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

Adrenal Steroidogenic Pathways

Regulation of Cortisol Secretion

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

Diurnal Pattern of Plasma Cortisol

ACTH Action on Fasiculata Cells to Stimulate Cortisol Secretion

Urine free cortisol Diagnostic test Total serum cortisol Serum ACTH

Mechanism of Cortisol Action Via Nuclear GR CBG Actions

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)

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

Cushings Disease Findings

Cushings Disease Findings

Findings in Cushings Syndrome

Purple stretch marks or striae (singular stria)

Glucocorticoid Actions to Cause Osteoporosis

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

Addisons Disease Findings

Mineralocorticoid Actions in Kidney and Other Sites

Steroid Regulation and Synthesis in Glomerulosa vs. Fasiculata

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

Actions of Renin and ACE to Generate ANG II

Hormonal Regulation of Blood Pressure

Regulation of Aldosterone

Urine Na +,Renin and Aldosterone Levels

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

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

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

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

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

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

Aldosteronoma

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

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

Differential Diagnosis of Hyperaldosteronism: Adenoma vs Hyperplasia

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.

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

Or overwhelmed by very high cortisol as in ectopic ACTH syndrome

Pheochromocytoma

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)

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.

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

“Incidentaloma”

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