9

e
2/ ,
gy
lo
io
sy
Ph
P
IS
R
C

Endocrine Physiology
 Biosynthesis of Adrenocortical Steroid Hormones

C
R
I
S
P

e
, 2/
gy
Zona Fasciculata – Formation of The lyase activity is actually part of the enzyme 17α-hydroxylase.
Glucocorticoids (Cortisol) lo zz
Since the enzyme has dual activity, it is called as dual-function
protein
io
zz For cortisol synthesis, pregnenolone is converted to DHEA is secreted by the adrenal in the form of its sulfate
17-hydroxypregnenolone by an enzyme 17α-hydroxylase ester, DHEAS, generated by DHEA sulfotransferase
17-hydroxypregnenolone is further converted to
sy

zz
17-hydroxyprogesterone by an enzyme 3β-hydroxysteroid Location of Adrenal Steroidogenic Enzymes
dehydrogenase
17-hydroxyprogesterone is converted to 11-Deoxycortisol by an Enzyme Location
Ph

zz
enzyme 21-hydroxylase
Cholesterol desmolase Mitochondria
zz 11-Deoxycortisol is ultimately acted upon by the enzyme
11β-hydroxylase to form cortisol 3β-Hydroxysteroid Smooth endoplasmic reticulum
dehydrogenase
P

Zona Reticularis – Formation of Adrenal 17-Hydroxylase/17, 20 lyase Mitochondria

Androgen Dehydroepiandrosterone [DHEA] 21-Hydroxylase Smooth endoplasmic reticulum
IS

zz For adrenal androgen synthesis, pregnenolone is converted to 11β-Hydroxylase Mitochondria

17-hydroxypregnenolone by an enzyme 17α-hydroxylase Aldosterone synthase Mitochondria
R

zz 17-hydroxypregnenolone is ultimately converted to DHEA by

CHAPTER 9  Endocrine Physiology

the enzyme 17,20-lyase

C

Congenital Adrenal Hyperplasia (CAH)

zz CAH occurs due to congenital defects in the enzymes involved in adrenal steroidogenesis
zz Hyperplasia is mainly due to the increase in ACTH secretion because of loss of feedback inhibition
zz These group of disorders are usually inherited as autosomal recessive
21-Hydroxylase Deficiency
zz This is the most common enzyme deficiency seen in nearly 95% of individuals with CAH
zz The gene for 21-Hydroxylase is located on the short arm of chromosome 6. It is also the location of human major histocompatibility
complex (MHC)
zz Because of 21-Hydroxylase deficiency, two important products namely progesterone and 17-hydroxyprogesterone accumulates in
serum
zz The ultimate effect is deficiency of cortisol and aldosterone
334
zz In 21-Hydroxylase deficiency, cholesterol is largely converted to adrenal androgens

Contd...
zz Clinical features of 21-Hydroxylase deficiency are,
 Dehydration, Hyperkalemia, Hyponatremia (salt losing form)

 Virilization

 Adrenogenital syndrome in females

11β-Hydroxylase Deficiency
zz In this condition, 11-Deoxycorticosterone accumulates C
zz 11-Deoxycorticosterone has got mineralocorticoid activity. So, the affected individuals have sodium and water retention leading to
hypertension – “Hypertensive form of CAH” R
17-Hydroxylase/17, 20 Lyase Deficiency
zz In this condition, there is no sex hormones are produced. So, female external genitalia is present
I
zz Aldosterone production is intact - sodium and water retention leading to hypertension – “Hypertensive form of CAH” S
zz The deficiency of cortisol is compensated by the glucocorticoid activity of corticosterone

3β-Hydroxysteroid Dehydrogenase Deficiency P

e
zz Adrenal cortex is capable of producing only DHEA (adrenal androgen) in this condition
zz Cortisol and aldosterone production is totally absent

2/
zz The condition is characterized by Dehydration, Hyperkalemia, Hyponatremia (salt losing form)

zz Since DHEA is a weak androgen, hypospadias in male and clitoral enlargement in the female

,
Lipoid adrenal Hyperplasia

gy
zz This condition is due to steroidogenic acute regulatory protein (StAR) deficiency
zz There is complete deficiency of all adrenal hormones—glucocorticoids, mineralocorticoids and sex hormones

zz This condition is characterized by,

 Dehydration, Hyperkalemia, Hyponatremia (salt losing form)

 Female external genitalia regardless of genetic sex lo

io
Regulation of Adrenal Cortical Hormones
sy

zz CRH is released from the paraventricular nucleus of

Secretion hypothalamus
zz Cortisol and adrenal sex steroids secretion are completely under zz It acts through its G- protein coupled receptors termed as
Ph

the control of Adrenocorticotropic tropic hormone (ACTH ) hCRH-RI and hCRH-RII

from anterior pituitary zz It is the only hypothalamic hormone known to have a binding
Hypothalamo-pituitary-adrenal (HPA) axis is the major protein in circulation called CRH-binding protein
neuroendocrine stress response mediator. Its components are, zz CRH levels are elevated in major depressive disorders and stress
P

Corticotropin Releasing Hormone (CRH) Adrenocorticotropic Hormone (ACTH)

IS

zz ACTH is secreted from the corticotrope cells

zz It is derived from the precursor protein termed as
Proopiomelanocortin (POMC)
R

zz Important products formed from POMC are,

 ACTH
C

 β-lipotropin (LPH)
 β-endorphin
 met-enkephalin
 α-melanocyte-stimulating hormone (α-MSH)
 Corticotropin-like intermediate lobe protein (CLIP)
Theory

zz CRH releases Adrenocorticotropic tropic hormone (ACTH )

from anterior pituitary 335
zz Major stimulus for CRH release is stress
 zz ACTH and cortisol secretion is pulsatile with a characteristic
circadian rhythm. It is high in the early morning and low in the
evening
zz 75% of the daily production of ACTH and cortisol occurs
between 4:00 AM and 10:00 AM

C Actions of ACTH
ACTH acts through its receptor termed as MC2R (melanocortin
R zz
2 receptor)
It mainly acts through cyclic AMP (cAMP) second messenger
I zz
system
S zz ACTH increases the secretion of cortisol and adrenal sex
steroids by,
P  increasing the import of cholesterol esters into adrenal
cortical cell

e
 cleaves cholesterol esters to cholesterol for import into the
mitochondria

2/
 Increasing the transcription of enzymes involved

,
Diagnostic tests assessing the HPA axis

gy
Dexamethasone Suppression Test
zz

It is typically used to diagnose Cushing's syndrome lo

Dexamethasone is an exogenous steroid that mimics the negative feedback of endogenous cortisol
io
There are two types of Dexamethasone suppression test. They are,
zz Low-dose dexamethasone (1 mg) suppression test
sy

zz High-dose dexamethasone (8 mg) suppression test

Ph
P
IS
R
CHAPTER 9  Endocrine Physiology

ACTH Stimulation Test

zz This test is exactly opposite where ACTH is used to stimulate cortisol production
zz In this test, cosyntropin (ACTH 1-24), 0.25 mg is injected and blood samples are collected at 0, 30, and 60 min for cortisol estimation

zz In normal individuals, cortisol level rise to >20 μg/dL exactly 30–60 min after cosyntropin stimulation

Mineralocorticoids – “Aldosterone”
zz Aldosterone is the major mineralocorticoid produced from zona glomerulosa
zz Other adrenal steroids with mineralocorticoid activity are,
 Deoxycorticosterone (DOC)
336  Corticosterone (also called as Compound B)
 Cortisol
zz Half-life of aldosterone is short. It is about 20 min
Regulation of Aldosterone Secretion  Surgery
 Anxiety
zz Conditions that increase aldosterone secretion are,
 Standing
 High potassium intake
 Hemorrhage
 Low sodium intake – activates Renin angiotensin
aldosterone system (RAAS)
C
Renin Angiotensin Aldosterone System (RAAS)
R
I
S
P

e
, 2/
gy
lo
io
sy

zz Decrease in ECF volume leading to renal hypoperfusion zz Sodium resorption

Ph

ultimately releases renin from kidney  Aldosterone increases sodium resorption by increase the
zz Renin activity of epithelial sodium channels (ENaCs) in principal
 Renin is released from the juxtaglomerular cells in the cells (P cells)
kidney  Without aldosterone, epithelial sodium channels (ENaCs)
 It convertes angiotensinogen produced from liver to is degraded by a protein called Nedd 4-2
P

angiotensin I  Aldosterone prevents degradation of ENaCs by inhibiting

zz Angiotensin II Nedd 4-2 through SGK1 (serum and glucocorticoid-
IS

 Angiotensin II is formed from angiotensin I by the action regulated kinase 1)

of enzyme Angiotensin-converting enzyme (ACE) present  Sodium resorption through ENaC is accompanied by
in lung water resorption that ultimately increases ECF volume
R

 Angiotensin II binds to AT1 receptors present in zona

glomerulosa and increases the secretion of aldosterone Epithelial Sodium Channels (ENaCs)
C

Blockers
Actions of Aldosterone
zz Aldosterone Receptor zz ENaC blocker drugs are,
 Aldosterone acts through nuclear receptor  Amiloride

 In the absence of aldosterone, its receptors is kept in  Triamterene

inactive state at cytoplasm by binding with chaperone
proteins (heat-shock proteins)
 Once the hormone binds, it gets activated and enter the
nucleus
zz These drugs block sodium and water resorption in collecting
tubules and hence useful as diuretic agents
Gain of function mutation of Epithelial sodium channels (ENaCs)
– “Liddle syndrome”
Theory

 Aldosterone receptor blocker drugs are spironolactone

zz In Liddle syndrome, there is reduced degradation of ENaCs
and eplerenone. They act as competitive antagonists
leading to enhanced sodium and water resorption
zz Major actions of aldosterone are,
zz Patients with Liddle’s syndrome classically manifest severe
 Sodium resorption – from urine, sweat, saliva and colon
 Water resorption (secondary effect) hypertension with hypokalemia
 Secretion of potassium ion (K+) zz This condition is sensitive to ENaC blocker amiloride treatment 337
 Secretion of H+ ion in urine (Urinary acidity)
 zz Secretion of potassium ion (K+)
 Aldosterone increases the secretion of potassium ion form principal cell through
 Renal outer medullary potassium (ROMK) channels
 High conductance “big” potassium (BK) channels
zz Secretion of H+ ion in urine
 Aldosterone increases secretion of H+ ion in urine by stimulating H+ ATPase present in the membrane of Intercalated cells in kidney
C  This action is considered to be the “Non – genomic action” of aldosterone

R Excessive Production of Aldosterone – “Hyperaldosteronism”

I Primary Hyperaldosteronism
This occurs because of excessive unregulated secretion of aldosterone by the adrenal cortex
S zz

zz Primary Hyperaldosteronism is the most common cause of aldosterone excess

P zz Causes of Primary Hyperaldosteronism are,

 Aldosterone-secreting adrenocortical adenoma - Conn’s syndrome

e
 Bilateral (micronodular) adrenal hyperplasia

2/
 Glucocorticoid-remediable hyperaldosteronism

Conn’s Syndrome
zz Its most common cause is aldosterone-producing adrenal adenomas

,
zz Clinical consequences of excess aldosterone are,

gy
 Sodium and water retention leading to expansion of ECF volume and hypertension

 Excess potassium excretion by kidney (K+ loss). Symptoms of such K+ loss are,

 Muscle weakness



Muscle cramps
Intestinal atony
lo
io
 Prolonged K+ depletion damages the kidneys (hypokalemic nephropathy), causing resistance to ADH – Nocturia is very
common
sy

 Excessive urinary excretion of H+ ion leading to metabolic alkalosis. Such alkalosis lowers may lower the plasma Ca2+ leading to
hypocalcemic tetany
zz Inspite of increase in extracellular fluid volume, edema doesn’t develop because of the phenomenon called “Aldosterone Escape”
Ph

“Aldosterone Escape Phenomenon”

zz Inspite of action of aldosterone on the renal tubules, Sodium excretion is increased during aldosterone excess
zz This is because of the increase in atrial natriuretic peptide (ANP) secretion that excretes sodium in response to increase in ECF volume

zz Primary Hyperaldosteronism is characterized by suppression of renin levels because of ECF volume expansion
P

zz Diagnosis of Primary Hyperaldosteronism

 Diagnostic screening test is measurement of plasma renin activity,plasma aldosterone and calculating plasma aldosterone-renin
IS

ratio (ARR)
 ARR screening is positive if the ratio is >750 pmol/L per ng/mL per hour
R

zz Treatment
CHAPTER 9  Endocrine Physiology

 For unilateral lesions - Laparoscopic adrenalectomy

C

 For bilateral adrenal hyperplasia – Aldosterone receptor antagonist drugs like spironolactone and eplerenone are useful

Glucocorticoid-Remediable Hyperaldosteronism
zz This is another important cause of primary aldosteronism

zz The cause is interesting where there is fusion between aldosterone synthase and 11β-hydroxylase and a “hybrid”enzyme is produced

zz What we know is ACTH can increase aldosterone only transiently. But in this condition, there is continuous elevation of aldosterone
levels by ACTH
zz This condition is inherited as autosomal dominant pattern

zz Treatment with low doses of dexamethasone inhibits ACTH and that ultimately inhibits aldosterone secretion

Secondary Hyperaldosteronism
zz In Secondary Hyperaldosteronism, the stimulus for aldosterone secretion comes from outside the adrenal gland
zz Most commonly it is due to excessive renin production by the juxtaglomerular apparatus of the kidney

zz Secondary hyperaldosteronism is characterized by high renin levels in contrast to primary hyperaldosteronism

338 Contd...
zz The causes of secondary hyperaldosteronism are,
 Renal artery stenosis

 Conditions that decreases intravascular volume like,

 Heart failure

 Chronic diuretic use

 Cirrhosis

 Nephrotic syndrome
C
 Bartter syndrome R
 Renal tubular acidosis
 Oral contraceptives I
Relation of Mineralocorticoid to Glucocorticoid Receptors – “Syndrome of Apparent Mineralocorticoid Excess (SAME)”
zz Cortisol has very high affinity for aldosterone mineralocorticoid receptor
S
zz But cortisol doesn’t act through mineralocorticoid receptor because of an enzyme 11β-hydroxysteroid dehydrogenase type 2 that
inactivates cortisol
P

e
zz If the enzyme, 11β-hydroxysteroid dehydrogenase type 2 is absent or inhibited, then cortisol can produce mineralocorticoid effects,

2/
The condition is called Syndrome of apparent mineralocorticoid excess (SAME)
zz Ingestion of licorice that contain glycyrrhetinic acid inhibits the enzyme 11β-HSD 2 and causes this syndrome

,
gy
Glucocorticoids –“ Cortisol”  Nephrosis
 Multiple myeloma
zz Cortisol is secreted mainly from the zona fasciculata
zz Half-life of cortisol in the circulation is about 60–90 min
Cortisol is considered to be a “stress hormone”
zz
zz
zz
It is a lifesaving hormone during stress lo
After release into the circulation, cortisol bind with its binding
Glucocorticoid Receptor
io
protein called as corticosteroid-binding globulin (CBG) or zz Free cortisol enters the cell directly and acts through nuclear
transcortin receptor
Cortisol is also generated inside the cell from inactive cortisone
sy

zz Corticosteroid-binding globulin (CBG) zz

 CBG is an α globulin produced from liver with the help of an enzyme termed as 11β-hydroxysteroid
 CBG levels are increased by estrogen dehydrogenase type 1 (11β-HSD1)
CBG levels (and therefore total serum cortisol levels) are In the absence of cortisol, its receptors is kept in inactive state
Ph

 zz
high during pregnancy at cytoplasm by binding with chaperone proteins (heat-shock
 CBG levels are depressed in, proteins)
 Cirrhosis zz Once the hormone binds, it gets activated and enter the nucleus
P
IS

Actions of Cortisol

Effect Mechanism Clinical features in Cushing

R

syndrome (Cortisol excess)

On carbohydrate • Cortisol is a “Hyperglycemic hormone” • Glucose intolerance
C

metabolism • It increases blood glucose mainly by neoglucogenesis • Diabetes mellitus

• Cortisol is anti-insulinic
• It increases the activity of Glucose-6-phosphatase
• Increases hepatic stores of glucose by promoting glycogenesis
• It decreases the utilization of glucose by cells
On protein • Cortisol is catabolic to proteins present in the muscle • Muscle weakness
metabolism • It releases alanine from muscle which is used for glucose production in • Proximal myopathy (steroid
neoglucogenesis myopathy)
• Cortisol is anabolic in liver. It increases the synthesis of plasma proteins
from liver
Theory

On fat • Cortisol is lipolytic • Dyslipidemia

metabolism • It Increase release of free fatty acids and glycerol • Weight gain, central obesity,
• It increases ketone body formation rounded face fat pad on back of
neck (“buffalo hump”)
Contd... 339
 Effect Mechanism Clinical features in Cushing
syndrome (Cortisol excess)
On immune • Cortisol is considered to be an universal anti-inflammatory agent • Increased susceptibility to
system • It inhibits the activity of phospholipase A2 infections
• It stabilizes the lysosomal membrane
C • It inhibits migration of circulating leucocytes to the site of inflammation
• It inhibits leukotrienes
R • It blocks the Inflammatory Response to Allergic Reactions
On blood cells • Cortisol decreases the blood levels of • Increased white blood cell count
I ƒƒ Eosinophils eosinopenia, hypercoagulation
ƒƒ Lymphocytes Increased risk of deep vein
S ƒƒ
ƒƒ
Basophils
Cortisol increases the blood levels of,
thrombosis and pulmonary
embolism
P ƒƒ
ƒƒ
Neutrophils
Monocytes

e
ƒƒ Platelets

2/
ƒƒ RBCs
Permissive action • Some amount of cortisol must be present for certain metabolic
reactions to occur but cortisol by itself doesn’t produce such reactions.
This effect is called permissive action

,
• Catecholamines action on lipolysis, bronchodilation, pressor responses

gy
requires the presence of cortisol
• Calorigenic action of glucagon requires the presence of cortisol
On nervous • Cortisol alters mood and behavior • Irritability
system • It increases appetite
lo • Emotional lability
• Depression
io
• Psychosis in severe cases
On heart • Cortisol increases cardiac output • Hypertension
• It Increases peripheral vascular tone • Hypokalemia
sy

• Edema
• Atherosclerosis
On kidney • It Increase glomerular filtration rate • Hypercalciuria
Ph

• It increases the excretion of calcium • Renal stones

• It Inhibits antidiuretic hormone secretion and action • Phosphaturia
• Inability to excrete water load
On bone • Cortisol increased bone resorption by increasing activity of osteoclasts • Osteopenia
• It inhibits bone formation by directly inhibit osteoblast bone-forming • Osteoporosis (vertebral fractures)
P

functions • Decreased linear growth in children

On connective • Cortisol inhibits fibroblast proliferation and collagen formation • Facial plethora
IS

tissues • Thin and brittle skin

• Easy bruising
• Delayed wound healing
R
CHAPTER 9  Endocrine Physiology

• Broad and purple stretch marks,

acne
C

• Hirsutism
On GI tract • Cortisol increase gastric acid secretion • Peptic ulcers
• It inhibits the intestinal absorption of calcium
• It increases the proliferation of GI mucosal epithelial cells (trophic
action)
On reproductive • Cortisol decreases the function of reproductive axis at hypothalamic, • In women – amenorrhea, infertility
system pituitary and gonadal levels • In men – loss of libido, impotence
• It inhibits the secretion of GnRH

  Medical Adrenalectomy
zz Certain drugs inhibit the synthesis of steroids from adrenal cortex. They are useful in treatment of Cushing's syndrome. Such drugs are,
 Aminoglutethimide – inhibits conversion of cholesterol to pregnenolone

 Mitotane
340  Ketoconozole

 Metyrapone
Adrenal Sex Steroids zz Dehydroepiandrosterone (DHEA) is converted to more potent
androgen testosterone in peripheral tissues like hair follicles,
zz Adrenal sex steroids produced from zona reticularis are,
breast
 Dehydroepiandrosterone (DHEA) – major one
 Dehydroepiandrosterone sulfate (DHEAS)
 Androstenedione Actions of Adrenal Androgens
Testosterone – only small amounts Since males have the more active androgens testosterone and
zz

“Dehydroepiandrosterone sulfate (DHEAS) is the most
zz
dihydrotestosterone, adrenal androgens have only weak effects
C
abundant circulating hormone in humans” But, in females, active androgens contributes about 50% of
zz Most important enzyme for adrenal sex steroid synthesis is
zz
circulating active androgens and is required for,
R
17,20-lyase activity of 17-Hydroxylase Axillary hair growth
zz Secretion of adrenal sex steroids are under the control of ACTH

 Pubic hair growth I
Libido

S
Clinical Importance of Adrenal Androgens–“Adrenogenital Syndrome” P

e
zz Adrenogenital Syndrome usually occurs due to an adrenocortical tumor that secretes excessive adrenal androgens

2/
zz It is also due to congenital adrenal hyperplasia
zz The predominant feature due to excessive adrenal androgens is Virilization
zz This condition is very devastating for a female. In Females, it causes female pseudo-hermaphroditism. Its clinical features are,

,
 Growth of beard

gy
 Deeper voice
 Masculine distribution of body hairs - Hirsuitism
 Baldness

zz
 Acne
 Clitoromegaly lo
In prepubertal boys, there is rapid development of male sexual organs (precocious pseudopuberty)
io
Adrenal Insufficiency (Hypoadrenalism) – “Addison’s Disease”
Adrenal Insuffciency is leads to insufficient secretion of adrenocortical hormones
sy

zz

zz It can be of two types,

 Primary adrenal Insuffciency

Ph

 Also called as Addison’s Disease

 Problem lies in adrenal gland itself
 Insufficient cortisol production leads to loss of negative feedback inhibition and increase in ACTH levels
 Secondary adrenal insufficiency
It is secondary to problems in pituitary or hypothalamus
P



 It is characterized by low levels of ACTH

Causes of Addison’s Disease
IS

zz Autoimmune adrenalitis
 This is the most common cause of Primary adrenal insufficiency
R

 It occurs as a part of autoimmune polyglandular syndromes (APS)

Autoimmune Polyglandular Syndromes (APS)

C

zz There are two types of APS. They are APS 1 and APS 2

zz APS 1

 Mainly caused by mutations in the autoimmune regulator gene (AIRE)

 It is also called as APECED - autoimmune polyendocrinopathy-candidiasisectodermal dystrophy

 It is inherited as autosomal recessive pattern

 APS 1 is responsible for 10 % case of Addison’s disease

zz APS 2

 It is much more common

 Associated with HLA-DR3

Theory

 Important features of APS 2 are,

 Adrenal insufficiency
 Thyroid autoimmune diseases
 Vitiligo
 Premature ovarian failure 341
Contd...
 Tuberculous Adrenalitis
zz A very frequent cause of Addison’s disease in developing countries
zz It usually results from the hematogenous spread of systemic tuberculous infection

zz 50% of the patients show calcification of adrenal glands

AIDS-Related Adrenal Insufficiency

C zz Usually occurs in the late stage of HIV infection

zz It is commonly seen as a part of opportunistic infection in AIDS by pathogens like,

R  Cytomegalo virus (CMV) – most common

 Mycobacterium avium complex (MAC)

I  M tuberculosis

S  Toxoplasma gondii

Bilateral Adrenal Hemorrhage

P zz It usually presents as acute adrenal insufficiency in children

zz It usually occurs as part of Neisseria meningitidis infection in the form of Waterhouse–Friderichsen syndrome

e
zz Other important causes of adrenal hemorrhage leading to adrenal insufficiency are,

2/
 Anticoagulant therapy

 Adrenal vein thrombosis

 Adrenal metastases

,
X-linked Adrenoleukodystrophy

gy
zz This condition is due to mutations in the X-ALD gene that normally codes for peroxisomal membrane transporter protein ABCD1

zz Peroxisomes are involved in oxidation of long chain and very long chain fatty acids

lo
zz Because of defective peroxisomal function, this condition is characterized by accumulation of very long chain fatty acids

zz In 15 % of cases, adrenal insufficiency is the sole manifestation of this disease

io
Addison’s disease
Clinical Features of Addison’s Disease
sy

Due to mineralocorticoid deficiency • Hyponatremia (80% of patients)

• Hyperkalemia
Ph

• Postural hypotension
• Small heart
• Abdominal pain
• Nausea
• Vomiting
P

Due to glucocorticoid deficiency • Hypoglycemia

IS

• Fatigue
• Weight loss
• Myalgia
R

• Anorexia
CHAPTER 9  Endocrine Physiology

• Normochromic anemia
• Lymphocytosis
C

• Eosinophilia
• Hypoglycemia
Due to adrenal androgen deficiency • Lack of energy
• Dry and itchy skin in women
• Loss of libido in women
• Loss of axillary and pubic hair in women

Other Important Symptoms

Hyperpigmentation
zz Since ACTH is derived from POMC, it has some intrinsic Melanocyte stimulating hormone (MSH) action

zz Very high levels of ACTH in Addison’s disease causes hyperpigmentation seen in,

 Skin creases
342
Contd...
  Nail beds
 Pressure points like knuckles, toes, elbows, and knees
 Buccal mucosa

 Gums

 Such hyperpigmentation is increased by exposure to sunlight

zz In secondary adrenal insufficiency, because of low levels of ACTH, there is paleness of skin C
Addisonian Crisis
zz In patients of Addison’s disease, levels of cortisol doesn’t increase during stressful situations like trauma, surgical operations R
zz They develop severe hypotension and shock termed as Addisonian Crisis

Diagnosis of Adrenal Insufficiency

I
zz ACTH stimulation test

 This test is the commonly accepted first line test for diagnosing adrenal insufficiency
S
 In this test, cosyntropin (ACTH 1-24), 0.25 mg is injected and blood samples are collected at 0, 30, and 60 min for cortisol estimation P
 The cut-off for adrenal insufficiency is cortisol levels of <18–20 μg/dL sampled 30–60 min after ACTH stimulation

e
zz Insulin tolerance test

2/
 This test is based on evoking hypoglycemia after injection of regular insulin 0.1 U/kg IV

 As a part of compensatory response, in normal individuals, cortisol must rise

 Normal response is defined as a rise in cortisol >20 μg/dL

,
 Elevated plasma renin levels – mineralocorticoid deficiency

gy
 Estimation of plasma ACTH levels
 Adrenal imaging by CT – to find out hemorrhagic, metastases as causes
Treatment of Adrenal Insufficiency
zz Involves replacement of “lifesaving” adrenocortical hormones
zz For acute adrenal insufficiency
lo
io
 Immediate rehydration by saline infusion (1L/hr)

 Glucocorticoid replacement - 100–200 mg hydrocortisone

sy

 Such high doses of hydrocortisone also provide adequate stimulation of mineralocorticoid receptors

zz For chronic adrenal insufficiency

 Glucocorticoid replacement - 15–25 mg hydrocortisone twice or thrice daily

Ph

 Mineralocorticoid replacement - 100–150 μg fludrocortisone

 Adrenal androgen replacement - Indicated mainly in women. Usually 25–50 mg DHEA is given
P

Adrenal Medulla
IS

zz Adrenal medulla constitutes 28% of adrenal gland

zz Hormones produced by adrenal medulla are the catecholamines namely,
 Epinephrine (90%)
R

 Nor epinephrine (10%)

 Dopamine
C

zz Catecholamine hormones are produced by the chromaffin cells of adrenal medulla

zz Chromaffin cells
 Are neural crest derivatives
 They are also called as phaeochromocytes)
 They are functionally similar to a post ganglionic neuron. The difference is that they don’t have dendrites and axons
 Chromaffin cells are exposed to high concentration of cortisol
 It is the cortisol that inhibits the neuronal differentiation of chromaffin cell to form dendrites and axons
 Instead, chromaffin cells of adrenal medulla releases catecholamines directly into the blood stream
 Chromaffin cells are present in locations other than adrenal medulla
Theory

 The largest extraadrenal Chromaffin cells lie along the sides of abdominal aorta and are termed as para-aortic bodies or organ of
Zuckerkandl

343
C
R
I
S
P

e
Regulation by Adrenal medulla

, 2/
High Yield Points

gy
Substances other than catecholamines produced by adrenal
medulla are,
zz Chromogranin A

zz ATP
lo
io
zz Opioid peptides like met – encephalin

zz Adrenomedullin - vasodilator
sy

Clinical Importance of Chromogranin A

Ph

Metabolism of Catecholamines
zz Chromogranin A is located in the secretory vesicles of neural zz Half-life of catecholamines is about 2 minutes
and endocrine cells zz Two groups of enzymes are involved in degradation of
It is elevated in pheochromocytoma catecholamines. They are,
P

zz
zz It is useful as a neuroendocrine marker of small-cell lung cancer  Monoamine oxidase (MAO)
Catechol-O-methyltransferase (COMT)
IS

(SCLC) 

zz It is useful as a tumor marker for Gastro intestinal and zz Major urinary excretion products of catecholamines are,
Pancreatic neuroendocrine tumors (NETs)  Vanillylmandelic acid (VMA)
R

 Metanephrine
CHAPTER 9  Endocrine Physiology

 Normetanephrine
Synthesis of Catecholamines
C

Actions of Epinephrine and

zz Catecholamines are synthesized from the amino acid “Tyrosine”
zz The rate limiting step of catecholamine synthesis is Tyrosine
Norepinephrine
Hydroxylase – The drug Metyrosine is the competitive inhibi- zz Epinephrine and norepinephrine acts through α- and
tor of tyrosine Hydroxylase β-adrenergic receptors
zz Tyrosine Hydroxylase requires tetrahydropteridine as a cofactor zz α-Receptors are divided into two groups namely α1 and α2
receptors
zz Epinephrine is the methylated product of nor epinephrine
zz β-receptors into three groups, β1, β2, and β3 receptors
zz The enzyme required for epinephrine synthesis is
Phenylethanolamine-N-Methyltransferase (PNMT) Effect on Carbohydrate Metabolism
zz Other than adrenal medulla, a special group of cells termed
zz Epinephrine is a hyperglycemic hormone. It increases blood
intrinsic cardiac adrenergic (ICA) cells also secretes epinephrine
glucose by,
 Stimulating glycogenolysis (through β2 receptors)
344
 Effect on Epinephrine Norepinephrine
 Increases glucose production through neoglucogenesis
Blood pressure Mild increase Markedly increase
 Inhibiting secretion of insulin (α2 action)
 Promoting the secretion of glucagon (β2 action) Heart rate Increases Decreases (reflex
bradycardia)
Effect on Lipid Metabolism Cardiac output Increases Decreases
zz Catecholamines promote lipolysis in adipose tissue by
stimulating hormone-sensitive lipase
Peripheral
resistance
Decreases Markedly increase C
zz Under the influence of catecholamines, free fatty acids are used
as energy resources mainly
R
Effect on Central Nervous System
zz They also cause increase in hepatic ketogenesis
zz Catecholamines increase alertness by activating reticular
I
Effect on Basal Metabolic Rate activating system (RAS)
S
zz Norepinephrine and epinephrine rise the basal metabolic rate Effect on Respiration
zz They increases body heat by cutaneous vasoconstriction that P
Epinephrine relaxes smooth muscles of bronchioles producing

e
zz
minimizes the heat loss
bronchodilation (β2 receptors)

2/
Effect on Cardiovascular System
Effect on GI Tract
zz Norepinephrine and epinephrine increase the force and rate of
zz Catecholamines causes relaxation of smooth muscles of wall of
cardiac contraction

,
the gut (β action)
They also increases the myocardial excitability

gy
zz
zz They causes contraction of sphincters of gut (α action)
zz Norepinephrine produces vasoconstriction (through α1 action)
zz Epinephrine causes vasodilation mainly in liver and skeletal Effect on Eyes
muscle through β2 action
zz If the subject is given α blocker and then if epinephrine is lo
injected, vasodilation and decrease in BP is seen. This effect is
zz
zz
Epinephrine causes dilation of pupil – Mydraiasis
It also causes relaxation of the ciliary muscle – flattening of lens
io
and improving the focus for farther objects
called “Vasomotor reversal of Dale”
sy

  Effects of Dopamine
zz Injected dopamine causes,
Ph

 Renal vasodilation

 Mesenteric vasodilation

 Increase in force of cardiac contraction – positive inotropy. This effect is mediated through β1-adrenergic receptors

 Increase in systolic blood pressure

P

 Inhibits renal Na, K, ATPase – leading to natriuresis

zz Dopamine is useful in treatment of heart failure and cardiogenic shock for its positive inotropic action
IS
R

“Catecholamine Producing Adrenal Tumors– Pheochromocytomas”

C

zz Pheochromocytoma derives its name from the black-colored staining caused by chromaffin oxidation of catecholamines
Pheochromocytoma – “10 % Tumor”
zz 10% - pheochromocytoma – malignant
zz 10% - in children

zz 10% - bilateral

zz 10% - familial (gene mutations in TMEM127, MAX, and SDHA)

zz 10% - multiple

zz 10 % - recur
Theory

zz 10 % - in persons without hypertension

Pheochromocytoma Assocoiated Syndromes

zz About 25 – 30% of Pheochromocytoma is associated with certain inherited syndromes. They are,
 Multiple endocrine neoplasia type 2 (MEN2)

 They are two type of MEN 2 syndrome. They are MEN2A and MEN2B 345
Contd...
  MEN2A is associated with,
— Medullary thyroid carcinoma (MTC)
— Pheochromocytoma (occurs in only 50% of these patients)
— Hyperparathyroidism
 MEN2B is associated with,
— MTC
C — Pheochromocytoma (occurs in only 50% of these patients)
— multiple mucosal neuromas
R — Marfanoid features
Von Hippel–Lindau syndrome (VHL)
I 

 VHL is an autosomal dominant disorder

S  This condition is associated with increased expression of vascular endothelial growth factor (VEGF) leading to angiogenesis
(new blood vessel formation)
P  Important features of VHL are,
— Cerebellar hemangioblastomas

e
— Pheochromocytoma (seen in 20 – 30 % of patients)
— clear cell renal carcinoma

2/
— pancreatic neuroendocrine tumors
— endolymphatic sac tumors of the inner ear
— Pancreatic and renal cysts – multiple

,
Neurofibromatosis type 1 (NF1)

gy


 NF1 was the first described pheochromocytoma syndrome

 NF1 is characterized by,
— multiple neurofibromas
— café au lait spots
— axillary freckling of the skin
lo
io
— Lisch nodules (iris)
— Pheochromocytoma (seen in 1% of patients)
sy

 Paraganglioma syndromes

Clinical Features of Pheochromocytoma

zz Excess levels of catecholamines in this condition causes,
Ph

 Hypertension – Dominant sign

 Headache

 Profuse sweating

 Palpitations and tachycardia

P

 Anxiety

 Weight loss
IS

 Erythrocytosis

 Elevated blood sugar

 Hypercalcemia
R
CHAPTER 9  Endocrine Physiology

 Panic attacks – Fear of death termed as “angor animi”

C

Diagnostic Tests
zz Measurement of 24 hour urinary estimation of

 Catecholamines

 Fractionated metanephrines

 Total metanephrines

zz Measurement of Plasma levels of Catecholamines and free metanephrines

zz Imaging tests like contrast enhanced CT and MRI

zz Metaiodobenzylguanidine (MIBG) scintigraphy

zz Somatostatin receptor scintigraphy

zz Fluoro-DOPA PET/CT
Treatment
zz Complete tumor removal by partial or total adrenalectomy

zz Preoperative administration of α1 receptor blocker phenoxybenzamine helps to control hypertension

346
CALCIUM HOMEOSTASIS AND THE Remember!
PHYSIOLOGY OF BONE
Important dietary sources of calcium
zz Normal serum calcium levels are 8.7–10.2 mg/dL. It is tightly
zz Best sources are milk and milk products
regulated with in this range
zz Other sources of calcium are,

ƒƒ Green leafy vegetables C

ƒƒ Cereals – Ragi is an important source
ƒƒ Vegetables – Sitaphal R
ƒƒ Drinking water – provides around 200 mg/
day I
S
Factors Affecting Absorption of
Calcium from GI Tract P

e
zz Active calcium absorption occurs mainly in the proximal small

2/
bowel (duodenum and proximal jejunum)
zz Absorption of calcium is facilitated by,
 Gastric acid
 Proteins in diet

,
zz Free calcium or ionized calcium is responsible for all the zz Absorption of calcium is inhibited by,

gy
important actions of calcium like,  Phytates
 Second messenger  Phosphates Forms insoluble
Blood coagulation (calcium is clotting factor IV) Oxalates calcium salts


 Muscle contraction
Exocytosis
lo 
 Fatty acids in diet

Physiology of Bone
io


 Nerve function
zz Adult human body contains around 1100 g of calcium
sy

Factors Affecting Distribution of zz Out of this, 99% of calcium resides in bones

Calcium zz Calcium is present along with phosphate in the form of
hydroxyapatites (Ca10 (PO4)6 (OH)2) in bones
Ph

zz Serum protein concentration

 Alterations in the binding protein levels directly affect total Composition of Bone
calcium levels
zz Bone is composed of two important components. They are,
 An increase in serum albumin levels by 1g/dl increases  Organic matrix – also called as osteoid
P

protein bound calcium by 0.8 mg/dl  Bone salts

zz pH changes and calcium levels
IS

 Alkalosis (increase in pH) increases the protein bound

calcium. This can lead to hypocalcemic tetany
Acidosis (decrease in pH) on the other hand, decreases
R


protein bound calcium and increases the free calcium
leading to hypercalcemia
C

Recommended Dietary Allowances (RDA) for Calcium

Group Calcium (mg/day)

Men and women 600
Pregnant women 1200
Lactating mother 1200
Infants (up to 1 year) 500
Theory

Children (1-3 years) 600

Boys and girls 800

Composition of bone 347

 Organic Matrix zz They are mainly derived from cells of mesenchymal origin
zz Important transcription factors required for osteoblast
zz Unmineralized organic portion of bone is called osteoid development are,
zz 90 – 95% of organic matrix is comprised of collagen type I  Runx2
zz It also contains proteins such as,  Bone morphogenic proteins (BMPs)
 Albumin  Indian hedgehog (Ihh)
C  Thrombospondin
Clinical Importance of Transcription
 Osteopontin
R  Fibronectin Factor Runx2
 Calcium binding proteins called as matrix gla protein,
I osteocalcin zz Runx2 regulates the expression of several important osteoblast
Proteoglycans proteins like,
S 
 Osterix

Bone Salts  Osteopontin

P zz Mainly composed of Calcium phosphate hydroxyapatites  Bone sialoprotein

e
(Ca10(PO4)6(OH)2) crystals  Type I collagen

 Osteocalcin

2/
zz Also contains magnesium, sodium, potassium, and carbonate
ions  Receptor-activator of NFκB ligand (RANKL)

zz Mutation in Runx2 causes cleidocranial dysplasia characterized

Types of Bone by hypoplasia or aplasia of clavicles and short stature

,
gy
zz There are two types of bones namely’
 Cortical bone zz Hormones that regulates osteoblast functions are,
 Also called as compact bone – it is the outer layer of  Parathormone (PTH)
 Vitamin – D


bones
Constitutes 80 % of the bone
Has low surface-to-volume ratio
lo  Insulin like growth factors (IGFs)

Osteocytes
io
 It receives nutrients through Haversian canals
 Collagen (Type I) is arranged in concentric layers zz Osteocytes are formed when an osteoblast becomes embedded
sy

around these canals forming osteons in the material it has secreted

 Trabecular bone zz They communicates with the surface osteoblasts through a
 Also called as cancellous or spongy bone series of canaliculi
Ph

 Is more metabolically active zz Osteocytes are the most abundant cells in bone
 Constitutes 20 % of the bone zz They are the major source of fibroblast growth factor 23
 It is present inside the cortical bone (FGF23) that regulates serum phosphate levels
zz Osteocytes produce a substance by name “sclerostin (SOST)”
 Has low surface-to-volume ratio
that inhibits the differentiation of osteoblasts which ultimately
P

Types of Cells in Bone zz

inhibits bone formation
Loss of function mutation of sclerostin gene leads to a condition
IS

There are three types of cells present in bone. They are, called sclerosteosis which is characterized by excessive bone
zz Osteoblasts mass
zz Osteocytes
R

Osteoclasts Osteoclasts
CHAPTER 9  Endocrine Physiology

zz

zz Osteoclasts are considered to be the “bone resorption cells”

C

zz They are derived from hematopoietic lineage (different from

osteoblasts)
zz Osteoclast differentiation is facilitated by osteoblasts and
inhibited by osteoprotegerin (OPG)
zz Osteoclasts are multinucleated cells
zz Osteoclast mediated bone resorption
 Specific region in bone where osteoclast causes bone
resorption is called “Howship’s lacunae”
 Osteoclast function is very much similar to the function of
Cells in bone lysosomes of cell
 The inside of an osteoclast is highly acidic. This is because
of a proton pump present in its ruffled border
Osteoblasts  Carbonic anhydrase II(CA II) is present inside osteoclasts
zz Osteoblasts are the “bone forming cells”. They secrete the that provides the necessary H+ ions
348 organic matrix and aid in its mineralization
  Proteases like cathepsin K act at such low pH and facilitates zz Bone remodeling serves two important functions. They are,
the resorption process  Repair microdamage within the skeleton – maintain bone
 Mutations in cathepsin K leads to Pyknodysostosis where strength
osteoclasts are present but do not function normally  Supply calcium to maintain serum calcium

Osteocytes – “The Major Regulators of

Bone Remodeling”
C
zz Remodeling of bone occurs along lines of force generated by R
mechanical stress
zz Osteocytes are considered to be the “mechanosensors” of bone I
zz Osteocytes send signals to the surface osteoblasts that recruit
osteoclasts S
zz Once formed, osteoclast perform the function of bone resorption
zz After resorption, new osteoblasts fill the resorbed spaces to P

e
form new bone
zz Once the new born is formed and mineralized, osteoblast inside

2/
it becomes osteocyte

High Yield Points

,
gy
Bone Remodeling How osteoblasts recruit osteoclasts??
zzOsteoblasts aid the differentiation of osteoclasts
zz We discussed the cells in bone individually
by secreting,
But they interact to produce bone remodeling
zz
zz Bone is a highly dynamic tissue that is constantly remodeled
throughout life
lo ƒƒ Macrophage colony-stimulating factor (M-CSF)
ƒƒ Receptor-activator of NFκB ligand (RANKL)
io
zz Compact bone renew at the rate of 4% per year for and trabecular that binds with RANK receptor in osteoclasts
bone renew at the rate of 20% per year
sy

Regulation of Bone Remodeling

Ph
P
IS
R
C

Parathormone and Vitamin – D zz It inhibits the function of osteoclasts and inhibit bone resorption
zz Major hormones like Parathormone and Vitamin – D don’t have
receptor in osteoclast (must know concept)
Estrogen
zz They activate osteoclast only indirectly through osteoblast zz Estrogen has receptor in both osteoblasts and osteoclasts
Theory

activation. Once activated, osteoblast releases paracrine factors zz Major actions of estrogen on bone are,
like M-CSF and RANKL that promotes the differentiation and  Inhibits bone resorption by,
further actions of osteoclast  Inducing apoptosis of osteoclasts
 Inhibiting differentiation, recruitment and activity of
Calcitonin osteoclasts by inhibiting RANKL and increasing the
production of osteoprotegerin 349
zz Calcitonin has receptor in osteoclasts  Increases osteoblast proliferation
 Increases synthesis of matrix proteins
 Remember!
Markers of bone turnover
zzBiochemical markers of bone formation and bone resorption are useful in diagnosis of osteoporosis
Bone formation (Osteoblast derived) markers are,
C zz Amino terminal propeptide of type I collagen (PIMP) — most preferred
zz Carboxy terminal propeptide of type I collagen (PICP)
R zz Osteocalcin

zz Bone specific alkaline phosphatase

I Bone resorption (Osteoclast derived) markers are,
S zz C-telopeptide (CTX)
zz N-telopeptide (NTX)

P zz Pyridinoline (PYD)

zz Deoxypyridinoline (DYD)

e
2/
Distraction Osteogenesis
zz Under the effect of slow and gradual distraction, bone and soft tissue would regenerate

,
This is the basic principle behind Ilizarov technique

gy
zz
zz Pulling the bone apart using Ilizarov fixator aids in regeneration of bone
zz Ilizarov technique is useful in treatment of,
 Fracture non-union


Limb length discrepancies
Blount’s Disease - growth disorder of the tibia lo
io
 Hypophosphatemic Rickets

Important Disorders of Bone Remodeling

sy

Excessive bone resorption – “Osteoporosis”

Ph

zz Osteoporosis is characterized by excessive osteoclast function leading to bone loss. There is marked loss of bone organic matrix. It is
characterized by severe impairment of osteoclast-mediated bone resorption
zz Fractures of vertebra, distal forearm (Colles fracture), hip are more common

zz This condition is very common in post-menopausal women due to estrogen deficiency

P

zz Important endocrine disorders associated with osteoporosis are Diabetes mellitus, Cushing’s syndrome, Hyperparathyroidism,
Thyrotoxicosis and Hyperprolactinemia
IS

zz Lack of physical activity – an important cause of osteoporosis leading to bone loss

zz Osteoporosis also occurs as a consequence of alcohol abuse and cigarette smoking

zz Drugs that cause osteoporosis

R

 Glucocorticoids – most common cause

CHAPTER 9  Endocrine Physiology

 Immunosuppressants – cyclosporine and tacrolimus

C

 Selective serotonin reuptake inhibitors

 Aromatase inhibitors

 Proton pump inhibitors

zz Diagnosis of osteoporosis is established by estimating bone density using dual-energy x-ray absorptiometry (DXA) of lumbar spine and
hip
Excessive bone formation – “Osteopetrosis”
zz This disease is also called as marble bone disease or Albers-Schonberg disease
zz Hallmark of this disease causation is the overexpression of Osteoprotegerin

zz Major factor that regulates the differentiation of osteoclasts is RANKL. This Osteoprotegerin is an inhibitor of RANKL

zz Mutations in Carbonic anhydrase II and Proton pump gene TCIRG1 are other important causes of osteopetrosis

zz Clinical features of osteopetrosis include,

 Paralysis of cranial nerves due to narrowing of the cranial foramina

 Hypocalcemia
350
Contd...
  Hypersplenism
 Pancytopenia
zz Osteoclast-derived tartrate-resistant acid phosphatase (TRAP) are elevated in osteopetrosis
zz Radiologically, there is alternating sclerotic and lucent bands seen in the iliac crests and vertebral bodies termed as Rugger jersey spine
zz Treatment involves bone marrow transplantation
Paget’s Disease C
zz Paget’s Disease is characterized by overactive osteoclastic bone resorption followed by a compensatory increase in osteoblastic new
bone formation R
zz This sequence leads to disorganized bone remodeling

zz Recent evidences suggest that infection with measles-related virus may be involved in causation of Paget’s disease
I
zz Clinical features of Paget’s disease,

 Pain - most common presenting symptom

S
 Headaches

 Softening of the base of the skull (platybasia)

P

e
 Long bone fractures - femoral shaft and subtrochanteric (most common)

2/
 Cardiac enlargement

 Calcific aortic stenosis

zz Paget’s Disease is characterized by elevated levels of alkaline phosphatase (ALP)

,
zz Treatment involves use of bisphosphonates and calcitonin

gy
  Drugs useful in treatment of bone disorders
lo
io
Bisphosphonates
zz Bisphosphonates are potent inhibitors of bone resorption. They also increase bone density
zz Important drugs in this group are,
sy

 Alendronate

 Risedronate
Ph

 Ibandronate

 Zoledronate

zz Alendronate and risedronate in particular, inhibit the farnesyl pyrophosphate synthase, involved in the mevalonate pathway. This
pathway is very important for survival of osteoclasts
zz Bisphosphonates are useful in treatment of,
P

 Osteoporosis

 Paget’s disease
IS

 Hypercalcemia of malignancy

zz Major adverse effect of these group of drugs are esophageal and gastric irritation
R

Denosumab
zz Denosumab is the human monoclonal antibody that is an inhibitor of RANKL
C

zz RANKL induces osteoclast differentiation

zz By inhibiting RANKL, Denosumab inhibits osteoclast formation and activity

zz It is useful in treatment of postmenopausal osteoporosis

Plicamycin
zz Plicamycin is also called as Mithramycin which is a cytotoxic antibiotic that interrupts DNA-directed RNA synthesis

zz It is useful in treatment of Paget’s disease and hypercalcemia

Strontium Ranelate
zz This drug promotes bone formation and inhibits bone resorption

zz It is useful in treatment of osteoporosis

Theory

Selective estrogen receptor modulators (SERM)

zz SERM drugs useful for the treatment of osteoporosis are,

 Raloxifene

 Tamoxifen

 Bazedoxifene/conjugated estrogen
351
 Remember!
Regulation of Serum Calcium Levels
zz Normal serum calcium levels are 8.7–10.2 mg/dL and it is tightly regulated within this range
zz Regulation of serum calcium levels can be understood with the help of this theme “Three Hormone – Three
organ”
C Three major hormones that regulate calcium levels are,
zz Parthormone
R zz Vitamin D
zz Calcitonin
I Three major body organs that aids in regulation of calcium levels are,
zz Bone
S zz Intestine
zz Kidney
P Three major hormones that regulate calcium levels are,
zz Parathormone

e
zz Vitamin D

2/
zz Calcitonin
Three major body organs that aids in regulation of calcium levels are,
zz Bone
zz Intestine

,
gy
zz Kidney

Parathormone (PTH) lo
io
zz Parathormone is produced from the parathyroid glands
zz Humans have four parathyroid glands located on the posterior surface of thyroid gland
sy

Parathyroid Histology
Ph
P
IS
R
CHAPTER 9  Endocrine Physiology

Parathyroid glands and its histology

zz Parathyroid glands are derived from third (Inferior parathyroid) and fourth (Superior parathyroid) pharyngeal pouches
zz Two types of cells are present in parathyroid glands. They are,
 Chief cells
 Most abundant cells that synthesize and secrete PTH
 Also called as principal cell
 Oxyphil cells
 Less abundant large cells with large number of mitochondria

Synthesis and Secretion of PTH

352 zz PTH is a large protein hormone containing 84 amino acids
zz Like all the other protein hormones, PTH is synthesized in Clinical Importance of PTH Receptors –
rough endoplasmic reticulum as preprohormone, modified
and packed in secretory vesicles in Golgi and finally released “Jansen’s Disease”
by exocytosis
zz Jansen’s Disease is due to activating mutations in PTH/PTHrP
zz Normal plasma level of PTH is 10–55 pg/ml
zz Half-life of PTH is 10 minutes receptor (PTH1R)
zz This condition is characterized by Hypercalcemia and C
Regulation of PTH Secretion hypophosphatemia with undetectable or low PTH levels
zz By far, the most important stimulus that increases PTH secretion
zz Abnormalities in bone are noted in this condition leading to R
is hypocalcemia short-limbed dwarfism
zz On the other hand, high calcium levels suppresses PTH secretion I
Ultimately, it is the ECF calcium levels that control PTH
zz
secretion
Actions of Parathormone (PTH) S
zz Calcium regulates PTH secretion by acting on its receptor called zz Parathormone is a calciotropic hormone that increases serum
Calcium sensing receptor (CaSR) calcium levels P

e
zz Calcium sensing receptor (CaSR) zz Out of the three organs, PTH acts directly in bone and kidney
 CaSR is a G-protein–coupled receptor present in chief cells but only indirectly in intestine

2/
of parathyroids
 Normally, calcium acting through this receptor inhibits PTH Actions on Bone
PTH secretion
zz PTH acts directly on bone to increase bone resorption mainly

,
 So, automatically when calcium levels are low, the
zz PTH receptors are only present in osteoblasts

gy
inhibition is relieved and PTH secretion is increased
zz Since the bone resorption cells osteoclasts don’t have receptors
 Other than parathyroids, CaSR is also present in
for PTH, it activates osteoclasts through initial activation of
 Calcitonin-producing C cells of thyroid
osteoblasts
Renal tubules

 Brain lo zz PTH activates osteoblasts which secretes M- CSF and RANKL
that aids in differentiation of osteoclasts
io
Calcium Sensing Receptor (CaSR) in zz Osteoclast mediated bone resorption ultimately increase serum
calcium levels
Pharmacology – The Drug “Cinacalcet”
sy

Continuous Administration vs Intermediate

zz Cinacalcet is the calcimimetic drug that activates the calcium- Administration of PTH
sensing receptor (CaSR)
Continuous administration of PTH promotes bone resorption
Ph

zz
zz This action ultimately inhibits PTH secretion
zz But intermittent administration of PTH leads to a net
zz Cinacalcet is useful in treatment of,
stimulation of bone formation rather than bone breakdown
 Secondary hyperparathyroidism in chronic kidney disease
zz Intermittent administration of PTH is used to prevent bone
 Parathyroid carcinoma resorption in osteoporosis. The drug is called “Teriparatide”
P

Clinical importance of Calcium sensing receptor – “Familial

Hypocalciuric Hypercalcemia (FHH)”
 Teriparatide
IS

zz Familial Hypocalciuric Hypercalcemia (FHH) is due to

inactivating mutations of CaSR
zz It is the recombinant form of PTH 1-34
zz Because of this mutation, there is exaggerated PTH secretion
R

zz It is given in dosage of 20 mcg subcutaneously daily for

leading to Hyperparathyroidism like state
treatment of osteoporosis
zz This condition is characterized by enhanced renal calcium
C

resorption leading to hypercalcemia

PTH Actions on Kidney
Parathormone (PTH) Receptors PTH acts directly in renal tubules to,
zz PTH produces all its actions by acting through three types of zz Increase calcium resorption from distal tubules through TRPV5
receptor zz Stimulation of renal 1α-hydroxylase enzyme activity
 PTH/PTHrP receptor zz Increase phosphate excretion from proximal tubules –
 This receptor is also called PTH-1 receptor “phosphaturic action”
 This receptor also binds parathyroid hormone–  PTH increases phosphate excretion by inhibiting the
sodium-phosphate cotransporter (NaPi-IIa) present in
Theory

related protein (PTHrP)

 PTH2 receptor proximal convoluted tubule
This receptor only binds PTH
PTH Actions on Intestine

 It is present in brain, placenta, and pancreas
 CPTH receptor zz As already stated, this action of PTH is indirect
 This receptor binds the carboxyl terminal of PTH zz PTH increases calcium absorption in the intestine by stimulating 353
the production of Vitamin D
 Disorders of Parathormone (PTH) Secretion
Hyperparathyroidism
zz Increased secretion of PTH is seen in hyperparathyroidism
C zz This disease can be,

 Primary hyperparathyroidism – due to problems in parathyroid gland itself

R  Secondary hyperparathyroidism – Here secondary increase in PTH is due to other organ problems (commonly kidney)

 Tertiary hyperparathyroidism – develops after a prolonged period of Secondary hyperparathyroidism

I Primary Hyperparathyroidism
zz The classical hallmark of this disease is elevated levels of PTH accompanied by hypercalcemia and hypophosphatemia
S zz Causes of Primary hyperparathyroidism

P  Solitary adenomas of chief cells – most common(80% of patients)

 As a part of Hereditary Syndromes like,

e
 Multiple endocrine neoplasia (MEN) syndrome – seen in MEN 1 (Wermer’s syndrome) and MEN2A

2/
 Hyperparathyroidism jaw tumor (HPT-JT) syndrome – associated with benign jaw tumors
zz Clinical features
 Majority of the features are due to elevated calcium levels

 The organs predominantly affected are kidney and bones

,
gy
 Renal manifestations

 Renal stones - calcium oxalate or calcium phosphate

 If the stone is large – urinary tract obstruction




Skeletal manifestations
It is called osteitis fibrosa cystica
lo
Polyuria and polydipsia due to urine concentrating defects
io


 It is characterized by increase in osteoclasts leading to subperiosteal resorption, osteoporosis and pathological fractures
GI manifestations (called as abdominal groans)
sy



 Peptic ulcer disease

 Constipation
Pancreatitis
Ph



 Neuropsychiatric manifestations (called as psychiatric moans)

 Depression
 Memory loss
 Poor concentration
P

 Fatigue
Tretamnent
IS



 Surgical resection of the adenoma is the definitive treatment of choice

 Drugs like bisphosphonates and calcimimetics are also useful
R

Secondary Hyperparathyroidism
CHAPTER 9  Endocrine Physiology

zz This condition is characterized by adaptive increase in PTH levels due to hypocalcemia

C

zz Associated with hypocalcemia and hyperphosphatemia

zz This is commonly seen in chronic kidney diseases and osteomalacia

zz This condition is typically reversible once the underlying cause is treated

zz Reduction in vitamin D levels due to fibroblast growth factor (FGF – 23) is another major stimulus for increase in PTH in secondary
hyperparathyroidism
zz Bone and kidney are predominantly affected leading to renal osteodystrophy

zz Treatment involves reduction of serum phosphate levels, Vitamin D analogues and cinacalcet

Tertiary Hyperparathyroidism
zz This condition develops after a long period of secondary hyperparathyroidism
zz Hallmark of this disease is unregulated parathyroid function leading to high levels of PTH and hypercalcemia

zz This condition won’t respond to any medical therapy

zz Treatment is surgical – parathyroid surgery

354 Contd...
Summary of Hyperparathyroidism
Parameters Primary Secondary Tertiary
hyperparathyroidism hyperparathyroidism hyperparathyroidism
Serum calcium Increase Decrease Increase
Serum phosphate Decrease Increase Increase
PTH Increase Increase Increase
C
Hypoparathyroidism
R
zz The causes of hypoparathyroidism can be,
 Hereditary
I
 Acquired S
Hereditary Causes
zz Hypoparathyroidism is associated with the following conditions, P

e
 DiGeorge syndrome – associated with problems in thymus and parathyroids

 Hypoparathyroidism, deafness, and renal dysplasia (HDR)

2/
 Kenney-Caffey syndrome – features includes hypoparathyroidism, short stature, osteosclerosis

 Mitochondrial dysfunction disorders like Kearns-Sayre syndrome (KSS) and MELAS syndrome

 Bartter’s syndrome

,
Acquired Causes

gy
zz Mainly due to inadvertent surgical removal of parathyroids during thyroid surgeries

zz Transient hypoparathyroidism – occurs after parathyroid surgeries

Clinical Features of Hypoparathyroidism

lo
zz Hall mark of hypoparathyroidism is hypocalcemia and hyperphosphatemia
zz Features of hypocalcemia are,
io
 Hypocalcemic tetany – there is increase in neuronal excitability leading to spontaneous tonic muscular contractions
 Reason for hyperexcitability is that low serum calcium levels moves more sodium ions entry into the cell leading to more frequent
action potential generation
sy

 Carpopedal spasm – There is flexion at metacarpophalangeal joints, extension at interphalangeal joint and opposition of thumb.
This deformity is also called obstetric hand
 Trousseau’s sign - Carpopedal spasm is evoked by occluding the blood supply to a limb by inflation of a sphygmomanometer cuff 20
Ph

mmHg above the patient’s systolic blood pressure for 3 min

 Chvostek’s sign - tapping the facial nerve at the angle of jaw leads to twitching of facial muscles
 Paresthesia of fingers, toes and circumoral regions

 prolongation of QT interval
Treatment
P

zz Acute hypocalcemia is managed with intravenous injection of 10 ml calcium gluconate diluted in 50 mL of 5% dextrose or 0.9% sodium
chloride injected over 5 minutes
IS

zz Chronic hypocalcemia due to hypoparathyroidism is managed with calcium supplements and vitamin D

Pseudohypoparathyroidism (PHP)
R

zz In this condition, PTH levels are usually elevated, but the ability of target tissues (particularly kidney) to respond to the hormone is
defective
C

zz There are three types of Pseudohypoparathyroidism (PHP) namely,

 PHP - IA

 PHP - IB

 PHP - II

zz Hallmark of this condition is Hypocalcemia and Hyperphosphatemia

zz PHP – IA is particularly associated with Albright’s hereditary osteodystrophy (AHO). This condition AHO is mainly due to reduced Gsα
protein activity due to mutation in GNAS gene
zz Important features of Albright’s hereditary osteodystrophy includes,

 Short stature
Theory

 Obesity

 Mental retardation

 Round facies

 Shortened fourth and fifth metacarpal and metatarsal bones

 Subcutaneous ossifications
355
Contd...
 zz Treatment of Pseudohypoparathyroidism is very similar to hypoparathyroidism except that doses of calcium and vitamin D are very
higher
Pseudopseudohypoparathyroidism (PPHP)
zz This condition is very similar to Pseudohypoparathyroidism but the biochemical parameters are normal
Summary of Hypoparathyroidism
C
Parameters Hypoparathyroidism Pseudohypoparathyroidism Pseudopseudo
R hypoparathyroidism

I Serum calcium Decrease Decrease Normal

Serum phosphate Increase Increase Normal
S PTH Decrease Increase Normal

e
VITAMIN D zz More specifically, it is the ultraviolet – B (UV-B) of a particular

2/
wavelength 280 – 320 nm is very essential for synthesis of
zz The active form of vitamin D is called vitamin D
1,25-dihydroxycholecalciferol or calcitriol zz The precursor present in skin on which UV – B rays act is called
Calcitriol increases serum calcium levels. It is one of the major

,
zz 7-dehydrocholesterol

gy
calciotropic hormones zz Highest concentration of 7-dehydrocholesterol is present in
malphigian layer of skin
Sources of Vitamin D zz 7-dehydrocholesterol is converted to Vitamin D3 or
zz
zz
The most important source of vitamin D is the sunlight
Only if the sunlight exposure is inadequate, dietary sources
becomes important
lo cholecalciferol by the action of UV-B rays

Role of Liver
io
zz Important dietary sources of vitamin D are, zz Vitamin D3 is transported in blood using vitamin D-binding
 Fish (Halibut) liver oils – richest source protein (DBP)
sy

 Liver zz In the liver, Vitamin D3 is 25-hydroxylated by an enzyme called

 Egg yolk 25-Hydroxylase
zz The product from liver is called 25-hydroxycholecalciferol or
Butter and cheese
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calcidiol
zz Vitamin D from plant sources is in the form of vitamin D2
whereas in animal sources, it is D3
Role of Kidney
Synthesis of Vitamin D – “The Sunshine zz 25-hydroxycholecalciferol is converted in the cells of the
P

proximal tubules of the kidneys to the active product called

Vitamin” 1,25-dihydroxycholecalciferol or calcitriol
IS

zz The responsible for this hydroxylation is called 1α-Hydroxylase

Role of Skin zz Rate limiting step in vitamin D synthesis is the formation of
calcitriol by the enzyme 1α-Hydroxylase
R

Major inducers of 1α-Hydroxylase enzyme are PTH and

CHAPTER 9  Endocrine Physiology

zz
hypophosphatemia
C

zz Major inhibitors of 1α-Hydroxylase enzyme are calcium, FGF23

and the product calcitriol itself (negative feedback)
zz Other locations of 1α-Hydroxylase are,
 Epidermal keratinocytes
 Placenta
 Pathologically – macrophages of granulomas and
lymphomas
zz Kidney also expresses another important enzyme called
24-Hydroxylase whose action forms the inactive metabolite
24,25-dihydroxyvitamin D

Vitamin D Receptor (VDR)

zz Vitamin D synthesis occurs by the action of ultraviolet (UV) zz Vitamin D produces all its actions by acting through its nuclear
356 rays on skin receptor termed as Vitamin D receptor (VDR)
zz VDR is expressed in parathyroid gland. 1,25(OH)2D acts in Action of 1,25(OH)2D in Bone
parathyroids to suppress the transcription of the PTH gene
zz 1,25(OH)2D is capable of both bone formation and bone
zz Mutations in vitamin D receptor leads to vitamin D resistant
resorption
rickets
zz 1,25(OH)2D increases bone formation by,
zz VDR is also expressed keratinocytes, breast cancer cells, and
 Vitamin D receptor is present in osteoblasts
prostate cancer and it has antiproliferative effect on these
regions
 It Increases bone matrix proteins osteocalcin and
osteopontin production from osteoblasts
C
zz Vitamin D analogue Calcipotriene (calcipotriol) is useful
as topical applications for the treatment of psoriasis for its
zz 1,25(OH)2D increases bone resorption by,
 Since VDR is not present in osteoclasts, it indirectly
R
antiproliferative effect on keratinocytes
activates osteoclast through the paracrine mediator
RANKL produced by osteoclast
I
Actions of 1,25(OH)2D  RANKL aids in osteoclast differentiation increases
S
zz 1,25(OH)2D is the only hormone capable of increasing intestinal osteoclast activity by binding through its receptor RANK
on osteoclasts
calcium absorption P

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Action of 1,25(OH)2D in Intestine Action of 1,25(OH)2D in Kidney

zz 1,25(OH)2D increases intestinal absorption of calcium by, 
 Increasing calbindin 9K
 Calbindin 9K is the calcium-binding protein present 
in intestine that is involved in the active transport of
2/
It facilitates Ca2+ reabsorption in the kidneys by increasing
TRPV5 expression in the proximal tubules
It also increases phosphate reabsorption from proximal
tubules by increasing the activity of sodium phosphate

,
calcium across the enterocyte cotransporter (NaPi-IIa)

gy
 Increasing calcium transporters namely TRPV5 and
TRPV6 (transient receptor potential vanilloid) Vitamin D and Immune Functions
 Increases the number of Ca2+–ATPase The enzyme 1α-Hydroxylase is expressed in immune cells
zz 1,25(OH)2D also increases phosphate absorption by intestine
lo zz
zz
zz
1,25(OH)2D induces the differentiation of immune cells
It also enhances the antimicrobial effects of macrophages and
io
monocytes particularly against Mycobacterium tuberculosis
sy

Vitamin D deficiency – Rickets and Osteomalacia

Ph

zz Osteomalacia is defined as a defect in the mineralization of bone seen in adults due to vitamin D deficiency, deficiency of phosphate
zz In children, it also affects the mineralization of cartilage in the growth plate leads to “Rickets”
zz These conditions are characterized by hypocalcemia, hypophosphatemia and secondary hyperparathyroidism
Defective mineralization of bones in children leads to bowing of weight-bearing extremities, the costochondral junctions are enlarged
P

zz
(“rachitic rosary”) and widening of growth plates
Clinical Manifestations
IS

zz

 bone pain

 muscle weakness
R

 waddling gait

zz Pseudofractures are seen radiologically

C

 Pseudofractures are the local bone resorption that has the appearance of a nondisplaced fracture seen in pubic rami, clavicles,
scapula
 Pseudofractures are also called as Looser’s zones

Diagnosis
zz Most specific test for diagnosis of Vitamin D deficiency is serum 25(OH)D level
zz 25(OH)D levels <15 ng/mL are associated with Vitamin D deficiency
zz Vitamin D levels more than 15 ng/mL are usually considered sufficient
Treatment
zz Recommended daily intake of vitamin D is 600 IU from 1 to 70 years of age
Theory

zz It is 800 IU for those over 70 years of age

zz Vitamin D metabolites like calcitriol in the dose of 50,000 IU weekly for 3–12 weeks followed by 800 IU daily is useful to treat vitamin
D deficiency
zz Vitamin D analogs should always be supplemented along with calcium in treatment

357
 CALCITONIN zz It also binds and act through PTH/PTHrP receptor
zz Major functions of PTHrP
zz Calcitonin is the calcium lowering hormone produced from the  It is involved in growth and development of cartilage in
parafollicular C cells of the thyroid gland fetus
zz Parafollicular C cells are derived from ultimobranchial body  It is involved in placental calcium transport
(from fourth pharyngeal pouch)  Development of teeth
C zz The gene for calcitonin produces not only calcitonin but also
another relayed protein called calcitonin gene related peptide
 In brain – it prevents excitotoxic neuronal damage

R zz
(CGRP)
Actions of calcitonin
Parathyroid Hormone–Related Protein
I 

It lowers serum calcium levels by acting in bone and kidney
In Bone
(PTHrP) and Hypercalcemia of Malignan-
S  Calcitonin receptors are present in osteoclasts zz cy is responsible for hypercalcemia of malignancy seen in,
PTHrP
 It inhibits bone resorption by inhibiting osteoclasts  Squamous cell carcinoma of the lung
P 

In kidney – it increases the excretion of calcium in urine
During pregnancy and lactation – calcitonin prevents
 Renal cell carcinoma

e
 Breast cancer
excess calcium loss
zz In spite of all the actions mentioned above, calcitonin deficiency

2/
have no definite effect in humans
zz Calcitonin receptors are also found in, Fibroblast Growth Factor23 (FGF23) –
 Brain - exerts analgesic effects an Important Regulator of Phosphate

,
 GIT Metabolism

gy
 Immune cells
zz Regulation of calcitonin secretion zz FGF23 is synthesized primarily by osteocytes
 Calcitonin secretion is increased by, zz Major action of FGF23 is to inhibit 1,25(OH)2D production
and phosphate reabsorption
�
�
Gastrin – most potent.
Β-Adrenergic agonists
Dopamine
lo zz High-phosphate diets increase FGF23 levels
io
�
� Estrogen Clinical Importance of FGF23 - X-Linked
� Cholecystokinin (CCK)
Hypophosphatemic Rickets (XLH)
sy

� Secretin
� Glucagon
zz Patients with XLH have high circulating levels of FGF23 due to
Ph

mutation in endopeptidase termed PHEX

Calcitonin in Pharmacology – The Drugs
zz Other conditions where FGF23 levels are elevated are,
“Salcatonin and Miacalcin”  Autosomal dominant hypophosphatemic rickets

 Autosomal recessive hypophosphatemic rickets – due to

zz Salcatonin and miacalcin are the calcitonin drugs useful in
mutations in dentin matrix protein-1 (DMP1)
P

treatment of,
 Tumor-induced osteomalacia (TIO) – usually seen in
 Paget’s disease – 100 U injected subcutaneously for 6 – 18
mesenchymal origin tumors
IS

months
 Osteoporosis zz All the above mentioned conditions are characterized by renal
 Hypercalcemia of malignancy phosphate wasting leading to hypophosphatemia
R
CHAPTER 9  Endocrine Physiology

Calcitonin as Tumor Marker – Medullary

C

Remember!
Carcinoma of Thyroid (MTC) Systemic hormones that affect calcium levels
Calcitonin serves of tumor marker for medullary carcinoma of
Hormone Action
zz
thyroid
zz Calcitonin is attributed to the symptom diarrhea in 30 % of Glucocor- Decreases plasma Ca2+ levels by
patients with MTC ticoids inhibiting osteoclasts
zz Hypercalcitoninemia (>90 pg/mL in the basal state) is seen in MTC Growth Increases intestinal absorption of
hormone Ca2+
OTHER IMPORTANT HORMONES THAT Thyroid Causes hypercalcemia, hypercalciuria
hormones
REGULATES SERUM CALCIUM AND
Estrogens Prevent bone resorption by inhibiting
PHOSPHATE LEVELS osteoclasts
Parathyroid Hormone–Related Protein Insulin Increases bone formation
358
(PTHrP)
zz PTHrP has marked structural similarity with PTH
Summary of Major Hormones that Affect Calcium and Phosphate Levels
PTH Vitamin D Calcitonin
Major stimulus for • Decrease in serum calcium • Decrease in serum calcium • Increase in serum calcium
secretion • Decrease in serum phosphate
• Increase in PTH
Action on bone • Increases bone resorption • Capable of both bone mineralization • Inhibits bone resorption C
and resorption
Action on intestine • Indirectly acts by increasing • Increases calcium and phosphate • - R
vitamin D absorption
Action on kidney • Increases calcium resorption • Increases calcium and phosphate • Increases calcium excretion
I
• Increases phosphate excretion resorption
(phosphaturic)
S
Overall effect • Increases serum • Increases serum calcium and • Decreases serum calcium P
• Decreases serum phosphate phosphate

e
2/
IMAGE-BASED QUESTIONS

,
gy
1. Identify the hormone that increases during exercise and 2. The following diagram is from adrenal gland.
sleep Hormone produced by the marked area A

lo in the following image is

io
sy
Ph
P
IS
R

a. Growth hormone b. Cortisol a. Aldosterone b. Cortisol

c. Estrogen d. Insulin c. Epinephrine d. Androgen
C

Image-Based Questions
ANSWERS WITH EXPLANATIONS

1. Ans. (a)  Growth hormone ƒƒ Fasting

ƒƒ Exercise
(Ref: GuytonTextbook of medical physiology, 13thed, p.945)
During sleep – Particularly deep sleep (NREM stage 3 &4)

Factors that increase growth hormone secretion 2. Ans. (a)  Aldosterone

•• The most potent factor that increases growth hormone (Ref: Ganong, 25th ed/p.353)
secretion is Hypoglycemia
•• Layer A is zona glomerulosa
ƒƒ Growth hormone is a “diabetogenic hormone”. It
•• It produces aldosterone
increases blood glucose levels
•• Other conditions that causes hypoglycemia like 359
ƒƒ Stress

Most Recent Questions of 2017-18 are given at the end of the Chapter