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

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

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. *
07/16/96
Transport of Cortisol
95% bound to corticosteroid binding globulin (CBG)
5% free, bioactive
cortisol half-life ( 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 *

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*
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 *

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*
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 *

29. Side Effects of Glucocorticoid Therapy

31. 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 *

32. 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 *

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)