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Ihp stress physiology and adrenal diseases 2013
- 1. • Lightheadness • Low blood pressure • Rapid heart rate • Salt craving • High blood potassium • Low blood sugar • Poor appetite • Weight loss • Tanned • Death if untreated
- 2. Child • Lightheadness Newborn • Low blood pressure • Low blood pressure • Rapid heart rate • Rapid heart rate • Salt craving • High blood potassium • High blood potassium • Low blood sugar • Low blood sugar • Poor appetite • Poor appetite • Weight loss • Weight loss • Tanned • Ambiguous genitalia • Death if untreated • Death if untreated
- 3. Child • Lightheadness Newborn Adolescent • Low blood pressure • Low blood pressure • High blood pressure • Rapid heart rate • Rapid heart rate • Salt craving • High blood potassium • High blood potassium • Low blood potassium • Low blood sugar • Low blood sugar • High blood sugar • Poor appetite • Poor appetite • Increased appetite • Weight loss • Weight loss • Weight gain • Tanned • Ambiguous genitalia • Poor growth • Death if untreated • Death if untreated • Death if untreated
- 4. Circadian Rhythm in ACTH and Cortisol ACTH Cortisol (pg/mL) (µg/dL) 15 20 5 1 6am 6pm 6am
- 6. The Stress Axis Behavioral Autonomic Hormonal [Sympathetic Nervous [Hypothalamic- System] Pituitary-Adrenal] Acute • Dilate eyes • Fear • Raise heart rate • Clarity of thought • Raise cardiac output • Anorexia • Maintain blood • Maintain blood • Loss of libido pressure pressure • Fight or flight • Raise breathing rate • Prevent • Bronchodilate ahypoglycemia Chronic • Prevent hypoglycemia • Loss of • Loss of reproductive • Increase blood to brain, areproductive behavior muscle abehavior and fxn • Decrease blood to skin • Loss of growth gut O W I D ED P IR L E A S US R DW FF AR DI
- 7. The Stress Axis Behavioral Autonomic Hormonal Sympathetic Hypothalamic- Nervous Pituitary-Adrenal System PVN CRH CRH VP III Amygdala Brainstem Stress-induced Catecholamines behaviors pregangionic effects Pituitary ACTH postgangionic Cortisol Epinephrine effects
- 8. The Hypothalamic-Pituitary-Adrenal Axis PVN CRH CRH VP III Ant Pit ACTH Glucocorticoid Effects Mineralocorticoid Suppress Growth Effects Suppress Fertility
- 9. Cortisol inhibits reproductive function by blocking kisspeptin gene expression Unstressed 5h restraint Kisspeptin mRNA Stress Lulu Wang, PhD
- 10. The Hypothalamic-Pituitary-Adrenal Axis PVN CRH CRH VP III Ant Pit ACTH Glucocorticoid Effects Mineralocorticoid Suppress Growth Effects Suppress Fertility
- 11. Pro-opiomelanocortin (POMC) Anterior Pituitary PC1 -KKRR - KR -KR -KR -KR N-terminal Joining α -MSH CLIP γ -LPH β-END Glycopeptide Peptide (112-124) (130-150) (153-207) (210-240) (1-76) (79-108) ACTH β -LPH (112-150) (153-240)
- 12. Pro-opiomelanocortin (POMC) Hypothalamus PC1 PC = proconvertase PC2 -KKRR - KR -KR -KR -KR N-terminal Joining α -MSH CLIP γ -LPH β-END Glycopeptide Peptide (112-124) (130-150) (153-207) (210-240) (1-76) (79-108) ACTH β -LPH (112-150) (153-240) MC1R MC4R MC2R skin hypothalamus adrenal
- 13. Genetic Deficiency of Human POMC Krude and Gruters Nat Genetics 19:155, 1998
- 14. Human Adrenal from Organ Transplant Donor
- 15. Structure of Adrenal Cortex Aldosterone Cortisol Adrenal Androgens Epinephrine
- 16. The Hypothalamic-Pituitary-Adrenal Axis PVHpc CRH CRH VP VP III Development Metabolism Immune Vascular Ant Pit ACTH Glucocorticoid Suppress Growth Mineralocorticoid Effects Suppress Fertility Effects
- 17. Fetal Lung Development Requires Glucocorticoid Normal Crh KO Crh KO + Glucocorticoid
- 18. The Hypothalamic-Pituitary-Adrenal Axis PVHpc CRH CRH VP VP III Development Metabolism Immune Vascular Ant Pit ACTH Glucocorticoid Suppress Growth Mineralocorticoid Effects Suppress Fertility Effects
- 19. Cortisol Maintains Blood Sugar during Fasting gen yco Gl Gly Amino Acids co LIVER oly gen sis - MUSCLE Cortisol Fatty Acids, Glycerol GLUCOSE FAT
- 21. • Lightheadness • Hypotension • Tachycardia • Salt craving • Hyperkalemia • Hypoglycemia • Anorexia • Weight loss • Hyperpigmentation • Death if untreated
- 22. PVN CRH III Glucocorticoid Pituitary ACTH
- 23. Clinical Findings in Addison’s Disease • Abnormal lytes 90 • Hypotension 90 • Salt craving 50 • Weakness 100 • Anorexia 100 • Weight loss 100 • Hyperpigmentation 95% • Death (untreated) 100
- 24. Types of Adrenal Insufficiency Hypothalamus CRH Tertiary •Steroid Rx-Withdrawal •Structural Secondary •Steroid Rx-Withdrawal Anterior Pituitary •Structural ACTH •Genetic (POMC, MCR2) Primary Adrenal •Autoimmune Cortisol, •Genetic (Adrenoleuko- Aldosterone dystrophy, DAX-1, CAH) + • Hemorrhage AII K •Infectious
- 25. Newborn • Hypotension • Tachycardia • Hyperkalemia • Hypoglycemia • Anorexia • Weight loss • Ambiguous genitalia • Death if untreated
- 26. Adrenal Hormone Synthesis Cholesterol HO Aldosterone Synthase 20-22 3ßHSD 21OHase (11ßOHase, 18OHase, Desmolase 18HSD) HO HO O =O =O HO =O HO =O = HO O--C zona glomerulosa HO O= O= O= Pregnenolone Progesterone Deoxycorticosterone Corticosterone O= Aldosterone 11ßOHase HO =O 17- HO =O HO OHase =O =O OH OH OH OH zona O= fasciculata HO O= O= Cortisol 17OH- 17OH- 11Deoxy- Pregnenolone Progesterone Cortisol OH Aromatase OH 17ßKetosteroid GONAD O O 17-20 Reductase = = zona Lyase O= HO reticularis Testosterone Estradiol HO O= Androstenedione NH-CH3 Dehydroepiandrosterone CHOH CHOH NH2 CH2 CH2 OH OH PNMT medulla Norepi- Epinephrine HO HO nephrine
- 27. Primary Adrenal Insufficiency in CAH Hypothalamus CRH Cortisol Deficiency •Hypotension •Tachycardia •Hypoglycemia •Anorexia? •Weight loss? Anterior Pituitary ACTH Aldosterone Deficiency •Hyperkalemia •Hypotension Adrenal •Tachycardia Adrenal Cortisol, Aldosterone Adrenal Androgen Excess Androgens •Females: virilization •Males: ??
- 28. Cushing Syndrome
- 29. • Hypertension • Hypokalemia • Hyperglycemia • Hyperphagia • Obesity • Poor growth • Death if untreated
- 30. Cushing Syndrome: Violaceous Striae Joe EK. Dermatology Online J. 9:16, 2003
- 35. Clinical Findings in Cushing Syndrome • Weight gain 90% • Facial plethora 95 • Moon facies 90 • Poor growth (children) 90 • Hirsutism 80 • Hypertension 75 • Hypokalemia 50 • Osteoporosis/fractures 50 • Bruising 50 • Striae 50 • Weakness 30
- 36. Types of Cushing Syndrome Hypothalamus CRH ACTH-Dependent • Cushing’s Disease • Ectopic ACTH Anterior Pituitary ACTH ACTH-Independent • Steroid Rx • Adrenal Tumors Adrenal Cortisol, Aldosterone Diagnostic studies? • Cushing syndrome • ACTH-dependent vs. -independent
- 37. Steroid Treatment: Cushing Syndrome + Adrenal Hypothalamus CRH Insufficiency Anterior Pituitary ACTH Adrenal cortisol Prednisone from CVS Cushing syndrome
- 40. Nicholas, James A., M.D., Philip D. Wilson, M.D., and Charles J. Umberger, Ph. D., "Induced Hypoadrenalism in Patients Requiring Orthopedic Surgery," Journal of the American Medical Association, May 18, 1957, vol. 164, No. 3, pp. 261-265. Nichols, John, M.D., "President Kennedy's Adrenals," Journal of the American Medical Association, July 10, 1967, vol. 201, No. 2, pp. 115-116.