OST 529 Systems Biology: Endocrinology

1. OST 529 Systems Biology: Endocrinology Keith Lookingland Associate Professor Dept. Pharmacology & Toxicology

2. Adrenocorticosteroids Goodman & Gilman’s “The Pharmacological Basis of Therapeutics” 10th Edition Chapter 60: 1649-1677

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

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

5. 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)

6. Adrenal Gland

9. Adrenocorticosteroids

10. Glucocorticoids

11. Transport of Cortisol • 95% bound to corticosteroid binding globulin (CBG) • 5% free, bioactive • cortisol half-life (90-110 min)

12. Metabolism of Cortisol

14. Hypothalamic-Pituitary-Adrenal (HPA) Axis

15. Circadian Rhythm of Cortisol Secretion

16. Mechanism of Glucocorticoid Action

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

18. Metabolic Actions of Cortisol

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

20. Immunosuppressive Actions of Cortisol

22. Mineralocorticoids

23. 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

24. Control of Aldosterone Secretion

25. Mechanisms of Aldosterone Action

26. 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

28. 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

29. Side Effects of Glucocorticoid Therapy

31. Synthetic Mineralocorticoids

32. Synthetic Mineralocorticoids Fludrocortisone • oral, injectable, topical compilations • mimics aldosterone action • sodium retention • potassium excretion • mineralocorticoid replacement adrenal insufficiency

33. 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

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

35. 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)

38. 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)