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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 Serum ACTH Total serum cortisol Urine free cortisol Diagnostic test Mechanism of Cortisol Action Via Nuclear GR Actions CBG 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 sideeffects 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 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 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 Nucleus ALDO “Escape” No Edema No escape “Escape” Na+ retention Na+ release 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 (11ß-HSD): The “protector” of the mineralocorticoid receptor 11-hydroxy Cortisol active 11-keto 11ß-HSD-II Cortisone inactive 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. Hormone Cortisone cannot bind the MR MR Defect in 11ß-HSD-No protection Apparent Mineralocorticod Excess (AME) Cortisol drives the MR Or overwhelmed by very high cortisol as in ectopic ACTH syndrome Pheochromocytoma MEN I (Wermer Syndrome) 3 P’s: parathyroid, pancreas & pituitary) 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. 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 protooncogene. 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” Beta blockers ACE inhibitors Angiotensin receptor blockers (ARBs) MR blocker