1. Adrenal Gland Dr Sandeep Associate professor

2. 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)

4. 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

5. Synthesis of cortisol and aldosterone starts with cholesterol The adrenal gland has two sources of cholesterol 1)It can import cholesterol from circulating cholesterol-containing LDL, through LDL receptor mediated endocytosis 1)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

6. Not substantially present in zona glomerulosa

7. 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

8. 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

9. Steroid hormone mechanism of action Most of the is through gene transcription but with exception of ACTH inhibition which occurs in seconds to minute

10. Regulation of cortisol secretion

11. 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

12. ACTH & cortisol secretion shows circadian rhythm

13. Factors affecting ACTH secretion Stimulatory factorsInhibitory factors Decreased blood cortisolIncreased blood cortisol Sleep-wake transitionopioids Stress, hypoglycemiaSomatostatin Psychiatric disturbances ADH Alpha-adrenergic agonist Beta-adrenergic antagonist Serotonin

14. Actions of glucocorticoids Glucocorticoids 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

15. 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

16. 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)

17. The mineralocorticoid Aldosterone No storage pool for aldosterone like cortisol Thus, secretion of aldosterone is Limited by rate at which glomerulosa cells can synthesize ACTH, increase in extracellular [K + ] and ANG II are imp secretagogues Once secreted ~37% of circulating Aldosterone remains free Rest weakly binds to CBG (~21%) and albumin (~42%)

18. 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

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

20. 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

21. It is characterized by hyperpigmentation of skin due to increase ACTH, which (contain fragment of α-MSH) Treatment is glucocorticoid and mineralocorticoid replacement

22. 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)

23. 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

24. References Medical Physiology – by Walter F Boron and Emile J Boulpaep. Physiology – by Linda S Costanzo.