ANATOMI & FISIOLOGI III

RHSC 3072
ENDOCRINE SYSTEM

PN. SUWAIBAH ABD HADI

JABATAN PEMBANTU PERUBATAN & BIOSAINS
KOLEJ ISLAM SAINS DAN TEKNOLOGI
Selepas kuliah ini, pelajar seharusnya dapat:

a)Memahami istilah-istilah sistem endokrin

b)Memahami mekanisma
c)Membezakan kalenjar endokrin dan eksokrin
Kalenjar rembes hormon
melalui duktus

Kalenjar rembes hormon terus ke darah

Modes Of Hormone Delivery :
a) ENDOCRINE:
– Most common (classical) mode, hormones
delivered to target cells by blood.
b) PARACRINE:
– Hormone released diffuses to its target cells
through immediate extracellular space.
– Blood is not directly involved in the delivery.
c) NEUROENDOCRINE:
– Hormone is produced and released by a
neuron, delivered to target cells by blood.

d) AUTOCRINE:
– Hormone released feeds-back on the cell of
origin, again without entering blood
circulation.
Major endocrine glands in the body
 HORMONE-TARGET CELL
SPECIFICITY
• Only target cells, or cells that have specific
receptors, will respond to the hormone’s
presence.
– The strength of this response will depend on:
• Blood levels of the hormone
• The relative numbers of receptors for that hormone
on or in the target cells
• The affinity (or strength of interactions) of the
hormone and the receptor.
HALF-LIFE, ONSET, and DURATION
of HORMONE ACTIVITY

• The affinity of hormones to their specific

receptors is typically very high
• The actual concentration of a circulating
hormone in blood at any time reflects:
– Its rate of release.
– The speed of its inactivation and removal from
the body.
• The half-life is the time required for the hormone
to loose half of its original effectiveness (or drop
to half of its original concentration.
• The time required for hormone effects to take
place varies greatly, from almost immediate
responses to hours or even days.
• In addition, some hormones are produced in an
inactive form and must be activated in the target
cells before exerting cellular responses.
• In terms of the duration of hormone action, it
ranges from about 20 minutes to several hours,
depending on the hormone.
CONTROL OF HORMONE RELEASE:

• The synthesis and secretion of most hormones

are usually regulated by negative feedback
systems.
• As hormone levels rise, they stimulate target
organ responses. These in turn, inhibit further
hormone release.
• The stimuli that induce endocrine glands to
synthesize and release hormones belong to one
of the following major types:
– Humoral
– Neural
– Hormonal
 Chemistry Of Hormones
• Peptide hormones: largest, most complex, and most common
hormones. Examples include insulin and prolactin
• Steroid hormones: lipid soluble molecules synthesized from
cholesterol. Examples include gonadal steroids (e.g
testosterone and estrogen) and adrenocortical steroids (e.g.
cortisol and aldosterone).
• Amines: small molecules derived from individual amino acids.
Include catecholamines (e.g. epinephrine produced by the
adrenal medulla), and thyroid hormones.
• Eicosanoids: small molecules synthesized from fatty acid
substrates (e.g. arachidonic acid) located within cell
membranes
Chemistry Of Hormones
 P ro te in K in a s e O

P ro te in O H + ATP P ro te in O P O + ADP
O
Pi H 2O
P ro te in P h o s p h a ta s e

 A protein kinase transfers the terminal phosphate

of ATP to a hydroxyl group on a protein.
 A protein phosphatase catalyzes removal of the
Pi by hydrolysis.
Adenylate Cyclase (Adenylyl
cAMP NH2
Cyclase) catalyzes:
ATP  cAMP + PPi N
N
Binding of certain hormones
(e.g., epinephrine) to the N N
outer surface of a cell
H2 O
activates Adenylate Cyclase 5' C 4'
H H 1'
to form cAMP within the cell. O
H 3' 2' H
Cyclic AMP is thus considered P O OH
O
to be a second messenger. O-
Phosphodiesterase enzymes cAMP NH2
catalyze:
N
cAMP + H2O  AMP N

The phosphodiesterase that N N

cleaves cAMP is activated by
phosphorylation catalyzed by H2 O
5' C 4'
Protein Kinase A. H H 1'
O
H 3' 2' H
Thus cAMP stimulates its P O OH
own degradation, leading to O
O-
rapid turnoff of a cAMP signal.
 hormone
signal

outside
A G-protein that is
part of a pathway GPCR plasma
membrane
that stimulates
Adenylate Cyclase   cytosol
AC
is called Gs & its GDP GTP
 subunit Gs. GTP GDP ATP cAMP + PP i

The subunit of a G-protein (G) binds GTP, & can

hydrolyze it to GDP + Pi.
 &  subunits have covalently attached lipid anchors that
bind a G-protein to the plasma membrane cytosolic surface.
Adenylate Cyclase (AC) is a transmembrane protein, with
cytosolic domains forming the catalytic site.
 hormone
signal

outside

GPCR plasma
The complex membrane

of  &    cytosol

AC
subunits G GDP GTP
inhibits G.
GTP GDP ATP cAMP + PP i

The sequence of events by which a hormone

activates cAMP signaling:
1. Initially G has bound GDP, and  &
subunits are complexed together.
 hormone
signal

outside

GPCR plasma
membrane

  cytosol

AC
GDP GTP

GTP GDP ATP cAMP + PP i

2. Hormone binding to a 7-helix receptor (GPCR) causes a

conformational change in the receptor that is transmitted to
the G protein. The nucleotide-binding site on G becomes
more accessible to the cytosol, where [GTP] > [GDP].
G releases GDP & binds GTP (GDP-GTP exchange).
 hormone
signal

outside

GPCR plasma
membrane

  cytosol

AC
GDP GTP

GTP GDP ATP cAMP + PP i

3. Substitution of GTP for GDP causes another

conformational change in G.
G-GTP dissociates from the inhibitory  complex &
can now bind to and activate Adenylate Cyclase.
 hormone
signal

outside

GPCR plasma
membrane

  cytosol

AC
GDP GTP

GTP GDP ATP cAMP + PP i

4. Adenylate Cyclase, activated by G-GTP, catalyzes

synthesis of cAMP.
5. Protein Kinase A (cAMP Dependent Protein
Kinase) catalyzes phosphorylation of various cellular
proteins, altering their activity.
Turn off of the signal:
1. G hydrolyzes GTP to GDP + Pi. (GTPase).
The presence of GDP on G causes it to rebind
to the inhibitory complex.
Adenylate Cyclase is no longer activated.
2. Phosphodiesterase catalyzes hydrolysis of
cAMP  AMP.
Turn off of the signal (cont.):
3. Hormone receptor desensitization occurs.
This process varies with the hormone.
 Some receptors are phosphorylated via G-
protein-coupled receptor kinases.
 The phosphorylated receptor may then bind to a
protein arrestin that blocks receptor-G-protein
activation & promotes removal of the receptor
from the membrane by clathrin-mediated
endocytosis.
4. Protein Phosphatase catalyzes removal by
hydrolysis of phosphates that were attached to
proteins via Protein Kinase A.
Pituitary Gland
Pituitary development:
The “Master Gland”
• The pituitary has been
called the “Master”
gland in the body.

• This is because most

of the pituitary
hormones control
other endocrine
glands
 Hormones of the anterior pituitary
There are 6 main hormones which are secreted by the
adenohypophysis:

1) Growth hormone (also known as somatotropin).

2) Thyroid-stimulating hormone (also known as
thyrotropin).
3) Adrenocorticotropic hormone (also known as
corticotropin).
4) Prolactin.
5) Follicle-stimulating hormone.
6) Luteinizing hormone.
Control of pituitary gland secretion
• Secretion of each hormone by the
adenohypophysis is controlled by
neurohormones secreted by nerves in the
hypothalamus.
• In most cases there are two
neurohormones controlling the secretion of
a pituitary hormone. One which stimulates
pituitary secretion and one which inhibits
pituitary secretion.
 Neurohormones:
• Are hormones secreted by nerve cells.
These are true hormones, since they are
secreted into the bloodstream.
• All are secreted by neurosecretory
neurons in the hypothalamus.
• They are secreted into the hypophyseal
portal system, which then carries the
blood to the anterior pituitary.
 Pituitary portal system
• Arterioles break into capillaries in the hypothalamus.
• The axons of the neurosecretory cells form plexuses
with these capillaries.
• Downstream, the capillaries combine into a vein
which carries the blood to the pars distalis.
• The vein breaks into a capillary network which
supplies all the cells of the anterior lobe.
• Thus, the neurohormones are carried directly (well,
sort of) from the hypothalamus to the
adenohypophysis.
Portal system
 Growth hormone (GH)
• Growth hormone is secreted by somatotrophs.

• GH is a protein hormone consisting of a single peptide chain

of 191 amino acids.

• GH secretion is stimulated by the secretion of Growth

Hormone Releasing Hormone (GHRH) by the hypothalamus.

• GH secretion is inhibited by the secretion of somatostatin by

the hypothalamus.

• GH activates a tyrosine kinase receptor.

 Functions of GH:
• GH has effects of every cell of the body, either
directly or indirectly. Primarily, it decreases the
uptake and metabolism of glucose. (Elevates
plasma glucose)

• Increases the breakdown of fat. (Increases the

blood levels of fatty acids)

• Increases the uptake of amino acids from the blood

and increases protein synthesis in cell. (Decreases
plasma amino acids)
 Actions of GH on
specific cell types:
a) Muscle cells:

• Increases amino acid uptake

• Increases protein synthesis
• Decreases glucose uptake

• Net result: Increased Lean body mass

b) Chondrocytes:

• increases uptake of sulfur

– increases chondroitin sulfate production
– increases DNA, RNA synthesis
– increases Protein synthesis
– increases Amino acid uptake
– increases Collagen synthesis
– increases Cell size and number

• Net result: Increased Linear growth

c) Hepatocytes:

• Stimulates the production of

somatomedins by the liver.

• These somatomedins directly regulate

metabolic function in target cells. They
are also called insulin-like growth factors,
or IGFs.
e) Adipocytes:

• Decreases glucose uptake

• Increases lypolysis

• Net result: Decreased Adiposity

• Other cell types in general:

– Increased protein synthesis

– Increased DNA, RNA synthesis
– Increased cell size and number

• Net result: Increased organ size

• Increased organ function
 Other considerations:

• GH has a short half-life of about 20

minutes. However, the IGFs are much
longer lived (T1/2 of about 20 hours).
GH and Insulin actions are correlated:
• When there is ample dietary intake of proteins and
carbohydrates, then amino acids can be used for protein
synthesis and growth.

• Under these conditions, both insulin and GH secretion are

stimulated.

– Net result: Amino acids are shunted to protein synthesis and glucose
is shunted to metabolism.

• However, under conditions where only carbohydrates are

ingested, insulin secretion is increased, but GH secretion is
decreased.

– Net result: Both glucose AND amino acids are shunted to metabolism.
Pathophysiology of abnormal GH
secretion:
• Hyposecretion:

• Pre-adolescents:
– Decreased GH secretion (or sensitivity) results in slow
growth and delayed onset of sexual maturation.
These children also tend to be slightly chubby.

• Post-adolescents:
– Generally, no serious problems are associated with
hyposecretion of GH in mature individuals. However,
in very severe cases there can be progeria (rapid and
premature aging).
 Hypersecretion:
• Pre-adolescents: (before closure of
epiphyseal plates)

• Hypersecretion results in gigantism, where

affected individuals grow extremely rapidly
and become abnormally tall (even over 2.4
m). Body proportions remain relatively
normal. Usually, there are cardiovascular
complications later in life.
• Post- adolescents: (after epiphyseal
closure).

• Hypersecretion results in tissue

enlargement. This is particularly true of the
bones, which get heavier and thicker. They
cannot elongate since the epiphyseal plates
are closed. A common symptom is a
coarsening of the facial features and
enlargement of the hands and feet. This
condition is known as acromegaly.
 Treatments of GH secretion
disorders:
• Hypersecretion is usually caused by a
tumour in the pituitary gland. Treatment
consists of surgical or radiation ablation of
the tumour mass.

• Hyposecretion is usually treated in children

by hormone replacement therapy. This is
generally not required in adults, unless GH
secretion is completely abolished.
 Prolactin (PRL)
• Structurally, very similar to growth hormone
(single peptide chain of 198 amino acids).

• PRL is secreted by mammotrophs (also

referred to as lactotrophs).

• Secretion of PRL is also under dual control

by the hypothalamus.
• Primarily under inhibitory control. This means that
if there is an injury to the hypophyseal portal
system which blocks hypothalamic regulation of the
pituitary gland, PRL levels increase. All other
pituitary hormone levels decrease when this
happens.

• Dopamine is secreted by neuroendocrine cells in

the hypothalamus and inhibits PRL release.

• PRL release is stimulated by thyrotropin releasing

hormone (TRH), vasoactive intestinal peptide (VIP)
and at least one other as yet unidentified factor.

• PRL activates a tyrosine kinase receptor.

 Functions of PRL:
• In humans, the only effects of PRL so far
identified are on reproduction and nursing.

• PRL is important in stimulating differentiation

of breast tissue during development.

• Stimulates further development of mammary

glands during pregnancy.
• Stimulates milk production (lactation) after
pregnancy.

• PRL has a role in regulation of the female

reproductive cycle. However, its precise role
has not be delineated yet. Excess PRL
secretion is know to block synthesis and release
of gonadotropins, disrupting menstruation and
causing infertility.

• PRL also can regulate male fertility, but how it

does so remains unclear.
 Pathophysiology of PRL secretion:
• Hyposecretion is never seen. However,
hyperprolactinemia (excess secretion of PRL)
is a fairly common disorder. Symptoms in
women usually include amenorrhea (cessation
of menstruation), galactorrhea (abnormal
lactation) and infertility. In men, infertility and
galactorrhea are the most common symptoms.
• Treatment usually consists of administration of
a dopaminergic agonist, such as
bromocriptine.
Thyroid Stimulating hormone
(TSH)
• TSH is a glycoprotein hormone composed
of 2 peptide chains a and b.
• The a subunit is called “unspecific”
because it is also incorporated into two
other unrelated pituitary hormones (LH
and FSH).
• The b subunit contains the biologically
active sites. However, it must be
combined with the a subunit in order for
the hormone to be active.
• TSH secretion is controlled very tightly by
the hypothalamus.

• TSH secretion is stimulated by

Thyrotropin-releasing hormone (TRH).
TRH is a tripeptide, meaning it is
composed of three amino acids.

• TRH secretion is stimulated by thermal

and caloric signals in the brain.
 Control of TSH secretion
• Negative control of TSH secretion occurs
in two ways:
– Triiodothyronien or T3 (which will be discussed
later) feeds back on the hypothalamus to
stimulate secretion of dopamine and
somatostatin. These two factors both function
as TSH-release inhibiting factors.

– T3 can feed back directly onto the thyrotrophs

to directly inhibit TSH secretion.
 Function of TSH:
• TSH stimulates the follicular cells of the
thyroid to induce a number of responses:

– TSH activates both the cAMP and PIP pathways:

• Increased cAMP
• Increased [Ca2+]i

• TSH can stimulate both cell growth (of

follicular cells) and secretion of T3 and
thyroxine ( T4 ).
 Adrenocorticotropic hormone
(ACTH)

• ACTH is a single peptide chain which is

relatively small (30 amino acids).

• ACTH secretion is primarily under

stimulatory control (i.e. there isn’t an
ACTH-release inhibitory factor).
• ACTH secretion is stimulated by
corticotropin releasing hormone (CRH).

• CRH secretion can be stimulated by a large

number of factors, most of which would be
considered stress factors.

• Examples; infection, trauma, sleep cycle,

anxiety, depression and others. (Just
remember stress).
 Functions of ACTH:
• ACTH stimulates the adrenal gland to secrete
cortisol.

• ACTH levels are associated with the sleep cycle.

• ACTH stimulates the cAMP pathway in

adrenocorticol cells.

• ACTH can directly inhibit CRH secretion (negative

feedback).
Follicular-Stimulating hormone (FSH)
Luteinizing Hormone (LH)
• These are generally grouped together and called
gonadotropines.
• Gonadotropins are secreted by the gonadotrophs, which
synthesize and secrete both LH and FSH.
• Both LH and FSH are peptide hormones.
• Secretion of gonadotropins is mainly under positive
control.
• Hypothalamus secretes gonadotropin-releasing hormone
(GnRH) which stimulates gonadotrophs to secrete both
LH and FSH.
 Functions of LH and FSH:
• LH and FSH stimulate secretion of the sex steroids by the
gonads. Mainly estrogen in women and testosterone in men.

• FSH also stimulates gonadal release of inhibin, which serves

as a negative feedback factor to block release of FSH by
pituitary.

• LH and FSH stimulate the gonadal release of activin, which

can have positive feedback on gonadotropin secretion by the
pituitary.

• Gonadal secretion of estrogen and testosterone can

negatively feedback on both the hypothalamus, to reduce
GnRH secretion, and the gonadotrophs directly, to reduce
gonadotropin secretions.
 Hormones of
the posterior pituitary:
• Remember that the neurohypophysis serves as a
storage organ for hormones produced by neurosecretory
cells in the hypothalamus.

• There are two hormones secreted by the

neurohypophysis:
– 1) antidiuretic hormone (ADH)
– 2) oxytocin

• Both hormones are peptide hormones containing 9

amino acid residues.

• They differ in only 2 amino acids, but have very different

functions.
• Both activate the PIP pathway in the target cells.
 ADH
• Term: diuresis ö means production of urine.

• ADH inhibits urine production, i.e. conserves water in the

body.

• Main target for ADH are the cells in the kidney which reabsorb
water (will be covered in detail in the section on renal
physiology).

• ADH secretion is stimulated by either an increase in the

osmotic concentration of the blood, or by a decrease in blood
volume
– usually sensed by a decrease in blood pressure.
• Secretion of ADH causes retention of water, which
will tend to counteract both an increase in blood
concentration and/or decrease in blood volume.
• cannot overcome serious blood loss.

• Conversely, excess consumption of water will

have two effects:
– increase blood volume (and pressure).
– decrease blood concentration.

• Under these conditions ADH secretion is inhibited.

– This results in formation of more urine, which is usually

fairly dilute.
– Blood loses water and thus volume.
 Oxytocin
• Release of oxytocin is under neural control
(like with ADH).

• However, unlike ADH, the release of oxytocin

is largely controlled by emotional state.

• Oxytocin specifically stimulates certain

smooth muscles to contract.

– Primarily those of the reproductive tract and

mammary glands.
• Oxytocin is required for nursing.

– Principally know as the “milk letdown factor”.

– It is secreted within seconds of the onset of

suckling.
• Sensory receptors in the nipples generate afferent
impulses that stimulate the hypothalamus,
triggering oxytocin secretion.
• Can actually be secreted in response to auditory
input, i.e. in nursing mothers in response to
hearing their babies cry.
 Effects of Oxytocin
• Oxytocin stimulation at low doses causes
rhythmic contractions of the uterus.

• Oxytocin stimulation at high dose causes

sustained tetanic uterine contractions.

• Oxytocin is often used to induce labour.

• It is now generally believed that oxytocin
believed that oxytocin produced by the fetus
plays a critical role in labour.

• Oxytocin is also used to stop post-partum

bleeding.

• The number of oxytocin receptors in uterine

smooth muscles increases towards the end of
pregnancy.

• Oxytocin affects smooth muscle cells in uterus

and vagina of non-pregnant women.
• There is clear evidence that oxytocin is involved
in sexual arousal and orgasm in both men and
women.

– What role it plays in men is unknown. However, it

may play a strong role in reinforcing the pair-bond.

• The role in women is only slightly better known.

– Oxytocin is secreted in response to vaginal distention

during intercourse.
– Oxytocin is also secreted in response to stimulation of
the nipples.
 Emotional considerations

• Oxytocin secretion during sexual

intercourse probably serves to reinforce
the male-female pair-bond.

– Often referred to as the “the cuddle hormone”

or “the love hormone” in the popular press.
• Secretion of oxytocin during and after
labour may play an important role in the
formation of the mother-child pair-bond.

– Oxytocin secreted during suckling may serve

to reinforce this pair-bond.
• Recent studies with knock out mice has
shown that oxytocin is critical in initiating
and maintaining maternal care.

– Oxytocin secreted in response to suckling can

cause uterine contractions which may play a
role in the recovery of uterine muscle tone
after pregnancy and may serve to shrink the
uterus back to normal.
 Thyroid Gland:
• Location and Structure
• The largest pure endocrine gland in the
body, located in the front of the neck, on
the trachea just below to the larynx.

• Its two lobes are connected by a median

tissue mass called the isthmus.

• Internally, it is composed of about 1 million

of round follicles. The walls of each follice
are formed by cuboidal and squamous
epithelial cells called follicle cells, which
produce thyroglobulin (glycoprotein).
• The lumen of each follicle stores colloid,
which consists primarily of molecules of
thyroglobulin.

• The follicular epithelium also consists of

parafollicular cells, a separate population
of endocrine cells that produce calcitonin,
a hormone involved in calcium
homeostasis.
 Thyroid hormones (THs)
• The two THs contain iodine and are called
thyroxin or T4 and triiodothyronine or T3.

• T4 and T3 have a very similar structure as each is

made up of two tyrosine amino acids linked
together and either 4 or 3 atoms of iodine,
respectively.

• T4 is the main hormone produced by the thyroid

and T3 has most if not all of biological activity as
all target tissues rapidly convert T4 to T3.
• Except for the adult brain, spleen, testes, and the
thyroid gland itself, THs affect all other types of
cells in the body where they stimulate activity of
enzymes especially those involved in glucose
metabolism

• Increase metabolic rate in target tissues, which

increases body heat production (calorigenic effect).

• THs also are critically important for normal growth

and development of skeletal and nervous systems
and maturation of reproductive system.
 Synthesis of thyroid hormones:
• Formation and storage of thyroglobulin.

– This process takes place in follicle cells and

the final product is packed into vesicles, their
contents are discharged into the lumen of the
follicle and become a major part of the colloid.
• Iodide trapping and oxidation to iodine.

– To produce functional iodinated hormones,

follicle cells accumulate iodide from the blood.
A protein pump (iodide trap), located on the
basal surface of follicle cells, actively
transports iodide into follicle cells where it is
oxidized and converted to iodine (I2).
• Iodination.

– Once formed, iodine is attached to tyrosine

amino acids which are part of the
thyroglobulin.

– Iodination of one tyrosine produces

monoiodotyrosine (MIT), iodination of two
tyrosines diiodotyrosine (DIT).
• Coupling.

– Then enzymes within the colloid link MITs

and DITs in a highly specific fashion, as a
result two DITs linked together result in T4 ,
while coupling of MIT and DIT produce T3.
• Coupling (cont.)

– Interactions between two DITs are more

frequent so more thyroxin.
– At this point both thyroid hormones are still
attached to thyroglobulin molecules in the
colloid.
• Colloid endocytosis.

– Colloid droplets containing iodinated

thyroglobulin are taken up by follicle cells by
endocytosis. These combine with lysosomes
to form phagolysosomes.
• Cleavage of the hormones for release.

– Within the phagolysosomes, the hormones

are cleaved from the thyroglobulin by
lysosomal enzymes. The free hormones then
diffuse through the basal membrane out of the
follicle cell and into the blood stream.
Transport and regulation of release:
• Most released T4 and T3 immediately bind to plasma
proteins, of which the most important is thyroxin-binding
globulin (TBG) produced by the liver.

• Binding proteins protect T4 and T3 from immediate

degeneration by plasma enzymes, also they allow T4 and
T3 to reach target tissues, often located a significant
distance away from the thyroid gland.

• Decreasing blood levels of thyroxin trigger release of

TSH from the anterior pituitary, which stimulates the
thyroid gland to produce more thyroxin.
Pathology of the thyroid gland function:

• Both hypo- and hyperactivity and of the thyroid gland can

cause severe metabolic disturbances.

• In adults, hypothyroidism is referred to as

– myxedema.

• Symptoms:

– Low metabolic rate, poor resistance to cold temperatures,

constipation, dry skin (especially facial), puffy eyes, lethargy and
mental sluggishness.
– If hypothyroidism results from lack of iodine the thyroid gland
enlarges to form a goiter.
• Severe hypothyroidism during the fetal
development and in infants is called
cretinism.

• Symptoms:
– A short disproportionate body, a thick tongue
and neck, and mental retardation.
– The condition is preventable by thyroid
hormone replacement therapy. However, once
developmental abnormalities and mental
retardation appear, they are not reversible.
 Hyperthyroidism:
• The most common form of hyperthyroidism is Grave's disease,
believed to be an autoimmune disease.

• The immune system produces antibodies that mimic TSH, which bind
to TSH receptors and permanently switch them on, resulting in
continuous release of thyroid hormones.

• Typical symptoms include metabolic rate, sweating, rapid and

irregular heartbeat, nervousness, and weight loss despite adequate
food intake.

• Often, exophthalmos, or protrusion of the eyeballs, occurs caused by

the edema of tissues behind the eyes followed by fibrosis.

• Treatments include surgical removal of the thyroid gland (very difficult

due to an extremely rich blood supply) or ingestion of radioactive
iodine (131I), which selectively destroys the most active thyroid cells.
Hyperthyroidism and Grave’s
Disease
Parathyroid Glands:
• The parathyroid
glands are small in
size and are found on
the posterior aspect of
the thyroid gland.

• Typically, there are

four of them but the
actual number may
vary.
 Histology of the Parathyroid
• The endocrine cells
within these glands
are arranged in
thick, branching
cords containing
oxyphil cells of
unclear function and
most importantly
large numbers of
chief cells that
secrete
parathyroid
hormone (PTH).
 PTH:
• Small protein

• Single most important hormone controlling

calcium homeostasis. Its release is triggered by
falling blood calcium levels and inhibited by
hypercalcemia (high blood calcium).

• There are three target organs for PTH:

– skeleton
– kidneys
– intestine
 PTH stimulates the following on
these target organs:
• Osteoclasts (bone absorbing cells) are stimulated to digest
bone and release ionic calcium and phosphates to the blood.

• Kidneys are stimulated to reabsorb calcium and excrete

phosphate.

• Intestines are stimulated to increase calcium absorption.

• Vitamin D is required for absorption of calcium from ingested

food.
– For vitamin D to exert this effect, it must first be converted by the
kidneys to its active form
– It is this conversion that is directly stimulated by PTH.
 Pathology of the parathyroid
glands:

• Because calcium is essential for so many

functions, including transmission of action
potentials, muscle contraction, pacemaker
activity in the heart, and blood clotting,
precise control of ionic calcium levels in
body fluids is absolutely critical. As a result
both hyper- and hypoparathyroidism can
have severe consequences.
 Hyperparathyroidism:
• Rare, usually the result of a parathyroid gland tumor.

• Results in severe loss of calcium from the bones.

• The bones soften and deform as their mineral salts are

replaced by fibrous connective tissue.

• Results in hypercalcemia

– Leads to, depression of the nervous system leading to abnormal

reflexes and weakness of the skeletal muscles, and formation of
kidney stones as excess calcium salts are deposited in kidney
tubules.
 Hypoparathyroidism:
• It is a PTH deficiency, which is a common
consequence of parathyroid trauma or
removal during thyroid surgery.

• The resulting hypocalcemia increases

excitability of neurons and may lead to tetany
resulting in uncontrollable muscle twitches
and convulsions, which if untreated may
progress to spasms of the larynx, respiratory
paralysis and death.
 ADRENAL GLANDS:
• The two adrenal
glands are pyramid-
shaped organs found
atop the kidneys.

• Each gland is
structurally and
functionally two
endocrine glands in
one.
• The inner adrenal
medulla is made up
of nervous tissue and
acts as part of the
sympathetic nervous
system. The outer
adrenal cortex forms
the bulk (about 80%)
of the gland. Each of
these regions
produces its own set
of hormones.
 Adrenal Medulla:
• It is made up of chromaffin cells which secrete the catecholamines
epinephrine (E) (adrenaline) and norepinephrine (NE)
(noradrenaline) into the blood.

• During the fight-or-flight responses, the sympathetic nervous system

is activated, including the chromaffin tissue and large amounts of
catecholamines (80% of which is E) are released.

• In most cases the two hormones have very similar effects on their
target organs. However, E is the more potent stimulator of the heart
rate and strength of contraction, and metabolic activities, such as
breakdown of glycogen and release of glucose).

• NE has great effect on peripheral vasoconstriction and blood

pressure.
 Adrenal Cortex:
• The cells of the adrenal cortex are arranged in
three distinct zones, each zone producing
corticosteroids.
• The Zona glomerulosa is the outer-most layer
of cells and it produces mineralocorticoids, that
help control the balance of minerals and water in
the blood.
• The zona fasciculata is composed of cells that
secrete glucocorticoids.
• The zona reticularis produce small amounts of
adrenal sex steroids.
Hormones of the Adrenal Cortex
• Mineralocorticoids
• Although there are several mineralocorticoids,
aldosterone is by far the most potent and
accounts for more than 95% of production. Its
main function is to maintain sodium balance by
reducing excretion of this ion from the body.

• The primary target organs of aldosterone are

kidney tubules where it stimulates reabsorption of
sodium ions from urine back to the bloodstream.

• Aldosterone also enhances sodium absorption

from sweat, saliva, and gastric juice.
• Secretion of aldosterone is induced by a number of
factors such as high blood levels of potassium, low
blood levels of sodium, and decreasing blood
volume and pressure.

• The reverse conditions inhibit secretion of

aldosterone.

• Glucocorticoids:

• Glucocorticoids influence metabolism of most body

cells, help us resist stress, and are considered to be
absolutely essential to life.
• The most important glucocorticoid in humans is cortisol, but
small amounts of cortisone and corticosterone are also produced.

• The main effect of cortisol is to promote gluconeogenesis or

formation of glucose from noncarbohydrate molecules, especially
fats and proteins.

• Cortisol also breaks down adipose (fat) tissue, released fatty

acids can be then used by many tissues as a source of energy
and "saving" glucose for the brain.

• Blood levels of glucocorticoids increase significantly during

stress, which helps the body to negotiate the crisis.

• Interestingly, chronic excess of cortisol has significant anti-

inflammatory and anti-immune effects and glucocorticoid drugs
are often used to control symptoms of many chronic inflammatory
disorders, such as rheumatoid arthritis or allergic responses.
Regulation of glucocorticoid secretion:

• It is provided by a typical negative feedback

system:

• increased (hypothalamus) CRH negative

• increased (adenohypophysis) ACTH

• increased (adrenal cortex) cortisol

• Gonadocorticoids (Sex Hormones)

– The amount of sex steroids produced by zona

reticularis is insignificant compared to the
amounts secreted by the gonads.
– These hormones may contribute to the onset
of puberty and the appearance of axillary and
pubic hair in both males and females.
– In adult women adrenal androgens (male sex
hormones, especially testosterone) may be, at
least partially, responsible for the sex drive.
 Pathology of the adrenal cortex
function:
• Hyperadrenalism :
– It is referred to as Cushing's disease and can be
caused by a cortisol-secreting tumour in the adrenal
glands, ACTH-secreting tumour of the pituitary, or
ACTH secreted by abdominal carcinoma.
– However, it most often results from the clinical
administration of pharmacological (very high) doses of
glucocorticoid drugs.
– The symptoms include a persistent hyperglycaemia,
dramatic loss of muscle and bone proteins, and water
and salt retention, leading to hypertension and edema
- one of its signs is a swollen "moon" face. The only
treatment is a surgical removal of tumour or
discontinuation of the drug.
• Hypoadrenalism :

– It is referred to as Addison's disease and

involves significant reduction in plasma
glucose and sodium, very high levels of
potassium and loss of weight. The usual
treatment is corticosteroid replacement
therapy.
THE ENDOCRINE PANCREAS:
• Located partially behind the stomach, the
pancreas is a mixed gland composed of
both endocrine and exocrine cells.

• More than 98% of the gland is made up of

acinar cells producing an enzyme-rich
juice that enters a system of ducts and is
delivered to the duodenum of the small
intestine during food digestion.
• The remaining 1-2% of cells form about 1
million of islets of Langerhans, tiny cell
clusters that produce pancreatic hormones.

• The islets have four distinct populations of

cells, the two most important ones are
alpha cells that produce hormone glucagon,
and more numerous beta cells that
synthesize insulin. In addition, delta cells
produce somatostatin and F cells secrete
pancreatic polypeptide (PP).
 Hormones of the Pancreas:
• Glucagon and insulin are directly responsible for the
regulation of blood glucose levels and their effects are
exactly opposite:

• insulin is hypoglycemic (it decreases blood glucose)

• glucagon is hyperglycemic (it increases blood glucose).

• Pancreatic somatostatin inhibits the release of both insulin

and glucagon and slows the activity of the digestive tract.

• PP regulates secretion of pancreatic digestive enzymes and

inhibits release of bile by the gallbladder.
 Glucagon:
• Glucagon is a 29 amino acid polypeptide with extremely potent
hyperglycemic properties. One molecule of this hormone can induce the
release of 100 million molecules of glucose into the blood.

• The major target organ of glucagon is the liver, where it promotes:

– Breakdown of glycogen to glucose (glycogenolysis)

– Synthesis of glucose from lactic acid and from noncarbohydrate molecules
such as fatty acids and amino acids (referred to as gluconeogenesis).

– Release of glucose into the blood by the liver

– All these effects ↑ blood sugar levels.

– Secretion of glucagon from the alpha cells is induced by, most importantly, low
blood sugar levels but also by high amino acid levels in the blood (e.g.
following a protein-rich meal). Rising blood sugar concentration and
somatostatin from the delta cells inhibit glucagon release.
 Insulin:
• Insulin is a 51 amino acid protein consisting of two polypeptide
chains linked by disulfide bonds. It is synthesized as part of a larger
molecule called proinsulin and packed into secretory vesicles where
its middle portion is excised by enzymes to produce functional
hormone, just before insulin is released from the beta cell.

• As mentioned earlier, insulin's main function is to lower blood sugar

levels but it also affects protein and fat metabolism.

• In general, insulin:

– Increases membrane transport of glucose into body cells, especially

muscle and liver cells
– Inhibits the breakdown of glycogen (it should not be confused with
glucagon!) into glucose,
– Increases the rate of ATP production from glucose
– Increases the rate of glycogen synthesis
– Increases the rate of glucose conversion to fat.
• Insulin binds to tyrosine kinase receptors, but
mechanism of action, including type(s) and specific
roles of second messengers, are poorly understood.

• The beta cells are stimulated to produce insulin

primarily by elevated blood sugar levels, but also by
high blood levels of amino acids and fatty acids.

• Several hormones also induce the release of

insulin, including glucagon, epinephrine, growth
hormone, thyroid hormones, and glucocorticoids.

• In contrast, somatostatin inhibits insulin release.