprotein that is structurally related to the subunit of
inhibin and TGFβ, is produced by the Sertoli cells of the fetal testis after 7
weeks and the prepubertal testis and causes the regression of the müllerian
ducts in boys during early fetal development and later in gestation by
granulosa cells of the fetal ovary.

Immunoassayable concentrations of AMH values rise from birth to relatively

high levels during the first year of life in males, decrease by age 10 years,
and decrease further during puberty. Newborn females have low or
nondetectable serum levels of AMH, which rise only slightly thereafter;
serum AMH concentrations are virtually nondetectable in most girls just
before puberty.
 Anti-Müllerian Hormone
This hormone assists in a male fetus’ reproductive development. Prior to
birth, AMH is made in the fetus’ testes and ovaries.

Around eight weeks after conception, a fetus has both Müllerian (female)
and Wollfian (male) ducts, which can develop into the male or female
reproductive system. If the fetus has XY (male) chromosomes, the testes will
produce AMH and the Müllerian ducts will disappear. Then, testosterone
produced in the testes will promote the development of the male
reproductive system. If a fetus has XX (female) chromosomes, a lack of
testosterone will cause the Wollfian duct to vanish and the Müllerian duct will
develop into the female reproductive system.

AMH also has role in puberty and in adult ovaries and testes. Within the
ovaries, it helps in the early development of follicles.
 Peptide YY

Body produces PYY when there is food in the digestive tract, especially food
that contains fat and protein. Eating high calorie foods causes the body to
produce more PYY than eating low calorie foods. PYY levels are the highest
two hours after eating but eventually PPY decreases. Most people have low
levels of PYY after not eating for a long period of time.

After eating, the hormone peptide YY (PYY) will be produced by the small
intestine and released into your bloodstream. PYY communicates to your
brain that you are full and decreases your appetite. The amount of PPY
released depends on the type and quantity of food eaten.

After it is released in your bloodstream, PYY binds to receptors, or cells that

receive signals, in the brain. It also functions by slowing down the movement
of food in the digestive tract.
 Prostaglandin
Prostaglandins are hormones created during a chemical reaction at the site
where an injury or other issue occurs. They are unique among hormones,
because unlike most of the chemical messengers, they are not secreted
from a gland. Instead, they are created at the time they are needed directly
where the problem exists.
Prostaglandins control several processes in the body, especially as it relates
to the healing process. When tissue is damaged or infected, this group of
hormones will create the reactions that cause pain, fever and inflammation,
which sparks the healing process. Prostaglandins also stimulate the
formation of a blood clot and the contraction of the blood vessel wall when
your body is bleeding. Once blood clots are no longer needed and the injury
begins to heal, another prostaglandin will stimulate the changes that allow
the clots to dissipate and the blood vessel wall to relax.
In women, prostaglandins assist in regulating the reproductive system. They
can start labor and control ovulation. Synthetic prostaglandins are
sometimes used to induce labor for pregnant women.
 Serotonin

Serotonin is the key hormone that stabilizes the mood, feelings of well-being,
and happiness. This hormone impacts the entire body. It enables brain cells
and other nervous system cells to communicate with each other. Serotonin
also helps with sleeping, eating, and digestion. However, if the brain has too
much serotonin, it may lead to depression. If the brain has too much
serotonin, it can lead to excessive nerve cell activity. It also helps reduce
depression, regulate anxiety, and maintain bone health.
 Serotonin
1. Serotonin is in the brain. It is thought to regulate mood, happiness, and
anxiety. Low levels of serotonin are linked to depression, while increased
levels of the hormone may decrease arousal.
2. Serotonin is found in your stomach and intestines. It helps control your
bowel movements and function.
3. Serotonin is produced when you become nauseated. Production of
serotonin increases to help remove bad food or other substances from the
body. It also increases in the blood, which stimulates the part of the brain
that controls nausea.
4. Serotonin is responsible for stimulating the parts of the brain that control
sleep and waking. Whether you sleep or wake depends on the area is
stimulated and which serotonin receptor is used.
5. Serotonin is released to help heal wounds. Serotonin triggers tiny arteries
to narrow, which helps forms blood clots.
6. Having very high levels of serotonin in the bones can lead to osteoporosis,
which makes the bones weaker.
 Kisspeptin
Kisspeptin, made in the hypothalamus, is an important hormone that starts the
release of several other hormones. Also called metastin, this interesting
hormone is connected to puberty and may also help stop the spread of cancer.

Kisspeptin enters into receptor sites in the pituitary gland, starting a reaction
that causes the gland to release neurotransmitters. Those neurotransmitters
then signal the release of luteinizing hormone and follicle stimulating hormone.
These hormones have a role to play in the production of testosterone and
estradiol. Without kisspeptin, this entire chain reaction would be damaged.

Kisspeptin has a secondary function that is not related to hormones. Its original
name, metastin, points to its ability to prevent the spread of cancer in the body.

Kisspeptin is released in conjunction with two other hormones: dynorphin and

neurokinin B. These two hormones are not understood well, but early research
indicates they may have a role in causing the release of kisspeptin.
 References
Devlin, Thomas: Textbook of Biochemistry with Clinical Correlations, 7th
Edition, 2011.

Belfiore, A. and LeRoith, D.: Principles of Endocrinology and Hormone

Action, 2018.

Kleine, B. and Rossmanith W.: Hormones and the Endocrine System,

2016.

Melmed, S. et al.: Williams Texbook of Endocrinology, 13th Edition, 2016.

 Pancreatic Hormones

Endocrine Module – Med 7524

(Biochemistry)
 Learning Competencies

1. Describe the anatomic relationship of the

pancreas to the other organs of the abdomen.
2. Discuss the different types of cells in the
Islets of Langerhans and the type of
hormones secreted.
3. Explain the structure of insulin and its insulin
receptor.
4. Discuss the biosynthesis and metabolism of
insulin.
5. Elaborate on the biologic effects of insulin.
6. Discuss the structure and functions of glucagon.
7. Discuss the structure and functions of somatostatin.
Anatomic Relationships of the Pancreas with Other Organs
 Islet cells of Langerhans
endocrine

⚫ Islets in direct contact

with capillary
⚫ 1-2% of pancreatic
mass
⚫ 4 cell types:
– Alpha – outer rim
– Beta – central region
– Delta- in between a & b
– PP cells or F cells- rare,
may also be in exocrine
portion

exocrine
Secretion of insulin by beta cells

GLUT 2 transporter has low affinity to glucose, activated only

when Glucose level is high
 Hormones of the Pancreas

⚫ Islets of Langerhans
- 1 to 2 million in number
- concentrated in the tail
- cell types:
* A (or α) – 25% glucagon
* B (or ß) – 70% insulin
* D (or δ) - <5% somatostatin
* F – trace pancreatic polypeptide
 Insulin
I. Biosynthesis
- first synthesized as preprohormone in polysome
(MW 11,500)
- leader peptide (pre) ctg. 23 hydrophobic amino acids
is removed in the cisternae of rough endoplasmic
reticulum producing proinsulin
- proinsulin (MW 9,000) has alpha and beta chains
separated by a C peptide
- C peptide is removed by trypsin-like protease in the
Golgi bodies producing insulin
Formation of human insulin from preproinsulin
Intracellular movements of insulin and its precursors
 II. Structure of Insulin

⚫ Polypeptide consisting of A and B chains linked by two

interchain disulfide bridges that connect A7 to B7 and
A20 to B19.
⚫ Third intrachain disulfide bridge connects cysteine
residues 6 and 11 of the A chain.
⚫ Highly conserved regions:
- positions of the 3 disulfide bonds
- hydrophobic residues in the C-terminal region of the
B chain
- amino and carboxyl terminal regions of the A chain
 III. Insulin Secretion
⚫ Human pancreas secretes 40-50 units of insulin daily
⚫ Represents 15-20% of insulin stored in the gland
⚫ Energy requiring process
⚫ Mediators involved in the release of insulin:
1. hyperglycemia – most important
2. Hormonal factors:
a) growth hormone, cortisol, placental lactogen,
estrogens, progestins and beta-adrenergic
agonists stimulate insulin release
b) alpha-adrenergic agonists, e.g. epinephrine,
inhibit insulin release
3. Pharmacologic agents – sulfonylurea cpds. e.g.
tolbutamide
 IV. Insulin Metabolism

⚫ No plasma carrier protein

⚫ Plasma half-life is less than 3-5 minutes
⚫ Liver is the major organ that metabolizes insulin
⚫ Two enzyme systems involved:
1. Insulin-specific sulfhydryl-dependent protease
2. Glutathione-insulin transhydrogenase which
reduces the disulfide bonds
 V. Mechanism of Action of Insulin
⚫ Insulin action begins when the hormone binds to a
specific insulin receptor in the plasma membrane of
target cell.
⚫ This interaction generates one or more transmembrane
signals.
⚫ This signal (or signals) modulates a wide variety of
intracellular events.
⚫ The diverse action of insulin can occur within seconds
or minutes such as glucose transport, protein
phosphorylation, enzyme activation and inhibition, &
RNA synthesis
⚫ Or after a few hours such as DNA and protein synthesis
and cell growth.
Insulin causes cells to recruit transporters from intracellular stores
 Characteristics of the Insulin Receptor

❖ Glycoprotein, contains sialic acid and galactose.

⚫ Heterodimer consisting of two subunits, α and β, in

the configuration α2β2 linked by disulfide bonds.

⚫ Alpha subunit is extracellular and it binds insulin via a

cysteine rich domain.

⚫ Beta subunit is a transmembrane protein that is

responsible for signal transduction.
 Characteristics of the Insulin Receptor

⚫ Cytoplasmic portion of the beta subunit has tyrosine

kinase activity and an autophosphorylation site.

⚫ Synthesized in the RER and glycosylated in Golgi

apparatus.

⚫ There are 20,000 insulin receptors per target cell.

⚫ Structure of insulin receptor is identical in all cells and

all species.
Insulin receptor
IRS = insulin receptor
substrate
 Chain of Events that Occur when
Insulin binds to Insulin Receptor
⚫ 1. Insulin receptors undergo conformational change.
⚫ 2. Receptors cross-link and form microaggregates.

⚫ 3. Receptors are internalized.

- a means of controlling receptor concentration
- in obesity the number of receptors is decreased
(down-regulation)
- Down-regulation explains part of the insulin
resistance in type 2 diabetes mellitus

⚫ 4. One or more signals are generated.

 Insulin Signaling Pathways
⚫ Binding of insulin stimulates intrinsic tyrosine
kinase activity of insulin receptor.
⚫ Results in increased phosphorylation of tyrosine
residues in insulin receptor.

⚫ Phosphorylated insulin receptors phosphorylates

specific signaling molecules called insulin receptor
substrates (IRS); IRS 1 to 4.
* IRS-1 is involved in growth of cells
* IRS-2 is involved in metabolism

⚫ Increased phosphotyrosine stimulates the activity of

many intracellular enzymes such as GTPases,
protein kinases and lipid kinases.
 VI. Effects of Insulin
A. Effects on Membrane Transport of Glucose
* When glucose and insulin levels are normal,
glucose transport across the cell membrane
determines the rate of glucose phosphorylation.

* When glucose and insulin are elevated, such as

after a meal, phosphorylation becomes rate-
limiting.

* Glucose enters cells by carrier- mediated

facilitated diffusion through glucose transporters.
 Glucose Transporters (GLUT)
⚫ GLUT 1 – ubiquitous and is the major transporter in the
brain.
⚫ GLUT 2 – principally located in the liver where it is
functionally associated with glucokinase.

⚫ GLUT 3 – found in the brain, kidney and placenta.

⚫ GLUT 4 – found in adipose tissue, cardiac and skeletal

muscle where it is functionally associated
with hexokinase; insulin-stimulated uptake
of glucose.
⚫ GLUT 5 – involved in the intestinal absorption of
dietary glucose.
 B. Fates of Ingested Glucose

⚫ 50% are converted to energy via glycolysis

⚫ 30 - 40% are converted to fats

⚫ 10 - 20% are converted to glycogen

 C. Effects on Carbohydrate Metabolism
⚫ Stimulates hepatic glycolysis through increased
activity of glucokinase, phosphofructokinase and
pyruvate kinase.

⚫ Stimulates glycogenesis through increased activity of

glycogen synthase.

⚫ Inhibits glycogenolysis through decreased activity of

glycogen phosphorylase and glucose 6-phosphatase.

⚫ Inhibits glucogeneogenesis by selectively inhibiting

transcription of the gene that codes for the mRNA for
phosphoenolpyruvate carboxykinase (PEPCK).
 D. Effects on Lipid Metabolism
1. Stimulates lipogenesis and triglyceride synthesis in
adipose tissue by:
⚫ a) Providing acetyl CoA and NADPH required for fatty
acid synthesis;
⚫ b) maintaining a normal level of the enzyme acetyl
CoA carboxylase, which catalyzes the conversion of
acetyl CoA to malonyl CoA, the committed step in
lipogenesis;
⚫ c) providing the glycerol involved in triacylglycerol
synthesis.

2. Inhibits lipolysis by decreasing the activity of

hormone-sensitive triglyceride lipase.
 E. Effects on Protein Metabolism
⚫ Insulin exerts anabolic effects by:
⚫ 1) promoting the uptake of amino acids into cells
⚫ 2) increasing synthesis of mRNA
⚫ 3) increasing translation of mRNA
⚫ 4) increasing protein synthesis
⚫ 5) increasing activity of enzymes through covalent
modification (dephosphorylation rxn)
 F. Effects on Cell Replication

⚫ Insulin stimulates proliferation of cells in cell

cultures.

⚫ Involved in the regulation of cell growth.

⚫ Potentiates the ability of several growth factors such

as FGF, PDGF and EGF.
 Diabetes Mellitus

⚫ Pathophysiology involving insulin is mostly

expressed as diabetes mellitus.
⚫ Caused by insulin deficiency or insulin resistance.

⚫ 90% are NIDDM (type 2) – patients are usually obese,

have elevated plasma insulin levels and have down-
regulated insulin receptors.

⚫ 10% are IDDM (type 1) – juvenile onset; destruction

of beta cells which is autoimmune in nature.
 Insulin-dependent diabetes mellitus
⚫ Once called juvenile-onset DM
⚫ Usually appears in childhood or in teens
⚫ Due to defective or absent β-cells
⚫ Β-cells destroyed by an autoimmune process
⚫ Characterized by:
* hyperglycemia – due to decreased uptake of glucose
and increased gluconeogenesis
* hyperlipoproteinemia (chylomicron & VLDL) – due to
low lipoprotein lipase activity
* ketoacidosis – increased lipolysis, increased beta
oxidation
⚫ Requires insulin for treatment
 Noninsulin-dependent diabetes mellitus
⚫ Also called maturity-onset diabetes mellitus
⚫ Occurs in middle-aged obese people
⚫ Characterized by:
* hyperglycemia – decreased uptake of glucose and
increased gluconeogenesis
* hypertriglyceridemia – due to increased VLDL bec. Of
increased hepatic TAG synthesis
* ketoacidosis not observed
* insulin is present at normal to elevated levels
* end-organ insulin resistance – due to increased
expression of tumor necrosis factor alpha (TNF-α)
* TNF-α impairs insulin receptor function
Maturity Onset Diabetes of the Young (MODY)

⚫ Genetic defects of pancreateic B cell

function
– Occurs in late childhood or before 25 y/o
– Partial defect in glucose induced insulin
release

– 5% cases in USA & europeans

– Strong family history of early onset diabetes;
autosomal dominant transmission

– Non-obese, initially achieve good control

without insulin treatment
 Glucagon
⚫ Synthesized in the A cells of pancreatic islet.
⚫ Single polypeptide chain with 29 amino acid
residues.
⚫ Initially synthesized as proglucagon.

⚫ Circulates in the plasma as free glucagon.

⚫ Half-life in the plasma is about 5 minutes.
⚫ Inactivated in the liver.

⚫ Secretion is stimulated by hypoglycemia.

⚫ Liver is the primary target organ.
⚫ Mechanism of action exerted through cAMP.
 Effects of glucagon: Main effects on liver

⚫ mechanism : activation of adenylate cyclase

and increased cAMP levels

⚫ increased hepatic glucose production

– Increased glycogenolysis ; (-) glycogen

synthesis
– cAMP→ PKA→phosphorylation of
glycogen phosphorylase = (+)
glycogenolysis

– cAMP→ PKA→ phosphorylation of

glycogen synthetase= (-) glycogenesis
 Somatostatin

⚫ Chromosome 3
⚫ D cells of islets of Langerhans
⚫ 14 aa (predominant in pituitary &
pancreas); 28 aa (predominant in GIT)
⚫ half life 3 minutes
⚫ physiologic levels 80 pg/ml/day
 References

1. Harper’s Illustrated Biochemistry 30th Edition

by Rodwell, Bender, Botham, Kennelly and Weil
2. Lehninger Principles of Biochemistry 5th Edition
by Nelson and Cox
3. Textbook of Biochemistry With Clinical Correlation
6th Edition by Thomas M. Devlin
4. Lippincott’s Biochemistry 5th Edition
by Champe and Harvey
5. Textbook of Medical Physiology 13th Edition
by Guyton and Hall
 Thyroid and Parathyroid
Hormones

Endocrine Module – Med 7524

(Biochemistry)
 Learning Competencies

1. Describe the structure of the thyroid and

parathyroid glands
2. Explain the hypothalamo-pituitary-thyroid
axis
3. Discuss the biosynthesis, regulation of
secretion, transport in the blood, metabolism
and the biologic functions of the thyroid,
parathyroid glands and calcitonin
4. Explain the pathophysiological mechanisms
of the different disorders of the glands
5. Discuss calcitonin
Thyroid Gland Parathyroid Gland
 Hypothalamo-thyroid
axis
➢ Tissues become sensitive
to epinephrine

➢ Increase cellular
respiration, O2 use and
metabolism

➢ Heat generation and

thermoregulation

➢ Growth and development

 Thyroid Hormones
⚫ There are two thyroid hormones:
1) T3 - triiodothyronine
2) T4 – tetraiodothyronine (thyroxine)

⚫ Important in regulating general metabolism.

- regulator of basal metabolic rate (BMR)

⚫ They require iodine for biologic activity.

⚫ Synthesis takes place in thyroglobulin.

 Thyroglobulin
⚫ Precursor of T3 and T4.
⚫ Large, iodinated, glycosylated protein.
⚫ Composed of two subunits.
⚫ Contain 114 tyrosine residues which are potential
sites of iodination.
⚫ It is a prohormone synthesized in the basal portion of
the follicular cell & stored in extracellular colloid.
⚫ 70% of iodide exists in the form of inactive
precursors: a) monoiodotyrosine (MIT) and
b) diiodotyrosine (DIT).
⚫ 30% of iodide are in the form of T3 and T4.
⚫ Normal T4:T3 ratio is 7:1.
 Three Phases of Thyroid Hormone
Synthesis
A. Iodine uptake and concentration of iodide

- there are 6 to 7 mg of iodine in the body, 90% of

which are in the thyroid gland
- thyroid tissue:blood ratio = 20:1
- thyroid gland is able to concentrate iodine against a
strong electrochemical gradient
- active transport is coupled to the ATPase dependent
Na-K pump
- involves sodium-iodide transporter, activity of
which is primarily controlled by TSH
 Inhibitors of Iodide Transporter
⚫ Class I - anions that compete with iodide
for its carrier and concentrated by the
thyroid.
e.g. perchlorate, perrhenate & pertechnetate
⚫ Class II - competitive inhibitors of iodide
transport but are not concentrated by the
thyroid.
e.g. thiocyanate

❖ Ouabain, an inhibitor of Na+/K–-ATPase,

which powers NIS transport.
 Oxidation of iodide
⚫ An obligatory step in iodide organification and thyroid
hormone biosynthesis

⚫ Involves a heme-containing thyroperoxidase (TPO)

- tetrameric protein
- requires hydrogen peroxide as an oxidizing agent

⚫ Inhibited by thiourea drugs (antithyroid drugs)

 B. Iodination of tyrosine
(organification of iodide)
⚫ Takes place in luminal thyroglobulin
⚫ Also involves thyroperoxidase
⚫ Formation of MIT (monoiodtyrosine) and
DIT (diiodotyrosine)
⚫ Coupling of iodotyrosyls to form thyronine
hormones:
⚫ DIT + DIT = T4 (thyroxine, tetraiodothyronine)
⚫ DIT + MIT = T3
⚫ Also inhibited by thiourea drugs
 C. Thyroglobulin hydrolysis
⚫ Removal of thyroglobulin from the colloid through
endocytosis and back to follicular cell.
⚫ Hydrolysis of thyroglobulin within phagolysosomes.
⚫ Stimulated by TSH
⚫ Inhibited by potassium iodide
⚫ Release of T4 and T3 into the blood stream bound to
thyroxine-binding globulin (TBG).

⚫ 50 ug of thyroid hormone iodide is secreted/day.

⚫ Daily iodide requirement is bet. 150 and 200 ug.
⚫ Iodide from MIT and DIT is scavenged by deiodinase.
 Transport of Thyroid hormones
⚫ One-half to two-thirds of T4 and T3 in the body is
extrathyroidal.
⚫ Most circulates in bound form to:
a) thyroxine-binding globulin (TBG) and
b) thyroxine-binding prealbumin (TBPA)

⚫ TBG is the most important

⚫ It has 100 times the affinity of TBPA
⚫ Has the capacity to bind 20 ug/dl of T4 & T3

⚫ Unbound thyroid hormones are responsible for

biologic activity
 Metabolism of Thyroid Hormones
➢ Plasma half-life of T4 is four to five times that of T3
➢ Extrathyroidal deiodination converts T4 to T3 (also
called reverse T3 or rT3)

➢ T3 binds to thyroid receptors with 10 times the

affinity of T4
➢ T3 is the metabolically active form of the hormone

➢ 80% of circulating T4 is converted to T3 in the liver

and kidney.
➢ Propylthiouracil and propranolol decrease the
conversion of T4 to T3
 Physiologic Effects of Thyroid Hormones
⚫ Regulator of development
⚫ Catalyst for oxidative reactions
⚫ Regulator of metabolic rates

⚫ A. Effects of moderate concentrations

⚫ - Anabolic effects, increased RNA synthesis,
⚫ increased amino acid transport and Increased protein
synthesis

⚫ B. Effects of high concentrations

- Negative nitrogen balance, decreased protein
synthesis, increased carbohydrate and lipid turnover and
uncoupling of oxidative phosphorylation
 Mechanism of Action
⚫ Thyroid hormones bind to specific high-affinity
receptors in the target cell nucleus.

⚫ Major effect is enhanced protein synthesis and

positive nitrogen balance.

⚫ They induce or repress proteins by increasing or

decreasing gene transcription.

⚫ T3 enhance transcription of growth hormone gene.

 Thyroid Hormones in Disease States
⚫ Goiter is enlargement of the thyroid gland.

⚫ Simple goiter represents an attempt to

compensate for decreased thyroid hormone
synthesis.
⚫ - elevated TSH is the common denominator
- caused by deficiency of iodine in the diet or
- metabolic defects involving the various steps in
thyroid hormone synthesis

⚫ Simple goiter is treated with exogenous thyroid

hormone
 Hyperthyroidism

➢ Also called thyrotoxicosis

➢ Hypermetabolic condition associated with
elevated levels of T4 and T3.
➢ Caused by excess synthesis and secretion of thyroid
hormone by the thyroid

Signs and symptoms: Nervousness, anxiety, increased

perspiration, heat intolerance, tremor, hyperactivity,
palpitations, weight loss despite increased appetite,
reduction in menstrual flow or oligomenorrhea (in
women and tachycardia or atrial arrhrythmia
 Most common forms of hyperthyroidism

⚫ - Graves’ disease (Basedow’s disease; most

common with 70-80%)
⚫ - Toxic multinodular goiter (Plummer disease; 15-20%)
⚫ - Toxic adenoma (Hurthle cell adenoma; 3-5%)

A. Hurthle cell adenoma

- a rare benign tumor, typically seen in women
between the ages of 70 and 80 years old
- typically such a mass is removed because it is not
easy to predict whether it will transform into the
malignant counterpart,
- a subtype of follicular thyroid cancer called a
Hürthle cell carcinoma.
B. Toxic multinodular goiter (Plummer disease)

➢ second most common cause of hyperthyroidism

➢ most thyroid nodules are harmless, but some
can be cancerous
➢ usually not a life-threatening condition
 C. Graves Disease
⚫ - Also called Basedow’s disease or Graves-Basedow
disease
⚫ - Caused by an antibody-mediated autoimmune
reaction
⚫ - Manifestations:

1. Goiter – a swelling in the neck just below the

adam’s apple
2. Exophthalmos – protuberance of one or both eyes
3. A non-pitting edema describe as “peau d’orange
(resembling the skin of an orange)
4. Fatigue, weight loss & other symptoms of
hyperthyroidism
 Exophthalmos lid retraction (upper)
lid lag (lower)
- both left eye affected
➢ In exophthalmos the immune system attacks the
muscles and fatty tissues around and behind the
eye, making them swollen.
 Hypothyroidism
- Due to insufficient production of thyroid hormone by
the thyroid gland
- Causes:

1. Iodine deficiency – most common cause world-wide

2. Hashimoto’s thyroiditis – autoimmune disease; a
condition in which your immune system attacks
your thyroid gland
3. Radioactive iodine therapy for hyperthyroidism
4. Secondary hypothyroidism – pituitary gland does not
produce enough TSH
5. Tertiary hypothyroidism – hypothalamus lacks
thyrotropin releasing hormone
 Chemistry and Metabolism of the
Parathyroid Hormone
A. Chemistry
- 84 amino acid polypeptide hormone
- biologic activity resides in N-terminal 1- 34 amino
acid residues
- 5th – 34th amino acids responsible for receptor
binding

B. Synthesis: PreproPTH

ProPTH → Parathormone
C. Storage
- Parathormone is stored in secretary granules
for release in response to a reduction in the levels
of ionized calcium.

D. Degradation
- Degraded by cathepsins in the parathyroid
gland and in the Kupffer cells in the liver.

E. Regulation of secretion

Decreased serum Ca → increases PTH secretion

 Mechanism of Action

PTH-receptor complex (+) adenylate cyclase

increased cAMP

increased calcium

phosphorylation of specific proteins by kinases

activation of enzymes
 Biologic Effects
-Maintenance of calcium balance
A. Long-term effect
- stimulate calcitriol synthesis increase
intestinal absorption of calcium

B. Effects on bones
- increased dissolution of bones increase
calcium in the ECF (largest effect)

C. Effects on kidney
- decreased renal excretion of calcium
increase calcium in ECF (rapid effect)
 Biologic effects

D. Effects on phosphate homeostasis

1. Increased removal of PO4 from bones
2. Increased renal excretion of PO4

Net effect – increased calcium and decreased

phosphate in ECF
 Pathophysiology

⚫ A. Hypoparathyroidism
1. Primary – autoimmune destruction
2. Secondary – accidental removal during
thyroid surgery

Biochemical hallmark – decreased calcium and

increased phosphate in the serum

Manifestations – increased neuromuscular

irritability, tetany and muscle cramps
 B. Pseudohypoparathyroidism

⚫ Deficiency of G adenylate cyclase regulatory

protein

⚫ Defective step beyond formation of cAMP

⚫ Biologically active PTH but there is end-organ

resistance
 C. Hyperparathyroidism

A. Causes:
- Parathyroid adenoma
- Parathyroid hyperplasia
- Ectopic production

B. Biochemical hallmark
- Increased serum Ca and decreased PO4
- Increased bone resorption
- Osteoporosis
- Kidney stones
 Calcitonin

➢ a hormone that is produced in humans by the

parafollicular cells (commonly known as C-cells) of
the thyroid gland
➢ peptide with 32 amino acids
➢ lowers blood levels of calcium by inhibiting the
resorption of bone
➢ involved in helping to regulate levels of calcium
and phosphate in the blood, opposing the action of
parathyroid hormone
➢ release is stimulated by increase in calcium levels
in the blood
 References

1. Harper’s Illustrated Biochemistry 30th Edition

by Rodwell, Bender, Botham, Kennelly and Weil
2. Lehninger Principles of Biochemistry 5th Edition
by Nelson and Cox
3. Textbook of Biochemistry With Clinical Correlation
6th Edition by Thomas M. Devlin
4. Lippincott’s Biochemistry 5th Edition
by Champe and Harvey
5. Textbook of Medical Physiology 13th Edition
by Guyton and Hall
MODULE: ENDOCRINE I

TITLE: ADRENAL HORMONES

Objectives

 At the end of the session, students will be able to:

1. List the hormones secreted by the adrenal glands

2. Understand the biosynthesis of the adrenocortical

hormones

3. Understand the biosynthesis of adrenomedullary hormones.

Adrenal Cortex Hormones
 Introduction
 Steroid hormones are produced by adrenal cortex
 Out of 50 steroids , only 7 are important and known to possess physiologic
activity
 All were derived from cholesterol which can be synthesized into acetate

 7 important hormones:
 11-dehydro corticosterone
 Corticosterone
 Cortisone
 Cortisol – major free circulating adrenocortical hormone in human plasma
 Aldosterone (mineralocorticoid)
 Androstenedione
 Dehydroepiandrosterone (DHE)
Classification: according to structure
 Two structural types:

1. C-21 steroids – having two carbon side chain at position 17 of the

D’ ring and contain 21 carbon atoms
• Those with –OH group at position 17, in addition to the side chain
are called 17-OH corticoids or 17-hydroxycorticosteroids
• Have glucocorticoids and mineralocorticoids

2. C-19 – having O2 atom or –OH group at position 17 and contain 19

carbon atoms.
• Most have = 0 group at position 17 – called “17-oxosteroids” (17-
ketosteroids)
• Have androgenic activity
Structure
Classification: According to Function
 3 types:

1. Glucocorticoids
• Primarily affect metabolism of carbohydrates, proteins and lipids, with
minor effects on water and electrolytes metabolism
• Ex. Cortisol, cortisone and corticosterone

2. Mineralocorticoids
• Primarily affect the reabsorption of Na+ and K+ and distribution of water in
tissues
• Ex. Aldosterone – chief mineralocorticoids, costicosterone, 11-
deoxycortisol and 11-deoxycorticosterone

3. Cortical sex hormones (androgens and estrogens)

• Primarily affect secondary sex characteristics
Relation of Structure with Functions
1. 3 structural features are essential for all known biological
actions of the natural C21 adrenocortical hormones:
• A double bond at C4 and C5
• A ketonic group (C=O) at C3
• A ketonic group (C=) at C20

2. Certain additional structural features have profound effect

upon the biological activity of these compounds
• An –OH group at C-21 enhances Na-retention and is required for
activity in carbohydrate metabolism
• An OH-group at C17 increases carbohydrate activity
• A –CHO group at C18 necessary for mineralocorticoid
Synthesis of Glucocorticoids

 Corticosteroids are synthesized by a common pathway from

cholesterol in the adrenal cortex

 Cholesterol is first changed to form pregnenolone

 Steps in the Synthesis of Glucocorticoids
 Synthesis occurs at zona fasciculata cells

1. Pregnenolone to 17-OH pregnenolone

• Occurs in smooth ER
• Enzyme: 17-α-hydroxylase

2. Conversion of 17-OH pregnenolone to 17-OH progesterone

• 2 enzymes: 3 β-OH-steroid dehydrogenase (NAD+ dependent) and Δ4,5-
isomerase
• Same pregnenolone may be first converted to progesterone
• 2 enzymes: dehydrogenase and isomerase; acted upon by 17-α-hydroxylase to form
17_OH progesterone

3. 17-OH progesterone to 11-deoxycortisol

• Enzyme: 21-hydroxylase in ER

4. 11-deoxycortisol is transferred to mitochondrion where it is acted by

enzyme 11-β-hydroxylase and converted to cortisol
Action of ACTH on Cortisol Formation

 ACTH stimulates synthesis and secretion of glucocorticoids through:

 Increasing the availability of “free cholesterol” in fasciculata cells

 Through cAMP, activates cholesteryl esterase that hydrolyzes cholesterol
esters and increases free cholesterol in cells
 Increases transfer of free cholesterol from plasma lipoprotein into
fasciculata cells

 Increases the conversion of cholesterol to pregenenolone – rate

limiting step

 Stimulates the HMP-shunt pathway by increasing the activity of G-6-

PD and phosphogluconate dehydrogenase

 Increases the binding of cholesterol to mitochondrial Cytochrome P450

necessary for hydroxylation reactions
Mechanism of Action
All steroids act primarily at the level of cell nucleus – increase m-
RNA synthesis and increased protein synthesis
 Binding of steroids to a corresponding specific receptor
protein in the cytosol – causing dissociation of the “hsp90”
stabilizer and permits conversion to the active configuration
 The steroid-receptor complex enters the nucleus and bind by
DNA-binding site to Hormone Responsive Element (HRE) of
specific nuclear genes
 Modulates the transcription rate of those genes – leading to
increase synthesis of many proteins
ADRENAL ANDROGENS

 Main hormones:

1. Dehydroepiandrostenedione (DHEA)

2. DHEA-SO4

3. Δ4-androstenedione – derived from DHEA

• Androstenedione – precursor of testosterone

4. 11-β-OH-androstenedione
MINERALOCORTICOIDS

 C21 steroids which influence mainly the metabolism of Na+

and K+.

 Aldosterone – is the chief mineralocorticoid,; produced at the

zona glomerulosa of the adrenal cortex

 Structurally it bears α-OH group at C11 and an aldehyde (-CHO)

group at C18
Biosynthesis

 Synthesized in zona glomerulosa cells only

 Only cell that contains the enzymes 18-hydroxylase and
18-hydroxysteroid dehydrogenase

 Aldosterone cannot be synthesized in other cell layers of

adrenal cortex
 Steps in Synthesis of Mineralocorticoids

1. Cholesterol is converted to pregnenolone.

2. Pregnenolone is converted to progesterone in smooth ER

3. Progesterone is then directly hydroxylated by the enzyme 21-hydroxylase

and forms 11-deoxy-corticosterone
• 17-α-hydroxylase is absent in zona glomerulosa

4. 11-deoxycorticosterone is translocated to mitochondrion, where it is

converted to corticosterone
• Reaction is catalyzed by 11-β-hydroxylase

5. Corticosterone is converted to 18-OH-corticosterone – occurs in

mitochondria

6. 18-OH-corticosterone is converted to aldosterone acted upon by 18-

hydroxysteroid dehydrogenase – occurs in mitochondria
Mechanism of Action

 Binds to a specific receptor in the cytosol, mineralocorticoid

receptors to form steroid-receptor complex
 Present in epithelial cells of distal tubules and collecting duct,
GIT, salivary gland ducts and sweat glands

 Steroid-receptor complex enters the nucleus and binds to

hormone responsive element (HRE) of specific genes –
increases transcription rates of genes
Aldosterone

 Exists both in aldehyde and hemi-acetal form; exists in

solution in hemi-acetal form
Actions of Aldosterone

A. Renal Effects of Aldosteron

1. Increase the rate of tubular reabsorption of Na – the most

important effect

2. Increases the reabsorption of chloride ions from the tubules

3. Increased renal excretion of K+

4. Effect on acid-base balance (alkalosis)

Actions of Aldosterone

B. Effects of aldosterone on Fluid Volume

1. Increases the quantities of Na+, Cl-, and HCO3- ions in the

ECF thereby increasing water tubular reabsorption by:
• Stimulating the hypothalamic ADH system
• Creating osmotic gradient across the tubular membrane
• Increases thirst

2. Mild to moderate increase in blood volume

Actions of Aldosterone

C. Effects on sweat glands, salivary glands and gastric mucosa

• Greatly reduces the loss of Na+ and Cl- in the glandular
secretions

• The effect on sweat gland – important to conserve body salt

in hot environment

• The effect in intestinal glands is important to prevent salt loss

in GI excretory products
Adrenal Medullary
Hormones
Hormones :

 Hormones isolated from the adrenal medulla, known as

catecholamines
 Epinephrine – more active; primarily synthesized and stored in
adrenal medulla
 Norepinephrine – primarily synthesized in sympathetic nervous
system; also in adrenal medulla

 Tyrosine – precursor amino acid

 Secreted by the chromaffin cells

hormones of adrenal medulla

80% of released
catecholamine is
epinephrine
secreted and stored
in the adrenal
medulla and
released in response
to appropriate
stimuli
biosynthesis of catecholamines

 Tyrosine hydroxylase

1. produces L-3,4-dihydroxyphenylalanine (L-DOPA)

2. is the rate limiting enzyme

3. iron-containing protein (ferric state)

4. exists in soluble and particle forms

5. uses molecular oxygen

6. requires tetrahydrobiopterin (BH4)

 the biosynthesis of catecholamines
 Aromatic L-amino acid (Dopa) decarboxylase

 also known as: tryptophan decarboxylase,

5-hydroxytryptophan decarboxylase

 it catalyzes several different

decarboxylation reactions:

 L-DOPA to dopamine

 5-HTP to serotonin

 tryptophan to tryptamine

 requires pyridoxal phosphate

 competitively inhibited by alpha-

methyldopa , and some antihypertensive
drugs like methyldopa
biosynthesis of catecholamines

Dopamine-beta-hydroxylase (DBH)

1. converts dopamine to norepinephrine

2. requires ascorbic acid as electron donor
3. has Cu in active site
4. use fumarate as modulator
the biosynthesis of catecholamines

 Phenylethanolamine-N-methyltransferase (PNMT)

1. soluble in cytoplasm

2. induced by glucocorticoids

3. uses SAM, methy donor

differences between epinephrine
and norepinephrine

 Epinephrine >> norepinephrine - in terms of

cardiac stimulation leading to greater cardiac
output (beta stimulation)
 Epinephrine < norepinephrine- in terms of
construction of blood vessels - leading to
increased peripheral resistance - increased arterial
pressure
 Epinephrine>> norepinephrine - in terms of
increasing metabolism
catecholamine mechanism of
signalling

 Epinephrine works on cells

via Ca+2 as a 2nd
messenger
 increases glycogenolysis
and gluconeogenesis
 increases release of
glucagon and cortisol
 Epinephrine can also work
via the cAMP signal
transduction pathway
 phosphorylation of
glycogen phosphorylase
 increases breakdown
of glycogen in the liver
the catecholamines mechanism of
signaling

 Binding to β1 and β2

stimulates G-proteins coupled to adenylate cyclase

 Binding to ⍺2

inhibits adenylate cyclase

 Binding to ⍺1

is coupled to phospholipase C
increases phosphoinositol, DAG and Ca+2
catabolism of catecholamines

1. Have very short t1/2 (10-30 sec)

2. Less than 5% is excreted in urine

3. Catabolized by:
A. Catechol-o-methy transferase (COMT)
B. Monoamine oxidase (MAO)
effects of epinephrine

 during stressful condition: fight-or-flight reaction

 neuronal signals from the brain trigger the release of epinephrine and
norepinephrine from adrenal medulla

 its effects on metabolism:

 acts primarily on liver, muscles and adipose tissue

 activates glycogen phosphorylase and inactivate glycogen

synthase (via cAMP-dependent phosphorylation of the enzymes )

 stimulates conversion of liver glycogen into blood glucose

Effects of Epinephrine
 promotes anaerobic breakdown of the glycogen of skeletal muscle into
lactate by fermentation

 stimulate glycolytic ATP formation

 stimulates fat mobilization in adipose tissue activating the triacylglycerol

via cAMP-dependent phosphorylation

 stimulates the secretion of glucagon and inhibits insulin, reinforcing its

effect of mobilizing fuels and inhibiting fuel storage
Thank you
References

1. Chatterjea, MN and Shinde, R. Textbook of Medical

Biochemistry. 8th ed. 2012

2. Harvey, R. et al. Lippincott’s Illustrated Reviews

Biochemistry. 5th ed. 2011
Metabolic Integration in the
Fed and Starve States

Endocrine Module – Med 7524

(Biochemistry)
 Learning competencies

1.Discuss the mechanisms that control the flow of

metabolites through metabolic pathways
2.Explain the metabolic role of the liver, adipose
tissue, skeletal muscles and brain in the well-
fed and fasting state
3.Discuss the intertissue relationships in the
starve-feed cycle
4.Compare the metabolic effects of insulin and
glucagon
 Four mechanisms that control the flow of
metabolites through metabolic pathways

◼ Availability of substrates

◼ Allosteric activation/inhibition of enzymes

◼ Covalent modification of enzymes

◼ Induction-repression of enzyme synthesis

 Time scale in which each mechanism
takes effect

◼ Substrate availability – within minutes

◼ Allosteric effect on enzymes – within minutes

◼ Covalent modification of enzymes – minutes

to hours

◼ Enzyme synthesis – hours to days

 Allosteric Effects

◼ Involve rate-limiting enzymes

◼ They give a sigmoid curve when concentration
of the enzyme is plotted vs reaction velocity
◼ Ex., Effects of fructose 2,6-bisphosphate

1) Activates phosphofructokinase →stimulation

of glycolysis

2) Inhibits fructose 1,6-bisphosphatase →

inhibition of gluconeogenesis
 Covalent Modification of Enzymes

◼ Involves addition or removal of phosphate

from ser, thr and tyr residues

◼ Ex., Effects of phosphorylation by kinase

◼ 1) Activation of glycogen phosphorylase

◼ 2) Inactivation of glycogen synthase

Induction/Repression of Enzyme Synthesis

◼ Enzymes involved are those that are needed

under selected physiologic conditions

◼ Example: in the fed state, insulin promote

synthesis of key enzymes involved in:

1. lipogenesis and triglyceride synthesis

2. DNA, RNA and protein synthesis
METABOLISM IN THE WELL-FED
(ABSORPTIVE) STATE
METABOLISM IN THE WELL-FED (ABSORPTIVE) STATE

LIVER: THE MAJOR PROCESSING

ORGAN OF THE BODY
 Role of the liver in carbohydrate
metabolism
◼ More of a glucose-producer during the day
except after meals
◼ Retains 60% of glucose from the diet

◼ Increased glucose metabolism is due to:

1. Increased formation of glucose 6-phosphate

by glucokinase (high Km for glucose)

2. Increased glycogenesis because of activation

of glycogen synthase
 Liver in CHO Metabolism
◼ 3. Increased HMP shunt due to:
- availability of glucose 6-PO4
- increased activity of glucose 6-PO4 DH
- increased utilization of NADPH for
hepatic fatty acid synthesis

◼ 4. Increased glycolysis due to

- activation of phosphofructokinase and
pyruvate kinase
- glucose is converted to acetyl CoA
- acetyl CoA → Krebs or lipogenesis
 Liver in CHO Metabolism

◼ 5. Decreased gluconeogenesis due to

- inactive pyruvate carboxylase 2o to
low levels of acetyl CoA

- high insulin:glucagon ratio leads to

inactivation or repression of:
a) phosphoenolpyruvate carboxykinase
(PEPCK)
b) fructose 1,6-bisphosphatase
 Role of the Liver in Fat Metabolism
◼ 1. Increased lipogenesis due to availability
of acetyl CoA and NADPH
- activation of acetyl CoA carboxylase

◼ 2. Increased TAG synthesis due to increased

availability of fatty acids
* Fatty acids are derived from:
a) lipogenesis
b) hydrolysis of TAG in chylomicron remnant

* Availability of glycerol 3-PO4 from glycolysis

 Role of the Liver in Protein Metabolism
◼ 1. Increased amino acid degradation due to
excess amino acids from the diet.
* AA are deaminated forming their carbon
skeletons (α-keto acids)
- exempted are the branched-chain AA

◼ 2. Release of surplus amino acids into the

blood

◼ 3. Increased protein synthesis

METABOLISM IN THE WELL-FED (ABSORPTIVE) STATE

ADIPOSE TISSUE: ENERGY STORAGE

SITE OF TRIACYLGLYCEROL
 Role of the Adipose Tissue in CHO
Metabolism

◼ 1. Increased glucose transport into fat cells

- due to sensitivity to insulin

◼ 2. Increased glycolysis due to increased

availability of glucose from the diet
- Glycolysis supply DHAP which is converted
to glycerol 3-PO4 for TAG synthesis

◼ 3. Increased activity of HMP shunt → NADPH →

inc. lipogenesis → inc. TAG synthesis
 Role of the Adipose Tissue in Fat
Metabolism

◼ 1. Increased lipogenesis
- de novo synthesis of fatty acid is not a
major pathway

◼ 2. Increased TAG synthesis due to:

a) release of fatty acid from hydrolysis of
TAGs in chylomicron and VLDL
catalyzed by lipoprotein lipase
b) availability of glycerol 3-PO4 coming
from DHAP (glycolysis)
 Adipose tissue in Fat Metabolism

◼ 3. Decreased lipolysis due to inactivation of

hormone-sensitive lipase

- insulin favors the dephosphorylated,

inactive state of lipase
METABOLISM IN THE WELL-FED (ABSORPTIVE) STATE

SKELETAL MUSCLE: AN
OXIDATIVE TISSUE

Oxygen consumption:
- 30% at rest
- 90% during strenuous exercise
 Role of the Skeletal Muscle in CHO
Metabolism

◼ 1. Increased glucose transport into muscle

- major source of fuel of resting muscle
◼ 2. Increased glycolysis

◼ 3. Increased glycogenesis due to increased

availability of glucose 6-PO4

- results from increased insulin:glucagon

ratio
 Role of the Skeletal Muscle in Fat and
Protein Metabolism

◼ Lipoprotein lipase releases fatty acids from

* chylomicrons and VLDL
◼ Fatty acids are only of secondary importance
as a fuel for muscle in the absorptive
state

- Increased uptake of amino acids and protein

synthesis
- Increased storage of ATP
- Increased storage of creatine phosphate
METABOLISM IN THE WELL-FED (ABSORPTIVE) STATE

BRAIN: ENERGY CONSUMER

RATHER THAN ENERGY GIVER

Accounts for 20% of oxygen

consumption of the body at rest
 Role of the Brain in CHO Metabolism

◼ Uses glucose exclusively as a fuel in the

absorptive state

◼ Dependent on the supply of blood glucose

◼ Oxidizes 140 g/day of glucose

◼ Does not store glycogen

 Role of the Brain in Fat Metabolism

◼ Does not store TAG

◼ Fatty acids do not sufficiently cross the

blood-brain barrier

◼ Does not use fatty acids for its energy needs

 METABOLISM IN THE
STARVE (FASTING) STATE
 Starvation
◼ Causes:
1. inability to obtain food
2. inability to eat because of disease
3. desire to lose weight rapidly

◼ During this catabolic periods there are

exchanges of substrate among organs

◼ There are two priorities of metabolism:

1. maintain adequate plasma levels of
glucose for use by the brain
2. mobilize fatty acids and ketone bodies
to supply energy to other tissues
The Role of the Liver in CHO Metabolism

◼ 1. Increased glycogenolysis
- due to phosphorylation and activation
of glycogen phosphorylase
- glycogen store is nearly depleted after
10 to 18 hours of fasting

◼ 2. Increased gluconeogenesis
- substrates used are amino acids, glycerol
and lactate
- starts 4 to 6 hours after the last meal
- maintains blood glucose during overnight
and prolonged fasting
The Role of the Liver in Fat Metabolism

◼ 1. Increased beta oxidation

- fatty acids obtained from lipolysis in
adipose tissue

◼ 2. Increased ketogenesis due to excess

acetyl CoA obtained from beta oxidation

- starts during the first days of starvation

- use for energy by the brain, heart, etc.
- slows down the loss of tissue protein
- reduces the need for gluconeogenesis
 The Role of Adipose Tissue in
Starvation
◼ 1. Carbohydrate metabolism
- decreased transport of glucose into fat cells
- decreased lipogenesis and TAG synthesis

◼ 2. Fat metabolism
a) Increased lipolysis due to phosphorylation
and activation of hormone-sensitive lipase
by catecholamines
- increased release of fatty acids

b) Decreased uptake of fatty acids due to

low activity of lipoprotein lipase
 Skeletal Muscle in Starvation

◼ 1. Carbohydrate metabolism
- decreased glucose transport into muscles
- due to decreased insulin:glucagon ratio

◼ 2. Lipid metabolism
- first 2 weeks, muscle uses fatty acids and
ketone bodies
- in 3 weeks, oxidizes fatty acids almost
exclusively
 Skeletal Muscle in Starvation

◼ 3. Protein metabolism
- first few days, there is rapid proteolysis
- amino acids are used for gluconeogenesis

- alanine and glutamine are the most

important gluconeogenic amino acids

- after several weeks, there is decreased

muscle proteolysis
- due to decline in the need for glucose
as source of energy for the brain
 The Brain during Starvation

◼ First days of starvation (early fasting), it

uses glucose exclusively

◼ In prolonged starvation (> 2 to 3 weeks of

fasting), it uses ketone bodies as fuel

*Utilization of ketone bodies reduce need for

protein catabolism for gluconeogenesis
 Metabolic interrelationships during the
early fasting state

◼ Hepatic glycogenolysis is the most important

source of blood glucose

◼ Cori cycle become active

- conversion of glucose to lactate (glycolysis) in
the peripheral tissues followed by conversion of
lactate back to glucose (gluconeogenesis) in the
liver

◼ Glucose-alanine cycle become active

 Metabolic interrelationships during the
fasting state
◼ Increased hepatic gluconeogenesis
◼ Substrates: lactate, glycerol and alanine

◼ Fatty acids cannot be converted to glucose

◼ Alanine and glutamine are the only two amino

acids released from the muscle in large amounts

◼ Glutamine becomes a major source of energy for

intestinal cells and cells of immune system

◼ Branched-chain α-keto acids become major

sources of glucose and ketone bodies
 Insulin Glucagon
Stimulus Hyperglycemia, Hypoglycemia,
amino acids amino acids,
epinephrine

Effect on memb. Activates Activates

tyrosine kinase adenylate
Receptor cyclase
activity of
insulin receptor

Increases Inhibits
Effect on CHO glycolysis; glycolysis
metabolism stimulates PFK

Stimulates Inhibits
glycogenesis glycogenesis
 References

1. Harper’s Illustrated Biochemistry 30th Edition

by Rodwell, Bender, Botham, Kennelly and Weil
2. Lehninger Principles of Biochemistry 5th Edition
by Nelson and Cox
3. Textbook of Biochemistry With Clinical Correlation
6th Edition by Thomas M. Devlin
4. Lippincott’s Biochemistry 5th Edition
by Champe and Harvey
5. Textbook of Medical Physiology 13th Edition
by Guyton and Hall