Endocrine

biohemistry
 The Endocrine System
Hormone action

The Endocrine System

• The nervous and endocrine systems act as a coordinated
interlocking super system, the neuroendocrine system.
• The endocrine system controls body activities by releasing
mediator molecules called hormones.
– hormones released into the bloodstream travel throughout the body
– results may take hours, but last longer
• The nervous system controls body actions through nerve
impulses.
– certain parts release hormones into blood
– rest releases neurotransmitters excite or inhibit nerve, muscle & gland cells
– results in milliseconds, brief duration of effects

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 0

The nervous system causes muscles to contract or glands to

secrete. The endocrine system affects virtually all body tissues
by
Thealtering
nervousmetabolism, regulating
system causes musclesgrowth and development,
to contract or glands toand
influencing
secrete. Thereproductive processes.
endocrine system affects virtually all body tissues
by altering metabolism, regulating growth and development, and
influencing
Parts of thereproductive processes.
nervous system stimulate or inhibit the release of
hormones.
Parts of themay
Hormones nervous
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system
promote stimulate
or inhibit or inhibit the
the generation of release
nerve of
hormones.
impulses.
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Hormones may promote or inhibit the generation of nerve
impulses.

General Functions of Hormones

General Functions
• of
HelpHormones
regulate:
– extracellular fluid
– metabolism
•– Helpbiological
regulate:clock
– extracellular
contraction offluid
cardiac &
– metabolism
smooth muscle
– biological clock
glandular secretion
– contraction
some immune of cardiac &
functions
• smooth
Growth muscle
& development
•– Reproduction secretion
glandular
– some immune functions
• Growth & development
• Hormones have powerful effects
• Reproduction
when present in very low
concentrations.
• Hormones have powerful effects
when present in very low
concentrations.

Endocrine Glands Defined

• Exocrine glands
 when present in very low
concentrations.

Endocrine Glands Defined

• Exocrine glands
– Endocrine
secrete products Glands
into ducts which Defined
empty into body cavities or body
surface
•– Exocrine
sweat, oil,glands
mucous, & digestive glands
– secrete products into ducts which empty into body cavities or body
• Endocrine
surface glands
–
– secrete products
sweat, oil, mucous, (hormones) into
& digestive bloodstream
glands
– pituitary, thyroid, parathyroid, adrenal, pineal
•–
–
Endocrine
hypothalamus,
secrete
glands
products Loading…
thymus, pancreas,ovaries,testes, kidneys, stomach,
(hormones)
liver, small intestine, into
skin, heart bloodstream
& placenta
– pituitary, thyroid, parathyroid, adrenal, pineal
–
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hypothalamus, thymus, pancreas,ovaries,testes, kidneys, stomach,
liver, small intestine, skin, heart & placenta

Hormone Receptors 0

Hormone Receptors

• Hormones only affect target cells with specific membrane

proteins called receptors

• Hormones only affect target cells with specific membrane 0

proteins called receptors

Hormone Receptors
 • Hormones only affect target cells with specific membrane
proteins called receptors

• Hormones only affect target cells with specific membrane 0

proteins called receptors

Hormone Receptors

• Although hormones Hormone

travel in blood Receptors
throughout the body, they
affect only specific target cells.
•– Target cells
Although have specific
hormones protein
travel in orblood
glycoprotein receptorsthe
throughout to which
body, they
hormones bind.
affect only specific target cells.
•– Receptors are
Target cells constantly
have being
specific protein synthesized
or glycoprotein andtobroken
receptors which
down.
hormones bind.
• Receptors are constantly being synthesized and broken
down.

Regulation of Hormone Receptors

• Receptors are constantly being synthesized & broken
down Regulation of Hormone Receptors
– range of 2000-100,000 receptors / target cell
•• Receptors are constantly being synthesized & broken
Down-regulation
– down
excess hormone leads to a decrease in number of receptors
–• range of 2000-100,000
receptors receptors / target
undergo endocytosis and arecell
degraded
•– Down-regulation
decreases sensitivity of target cell to hormone
•– Up-regulation
excess hormone leads to a decrease in number of receptors
–• receptors
deficiency undergo endocytosis
of hormone and are degraded
leads to an increase in the number of receptors
–
– decreases
target tissue becomes more sensitivehormone
sensitivity of target cell to to the hormone
• Up-regulation
– deficiency of hormone leads to an increase in the number of receptors
– target tissue becomes more sensitive to the hormone

Circulating and Local Hormones

 Circulating and Local Hormones

• Hormones that travel in blood and act on distant target cells

are called circulating hormones or endocrines.
• Hormones that act locally without first entering the blood
stream are called local hormones.
– Those that act on neighboring cells are called paracrines.
– Those that act on the same cell that secreted them are termed autocrines.

Endocrine hormones
travel through blood
to reach target cell

Paracrines act on Autocrines act on the

neighboring cells cell that has
secreted them

Circulating & Local Hormones

• Circulating
hormones
• Local hormones
– paracrines
– autocrines

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 0

Chemical Classes of Hormones

Chemical Classes of Hormones

• Lipid-soluble hormones include the steroids, thyroid
hormones, and nitric oxide, which acts as a local hormone in
• several tissues.
Lipid-soluble hormones include the steroids, thyroid

•
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hormones, and nitric oxide, which acts as a local hormone in
several tissues.hormones include the amines; peptides,
Water-soluble

•
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proteins, and glycoproteins; and eicosanoids.
Water-soluble hormones include the amines; peptides,
proteins, and glycoproteins; and eicosanoids.

Lipid-soluble Hormones 0

•
Lipid-solubleSteroids
Hormones
– lipids derived from cholesterol on
SER
•– Steroids
different functional groups attached
– lipids
to corederived from cholesterol
of structure provide on
SER
uniqueness
– different functional groups attached
• Thyroid hormones
to core of structure provide
– uniqueness plus attached iodines
tyrosine ring
are lipid-soluble
• Thyroid hormones
•– Nitric oxide
tyrosine ringisplus
gasattached iodines
are lipid-soluble
• Nitric oxide is gas

Water-soluble Hormones 0

• Hormones
Water-soluble Amine, peptide and protein
 Water-soluble Hormones
• Amine, peptide and protein
hormones
– modified amino acids or amino acids
put together
– serotonin, melatonin, histamine,
epinephrine
– some glycoproteins
• Eicosanoids
– derived from arachidonic acid (fatty
acid)
– prostaglandins or leukotrienes

General Mechanisms of Hormone Action

Hormone binds to cell surface or receptor inside target cell
Cell may then
• synthesize new molecules
• change permeability of membrane
• alter rates of reactions
Each target cell responds to hormone differently
At liver cells---insulin stimulates glycogen synthesis
At adipocytes---insulin stimulates triglyceride synthesis

Same hormone can act

differently on different
target cells

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 Action of Lipid-Soluble Hormone

• Lipid-soluble hormones bind to and activate receptors

within cells.
– The activated receptors then alter gene expression which results in the
formation of new proteins.

– The new proteins alter the cells activity and result in the physiological
responses of those hormones.

On DNA we have a
sequence called hormone
response element HRE, the
Receptors for thyroid Steroids receptors hormone receptor complex
hormones are in the are in the cytoplasm attaches to HRE,making a
nucleus new mRNA ,which then
makes a new protein

Action of Lipid-Soluble Hormones

• Hormone diffuses through

phospholipid bilayer &
into cell
• Binds to receptor turning
on/off specific genes
• New mRNA is formed &
directs synthesis of new
proteins
• New protein alters cell’s
activity

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 Action of Water-Soluble Hormones

• Water-soluble hormones alter cell functions by activating

plasma membrane receptors, which set off a cascade of
events inside the cell.
– The water-soluble hormone that binds to the cell membrane receptor is the
first messenger.
– A second messenger is released inside the cell where hormone stimulated
response takes place.
After hormone binds to
receptor with specific
information

1st messenger 2nd messenger

(In the cell)

Categories of second messengers

1. Cyclic nucleotides (cAMP; cGMP)

2. Ca2+
3. Phosphatidyl inositol
4. Thyrosine Kinase
 Action of Water-Soluble Hormones

• The hormone binds to the membrane receptor.

• The activated receptor activates a membrane G-protein
which turns on adenylate cyclase.
• Adenylate cyclase converts ATP into cyclic AMP which
activates protein kinases.
• Protein kinases phosphorylate enzymes which catalyze
reactions that produce the physiological response.
• Since hormones that bond to plasma membrane receptors
initiate a cascade of events, they can induce their effects at
very low concentrations.
Receptors are either stimulator or inhibitory

Hormones are either stimulator or inhibitory

If hormone is S it binds to a S receptor

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Action of Water-Soluble Hormones

• Can not diffuse through plasma
membrane
• Hormone receptors are integral
membrane proteins
– act as first messenger
• The hormone binds to the membrane
receptor.
• The activated receptor activates a
membrane G-protein which turns on
adenylate cyclase.
• Adenylate cyclase converts ATP into
cyclic AMP which activates protein
kinases.
• Protein kinases phosphorylate enzymes
which catalyze reactions that produce
the physiological response.

Active phosphorylase brakes down glycogen

increasing the amount of glucose.

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 which catalyze reactions that produce
the physiological response.

Water-soluble Hormones 0

• Cyclic
Water-soluble AMP is the 2nd
Hormones
messenger
•– kinases
Cyclic AMP in
is the
the cytosol
2nd
speed up/slow down
messenger
– physiological
kinases in the cytosol
responses
speed up/slow down
• physiological
Phosphodiesterase
responses
inactivates cAMP by
• inhibiting adenylate
Phosphodiesterase
cyclase
inactivates cAMP by
• inhibiting
Cell adenylate
response is turned off
cyclase
unless new hormone
• molecules
Cell arrive
response is turned off
unless new hormone
molecules arrive 0

cAM
P
cAM
P
 Second Messengers
• Some hormones exert their
Second influence by increasing the
Messengers
synthesis of cAMP
•– ADH, TSH, ACTH, glucagon and epinephrine
Some hormones exert their influence by increasing the
• Some exert
synthesis of their
cAMP influence by decreasing the level of cAMP
– growth hormone inhibiting hormone
– ADH, TSH, ACTH, glucagon and epinephrine
•• Other
Some substances
exert their can act as
influence by 2nd messengers
decreasing the level of cAMP
– calcium ions
– growth hormone inhibiting hormone
– cGMP
•• Other substances
A hormone can
may use act as 2nd
different 2nd messengers
messengers in different
– calcium ions
– target
cGMP cells
• A hormone may use different 2nd messengers in different
target cells

Amplification of Hormone Effects 0

 Amplification of Hormone Effects

• Single molecule of hormone binds to receptor

• Activates 100 G-proteins
• Each activates an adenylate cyclase molecule which
then produces 1000 cAMP
• Each cAMP activates a protein kinase, which may
act upon 1000’s of substrate molecules
• One molecule of epinephrine may result in
breakdown of millions of glycogen molecules into
glucose molecules

Cholera Toxin and G Proteins

• Toxin is deadly because it produces massive watery

diarrhea and person dies from dehydration
• Toxin of cholera bacteria causes G-protein to lock in
activated state in intestinal epithelium
• Cyclic AMP causes intestinal cells to actively transport
chloride (Na+ and water follow) into the lumen
• Person die unless ions and fluids are replaced & receive
antibiotic treatment

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Principles of Human Anatomy and Physiology, 11e
Phosphatidyl inositol 0

Inositol trisphosphate (IP3) and diacylglycerol

(DAG)
Peptide and protein hormones like vasopressin, thyroid-
stimulating hormone (TSH), and angiotensin and
neurotransmitters like GABA bind to G protein-coupled
receptors (GPCRs) that activate the intracellular
enzyme phospholipase C (PLC). As its name suggests, it
hydrolyzes phospholipids — specifically phosphatidylinositol-
4,5-bisphosphate (PIP2) which is found in the inner layer of the
plasma membrane. Hydrolysis of PIP2 yields two products:
diacylglycerol (DAG)
inositol-1,4,5-trisphosphate (IP3)

Principles of Human Anatomy and Physiology, 11e 0

 inositol-1,4,5-trisphosphate (IP3)

Principles of Human Anatomy and Physiology, 11e 0

Principles of Human Anatomy and Physiology, 11e 0

diacylglycerol (DAG): DAG remains in the inner layer of the

plasma membrane. It recruits Protein Kinase C (PKC) —
a calcium-dependent
diacylglycerol (DAG):kinase
DAG that phosphorylates
remains in the inner many
layer ofother
the
proteinsmembrane.
plasma that bring about the changes
It recruits in the cell.
Protein Kinase As its —
C (PKC) name
suggests, activation ofkinase
a calcium-dependent PKC requires calcium ions.many
that phosphorylates These are
other
made available
proteins by about
that bring the action of the other
the changes second
in the messenger
cell. As its name —
IP3.
suggests, activation of PKC requires calcium ions. These are
inositol-1,4,5-trisphosphate
made available by the action of(IP3):
diffuses
IP3.
the other Loading…
This soluble
second molecule
through the cytosol and binds to receptors on the
messenger —

endoplasmic reticulum causing(IP3):

inositol-1,4,5-trisphosphate
(Ca2+) into
diffuses the cytosol.
through The and
the cytosol
the release
rise binds
Loading…
of calcium
This soluble
in intracellular calcium
to receptors
ions
molecule
on thetriggers
the response.reticulum causing the release of calcium ions
endoplasmic
(Ca2+) into the cytosol. The rise in intracellular calcium triggers
the response.

Principles of Human Anatomy and Physiology, 11e 0

Principles of Human Anatomy and Physiology, 11e 0

Calmodulin dependent protein kinases:

These kinases are inactive until they bind calmodulin which has
4Calmodulin
calcium ions bound protein kinases:
dependent
Calmodulin
These kinases are inactive calcium
(intracellular until theybinding Proteins)which
bind calmodulin has 4 has
4calcium ions
calcium ionsbound,
boundit is bound by target proteins which activate
them..
Calmodulin (intracellular calcium binding Proteins) has 4
calcium ions bound, it is bound by target proteins which activate
them..

Principles of Human Anatomy and Physiology, 11e 0

Principles of Human Anatomy and Physiology, 11e 0

Principles of Human Anatomy and Physiology, 11e 0

Principles of Human Anatomy and Physiology, 11e 0

The Insulin Receptor

The Insulin Receptor

➢ Responsible for clearance of glucose
➢ In addition to binding insulin, it possesses a tyrosine
➢ Responsible
kinase activityfor clearance of glucose
➢ In
It isaddition
involvedto in
binding
many insulin,
cellular itactivities
possesses a tyrosine
kinase activity
➢ It is involved in many cellular activities
Insulin-mediated glucose transport signaling pathway
Insulin-mediated glucose transport signaling pathway
Insulin
Insulin-mediated glucose transport signaling pathway
Insulin-mediated glucose transport signaling pathway
IR a Insulin
a
b b
Cell membrane IR a a
b b
Cell membrane

P
IRS
PI3K

P
IRS
Glut4 PI3K
Akt
P

Glut4 Akt
P

Insulin-mediated glucose transport signaling pathway

Insulin-mediated glucose transport signaling pathway
 Insulin-mediated glucose transport signaling pathway
Insulin-mediated glucose transport signaling pathway

IR Insulin
glucos a a
e b b Cell membrane

P
IRS
PI3K

Akt
P

Xiao Chen, 2006

Hormonal Interactions
• The responsiveness of a target cell to a hormone depends
on the hormone’s concentration, the abundance of the target
cell’s hormone receptors, and influences exerted by other
hormones.
• Three hormonal interactions are the
– permissive effect
– synergistic effect
– antagonist effect

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 Hormonal Interactions
• Permissive effect
– a second hormone, strengthens the effects of the first
– thyroid strengthens epinephrine’s effect upon lipolysis
• Synergistic effect
– two hormones acting together for greater effect
– estrogen & LH are both needed for oocyte production
• Antagonistic effects
– two hormones with opposite effects
– insulin promotes glycogen formation & glucagon stimulates glycogen
breakdown

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 Hypothalamus and Pituitary
• The hypothalamus-pituitary unit is the most
dominant portion of the entire endocrine system.
• The output of the hypothalamus-pituitary unit
regulates the function of the thyroid, adrenal and
reproductive glands and also controls somatic
growth, lactation, milk secretion and water
metabolism.

Hypothalamus and Pituitary

• Pituitary function depends on the hypothalamus

and the anatomical organization of the
hypothalamus-pituitary unit reflects this
relationship.
• The pituitary gland lies in a pocket of bone at the
base of the brain, just below the hypothalamus
to which it is connected by a stalk containing
nerve fibers and blood vessels. The pituitary is
composed to two lobes-- anterior and posterior
 The pituitary gland
HYPOTHALAMUS
Hypothalamus secretes ADH & oxytocin carried from
releasing factors hypothalamus

INFUNDIBULUM

Thyroid stimulating
hormone
Adrenocorticotropic
hormone
Antidiuretic hormone
Gonadotropic hormones
ANTERIOR POSTERIOR Oxytocin
(FSH & LH)
LOBE LOBE
Growth hormone
Prolactin
 Posterior pituitary gland

General Functions of the hypothalamus

1. Controls body temperature.

2. Controls the cardiovascular system.
3. Controls food intake & body weight.
4. Controls thirst & water balance.
5. Involved in sleep & wakefulness.
6. Involved in emotional reactions.
7. Involved in reactions to stress.
8. Controls ovarian secretions during ovarian cycle.
9. Controls testicular secretions.
 Hypothalamus Releasing Hormones:
Secretion

• Is influenced by emotions
• Can be influenced by the metabolic state of the
individual
• Delivered to the anterior pituitary via the
hypothalamic-hypophyseal portal system

Hypothalamic Releasing Hormones

Seven releasing hormones are made in the hypothalamus

– Thyrotropin-releasing hormone (TRH)
– Corticotropin-releasing hormone (CRH)
– Gonadotropin-releasing hormone (GnRH)
– Growth hormone-releasing hormone (GHRH)
– Growth hormone-release inhibiting hormone (GHIH)
– Prolactin-releasing factor (PRF)
– Prolactin-inhibiting hormone (PIH)
 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

Hypothalamic hormones

Hypothalamus

GnRH GHRH GHIH/SS TRH PRIH PRH CRH

+ + - - + + - + +
FSH & LH GH TSH Prolactin ACTH
Anterior Pituitary
 The Pituitary gland (hypophysis):

 Small gland ( 1cm diameter;  0.5 to 1 gm weight).

 Lies in sella turnica, a bony cavity at the base of the brain.
 Connected to the hypothalamus by the pituitary stalk or
(hypophysial; infundibulum).

 Structurally & functionally

divided into 2 lobes:

1) Anterior lobe (2/3),

2) Posterior lobe (1/3).

Anterior Pituitary

Is also called the Adenohypophysis

Secretes tropic hormones in a pulsatile fashion
Synthesizes various hormones in various specific cell
populations
 Anterior Pituitary Hormones

Each of anterior pituitary hormone is synthesized

by a cell population.
Corticotropes - ACTH
Lactotropes - Prolactin
Somatotropes - GH
Thyrotropes - Thyrotropin
Gonadotropes - FSH, LH

Anterior pituitary: adenohypophysis

• Anterior pituitary: connected to the hypothalamus

by the superior hypophyseal artery.
• The anterior pituitary produces six peptide
hormones:
• prolactin
• growth hormone (GH)
• thyroid stimulating hormone (TSH)
• follicle-stimulating hormone (FSH)
• luteinizing hormone (LH)
• adrenocorticotropic hormone (ACTH)
 Anterior Pituitary Hormones
Growth Hormone (GH, Somatotropin): primary hormone responsible for
regulating body growth, and is important in metabolism
Thyroid-stimulating Hormone (TSH): stimulates secretion of thyroid
hormone & growth of thyroid gland
Adrenocorticotropic Hormone (ACTH): stimulates cortisol secretion by the
adrenal cortex & promotes growth of adrenal cortex
Follicle-stimulating Hormone (FSH): Females: stimulates growth &
development of ovarian follicles, promotes secretion of estrogen by ovaries.
Males: required for sperm production
Luteinizing Hormone (LH): Females: responsible for ovulation, formation of
corpus luteum in the ovary, and regulation of ovarian secretion of female sex
hormones. Males: stimulates cell in the testes to secrete testosterone
Prolactin: Females: stimulates breast development and milk production.
Males: involved in testicular function

HYPOTHALAMIC EFFECTS ON THE

HORMONE ANTERIOR PITUITARY
Thyrotropin-releasing hormone Stimulates release of TSH
(TRH) (thyrotropin) and Prolactin
Corticotropin-releasing hormone Stimulates release of ACTH
(CRH) (corticotropin)
Gonadrotropin-releasing Stimulates release of FSH and
hormone (GnRH) LH (gonadotropins)
Growth hormone-releasing Stimulates release of growth
hormone (GHRH) hormone
Growth hormone-inhibiting Inhibits release of growth
hormone (GHIH) hormone
Prolactin-releasing hormone Stimulates release of prolactin
(PRH)
Prolactin-inhibiting hormone Inhibits release of prolactin
(PIH)
 Anterior Pituitary Hormones

Hormones Target Principal action

tissue
1. Growth hormone Most (+) protein synthesis & growth;
(GH, or somatotropin) tissue lipolysis; bl glucose

2. Thyroid-stimulating hormone Thyroid (+) thyroid hormones

(TSH, or thyrotropin) gland
3. Adrenocorticotropic hormone Adrenal (+) glucocorticoids
(ACTH, or corticotrophins) cortex
4. Follicle-stimulating hormone Gonads (+) gamete production, (+)
(FSH, or folliculotropin) estrogen in ♀

5. Luteinizing hormone Gonads (+) sex hormones; ovulation &

(LH, or luteotropin) corpus luteum formation in
females; (+) testosterone in ♂
6. Prolactin (PRL) Mammary (+) milk in lactating ♀; regulates ♂
glands reproductive system
 Anterior Pituitary Hormones

Anterior pituitary hormones

Anterior Pituitary

FSH & LH GH TSH Prolactin ACTH

+ + + + +
Thyroid Mammary Adrenal
Gonads Most tissues
gland glands cortex

 estrogen;
 protein synthesis; + T4; + milk;  glucocorticoids
progeterone;
 Lipolysis; & + T3 + breast dvlp.
+ testosterone
 blood glucose + thyroid regulate ♂
+ gametes; growth reproductive
+ ovulation; system
 ACTH synthesis

ACTH

Processing and cleavage of pro-opiomelanocortin (POMC)

ACTH
 ACTH is made up of 39 amino acids
 Regulates adrenal cortex and synthesis of
adrenocorticosteroids
 -MSH resides in first 13 aa of ACTH
 -MSH stimulates melanocytes and can darken skin
 Overproduction of ACTH may accompany increased
pigmentation due to -MSH.
 -endorphin

• Produced as a result of ACTH synthesis

• Binds to opiate receptors
• Results in “runner’s high”
• Role in anterior pituitary not completely understood
• One of many endogenous opioids such as
enkephalins

Melanocyte-stimulating hormone
(MSH)

• MSH peptides derived by proteolytic cleavage of

POMC
• -MSH has antipyretic and anti-inflammatory effects
• Four MSH receptors identified
• May inhibit feeding behavior • Può inibire il comportamento alimentare

• ACTH has MSH-like activity

• However– MSH has NO ACTH like activity
 Posterior Pituitary: neurohypophysis

• Posterior pituitary:
• An outgrowth of the hypothalamus composed of neural
tissue.
Hypothalamic neurons pass through the neural stalk and
end in the posterior pituitary. Hormones synthesized in
the hypothalamus are transported down the axons to the
endings in the posterior pituitary.
Hormones are stored in vesicles in the posterior pituitary
until release into the circulation
Principal Hormones: Vasopressin & Oxytocin

Posterior Pituitary

Comprised of the endings of axons from cell bodies in the

hypothalamus (supraoptic and paraventricular)
Axons pass from the hypothalamus to the posterior pituitary via
the hypothalamohypophysial tract
Posterior pituitary hormones are synthesized in the cell bodies
of neurons in the supraoptic and paraventricular nuclei
 posterior pituitary gland

Secretion of Posterior Pituitary Hormones

om

Figure 7-12: Synthesis, storage, and release of posterior pituitary hormones

 Posterior pituitary hormones:
ADH (VP) and Oxytocin
 Both are synthesized in the cell bodies of
hypothalamic neurons
 ADH: supraoptic nucleus
 Oxytocin: paraventricular nucleus
 Both are synthesized as preprohormones and
processed into nonapeptides (nine amino acids).
 They are released from the termini in response to an
action potential which travels from the axon body in
the hypothalamus

Structures of ADH and oxytocin

 Oxytocin:
Stimulates myoepithelial contractions

 In uterus during parturition(Child Birth)

 In mammary gland during lactation

Oxytocin:
Milk ejection from lactating mammary gland

 sucking is major stimulus for release.

 sensory receptors in nipple connect with nerve fibers to
the spine, then impulses are relayed through brain to
paraventricular nucleus where cholinergic synapses fire on
oxytocin neurons and stimulate release.
 Oxytocin
Uterine contractions

• Reflexes originating in the cervical, vaginal and

uterus stimulate oxytocin synthesis and release via
neural input to hypothalamus
• Increases in plasma at time of ovulation, parturition,
and coitus

ADH
Conserve body water and regulate tonicity of
body fluids

 Also known as vasopressin

 Regulated by osmotic and volume stimuli
 Water deprivation increases osmolality of
plasma which activates hypothalmic
osmoreceptors to stimulate ADH release
 Feedback Loops

Hypothalamus

Anterior
Pituitary
Corticotropin
Adrenal
releasing factor
+ Cortex

-Corticotropin

Cortisol

Feedback Control of the Anterior Pituitary

• Short feedback
loop:
– Retrograde transport of
blood from anterior
pituitary to the
hypothalamus.
• Hormone released by
anterior pituitary
inhibits secretion of
releasing hormone.

• Positive feedback
effect:
– During the menstrual
cycle, estrogen
stimulates “LH surge.”
Hormones of the Adrenal Cortex

0
 Adrenal Glands
The outer part is called the adrenal cortex, which
produces many different hormones called
corticosteroids. This includes cortisol. These
hormones regulate the salt and water balance in the
body, prepare the body for stress, regulate
metabolism, interact with the immune system, and
induce sexual function.

The inner part, which is called the adrenal medulla,

produces
catecholamines, such as epinephrine. Epinephrine
also known as adrenaline, increase the blood pressure
and heart rate during times of stress.
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Adrenal Glands

0
 Hormones of adrenal cortex
Three general classes of steroid hormones based on predominant functions

Mineralocorticoids: 21 carbon containing steroids ,

synthesized by zona glomerulosa, regulate
water and electrolyte balance. Aldosterone is
the most prominent mineralocorticoid.

Glucocorticoids: Also 21 carbon steroids, produced mostly

in zona fasciculata and affect glucose (hence
the name), amino acid and fat metabolism.
Cortisol (also known as hydrocortisone) is most
important GC in humans.

Androgens: The zona reticularis and fasciculata produce

significant amounts of androgen precursor
DHEA (dehydroepiandrosterone) and
androstenedione (both 19 carbon).
0

Synthesis of Adrenocortical Hormones

• Made from cholesterol taken from LDLs in the blood and
stored in adrenocortical cells

• Adrenocortical cells stimulated by ACTH or cAMP.

Cholesterol

0
 Synthesis of Adrenocortical Hormones

Synthesis of Adrenocortical Hormones

0
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 Storage and Secretion

• Little (if any) storage of steroid hormones , directly

go into circulation as and when they are produced
• Cortisol release follows the diurnal rhythm of
ACTH release. Highest levels in the morning
shortly after awakening and lowest in the evening
and early morning.

Plasma Transport
• Cortisol circulates in plasma bound to proteins
or as free.
• Transcortin or corticosteroid binding globulin (CBG)
binds cortisol.
• Most of the steroid hormones bind to CBG.
• Cortisol binds CBG and has a half life of 1.5 - 2
hrs. 8-10% Cortisol is free.

• Progesterone and deoxycorticosterone also bind

CBG strongly.
• Corticosterone binds CBG with less affinity.
• Aldosterone does not have a specific protein but
binds weekly with albumin
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 Degradation and Excretion
• Glucocorticoids: Cortisol, Cortisone and 11-
deoxycortosol are reduced by NADPH dependant
enzymes and conjugated with either glucoronate or
sulfate which render them water soluble. About 70%
of the conjugated steroids are excreted in the urine ,
20% in feces and rest exit through the skin.
• Mineralocorticoids: Aldosterone is very rapidly
cleared from the plasma by liver because it lacks a
specific protein carrier. It is converted to
tetrahydroaldosterone 3-glucoronide which is
excreted in urine.
• Androgens: are excreted as 17-keto compounds
including DHEA (sulfate) as well as androstenedione
and its metabolites. Small amounts of testosterone
secreted by adrenals are also converted to 17-keto
compounds like androsterone and etiocholanolone
which are excreted in urine. 0

Metabolic functions of corticosteroids

Glucocorticoid hormones: the most important are

Cortisol, cortisone and Corticosterone
• Effects on Carbohydrate metabolism:
• ↑es Gluconeogenesis and glucose output
• ↑es amino acid utilization
• ↑es glycogen storage
• ↓es glucose uptake by tissues other than liver
• Effects on Lipid metabolism:
• ↑es lipolysis
• ↑es circulating free fatty acids (FFA)
• ↓ es utilization of FFA for TG synthesis.
0
• Effects on Protein metabolism:
• ↑es degradation of proteins in extra hepatic tissues
• ↑es protein synthesis in liver
• Effects on Nucleic acid metabolism:
• promotes transcription of specific genes in liver.
• Effects on water and electrolyte metabolism:
• Mediated through ADH , causes decrease in ADH
• Other biochemical functions:
• Suppress immune response in high doses (esp. cortisol)
• Modulate response of catecholamines

Hormones of the Adrenal Cortex

0
 Metabolic functions of adrenocorticosteroids

Androgens: DHEA and androstenedione are

precursors of testosterone which is the most potent
androgen. General Biochemical functions of androgens
are:
• Growth, development and maintenance of male
reproductive organs
• Effect on protein metabolism: promote protein
synthesis , positive nitrogen balance and increase
muscle mass.

• Effect on carbohydrate and fat metabolism:

increase glycolysis, lipolysis and TCA cycle

• Effect on mineral metabolism: Promote mineral

deposition and bone growth.
0

Metabolic functions of adrenocorticosteroids

Mineralocorticoid hormones: The most active and

potent mineralocorticoid is Aldosterone.

• ↑es reabsorption of sodium by the distal

convoluted tubules of kidney. Water follows
sodium , thus leads to water retention

• ↑es Excretion of K+, H+ and NH+4 ions in urine.

• Acts on all epithelial cells that exchange Na and

water( kidney , GI tract , salivary glands etc)

• Promotes synthesis of transport proteins (pumps)

which facilitate Na and water movement across
cell membranes. 0
Hormones of the Adrenal Cortex

Hormones of Adrenal medulla

chromaffin cells produce

Adrenaline
Noradrenaline
 Catecolamine hormones:
Water soluble compound epinephrine and
norepinephrine; produced in brain as neurotransmitter
and in endocrine hormone in adrenal gland; stored
secretary vesicle; exocytosis; bind to receptor;
generate second messenger

Hormones of medulla - catecholamines

• Epinephrine, norepinephrine and DOPA

• Nature – derivatives of tyrosine
• Excretion is regulated by sympathetic nervous system
and brain cortex

Epinephrine Norepinephrine
Stress and The Adrenal Glands

Functions of catecholamines:

Stress hormones. Contraction of vessels, increase the blood

pressure, accelerate pulse. Contraction of uterus muscles.
Epinephrine relaxes the muscles of bronchi and intestine.
On carbohydrate metabolism:
-activates the decomposition of glycogen in liver and muscles
-activates glycolysis, TAC and tissue respiration
On protein metabolism
-accelerate the decomposition of proteins
On lipid metabolism
-activates lipase, mobilization of lipids and their oxidation
 Adrenal medulla :
Hyper secretion of the adrenal medulla
caused by a tumor (pheochromocytoma)
results in excessive secretion of
catecholamines, of which 80% is epinephrine
and the remainder is norepinephrine

DISORDERS OF THE ADRENAL GLAND

ADRENAL GLAND HYPOFUNCTION
• (Addisons Disease
Insufficiency )
of adrenocortical steroids causes problems
through the loss of mineralocorticoid (aldosterone) and
glucocorticoid (cortisol) action
• Impaired secretion of cortisol results :in decreased
gluconeogenesis, leading to hypoglycemia. The
glomerular filtration rate and gastric acid production
decrease, leading to a reduction in urea nitrogen excretion,
causing anorexia and weight loss
• Reduced aldosterone secretion causes potassium, sodium,
and water imbalances. Potassium excretion is
decreased,causing hyperkalemia; sodium and water
excretion is increased, causing hyponatremia and
hypovolemia. Potassium retention also promotes
reabsorption of hydrogen ions, which can ultimately lead to
acidosis
 DISORDERS OF THE ADRENAL GLAND
ADRENAL GLAND HYPOFUNCTION
Addison crisis
• Acute adrenal insufficiency, or Addison crisis, is
a life threatening event in which the physiologic
need for glucocorticoid and mineralocorticoid
hormones is greater than the available supply

• In most cases, acute adrenal insufficiency occurs

in response to a stressful event (e.g., surgery,
trauma, or severe infection.

DISORDERS OF THE ADRENAL GLAND

HYPERFUNCTION (Cushing's syndrome)
• Hypersecretion by the adrenal cortex may result in
excessive amounts of glucocorticoids, leading to
hypercortisolism (e.g., Cushing's syndrome),
hyperaldosteronism (excessive mineralocorticoid
production), or excessive androgen production
 DISORDERS OF THE ADRENAL GLAND
PERFUNCTION
• The client with Cushing's syndrome has alterations of nitrogen,
carbohydrate, and mineral metabolism. An increase in total
body fat results from slow turnover of plasma fatty acids, and a
redistribution of fat produces the typical body pattern of trancal
obesity, "buffalo hump," and "moon face“
• Increases in the breakdown of tissue protein and an increase in
urine nitrogen excretion also occur, resulting in decreased
muscle mass, atrophic (thin) skin, and bone density loss
• High levels of corticosteroids kill lymphocytes and shrink
organs containing lymphocytes, such as the liver, the spleen,
and the lymph nodes. Thus protection of the inflammatory and
immune responses is reduced .Reddish purple striae
("stretch marks") are often present on the abdomen,
upper thighs, and upper arms because of the
degradative effect of cortisol on collagen

DISORDERS OF THE ADRENAL GLAND

HYPERFUNCTION
• In most cases, increased androgen production
causes acne, hirsutism (increased hair growth),
and occasionally, clitoral hypertrophy
• Increased androgen production can also interrupt
the normal hormone feedback mechanism for the
ovary, decreasing the ovary's production of
estrogens and progesterone. Oligomenorrhea
(scant or infrequent menses) occurs as a result
 DISORDERS OF THE ADRENAL GLAND
HYPERFUNCTION
Hyperaldosteronism
• In clients with hyperaldosteronism, increased secretion
of aldosterone results in mineralocorticoid excess.
• Primary hyperaldosteronism (Conn's syndrome) is due
to excessive secretion of aldosterone from one or both
adrenal glands, which is most commonly caused by an
adenoma.
• In a person with secondary hyperaldosteronism, the
continuous excessive secretion of aldosterone is caused
by high levels of angiotensin II that are due to high
plasma renin activity. Causes of this renin activation
include renal hypoxemia and the use of thiazide
diuretics.

DISORDERS OF THE ADRENAL GLAND

HYPERFUNCTION
• Increased aldosterone levels affect the renal
tubules and cause sodium retention with
potassium and hydrogen ion excretion.

• Hypernatremia, hypokalemia, and metabolic

alkalosis result.

• Sodium retention increases blood and interstitial

fluid volume, which elevates blood pressure and
suppresses renin production. The elevated blood
pressure may cause strokes and renal damage.
 DISORDERS OF THE ADRENAL
GLAND HYPERFUNCTION
Pheochromocytoma
• Pheochromocytoma is a catecholamine-producing
tumor that arises in chromaffin cells
• Pheochromocytomas release the catecholamines
epinephrine and norepinephrine (NE). Excessive
epinephrine and NE stimulate alpha receptors and
beta receptors and can have wide-ranging adverse
effects mimicking stimulation of the sympathetic
division of the autonomic nervous system

Clinical features of Cushing’s syndrome

Signs and symptoms associated with Cushing’s
syndrome vary but frequently include:

Obesity in the torso with thinner arms and legs

Large rounded face (moon face)

Increased fat in the neck and shoulder area
Thin fragile skin that bruises easily and heals
slowly.
Purplish streaks that look like stretch marks on
their abdomen, thighs, and buttocks.
Muscle weakness
Osteoporosis
High blood pressure
Increased blood sugar
DISORDERS OF THE ADRENAL GLAND
HYPERFUNCTION
 Thyroid
gland
Thyroid
gland

A butterfly-shaped organ, the thyroid gland is located anterior to the

trachea, just inferior to the larynx . The medial region, called the
isthmus,
A is flanked organ,
butterfly-shaped by wing-shaped
the thyroid leftgland
and right lobes.anterior
is located Each oftothe
the
thyroid lobes
trachea, are embedded
just inferior with parathyroid
to the larynx . The medialglands,
region,primarily
called theon
their posterior
isthmus, surfaces.
is flanked The tissue ofleft
by wing-shaped theand
thyroid
right gland
lobes.isEach
composed
of the
mostly
thyroid of thyroid
lobes follicles. The
are embedded withfollicles are made
parathyroid up of
glands, a central
primarily on
cavityposterior
their filled with a sticky
surfaces. fluid
The called
tissue colloid.
of the Surrounded
thyroid by a wall
gland is composed
of epithelial
mostly follicle
of thyroid cells, the
follicles. Thecolloid is the
follicles arecenter
made ofup thyroid
of a central
hormone
cavity production,
filled and that
with a sticky fluidproduction is dependent
called colloid. on the
Surrounded by a wall
hormones’
of epithelialessential and unique
follicle cells, component:
the colloid iodine.of thyroid
is the center
hormone production, and that production is dependent on the
hormones’ essential and unique component: iodine.
 Loading…

Chemistry of Thyroid Hormones

Thyroid hormones are derivatives of the the amino acid tyrosine
bound covalently to iodine. The two principal thyroid hormones
are:
thyroxine (also known as T4 or L-3,5,3',5'-tetraiodothyronine)
triiodothyronine (T3 or L-3,5,3'-triiodothyronine)
A large majority of the thyroid hormone secreted from the
thyroid gland is T4, but T3 is the considerably more active The
principle carrier of thyroid hormones is thyroxine-binding
globulin, a glycoprotein synthesized in the liver. Two other
carriers of import are transthyrein and albumin.
 Loading…

SYNTHESIS AND RELEASE OF THYROID

HORMONES
Hormones are produced in the colloid when atoms of the mineral
iodine attach to a glycoprotein, called thyroglobulin, that is secreted
into the colloid by the follicle cells.
Binding of TSH to its receptors in the follicle cells of the thyroid
gland causes the cells to actively transport iodide ions (I–) across
their cell membrane, from the bloodstream into the cytosol. As a
result, the concentration of iodide ions “trapped” in the follicular
cells is many times higher than the concentration in the bloodstream.
Iodide ions then move to the lumen of the follicle cells that border the
colloid. There, theo ions undergo oxidation (their negatively charged
electrons are removed). The oxidation of two iodide ions (2 I–)
results in iodine (I2), which passes through the follicle cell membrane
into the colloid
results inThere,
colloid. iodinethe
(I2), which
ions passes
undergo through(their
oxidation the follicle cell membrane
negatively charged
into the colloid
electrons are removed). The oxidation of two iodide ions (2 I–)
results in iodine (I2), which passes through the follicle cell membrane
into the colloid

• Thyroid Follicle

• Thyroid Follicle

In the colloid, peroxidase enzymes link the iodine to the tyrosine

amino acids in thyroglobulin to produce two intermediaries: a
In the colloid, peroxidase enzymes link the iodine to the tyrosine
amino acids in thyroglobulin to produce two intermediaries: a
tyrosine attached to one iodine and a tyrosine attached to two
iodines. When one of each of these intermediaries is linked by
covalent bonds, the resulting compound is triiodothyronine (T3), a
thyroid hormone with three iodines. Much more commonly, two
copies of the second intermediary bond, forming
tetraiodothyronine, also known as thyroxine (T4), a thyroid
hormone with four iodines.
These hormones remain in the colloid center of the thyroid follicles
until TSH stimulates endocytosis of colloid back into the follicle
cells. There, lysosomal enzymes break apart the thyroglobulin
colloid, releasing free T3 and T4, which diffuse across the follicle
cell membrane and enter the bloodstream

Thyroid hormone regulates the basal metabolic rate and is

important for growth and development. Thyroid hormone is
particularly important for brain development, but hypothyroidism
(low thyroid hormone) also leads to decreased muscle mass and
skeletal development.

The main activity of the thyroid hormones T3 and T4 is to boost

the basal metabolic rates of proteins, fats, and carbohydrates as
well as vitamins.
Hyperthyroidism occurs when the thyroid gland produces
excessive amounts of thyroid hormones. The most common cause of
hyperthyroidism is Graves’ disease. Graves’ disease is an
autoimmune disorder in which abnormal antibodies produced by the
immune system stimulate the thyroid to secrete excessive quantities
of its hormones . Graves’ disease often results in the formation of an
enlarged thyroid (goiter) because of the continued stimulation to
produce more hormones. Loading…
Other causes of hyperthyroidism include:
- excess iodine, a key ingredient in T4 and T3
- thyroiditis, or inflammation of the thyroid, which causes T4 and T3
to leak out of the gland
- tumors of the ovaries or testes
- benign tumors of the thyroid or pituitary gland
- large amounts of tetraiodothyronine taken through dietary
supplements or medication
.

Besides a goiter, other signs and symptoms of hyperthyroidism

may include protruding eyes(exophthalmos), a condition that’s
related to Graves’ disease., heart palpitations, excessive sweating,
diarrhea, weight loss despite increased appetite, muscle weakness,
and unusual sensitivity to heat. Medications can be prescribed to
mitigate the symptoms of the disease
Hypothyroidism occurs when the thyroid gland produces
insufficient amounts of thyroid hormones. It can result from surgical
removal of the thyroid or dietary iodine deficiency. In cases of
iodine deficiency, the negative feedback loop controlling the release
of thyroid hormone causes repeated stimulation of the thyroid. This
results in the thyroid gland growing in size and producing a goiter
Other cause of hypothyroidism is Hashimoto’s thyroiditis. This is
another autoimmune disease, but in this case, the immune system
destroys the thyroid gland, producing hypothyroidism.
Hypothyroidism produces many signs and symptoms such as
abnormal weight gain, tiredness, baldness, cold intolerance, and
slow heart rate. Hypothyroidism is generally treated with thyroid
hormone replacement therapy.

Regulation of thyroid
hormones
The pituitary gland and hypothalamus both control the thyroid. When
thyroid hormone levels drop too low, the hypothalamus secretes TSH
Releasing Hormone (TRH), which alerts the pituitary to produce thyroid
stimulating hormone (TSH). The thyroid responds to this chain of events
by producing more hormones
Feedback loops are used extensively to regulate secretion of hormones in the
hypothalamic-pituitary axis. When large amounts of hormones thyroxine
and triiodothyronine (T4 and T3) are synthesized and secreted by thyroid
glands inhibition of TRH secretion by large loop leads to shut-off of TSH
secretion, which leads to shut-off of thyroid hormone secretion. As thyroid
hormone levels decrease below the threshold, negative feedback is relieved,
TRH secretion starts again, leading to TSH secretion.
Endo histology-
embryology-anatomy
Theory
 ENDOCRINE SYSTEM

OBJECTIVES
• Introduction
• Anatomy of Hypothalamus & Pituitary gland
• Development of Pituitary gland
• Microscopic study of Pituitary gland
 Endocrine Organs
• Purely endocrine organs
– Pituitary gland
– Pineal gland
– Thyroid gland
– Parathyroid glands
– Adrenal gland

• Endocrine cells in other organs

– Pancreas
– Thymus
– Gonads
– Hypothalamus
– DNES

Exocrine Endocrine

4
Endocrine vs. Exocrine

• Exocrine Glands
– Have ducts
– Secrete substance onto body surface
or into body cavity
– salivary, mammary, pancreas, liver

• Endocrine Glands
– No ducts
– Secrete product into blood stream
– Either stored in secretory cells
or in follicle surrounded by secretory cells
– Hormones travel to target organ to increase response

JUXTACRINE
 Hormone + Receptor

Intracellular receptors
Cell surface receptors

Mechanisms of hormone release

(a) Humoral: in response to changing levels of ions or nutrients in the blood
(b) Neural: stimulation by nerves
(c) Hormonal: stimulation received from other hormones

8
 Control of Endocrine Function
A. Positive Feedback mechanisms
B. Negative Feedback mechanisms

A. Positive Feedback

• Not common
• Classic example:
Action of OXYTOCIN on uterine
muscle during birth

10
 B. Negative Feedback
• Most common control mechanism
• Level of hormone in blood or body’s
return to homeostasis shuts off loop
at hypothalamus and pituitary

11

Hypothalamus &
Pituitary Gland

12
 Hypothalamus
 Paraventricular
 Supraoptic
 Infundibular
 Dorsomedial
 Ventromedial
 Preoptic
 Suprachiasmatic
 Posterior
 Anterior
 Preoptic
 Lateral
 Tuberomamitlary
 Lateral tuberal
13

Neurosecretory cells in Hypothalamus

• Neuronal connection to POSTERIOR pituitary

• Antidiuretic Hormone (ADH), Oxytocin
• Neurophysins

14
 Pituitary Gland

Pituitary Gland Development

Pituitary Gland

18
PituitaryPituitary
Circulation
Circulation

19

3 types hormones

20
Pituitary Gland Histology

Anterior pituitary
1.Pars distalis(75%)
Chromophil
 Acidophil
• Somatotropic
• Mamotropic
 Basophil
• Gonadotropic(FSH-LH)
• Corticotropic(POMC:ACTH-
LPH)
• Thyrotropic
Chromophob
 Stem&undifferentiated
cells 22
 Anterior pituitary

23

Pars Tuberalis

FSH LH
Pars Intermedia

MSH
POMC
Lipotropin

β endorphin

Cells and hormones of the anterior pituitary

LM Cell type Hormone Releasing (+) or
staining inhibiting (-) horm.
Acidophil Somatotrophs Growth hormone (GH) GHRH (+)
= somatotropin Somatostatin (-)
Acidophil Mammotrophs Prolactin (PRL) [Dopamine (-)
= lactotrophs estrogen (+)]
Basophil Thyrotrophs Thyroid stimulating TRH (+)
hormone (TSH)
= thyrotropin
Basophil Gonadotrophs Luteinizing hormone GnRH (+)
(LH), follicle
stimulating hormone
(FSH); both =
gonadotropin
Basophil Corticotrophs Adrenocorticotropin CRH (+)
(human) (ACTH) = corticotropin
 Control of Secretion in the Adenohypophysis

1. Feedback loop
2. Hormones from outside the feedback loop
- The proteins inhibin and activin Control release of FSH and LH
- Polypeptide ghrelin Stimulates GH
- Oxytocin Increases secretion of prolactin

3 STIMULUS

Hypothalamus
Releasing Hormone
(Release-Inhibiting Hormone)

Pituitary
Stimulating
Hormone

Gland
Target
Hormone 28
 Pituitary Adenomas

Posterior pituitary
• Unmyelinated axons
• Glial cells (Pituicyte)
• Neurosecretory bodies (Herring)

30
 Posterior Pituitary Hormones
• Manufactured in Hypothalamus, released from Post. Pit.
• Oxytocin from Paravetricular N.(Neurophysin I)
– Target = smooth ms. Uterus and Breast (&brain)
– Function = labor and delivery, milk ejection,(pair bonding)
• Vasopressin from Supraoptic N. (Neurophysin II)
– Target = kidneys
– Function = water reabsorption

31

• Releasing hormones of hypothalmus

Secreted like neurotransmitters from neuronal axons into capillaries and veins
to anterior pituitary (adenohypophysis)
TRH (thyroid releasing hormone) -----turns on TSH
CRH (corticotropin releasing hormone) -----turns on ACTH
GnRH (gonadotropin releasing hormone) ---turns on FSH and LH
PRF (prolactin releasing hormone) -----turns on PRL
GHRH (growth hormone releasing hormone) ----turns on GH

• Inhibiting hormones of hypothalmus

PIF (prolactin inhibiting factor) -----turns off PRL
GIH (growth hormone) inhibiting hormone ---turns off GH

32
 33

OBJECTIVES

• Anatomy of Adrenal glands

• Development of Adrenal glands
• Microscopic study of Adrenal glands
 Adrenal Glands

35

• Adrenal cortex
• Adrenal medulla
Adrenal Gland Development
ECTODERM

MESODERM

Adrenal Gland Circulation

1
2

3
4

38
 Adrenal Gland Histology

39

Adrenal Gland Histology

Zona Glumerolosa (15%)
MINERALOCORTICOIDS

Zona Fasiculata (75%) GLUCOCORTICOIDS

Zona Reticulata (10%) Androgens

40
 Adrenal cortex, human, H&E, LM

Humio Mizoguti, Kobe Univ Sch Med, slide 547

Adrenal cortex
• Zona glomerulosa
– Main hormone: Aldosterone (a mineralocorticoid).
– General function: Maintain blood electrolyte balance.
– Main control: Angiotensin II.

• Zona fasciculata
– Main hormone: Cortisol (a glucocorticoid).
– General function: Includes regulating glucose and fatty acid
metabolism, and response to stress.
– Main control: Pituitary ACTH.

• Zona reticularis
– Hormones: Some cortisol and androgens.
– Function and control: Similar to zona fasciculata.
Adrenal Gland cortex Histology

44
Medulla

45

The General Adaptation Syndrome(Medulla)

46
 Pancreas Anatomy

The Pancreas

Exocrine and endocrine cells

• Acinar cells (forming most of the pancreas)

– Exocrine function
– Secrete digestive enzymes

• Islet cells (of Langerhans)

– Endocrine function

48
 Pancreas Histology

49

Pancreatic islet endocrine cells

Alpha cells: secrete glucagon raises blood sugar mostly in periphery

Beta cells: secrete insulin lowers blood sugar central part (are more abundant)
Delta cells:secrete somatostatin inhibits glucagon
PP cells

50
 OBJECTIVES
• Anatomy of Thyroid gland
• Embryology of Thyroid gland
• Microscopic study of Thyroid gland
• Anatomy of Parathyroid glands
• Embryology of Parathyroid glands
• Microscopic study of Parathyroid glands

Thyroid Gland Anatomy

Thyroid Circulation & Innervation

Thyroid Development
 Thyroglossal Cysts

Microscopic structure
• The gland is surrounded by a thin
fibrous capsule.
• Septa from the capsule extend into
the gland & divide it into lobules.
• Lobules are made up of spherical
masses called follicles.
• Follicle has a cavity filled with
homogenous material called
colloid.
• Secrete 2 hormones: tri-
iodothyronine (T3) & tetra-
iodothyronine (T4) or thyroxine.
• Thyroid is composed of spherical follicles
– Follicle cells: produce thyroglobulin, the precursor of
thryoid hormone (thyroxin)
– Follicular cells are normally cuboidal in shape.
– Colloid lumen is of thyroglobulin
– Parafollicular “C” cells: produce calcitonin

57

Thyroid Histology

58
Thyroid Control : Negative Feedback

59

Thyroid Secretion
Iodine deficiency
 Parathyroid Anatomy

63

Parathyroid Development
 Parathyroid cells

• Chief cells produce PTH

– Parathyroid hormone, or
parathormone
– A small protein hormone
• Oxyphil cells (unknown
function)

65

Parathyroid Histology

66
 Parathyroid Histology

Parathormone

Parathormone

Osteoblast

Osteoclast stimulating
hormone(substance)

Osteoclast
Parathormone

Calcium regulation
Endo physiology
Theory
 TEHRAN UNIVERSITY OF MEDICAL SCIENCES
SCHOOL OF MEDICINE, DEPARTMENT OF PHYSIOLOGY

Introduction to Endocrinology

Dr Faghihi
Professor of physiology

OBJECTI VES
After studying this chapter, you should be able to describe:

Define the terms endocrine, paracrine, and autocrine.

Define the terms hormone, target cell, and receptor.

Describe the chemical structure and synthesis of hormones.

Understand the control mechanisms of hormone secretion.

Understand the role of hormone-binding proteins.

 OBJECTI VES

Explain the effects of secretion, degradation, and excretion

on plasma hormone concentrations.

Understand the regulation of number and sensitivity of

hormone receptors.

Compare plasma membrane and intracellular receptors.

Understand the major differences in mechanisms of action of

peptides, steroid, and thyroid hormones.

Coordination of Body Functions

by Chemical Messengers

Modes of Action
Can be categorized by the site of action relative to the site of secretion
- Endocrine
- Neurocrine
- Paracrine
- Autocrine
 1- Endocrine Signaling

Endocrine cell Target Cell

Hormone Travels In Bloodstream

2- Neuroendocrine Signaling
Neuron
Target Cell

NeuroHormone Travels In
Bloodstream

secreted by nerve endings, via axonal transport and then via blood
3- Paracrine Signaling
Target Cells

4- Autocrine Signaling
principal
endocrine glands
 Kidney

Heart

Stomach

Small intestine

Adipocytes

The multiple hormone systems play a key role in

regulating almost all body functions

including:
 metabolism,
 growth and development,
 homeostasis (water and electrolyte balance,
regulation of blood volume & pressure, heart rate,
body temperature, acid & base balance, maintenance
of muscle mass and bone mass)
 reproduction,
 and behavior
 Chemical Structure and
Synthesis of Hormones

Three general classes of hormones exist:

Proteins and polypeptides
Steroids
Derivatives of the amino acid tyrosine

Biosynthesis of Peptide Hormones

Protein Hormones Are Stored
in Secretory Vesicles Until Needed
Secretion of the hormones by exocytosis

Steroid Hormones

Pre vit D3 Vit D3

Steroid Like
 Biosynthesis of Steroid Hormones
ACTH
FSH
LH
cAMP

Cholesterol
ester

LDL Cholesterol Pregnenelone

HDL Cholesterol

Aldosterone Pregnenelone

Acetat Cortisole

Mitochondria
Progesterone

Adrenal Cortex Testosterone

Estradiol
Steroid Hormones Are Usually
Synthesized from Cholesterol Smooth Endoplasmic
and Are Not Stored Reticulum
Gonads

Amine Hormones are Derived from Tyrosine

Catecholamines

Thyroid Hormone

Catecholamines
 Hormone Secretion
 Hormone Secretion After a Stimulus, and
Duration of Action of Hormones

 Concentrations of Hormones in Blood

 Control of Hormone Secretion

- Neural Control
- Chronotropic control
- Feedback Control

Chronotropic control
Circadian Rhythm
Rhythms based on the 24 hours cycle (circa= about, dies= day).
e.g. cortisol secretion is maximal 4-8 a.m.

Infradin Rhythm
Those with a period longer than 24 hours. e.g. 28 day menstrual
cycle in woman, seasonal reproductive periods in animals.

Ultradin Rhythm
Those with a shorter period (pulsatile)
 Human menstural cycle
Infradian Rhythm

Circadian Rhythm
 Suprachiasmatic nucleus in the hypothalamus
control circadian rhythm

Feedback Control of Hormone Secretion

 j

h
 Transport of Hormones in the Blood

 Water-soluble hormones (peptides and

catecholamines)

 Lipid-soluble hormones (Steroid and thyroid

hormones)

Transport Proteins

 Non Specific
- Albumin & Prealbumin

 Specific
- Globulin
Thyroxine-Binding Globulin (TBG)
Sex Hormone Binding Globulin (SHBG)
Cortisol Binding Globulin (CBG)
Clearance of Hormones from the Blood

(1) binding with the tissues

(2) metabolic destruction by the tissues

(3) excretion by the liver into the bile

(4) excretion by the kidneys into the urine

Clearance of Hormones from the Blood

Metabolic clearance rate

= Rate of disappearance of
hormone from the plasma
/Concentration of hormone
 Target Cell Activation

 Target cell activation depends upon three factors

 Blood levels of the hormone

 Relative number of receptors on the target cell

 The affinity of those receptors for the hormone

Regulation of number and sensitivity of receptors

 Up-regulation – target cells form more

receptors in response to the hormone

 Down-regulation – target cells lose receptors

in response to the hormone
 Temporary Sequestration of the Receptor

Internalization
Recycling
e.g.: LDL receptor

Destruction of the Receptors by Lysosomes

 Receptor Inactivation

Inactivation of Signaling Protein

 Production of Inhibitory Protein

Decreased production of the receptors

locations of hormone receptors

 In the cell membrane
 In the cell cytoplasm
 In the cell nucleus
Intracellular Hormone Receptors and Activation of Genes

Downloaded from: StudentConsult (on 27 May 2006 01:16 PM)

© 2005 Elsevier

Nuclear Hormone Receptors and Activation of Gene

Hormones That Act Mainly on the Genetic Machinery of the Cell

glucocorticoids suppress
the transcription nuclear
factor κB, which reduce
inflammation.

Cell membrane Hormone Receptors

 Enzyme-Linked Hormone Receptors

Tyrosine kinase receptor

Figure 15-53a Molecular Biology of the Cell (© Garland Science 2008)

Tyrosine Kinase Associated Receptors (Cytokine Receptors)
(MAPK & PI3K)

Downloaded from: StudentConsult (on 27 May 2006 01:16 PM)

© 2005 Elsevier
G Protein–Linked Hormone Receptors
(Serpentine Receptors)

G-protein
Table 15-3 Molecular Biology of the Cell (© Garland Science 2008)
Adenylyl Cyclase–cAMP Second Messenger System

cAMP for Mediating Intracellular Hormonal Functions

Hormones That Use the Adenylyl Cyclase–cAMP Second Messenger System

Stimulatory G protein (Gs)

CRH, GHRH
FSH ,LH, TSH, ACTH
ADH (V2)
Calcitonin
Parathyroid hormone
 Glucagon
hCG
Catechol amines (β receptors)

 Inhibitory G protein (Gi)

 Dopamine
 Somatostatin

Cell Membrane Phospholipid Second Messenger System

GnRH

GHRH

TRH

ADH(V1)

Oxytocin
Calcium-Calmodulin Second Messenger System
Measurement of Hormone Concentrations in
the Blood

Radioimmunoassay

Enzyme-Linked Immunosorbent Assay (ELISA)

Adenohypophysis
 session

Dr Faghihi
Professor of physiology

Objectives
After studying this chapter, you should be able to define:

➢ Physiology of bone.

➢ Bone formation and resorption.

➢ Homeostasis of calcium and phosphate concentrations, and how

this is accomplished.

➢ Mechanisms of calcium and phosphate absorption and excretion.

➢ Major hormones (parathyroid H. Vit D and calcitonin) regulate

calcium and phosphate homeostasis and their sites of synthesis as
well as targets of their action.

➢ Pathophysiology of Parathyroid Hormone, Vitamin D, and Bone

 Bone Physio
BoneTissue is composed d
of ogqmatg.gsforms
f
Bone tissue
similar
under tocartilage
in Caphosphateppt odoesnot
stretchunder

i
osteoid
form
bearthepres
sure stress

➢ Organic matrix When boneformation

against
is
tension se stress
complete it is resistant

• 90 – 95% Collagen fibers Osteoid

• 1 – 2% NonCollagen Proteins
• Ground substance
➢ Bone salt
hydroxyapatite
Ca10(PO4)6(OH)2

➢ Hydroxyapatite Does Not Precipitate in ECF

The levels of pyrophosphate in bone are regulated by:

➢ Tissuenonspecific alkaline phosphatase (TNAP)

➢ Nucleotide pyrophosphatase phosphodiesterase1

(NPP1) TNAP breaksdown pyrophosphate d thus Ises it
levels
NPPI Gses production
of pyrophosphate
➢ Ankylosis protein (ANK) Anik atfrominsidethecell
trysporgpjgpq.ph

balance
hw these is imp forppt ofCa
➢ Precipitation of Calcium Under Abnormal Conditions
 when level of Ca phos over comespyrophosphate
levels in cells tissue on when cells tissue
show neurosis then
ppt occurs

Calcium Exchange Between Bone and ECF

Deposition and Resorption of Bone

Remodeling of Bone
b w bone beef there is constant co Phosp
exchange
this exchange is hormone regulated

We have constant bone resorption formation

se it is done by osteoblast
notuosteoplasts

Osteocyte osteoblast cells bone

roy
d cells
are
Yconnected to as
each other by
june
gap Bone Cells ostopblasts

afterboneformation
these are entrapped
withinosteoid
osteocyte
synthesised
osteoblas
by
Meinhof osteoclast faces home has at
pump
a chloride cha
n nel
these acids secreted to bones
secrete acid
dies crystals citric acid
f lactic au

3 weeks
after lysosomal
it makes ens that
a lacuna bone
Em
diameter
digests
matrix

Osteoclast memes has calcitonin receptor

he binds to iltrecepto
via Gs
inhibits osteoclast
inhibits bone
resorption
activity
q rank receptor
RANK ligand Finds tilt
PG É's RANK
latter ctivates

boneryorption
prevents inhibited
its
effect by
calcitonin
RANKL is a member of the tumor necrosis factor (TNF) cytokine family
OPG; from the Latin osteo [bone] + protegere [to protect])
 blast
soy
ET

Each new area of bone deposited is called an osteon and

the haversian canal remains of the original cavity

al we have nub
Incan Dvolkman's carnal
heconnectionbow 2
 Osteocytes and their
Osteon cytoplasmic connections
the haversian canal
through which the
blood vessels run

ECF
 blase

L Get bloodvessel

1
junction bone So
fluid
blast cyte connect to each other make osteocytic
memes isolate hlood

99 t
J it fd.la cystaform
in is in

I less than is jointed

crystallised
hydroxyapatite crystal

exchangable Ca in bone
fluidprovides rapid buffer
mechanism co levels in plasma
for regulating
bone
fluid plasma

crystallised
ca
É plasma

Bone Deposition and Absorption Are

Normally in Equilibrium
hone mass is in various stagesgave
diff
osteoblast 9
osteoblast osteoclast
osteoclast

Bone
Mass
➢ Value of Bone Remodeling

➢ Stress on Bone Deposition

➢ Repair of a Fracture Activates

Osteoblasts
901 of it Non how ie intracellular
t d
entrance ca levels are
regulatedby hormones

functional ca 9.5 10
ca in plasma mg de only to i
Iggy
e functional
Total quantity of inorganic phosphorus in the plasma is about
3-5 mg/dl

821 of phosphate is free functional

Cal phosphate make a complex
no function
theyhave

mewls excitability as an extracellular

regulation of
signal Ig sensitive hypocalcemic
condition
very
to Ca levels 6 excitable cell discharge
in
spontaneously
slight changes
co level have diverse t
m cells contract
effects have
we
tetany
f E
laryngealtetany
is v
dangerous

ca is absorbed intestine it occurs

ingested from
in presence
of VDact
PIM vit D act stimulate breaks in kid
Stimulate how resorption

late portion DCT 17 there is Pete P when

of
Ca level ie low in

body
PTH opens Ca channels in mesh open
in apical they
a
pump halo lat numb ing ca resorption
Hypocalcemic tetany in the hand, called carpopedal spasm
 Absorption and Excretion of Calcium

500 mg

500 mg

Calbindin ca
moves bindingprot • 70% of calcium is reabsorbed from
Ca from apical to basolatmems proximal tubule, 20% from thick ascending
limb and 10% from collecting tubule and late
gh la level of Ca in thickascending
reabsorhtion distal tubule
Ace • Calcium cannot be reabsorbed from
Imh collecting duct, it’s excreted
G vice versa • Calcium reabsorption from collecting
tubule and late distal tubule is dependent on
calcium plasma levels
• When [Ca] decreases à PTH increases à
PTH binds to the receptor complexed Gs
protein in basolateral membrane of cells (in
late distal and collecting tubules) à cAMP in
these cells increases à Ca channels in apical
membrane open and Ca pumps in basolateral
membrane activated à calcium enters to the
cell à calcium pumped into interstitial fluid
Absorption and Excretion of Phosphate

Digested phosphate
can easily be absorbedfrom
intestine but act Ds Asee this absorption

Phosphate transport along the nephron

is excreted in urine reabsorption phosphate
Phosphate
PCTdepends on phosphatesePIMlevels g
from
PH binds to its receptors in proximaltubules
cases reabsorption
of phosphate
 Vitamin D
• In basal keratinocyte, 7-dehydrocholesterol is converted to vit D3
under effect of UV light
• D3 enters blood stream and binds to vit D binding proteins in the liver
• Dietary vit D2 and D3 are absorbed from intestine by enterocytes, so
Vit D can reach to the liver by 2 ways:
• 1. chylomicron form in lymph vessels that drain to blood
• 2. directly by the portal blood
• When Vit D enters the liver, it’s converted to 25-hydroxyvitamin D by
action of 25- hydroxylase
• 25-hydroxyvitamin D (25-hydroxycholecalciferol) leaves the liver and
enters blood stream
• In proximal tubules of nephron, there’s 1 alpha-hydroxylase that
converts 25-hydroxyvitamin D to 1.25-dihydroxyvitamin D which is the
active form of vitamin D.
• 1.25-dihydroxyvitamin D is a hormone that has effects on gut, bone
and kidneys
• This hormone regulates its own formation by negative feedback, it
inhibits 1 alpha hydroxylase and activates 24-hydroxylase
Formation of 1,25(OH)D in the Kidneys and Its Control by PTH, Ca and Other Factors
I hydroxylase is

Ifactivated by
PTH low Ca
low phosphate
4
sactivateson
oit D
this Vit Dact
has main effect
on intestine but
also
affects
Kida
bone

is in nucleus
water
“Hormonal” Effect of Vitamin D to Promote Intestinal Calcium Absorption

MNyat.VE
 Absorption of calcium from luminal side of intestinal into the extracellular fluid

plasma membrane calcium ATPase (PMCA)

Regulation of
vitamin D activation

production a secretion of
hormones is controlled
but production of wit Dy
ie
not controlled leap in skin
activation of witDy is
aly
controlled
ainging
 U in dorsal
y side
of
Parathyroid Glands thyroidglar

➢ Tiny glands
embedded in the
posterior aspect of
the thyroid
➢ Cells are arranged
in cords containing
oxyphil and chief
cells

Figure 15.10a
 kidney intestine
activated

a sesca absorption GsesCa

in bone f sesca
reabsorption absorption
 Effects of Ca on
parathyroid cell Msgcamein a Gq Mj
Hses exocytosisofPTH
inhibits
perlevels Q
Ila Gi

D activate per
production 6
PMsecretion

PTH
release

peifaved
asvesicles

Control of PTH
Secretion by Ca i

Ion Concentration

q
 Effect of activated Vit D on PTH synthesis

has
effecton
Parathyroidcells
I see PTH

TH LD ses ca t Usesphosphate levels

➢Effect of PTH on Ca and P Concentrations in the ECF

 Effects of PTH on the Kidney

➢ Activate Vit D
Vitamin D also increases calcium
and phosphate reabsorption by the

o
epithelial cells of the renal tubules

➢ Ca reabsorption n

➢ PO4 reabsorption d
tubules
in kidney in proximal PTHbinds
here are pithreceptors
here inhibitsphosphatereabsorption

PTH increases reabsorption of magnesium ions and hydrogen ions Pete triesto a
seiinti.se ia
while it decreases reabsorption of sodium, potassium, and amino acid ions level thus d see
phosphate levels

receptor on osteoblast
activates fast exchange
Effects of PTH on the Bone
➢ Osteocytic osteolysis
fittFresorption
04 91 5
➢ Osteoclastic osteolysis
activated by PTH but Plm
osteoclast
has no receptor ORGosteoclastic
➢ late effect:
osteolysis
o
Enhance both osteoblastic
and osteoclastic activity
9 see
fherhone resorption
9 ses
bone formation also
 PTH binds to receptors on the adjacent osteoblasts, causing them
to release cytokines, including osteoprotegerin ligand (OPGL), which
is also called RANK ligand

Toblast
give
Ifceostolast
to makeRAKI
(RANKL)

hasreceptor
on osteoclast
activatesit
thus

Vitamin D plays important roles in bone resorption and

bone deposition.
Administration of extreme quantities of vitamin D
causes resorption of bone.

Vitamin D in smaller quantities promotes bone

calcification. it enhances the mineralization of bone.
 Osteoblasts also produce OPG,
called osteoclastogenesis inhibitory factor (OCIF),
inhibits OPGL (RANKL),
so inhibits bone resorption

inhibits boneresorption

produced
3
after
weeks

Novel drugs that mimic the

action of OPG
O by blocking the
interaction of RANKL with its
receptor appear to be useful for
treating bone loss in
postmenopausal women and in
some patients with bone cancer.
 Ca level go up
calcitonin is it
produced
L s es Ca level

O
d
9 see bone
formation g
ca levelin blood d see
 Effects of PTH & Cacitonin on the Bone
shows effects bout
H kidney
smalloff
d Ses ca Phos reabsorption

Effects of Calcitonin on the Bone

➢ Osteocytic osteolysis

➢ Osteoclastic osteolysis

➢ long period:
Reduced osteoclastic and osteoblastic activity
bone resorption d see
me home formation f see
Calcium Homeostasis
 Pathophysiology of Parathyroid Hormone, Vitamin D, and Bone Disease
➢ Hypoparathyroidis in this Pete Dsee discharge
excitable
ofsome
Cayyangppontaneous

tetany
➢ Pseudohypoparathyroidism laryngealspasm

pilereceptors signaling pathway has problem

Le Pla is okay
➢ Primary Hyperparathyroidism
hedue to adenoma tumor cancer pen ons y bone resorption

➢ Secondary Hyperparathyroidism
Bone Disease

PH gland is okay mtvitDdefisenggy

Effects of Hypercalcemia
➢ Rickets Caused by Vitamin
Parathyroid Poisoning and D Deficiency
Metastatic Calcification
Tt n names
wit Ddef
bId of Kidney Stones
n
of Formation
Plasma Concentrations of Calcium and Phosphate
➢ Osteomalacia-"Adult Rickets."
Decrease in Rickets
adult rickets d causesdisess
VitDactivated in kidney it Rickets Weakens the Bones
➢ Osteoporosis-Decreased Bone Matrix
Osteomalacia and Rickets Caused by Renal Disease
Tetany in Rickets
o_0
lowbone density
➢ Osteopetrosis Msed bone matrix
bonedensity
nigh

Osteoporosis—Decreased Bone Matrix

In osteoporosis the osteoblastic activity in the bone is
usually less than Normal

The many common causes of osteoporosis are:

(1) lack of physical stress on the bones
(2) Malnutrition
(3) lack of vitamin C
(4) postmenopausal lack of estrogen
(5) old age
(6) Cushing’s syndrome
(7) many diseases of deficiency of protein metabolism can
cause osteoporosis
Adrenal glands
The two adrenal glands lie at the superior poles of the two kidneys.

The adrenal medulla, is functionally related to the sympathetic nervous system; it secretes the
hormones epinephrine and norepinephrine in response to sympathetic stimulation. these hormones
cause the same effects as direct stimulation of the sympathetic nerves in all parts of the body.

The adrenal cortex secretes corticosteroids. These hormones are all synthesized from cholesterol they
have different but very important functions

CORTICOSTEROIDS: MINERALOCORTICOIDS, GLUCOCORTICOIDS, AND ANDROGENS

Two major types of adrenocortical hormones, the mineralocorticoids and the glucocorticoids,
are secreted by the adrenal cortex.
In addition to these hormones, small amounts of sex hormones are secreted, especially
androgenic hormones, which exhibit the same effects in the body as the male sex hormone
testosterone.
The mineralocorticoids (aldosterone) affect the electrolytes (the “minerals”) of the extracellular
fluids, especially sodium and potassium.
The glucocorticoids (cortisol) have important effects that increase blood glucose concentration.

1. The zona glomerulosa (15%)

○ a thin layer of cells, lies just underneath the capsule.
○ the only cells capable to secrete aldosterone because they contain aldosterone synthase.
○ The secretion is controlled by the extracellular fluid concentrations of angiotensin II and
potassium, both of which stimulate aldosterone secretion.

2. The zona fasciculata (75%)

○ the middle and widest zone
○ secretes the glucocorticoids cortisol and corticosterone, adrenal androgens and estrogens.
○ The secretion is controlled by adrenocorticotropic hormone (ACTH).

3. The zona reticularis (10%)

○ the inner zone of the cortex
○ secretes the adrenal androgens dehydroepiandrosterone and androstenedione, estrogens
and some glucocorticoids.
○ ACTH also regulates secretion of these cells, although other factors such as cortical
androgen stimulating hormone, released from the pituitary, may also be involved.

ü angiotensin II that increases the secretion of aldosterone and cause hypertrophy of the
zona glomerulosa have no effect on the other two zones.
ü Similarly, factors such as ACTH that increase secretion of cortisol and adrenal androgens
and cause hypertrophy of the zona fasciculata and zona reticularis have little effect on the
zona glomerulosa.

Adrenocortical Hormones Are Steroids Derived from Cholesterol.

Ø All human steroid hormones are synthesized from cholesterol.
Ø 80% of the cholesterol used for steroid synthesis is provided LDLs in the plasma.
Ø The LDLs diffuse from the plasma into the interstitial fluid and attach to specific receptors
contained in structures called coated pits on the adrenocortical cell membranes.

Adrenocortical Hormones Are Bound to Plasma Proteins.

v the cortisol in the plasma binds to cortisol-binding globulin or transcortin and to
albumin.
v This high degree of binding to plasma proteins slows the elimination of cortisol from
the plasma, so it has long half life.
v Only about 60% of circulating aldosterone combines with the plasma proteins, so
about 40% is in the free form; as a result, aldosterone has a relatively short half-life
minutes.
v These hormones are transported throughout the extracellular fluid compartment in
both the combined and free forms

Adrenocortical Hormones Are Metabolized in the Liver.

§ The adrenal steroids are degraded mainly in the liver and are conjugated especially to
glucuronic acid and to sulfates.
§ These substances are inactive.
§ About 25 percent of these conjugates are excreted in the bile and then in the feces, and
the remaining conjugates enter the circulation, are highly soluble in the plasma, and are
therefore filtered by the kidneys and excreted in the urine.
§ Diseases of the liver depress the rate of inactivation of adrenocortical hormones, and
kidney diseases reduce the excretion of the inactive conjugates.

FUNCTIONS OF THE MINERALOCORTICOIDS— ALDOSTERONE

ü Aldosterone Is the Major Mineralocorticoid Secreted by the Adrenals.
ü Aldosterone Increases Renal Tubular Reabsorption of Sodium and Secretion of
Potassium.
ü Excess Aldosterone Increases ECF Volume and Arterial Pressure But Has Only a
Small Effect on Plasma Sodium Concentration
ü Excess Aldosterone Causes Hypokalemia and Muscle Weakness; Aldosterone
Deficiency Causes Hyperkalemia and Cardiac Toxicity
ü Excess Aldosterone Increases Tubular Hydrogen Ion Secretion and Causes
Alkalosis
ü ALDOSTERONE STIMULATES SODIUM AND POTASSIUM TRANSPORT IN SWEAT
GLANDS, SALIVARY GLANDS, AND INTESTINAL EPITHELIAL CELLS

REGULATION OF ALDOSTERONE SECRETION

Regulation of aldosterone secretion by the zona glomerulosa cells is independent of regulation
of cortisol and androgen secretion by the zona fasciculata and zona reticularis.

The following factors play essential roles in regulation of aldosterone:

1. Increased potassium ion concentration in ECF greatly increases aldosterone secretion.
2. Increased angiotensin II concentration in ECF greatly increases aldosterone secretion.
3. Increased sodium ion concentration in ECF very slightly decreases aldosterone secretion.
4. ACTH from the anterior pituitary gland has little effect in controlling the rate of secretion

EFFECTS OF CORTISOL ON CARBOHYDRATE METABOLISM

○ Stimulation of Gluconeogenesis.
○ Elevates Blood Glucose Concentration and “Adrenal Diabetes.”

EFFECTS OF CORTISOL ON PROTEIN METABOLISM

Ø Cortisol Increases Liver and Plasma Proteins.
Ø Increased Blood Amino Acids, Diminished Transport of Amino Acids Into Extrahepatic
Cells, and Enhanced Transport Into Hepatic Cells.

EFFECTS OF CORTISOL ON FAT METABOLISM

• promotes mobilization of fatty acids from adipose tissue.
• Excess Cortisol Causes Obesity

CORTISOL IS IMPORTANT IN RESISTING STRESS AND INFLAMMATION

Anti-inflammatory Effects of High Levels of Cortisol
Five main stages of inflammation occur:
(1) release from the damaged tissue cells of chemicals such as histamine, bradykinin,
proteolytic enzymes, prostaglandins, and leukotrienes that activate the inflammation
process
(2) an increase in blood flow in the inflamed area caused by some of the released products
from the tissues
(3) leakage of large quantities of almost pure plasma out of the capillaries into the damaged
areas because of increased capillary permeability, followed by clotting of the tissue fluid,
thus causing a nonpitting type of edema;
(4) infiltration of the area by leukocytes
(5) after days or weeks, ingrowth of fibrous tissue that often helps in the healing process.

Cortisol Prevents the Development of Inflammation by Stabilizing Lysosomes and by Other

Effects.
Cortisol has the following effects in preventing inflammation:
1. Cortisol stabilizes lysosomal membranes.
2. Cortisol decreases permeability of the capillaries
3. Cortisol decreases both migration of white blood cells into the inflamed area and
phagocytosis of the damaged cells.
4. Cortisol suppresses the immune system, causing lymphocyte reproduction to decrease
markedly
5. Cortisol attenuates fever mainly because it reduces release of interleukin-1 from white
blood cells, which is one of the principal excitants to the hypothalamic temperature control
system. The decreased temperature in turn reduces the degree of vasodilation.
Thus, cortisol has an almost global effect in reducing all aspects of the inflammatory
process.

Cortisol Causes Resolution of Inflammation

Cortisol Blocks the Inflammatory Response to Allergic Reactions.

Effect on Blood Cells and on Immunity in Infectious Diseases.

Cortisol increases the production of red blood cells
When excess cortisol is secreted by the adrenal glands, polycythemia often results, and
conversely, when the adrenal glands secrete no cortisol, anemia often results.

Pain stimuli caused by physical stress or tissue damage are transmitted first upward through
the brain stem and eventually to the median eminence of the hypothalamus, as shown in
Figure 78-7. Here CRF is secreted into the hypophysial portal system. Within minutes the
entire control sequence leads to large quantities of cortisol in the blood.
Mental stress can cause an equally rapid increase in ACTH secretion. This increase is
believed to result from increased activity in the limbic system, especially in the region of the
amygdala and hippocampus, both of which then transmit signals to the posterior medial
hypothalamus.

Inhibitory Effect of Cortisol on the Hypothalamus and on the Anterior Pituitary to Decrease
ACTH Secretion.
Cortisol has direct negative feedback effects on (1) the hypothalamus to decrease the formation
of CRF and (2) the anterior pituitary gland to decrease the formation of ACTH. Both of these
feedbacks help regulate the plasma concentration of cortisol. That is, whenever the cortisol
concentration becomes too great, the feedbacks automatically reduce the ACTH toward a
normal control level.

Circadian Rhythm of Glucocorticoid Secretion

the plasma cortisol level ranges between a high of about 20 µg/dl an hour before arising in the
morning and a low of about 5 µg/dl around midnight.
Pancreas gland
The pancreas, in addition to its digestive functions, secretes two important hormones, insulin
and glucagon, that are crucial for normal regulation of glucose, lipid, and protein metabolism.
Although the pancreas secretes other hormones, such as amylin, somatostatin, and pancreatic
polypeptide, their functions are not as well established. The main purpose of this chapter is to
discuss the physiological roles of insulin and glucagon and the pathophysiology of diseases,
especially diabetes mellitus, caused by abnormal secretion or activity of these hormones.

Physiological Anatomy of the Pancreas

The pancreas is composed of two major types of tissues:
(1) the acini, which secrete digestive juices into the duodenum
(2) the islets of Langerhans, which secrete insulin and glucagon directly into the blood.

Each islet is organized around small capillaries, into which its cells secrete their hormones. The
islets contain three major types of cells—alpha, beta, and delta cells—that are distinguished
from one another by their morphological and staining characteristics.

ü The beta cells (60%) lie in the middle of islet and secrete insulin and amylin, a hormone
secreted in parallel with insulin, its function is not well understood.
ü The alpha cells (25%) secrete glucagon
ü the delta cells, (10%) secrete somatostatin.

In addition, the PP cell, is present in small numbers in the islets and secretes a hormone of
uncertain function called pancreatic polypeptide.

There's cell-to-cell communication and direct control of secretion of some of the hormones by
the other hormones.
insulin inhibits glucagon secretion, amylin inhibits insulin secretion, and somatostatin inhibits
the secretion of both insulin and glucagon.

INSULIN CHEMISTRY AND SYNTHESIS

Ø Insulin is a small protein.
Ø Human insulin is composed of two amino acid chains, connected to each other
by disulfide linkages. When the two amino acid chains are split apart, the
functional activity of the insulin is lost.
Ø Insulin is synthesized in beta cells, beginning with translation of the insulin
RNA by ribosomes attached to the endoplasmic reticulum to form pre-
proinsulin, but it is then cleaved in the RER to form a proinsulin consisting of
three chains of peptides, A, B, and C. Proinsulin is then cleaved in the Golgi
apparatus to form insulin, which is composed of the A and B chains connected
by disulfide linkages, and the C chain peptide, called connecting peptide (C
peptide).
Ø The insulin and C peptide are packaged in the secretory granules and secreted
in equimolar amounts.
Ø The proinsulin and C peptide have no insulin activity.
Ø However, C peptide binds to G protein–coupled membrane receptor, and
elicits activation of at least two enzyme systems, sodium-potassium ATPase
and endothelial nitric oxide synthase.

ACTIVATION OF TARGET CELL RECEPTORS BY INSULIN AND THE RESULTING CELLULAR EFFECTS
insulin first binds to a membrane receptor protein
The insulin receptor is a combination of four subunits bound together by disulfide linkages: two
alpha subunits that lie outside the cell membrane and two beta subunits that penetrate
through the membrane.
The insulin binds with the alpha subunits on the outside of the cell, but because of the linkages
with the beta subunits, they become autophosphorylated.
Thus, the insulin receptor is an example of an enzyme-linked receptor.
Autophosphorylation of the beta subunits activates tyrosine kinase, which in turn causes
phosphorylation of multiple other intracellular enzymes, including a group called insulin-
receptor substrates (IRS).
Different types of IRS (e.g., IRS-1, IRS-2, and IRS-3) are expressed in different tissues.
In this way, insulin directs the intracellular metabolic machinery to produce the desired effects
on carbohydrate, fat, and protein metabolism.

EFFECT OF INSULIN ON CARBOHYDRATE METABOLISM

ü Insulin Promotes Muscle Glucose Uptake and Metabolism
ü Storage of Glycogen in Muscle
ü Quantitative Effect of Insulin to Facilitate Glucose Transport Through the
Muscle Cell Membrane
ü Insulin Promotes Liver Uptake, Storage, and Use of Glucose
ü Glucose Is Released From the Liver Between Meals
ü Insulin Promotes Conversion of Excess Glucose Into Fatty Acids and Inhibits
Gluconeogenesis in the Liver.

Insulin has no effect on Glucose Uptake and Usage by the Brain

EFFECT OF INSULIN ON FAT METABOLISM

Ø Insulin stimulates Fat Synthesis and Storage
Ø Insulin Deficiency Increases Use of Fat for Energy
Ø Insulin Deficiency Causes Lipolysis of Storage Fat and Release of Free Fatty Acids.
Ø Insulin Deficiency Increases Plasma Cholesterol and Phospholipid Concentrations
Ø Excess Usage of Fats During Insulin Deficiency Causes Ketosis and Acidosis.

EFFECT OF INSULIN ON PROTEIN METABOLISM AND GROWTH

v Insulin Promotes Protein Synthesis and Storage
v Insulin Deficiency Causes Protein Depletion and Increased Plasma Amino Acids
v Insulin and Growth Hormone Interact Synergistically to Promote Growth

GLUCAGON AND ITS FUNCTIONS

Ø Glucagon, a hormone secreted by the alpha cells of the islets of Langerhans
Ø has functions opposed to those of insulin.
Ø increase the blood glucose concentration

Glucagon EFFECTS ON GLUCOSE METABOLISM

(1) breakdown of liver glycogen (glycogenolysis)
(2) increased gluconeogenesis in the liver.
Both of these effects greatly enhance the availability of glucose to the other organs of
the body.

Glucagon in high concentrations:

(1) enhances the strength of the heart
(2) increases blood flow in some tissues, especially the kidneys
(3) enhances bile secretion
(4) inhibits gastric acid secretion.
These effects of glucagon are probably of much less importance in the normal
function of the body compared with its effects on glucose.

Diabetes Mellitus
There are two general types of diabetes mellitus:
1. Type 1 diabetes, also called insulin-dependent diabetes mellitus, is caused by lack of
insulin secretion.
2. Type 2 diabetes, also called non–insulin-dependent diabetes mellitus, is initially
caused by decreased sensitivity of target tissues to the metabolic effect of insulin.
(insulin resistance).

As a result, blood glucose concentration increases, cell utilization of glucose decreases,

and utilization of fats and proteins increases.
Thyroid gland
The thyroid gland, located below the larynx on each side of and anterior to the
trachea.
The thyroid secretes thyroxine (T4) and triiodothyronine (T3).
Both of these hormones increase the metabolic rate of the body.
Thyroid secretion is controlled by thyroid stimulating hormone (TSH) secreted by
the anterior pituitary gland.

SYNTHESIS AND SECRETION OF THE THYROID METABOLIC HORMONES

thyroid gland secretes thyroxine T4 more than triiodothyronine T3.
almost all the thyroxine T4 is converted to triiodothyronine T3 in the tissues,
so both are functionally important, but they differ in rapidity and intensity
of action.
Triiodothyronine T3 is more potent as thyroxine T4
T3 is present in the blood in smaller quantities and persists for a shorter
time compared with T4.

PHYSIOLOGICAL ANATOMY OF THE THYROID GLAND

thyroid gland is composed of large numbers of follicles filled with colloid
and lined with cuboidal epithelial cells that secrete into the follicles.
The major constituent of colloid is thyroglobulin, which contains the thyroid
hormones.
Once the secretion has entered the follicles, it must be absorbed back into
the blood before it can function in the body.

IODIDE PUMP—THE SODIUM-IODIDE SYMPORTER (IODIDE TRAPPING)

The first stage in the formation of thyroid hormones is transport of
iodides from the blood into the thyroid glandular cells and follicles.
The basal membrane of the thyroid cell has sodium-iodide symporter (1
iodide in, 2 sodium in) which pumps the iodide actively to the interior of
the cell.
The energy for transporting iodide against a concentration gradient
comes from the sodium-potassium ATPase pump which pumps sodium
out of the cell, thereby establishing a low intracellular sodium
concentration and a gradient for facilitated diffusion of sodium into the
cell.
This process of concentrating the iodide in the cell is called iodide
trapping.
The rate of iodide trapping by the thyroid is influenced by the
concentration of TSH

Formation and Secretion of Thyroglobulin by the Thyroid Cells.

The RER and Golgi apparatus synthesize and secrete thyroglobulin into
the follicles.
Each molecule of thyroglobulin tyrosine amino acids that combine with
iodine to form the thyroid hormones.
T3 and T4 hormones remain part of the thyroglobulin during synthesis
of the thyroid hormones and even as stored hormones in the follicular
colloid

Oxidation of the Iodide Ion.

first step in the formation of thyroid hormones is conversion of
iodide ions to an oxidized form of iodine which is then capable
of combining directly with tyrosine.
This oxidation is promoted by the enzyme peroxidase and
hydrogen peroxide.
The peroxidase is either located in the apical membrane of the
cell or attached to it, thus providing the oxidized iodine at
exactly the point in the cell where the thyroglobulin molecule
issues.

Iodination of Tyrosine and Formation of the Thyroid Hormones—

“Organification” of Thyroglobulin.
The binding of iodine with the thyroglobulin molecule is called
organification of the thyroglobulin.
Oxidized iodine will bind directly but slowly with tyrosine.
In thyroid cells, the oxidized iodine is associated with thyroid
peroxidase enzyme.

Storage of Thyroglobulin.
After synthesis of the thyroid hormones, each thyroglobulin
molecule contains a lot of thyroxine molecules and a few
triiodothyronine molecules.
The thyroid gland stores thyroid hormones to supply the body
with its requirements for 2 to 3 months.
Therefore, when synthesis of thyroid hormone decreases, the
effects are observed after several months

RELEASE OF THYROXINE AND TRIIODOTHYRONINE FROM THE

THYROID GLAND
thyroxine and triiodothyronine are cleaved from the thyroglobulin
molecule, and then these free hormones are released in the blood.

1. The apical surface of thyroid cells sends extensions around small

portions of the colloid to form pinocytic vesicles that enter the
apex of the thyroid cell.
2. Then lysosomes in the cell cytoplasm fuse with these vesicles to
form digestive vesicles containing proteases that digest the
thyroglobulin molecules and release thyroxine and
triiodothyronine in free form
3. T3 and T4 then diffuse through the base of the thyroid cell into
the surrounding capillaries.

THYROID HORMONES INCREASE TRANSCRIPTION OF LARGE NUMBERS

OF GENES
thyroid hormone activates nuclear transcription of large numbers of
genes for protein synthesis. The net result is an increase in functional
activity throughout the body.

Thyroid Hormones Activate Nuclear Receptors.

v The thyroid hormone receptors are either attached to the DNA
strands or located in proximity to them.
v The thyroid hormone receptor forms a heterodimer with retinoid
X receptor (RXR) on the DNA.
v After binding with thyroid hormone, the receptors become
activated and initiate the transcription process.
v However, not all the proteins are increased by similar percentages
v the actions of thyroid hormone result from the enzymatic and
other functions of these new proteins.

↑ Cardiac output ↑ Tissue blood flow ↑ Heart rate ↑ Heart

strength ↑ Respiration ↑ Cardiac output ↑ Tissue blood flow ↑
Heart rate ↑ Heart strength ↑ Respiration ↑ Mitochondria ↑ Na+-
K+-ATPase ↑ O2 consumption ↑ Glucose absorption ↑
Gluconeogenesis ↑ Glycogenolysis ↑ Lipolysis ↑ Protein synthesis
↑ BMR

THYROID HORMONES INCREASE CELLULAR METABOLIC ACTIVITY:

Ø Thyroid Hormones Increase the Number and Activity of
Mitochondria.
Ø Thyroid Hormones Increase Active Transport of Ions Through Cell
Membranes

EFFECTS OF THYROID HORMONE ON SPECIFIC BODY FUNCTIONS:

Stimulation of Carbohydrate Metabolism

Stimulation of Fat Metabolism: lipids are mobilized rapidly from the fat
tissue, which decreases the fat stores

Increased Requirement for Vitamins: Because thyroid hormone

increases the quantities of enzymes and because vitamins are essential
parts of some of the enzymes or coenzymes. Therefore, vitamin
deficiency can occur when excess thyroid hormone is secreted, unless at
the same time increased quantities of vitamins are made available.

Increased Blood Flow and Cardiac Output: Increased metabolism in the

tissues causes rapid utilization of oxygen than normal and the release of
greater than normal quantities of metabolic end products from the
tissues. These effects cause vasodilation in most body tissues, thus
increasing blood flow.

Increased Heart Rate because of increased heart output

Increased Heart Strength: The increased enzymatic increases the

strength of the heart.

Normal Arterial Pressure.

Increased Respiration. The increased rate of metabolism increases the

utilization of oxygen and the formation of carbon dioxide.

Increased Gastrointestinal Motility: thyroid hormone increases both

the rates of secretion of the digestive juices and the motility of the
gastrointestinal tract. Hyperthyroidism therefore often results in
diarrhea, whereas lack of thyroid hormone can cause constipation

Excitatory Effects on the Central Nervous System. thyroid hormone

increases the rapidity of cerebration. conversely, lack of thyroid
hormone decreases rapidity of cerebration. A person with
hyperthyroidism is extremely nervous.

Effect on the Function of the Muscles. A slight increase in thyroid

hormone makes the muscles react with vigor, but when the quantity of
hormone becomes excessive, the muscles become weakened because
of excess protein catabolism. Conversely, lack of thyroid hormone
causes the muscles to become sluggish, and they relax slowly after a
contraction.

Effect of Thyroid Hormone on Sexual Function. In men, lack of thyroid

hormone causes loss of libido; a great excess of the hormone, causes
impotence. In women, lack of thyroid hormone often causes
menorrhagia and polymenorrhea (excessive and frequent menstrual
bleeding respectively), also may causes irregular periods and
occasionally even amenorrhea (absence of menstrual bleeding).