1. Adrenal Physiology David Feldman Glucocorticoids Mineralocorticoids Catecholamines/Adrenal Medulla Adrenal Causes of Hypertension ◦ Cushings Syndrome ◦ Primary Aldosteronism (Conn’s Syndrome) ◦ Pheochromocytoma

5. Adrenal Steroidogenic Pathways

8. Regulation of Cortisol Secretion

9. Hypothalamic-Pituitary-Adrenal (HPA) Axis Diurnal rhythm Emotion Trauma Stress

10. Diurnal Pattern of Plasma Cortisol

11. ACTH Action on Fasiculata Cells to Stimulate Cortisol Secretion

13. Urine free cortisol Diagnostic test Total serum cortisol Serum ACTH

14. Mechanism of Cortisol Action Via Nuclear GR CBG Actions

17. Glucocorticoids as Drugs Used in pharmacological doses Many uses including immunosuppression and anti-inflammation ◦ Asthma, arthritis, COPD, cancer, transplants, etc. Current drugs can separate GR from MR but NOT reduce other side- effects Many side-effects ◦ Diabetes, osteoporosis, infection, adrenal suppression, etc ◦ Iatrogenic Cushings Syndrome Future drugs (SGRMs) being designed to avoid side-effects by selective activation of actions (like SERMs)

20. Etiology of Spontaneous Cushings Syndrome Pituitary adenoma (Cushings Disease) 70% Adrenal disease 17% ◦ Adenoma 10% ◦ Carcinoma 7% Ectopic ACTH Syndrome 12%

21. Cushings Disease Findings

22. Cushings Disease Findings

23. Findings in Cushings Syndrome

25. Purple stretch marks or striae (singular stria)

29. Glucocorticoid Actions to Cause Osteoporosis

30. Adrenal Insufficiency Adrenal Disease -High ACTH (Addisons) Pituitary Disease-Low ACTH

31. Addisons Disease Findings

33. Mineralocorticoid Actions in Kidney and Other Sites

34. Steroid Regulation and Synthesis in Glomerulosa vs. Fasiculata

35. Renal Regulation of Blood Pressure: The Renin-Angiotensin System (RAS)

36. Actions of Renin and ACE to Generate ANG II

37. Hormonal Regulation of Blood Pressure

38. Regulation of Aldosterone

39. Urine Na +,Renin and Aldosterone Levels

40. Regulation of Ang and Aldo Secretion and Blood Pressure Vasoconstriction Blood pressure

41. Salt-sensitivity is leading to hypertension in a large number of people Blood pressure is controlled by the renin-angiotensin system (RAS). Polymorphisms in two critical genes in the RAS have been identified thus far to cause salt-sensitivity. 1. A genetic variant of the angiotensinogen (AGT) gene leads to increased production of angiotensinogen. People carrying this variant are salt-sensitive, meaning they keep more sodium in the blood than non-carriers do. High sodium level increases blood volume, leading to increased blood pressure. Therefore, carriers of this AGT variant have a higher risk for hypertension. 2.The most common genetic variation related to the RAS system is in the ACE gene. ACE I/D means insertion or deletion polymorphism of the angiotensin-converting enzyme (ACE) gene. Carriers of the D variant of the ACE gene are more likely to develop hypertension with a diet high in sodium and low in potassium. Over 50% of Africans and Caucasians and about 40% of Asians carry this variant. Variant D carriers make more ACE protein which results in a more active RAS system than that of variant I carriers. The current trend to limit dietary salt intake will benefit these individuals

42. Mechanism of Aldosterone Action via MR MR MR/Aldo ALDO Nucleus

43. Na + retention “Escape” No escape Na + release “Escape” No Edema

44. Mineralocorticoid Excess Causes Na + Retention, K + loss, Hypertension, No Edema

45. Aldosteronoma Causes Na + Retention, K + Loss, Suppressed Renin and Hypertension

46. Aldosteronoma

47. Clinical Clues to Primary Aldosteronism Spontaneous hypokalemia Diuretic-induced hypokalemia Refractory hypertension Family history of primary aldosteronism

51. Differential Diagnosis of Hyperaldosteronism: Adenoma vs Hyperplasia John Luetscher Co-discoverer of aldosterone

52. Differential Diagnosis of Hyperaldosteronism: Adenoma vs Hyperplasia

53. 11-Beta Hydroxysteroid Dehydrogenase (11 ß -HSD): The “protector” of the mineralocorticoid receptor Cortisone inactive Cortisol active 11ß-HSD-II 11-keto 11-hydroxy Cortisol is present in great excess in the circulation. CBG protects some from access to MR but free cortisol is still high enough and could inappropriately bind to the MR and act as a mineralocorticoid. 11ß-HSD-1 prevents this by converting cortisol to cortisone which can no longer bind to the MR.

54. MR Defect in 11ß-HSD-- No protection Apparent Mineralocorticod Excess (AME) Cortisol drives the MR Cortisone cannot bind the MR Hormone

55. Or overwhelmed by very high cortisol as in ectopic ACTH syndrome

58. Pheochromocytoma

61. MEN I (Wermer Syndrome) 1. Parathyroid hyperplasia (Hyperparathyroidism (usually 4 gland hyperplasia) 2. Tumors of the pancreas gastrinomas (Zollinger-Ellison Syndrome pancreatic islets (insulinoma, glucagonoma); 3. Pituitary tumors prolactinoma, Cushing disease, etc. 4. Other tumors including Carcinoid, lipomas and angiofibromas Cause: Rare autosomal dominant mutations in the gene encoding menin, a tumor suppressor. 3 P’s: parathyroid, pancreas & pituitary)

62. MEN IIA (Sipple Syndrome) 1.Pheochromocytoma 2.Medullary thyroid carcinoma (C-cell hyperplasia to cancer) 3. Hyperparathyroidism MEN IIB 1.Pheochromocytoma 2.Medullary thyroid carcinoma 3. Hyperparathyroidism 4.Multiple mucosal neuromas 5.Marfanoid habitus Cause: MEN II is caused by mutations that constitutively activate the RET proto- oncogene.

68. Adrenal Diseases Causing Hypertension Hypercortisolism, Cushing’s syndrome Hyperaldosteronism, Conn’s syndrome Pheochromocytoma Apparent Mineralocorticoid Excess (AME) ◦ 11ß-HSD defect ◦ Ectopic ACTH overwhelming 11ß-HSD

73. “Incidentaloma”

75. Angiotensin receptor blockers (ARBs) ACE inhibitors MR blocker Beta blockers