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

OST 529 Systems Biology: Endocrinology

Keith Lookingland

Associate Professor

Dept. Pharmacology & Toxicology

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

Transport of Cortisol

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

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

• 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

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 • 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

Side Effects of Glucocorticoid Therapy

Synthetic Mineralocorticoids

Synthetic Mineralocorticoids

Fludrocortisone– oral, injectable, topical compilations – mimics aldosterone action

• sodium retention• potassium excretion

– mineralocorticoid replacement adrenal insufficiency

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)