OST 529 Systems Biology: Endocrinology * 07/16/96 OST 529 Systems Biology: Endocrinology Keith Lookingland Associate Professor Dept. Pharmacology & Toxicology *

Adrenocorticosteroids * 07/16/96 Adrenocorticosteroids Goodman & Gilman’s “The Pharmacological Basis of Therapeutics” 10th Edition Chapter 60: 1649-1677 *

Hormone Negative Feedback Hypothalamic-Pituitary Systems Thyroid Axis (Thyroid Hormones) Adrenocortical Axis (Glucocorticoids) Ovarian Axis (Estrogen/Progesterone) Testicular Axis (Testosterone)

Peripheral Substrate Systems Glucose - Insulin/Glucagon Sodium/Potassium - Aldosterone Calcium - PTH/Calcitonin/Vitamin D

Adrenocorticosteroids Glucocorticoids + Mineralocorticoids Synthesis and metabolism Secretion Actions Adrenocortical Insufficiency Addison’s disease (primary & secondary) Adrenocortical Hyperactivity Congenital adrenal hyperplasia Cushing’s disease Conn’s syndrome (primary aldosteronism)

Adrenal Gland

Adrenocorticosteroids

Glucocorticoids

* 07/16/96 Transport of Cortisol 95% bound to corticosteroid binding globulin (CBG) 5% free, bioactive cortisol half-life (90-110 min) 1% thyroid hormones in free, bioactive form TBP protects against degradation resulting in prolonged half lives (6-7 days) Alterations in TBG alter total (free and bound) blood thyroid hormone levels *

Metabolism of Cortisol

Hypothalamic-Pituitary-Adrenal (HPA) Axis

Circadian Rhythm of Cortisol Secretion

Mechanism of Glucocorticoid Action

Physiological Actions of Glucocorticoids Metabolic Glucose Availability for the Brain Anti-inflammatory Immunosuppression

Metabolic Actions of Cortisol

Anti-inflammatory Actions of Cortisol phagocytic cell function pyrogens,elastase,collagenase reduces edema capillary permeability arteriole vasoconstriction blocks basophil histamine

Immunosuppressive Actions of Cortisol

Mineralocorticoids

Transport and Metabolism of Aldosterone * 07/16/96 Transport and Metabolism of Aldosterone weakly bound to plasma proteins 95% free, bioactive aldosterone half-life (20-30 min) degraded in liver, secreted in urine as a water soluble conjugate 1% thyroid hormones in free, bioactive form TBP protects against degradation resulting in prolonged half lives (6-7 days) Alterations in TBG alter total (free and bound) blood thyroid hormone levels *

Control of Aldosterone Secretion

Mechanisms of Aldosterone Action

Adrenocortical Insufficiency Primary (Addison’s Disease) hyposecretion of both cortisol & aldosterone hypersecretion of ACTH (loss of negative feedback) glucocorticoid insufficiency weakness, fatigue inability to maintain fasting plasma glucose mineralocorticoid insufficiency sodium loss, potassium retention dehydration Secondary defect in hypothalamic-pituitary axis hyposecretion of ACTH and cortisol

Synthetic Glucocorticoids * 07/16/96 Synthetic Glucocorticoids Cortisol short-acting orally active glucocorticoid replacement adrenal insufficiency Triamcinolone intermediate-acting topical localized allergic and arthritic disorders Dexamethasone long-acting diagnostic Dexamethasone Suppression Test 1% thyroid hormones in free, bioactive form TBP protects against degradation resulting in prolonged half lives (6-7 days) Alterations in TBG alter total (free and bound) blood thyroid hormone levels *

Side Effects of Glucocorticoid Therapy

Synthetic Mineralocorticoids * 07/16/96 Synthetic Mineralocorticoids 1% thyroid hormones in free, bioactive form TBP protects against degradation resulting in prolonged half lives (6-7 days) Alterations in TBG alter total (free and bound) blood thyroid hormone levels *

Synthetic Mineralocorticoids * 07/16/96 Synthetic Mineralocorticoids Fludrocortisone oral, injectable, topical compilations mimics aldosterone action sodium retention potassium excretion mineralocorticoid replacement adrenal insufficiency 1% thyroid hormones in free, bioactive form TBP protects against degradation resulting in prolonged half lives (6-7 days) Alterations in TBG alter total (free and bound) blood thyroid hormone levels *

Adrenocortical Hyperactivity Congenital Adrenal Hyperplasia primary defect in cortisol biosynthetic enzymes 21-B hydroxylase shunts precursors into androgen pathway compensatory increase in ACTH (loss of negative feedback) adrenal hypertrophy virilization of physical features im cortisone/dexamethasome to suppress ACTH oral cortisol

Adrenocortical Hyperactivity Cushing’s Syndrome adrenal hyperplasia secondary to ACTH-secreting pituitary or ectopic tumor loss of negative feedback unresponsive to low dose dexamethasone

Adrenocortical Hyperactivity Cushing’s Syndrome excessive glucocorticoid activity muscle atrophy, thinning of skin (protein catabolism) facial & truncal obesity (lipid deposition insulin-dependent adipocytes) poor wound healing (immunosuppression) surgical removal of tumor (oral cortisol) adrenalectomy (oral cortisol & fludrocortisone)

Adrenocortical Hyperactivity Primary Aldosteronism (Conn’s Syndrome) aldosterone-secreting adrenal adenoma excessive mineralocorticoid activity (electrolyte imbalance) hypertension (sodium retention) muscle weakness, tetany (potassium excretion) adrenalectomy (oral cortisol & fludrocortisone) spironolactone aldosterone receptor antagonist genomic actions (slow onset of action)