Adrenal Gland

Dr SandeepAssociate professor

In human adrenal glands weigh ~4g, are located above upper pole of each kidney in the retroperitoneal space

They produce 4 principle hormones 1) cortisol, 2) aldosterone, 3) epinephrine, and 4) norepinephrine

Adrenal gland is composed of inner medulla (neural crest) and outer cortex (derived from mesoderm)

Zona glomerulosa synthesize and secrete mineralocorticoid Aldosterone

Zona fasciculata and reticularis, synthesize and secrete Cortisol

Cortisol is also known as Glucocorticoid because it regulates plasma glucose levels

Aldosterone is known as Mineralocorticoid because it promotes salt and water retention by kidney

Synthesis of cortisol and aldosterone starts with cholesterol

The adrenal gland has two sources of cholesterol1) It can import cholesterol from circulating

cholesterol-containing LDL, through LDL receptor mediated endocytosis

2) It can synthesize cholesterol de novo from acetate

The enzymes catalyzing the conversion of cholesterol to its active steroid hormones require cytochrome-P450, oxygen, and NADPH

Not substantially present in zona glomerulosa

The cortisol diffuses out of cell into plasma

~90% of the cortisol is transported bound to corticosteroid-binding globulin (CBG) also known as transcortin (made in liver)

Transcortin is 383-aa glycoprotein, has ~30 fold affinity for cortisol than aldosterone

An additional ~7% circulating cortisol is bound to albumin

~3-4% is free from

Clearance of cortisol form the body depends principally on the liver and kidney

Formation of inactive metabolite “cortisone” by the action of 11β-hydroxysteroid dehydrogenase

Steroid hormone mechanism of action

Most of the is through gene transcription but with exception of ACTH inhibition which occurs in seconds to minute

Regulation of cortisol secretion

CRH secreting neurons in hypothalamus are under higher CNS control, this is proved by 2 imp events

1) Circadian and pulsatile release of ACTH and cortisol secretion

2) Integration of higher center signal that modulate body response to stress

The pituitary secretes ACTH with a circadian rhythm

Suprachiasmatic nucleus of hypothalamus present above optic chiasma receive input from retina

ACTH & cortisol secretion shows circadian rhythm

Factors affecting ACTH secretion

Stimulatory factors Inhibitory factorsDecreased blood cortisol Increased blood cortisolSleep-wake transition opioidsStress, hypoglycemia SomatostatinPsychiatric disturbancesADHAlpha-adrenergic agonistBeta-adrenergic antagonistSerotonin

Actions of glucocorticoidsGlucocorticoids are essential for life. If the adrenal cortex is removed or is not functioning, exogenous glucocorticoids must be administered or death will ensue. The actions of glucocorticoids (e.g., cortisol) are essential for 1) Gluconeogenesis (diabetogenic): – Increases protein catabolism to provide amino acids for

gluconeogenesis

– Increases lypolysis, which provides additional glycerol for gluconeogenesis

– Decreases glucose utilization by tissue and decreases insulin sensitivity of adipose tissues

2. vascular responsiveness to catecholamines (permissive action by upregulating α-adrenergic receptors

3. Anti inflammatory action: suppression of inflammatory and immune responses- induces synthesis of lipocortin Inhibitor of Phospholipase A2.

Phospholipase A2 liberates arachidonic acid from membrane phospholipids provides precursor for prostagladin and leukotrines

4) Suppression of immune response: Cortisol inhibits IL-2 production and proliferation of T-lymphocytes

5) Inhibition of bone formation: Act on bone to inhibit osteoblasts, collagen type-2 (present in bone matrix) and Ca2+ absorption in GI tract

6) modulation of CNS function (alteration of mood and cognition)

The mineralocorticoid Aldosterone

No storage pool for aldosterone like cortisol

Thus, secretion of aldosterone isLimited by rate at which glomerulosacells can synthesize

ACTH, increase in extracellular [K+] and ANG II are imp secretagogues

Once secreted ~37% of circulatingAldosterone remains free

Rest weakly binds to CBG (~21%) and albumin (~42%)

The major action of aldosterone is to stimulate Na and water reabsorption and secrete K

Aldosterone has similar action on colon, salivary glands, and sweat glands

In the target cells of renal tubules, distal tubule and collecting ducts (acts on principal cells)

Increases transcription of Na-K pump thus, augments distal Na reabsorption

Increases expression of Na channels and Na/K/Cl cotransporters

Net effect is Na reabsorption and K secretion

Renin-ANG II, K, and ACTH stimulate aldosterone secretion

Pathophysiology of adrenal cortex

Addison’s disease: Caused by autoimmune disorder resulting in destruction of all the zones

Decrease in circulating levels of cortisol, aldosterone, and adrogens

Loss of glucocorticoids results in, hypoglycemia, anorexia, weight loss, nausea, vomiting and weakness

It is characterized by hyperpigmentation of skin due to increase ACTH, which (contain fragment of α-MSH)

Treatment is glucocorticoid and mineralocorticoid replacement

Cushing’s syndrome: Results due to chronic excess of glucocorticoids

Clinical symptoms are hyperglycemia, proteolysis, muscle wasting, central obesity, round face, buffalo hump and hypertension, Striae (caused by loss connective tissue)

Conn’s syndrome: Primary hyperaldosteronism, due to aldosterone secreting tumors

Excessive Na reabsorption, K secretion and H secretion

Leads to increase in ECF volume, hypertension, hypokalemia, metabolic alkolosis

Treatment is administration of aldosterone antagonists such as spiranolactone

References

• Medical Physiology – by Walter F Boron and Emile J Boulpaep.

• Physiology – by Linda S Costanzo.