•   Lightheadness•   Low blood pressure•   Rapid heart rate•   Salt craving•   High blood potassium•   Low blood sugar•   ...
Child•   Lightheadness                    Newborn•   Low blood pressure     • Low blood pressure•   Rapid heart rate      ...
Child•   Lightheadness                    Newborn                Adolescent•   Low blood pressure     • Low blood pressure...
Circadian Rhythm in ACTH and              CortisolACTH                       Cortisol(pg/mL)                    (µg/dL)   ...
The Stress AxisBehavioral             Autonomic                    Hormonal                       [Sympathetic Nervous    ...
The Stress AxisBehavioral         Autonomic                Hormonal                   Sympathetic              Hypothalami...
The Hypothalamic-Pituitary-Adrenal Axis                          PVN              CRH         CRH              VP    III  ...
Cortisol inhibits reproductive function by blocking            kisspeptin gene expressionUnstressed            5h restrain...
The Hypothalamic-Pituitary-Adrenal Axis                          PVN              CRH         CRH              VP    III  ...
Pro-opiomelanocortin (POMC)                             Anterior Pituitary         PC = proconvertase                     ...
Pro-opiomelanocortin (POMC)                                Hypothalamus                                    PC1            ...
Genetic Deficiency of Human POMC               Krude and Gruters Nat Genetics 19:155, 1998
Human Adrenal from Organ Transplant Donor
Structure of Adrenal Cortex              Aldosterone              Cortisol              Adrenal Androgens              Epi...
The Hypothalamic-Pituitary-Adrenal Axis                          PVHpc              CRH         CRH              VP       ...
Fetal Lung Development Requires Glucocorticoid   Normal            Crh KO         Crh KO +                                ...
The Hypothalamic-Pituitary-Adrenal Axis                          PVHpc              CRH         CRH              VP       ...
Cortisol Maintains Blood Sugar               during Fasting            gen        yco      Gl Gly                  Amino A...
Adrenal Insufficiency
•   Lightheadness•   Hypotension•   Tachycardia•   Salt craving•   Hyperkalemia•   Hypoglycemia•   Anorexia•   Weight loss...
PVN          CRH    III                GlucocorticoidPituitary   ACTH
Clinical Findings in    Addison’s Disease•   Abnormal lytes      90•   Hypotension         90•   Salt craving        50•  ...
Types of Adrenal Insufficiency  Hypothalamus       CRH               Tertiary                                       •Stero...
Newborn• Hypotension• Tachycardia•   Hyperkalemia•   Hypoglycemia•   Anorexia•   Weight loss•   Ambiguous genitalia•   Dea...
Adrenal Hormone Synthesis  Cholesterol   HO                                                                     Aldosteron...
Primary Adrenal Insufficiency in CAH Hypothalamus CRH                          Cortisol Deficiency                        ...
Cushing Syndrome
•   Hypertension•   Hypokalemia•   Hyperglycemia•   Hyperphagia•   Obesity•   Poor growth•   Death if untreated
Cushing Syndrome: Violaceous Striae                        Joe EK. Dermatology Online J.                        9:16, 2003
Clinical Findings in Cushing Syndrome•   Weight gain              90%•   Facial plethora          95•   Moon facies       ...
Types of Cushing SyndromeHypothalamus                 CRH                                       ACTH-Dependent            ...
Steroid Treatment:           Cushing Syndrome + Adrenal   Hypothalamus                CRH                        Insuffici...
Nicholas, James A., M.D., Philip D. Wilson, M.D., and Charles J.Umberger, Ph. D., "Induced Hypoadrenalism in PatientsRequi...
Ihp stress voice
Ihp stress voice
Ihp stress voice
Ihp stress voice
Ihp stress voice
Ihp stress voice
Ihp stress voice
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Ihp stress voice

  1. 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. 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. 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. 4. Circadian Rhythm in ACTH and CortisolACTH Cortisol(pg/mL) (µg/dL) 15 20 5 1 6am 6pm 6am
  5. 5. The Stress AxisBehavioral 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 ahypoglycemiaChronic • 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
  6. 6. The Stress AxisBehavioral 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
  7. 7. The Hypothalamic-Pituitary-Adrenal Axis PVN CRH CRH VP III Ant Pit ACTH Glucocorticoid EffectsMineralocorticoid Suppress Growth Effects Suppress Fertility
  8. 8. Cortisol inhibits reproductive function by blocking kisspeptin gene expressionUnstressed 5h restraint Kisspeptin mRNA StressLulu Wang,PhD
  9. 9. The Hypothalamic-Pituitary-Adrenal Axis PVN CRH CRH VP III Ant Pit ACTH Glucocorticoid EffectsMineralocorticoid Suppress Growth Effects Suppress Fertility
  10. 10. Pro-opiomelanocortin (POMC) Anterior Pituitary PC = proconvertase PC1 -KKRR - KR -KR -KR -KR N-terminal Joining α -MSH CLIP γ -LPH β-ENDGlycopeptide Peptide (112-124) (130-150) (153-207) (210-240) (1-76) (79-108) ACTH β -LPH (112-150) (153-240)
  11. 11. 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
  12. 12. Genetic Deficiency of Human POMC Krude and Gruters Nat Genetics 19:155, 1998
  13. 13. Human Adrenal from Organ Transplant Donor
  14. 14. Structure of Adrenal Cortex Aldosterone Cortisol Adrenal Androgens Epinephrine
  15. 15. The Hypothalamic-Pituitary-Adrenal Axis PVHpc CRH CRH VP VP III Development Metabolism Immune Vascular Ant Pit ACTH Glucocorticoid Suppress GrowthMineralocorticoid Effects Suppress Fertility Effects
  16. 16. Fetal Lung Development Requires Glucocorticoid Normal Crh KO Crh KO + Glucocorticoid
  17. 17. The Hypothalamic-Pituitary-Adrenal Axis PVHpc CRH CRH VP VP III Development Metabolism Immune Vascular Ant Pit ACTH Glucocorticoid Suppress GrowthMineralocorticoid Effects Suppress Fertility Effects
  18. 18. Cortisol Maintains Blood Sugar during Fasting gen yco Gl Gly Amino Acids coLIVER oly gen sis - MUSCLE Cortisol Fatty Acids, Glycerol GLUCOSE FAT
  19. 19. Adrenal Insufficiency
  20. 20. • Lightheadness• Hypotension• Tachycardia• Salt craving• Hyperkalemia• Hypoglycemia• Anorexia• Weight loss• Hyperpigmentation• Death if untreated
  21. 21. PVN CRH III GlucocorticoidPituitary ACTH
  22. 22. 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
  23. 23. Types of Adrenal Insufficiency Hypothalamus CRH Tertiary •Steroid Rx-Withdrawal •Structural Secondary •Steroid Rx-WithdrawalAnterior Pituitary •Structural ACTH •Genetic (POMC, MCR2) Primary Adrenal •Autoimmune Cortisol, •Genetic (Adrenoleuko- Aldosterone dystrophy, DAX-1, CAH) + • Hemorrhage AII K •Infectious
  24. 24. Newborn• Hypotension• Tachycardia• Hyperkalemia• Hypoglycemia• Anorexia• Weight loss• Ambiguous genitalia• Death if untreated
  25. 25. 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 =O17- HO =O HOOHase =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 O17-20 Reductase = = zonaLyase O= HO reticularis Testosterone Estradiol HO O= Androstenedione NH-CH3Dehydroepiandrosterone CHOH CHOH NH2 CH2 CH2 OH OH PNMT medulla Norepi- Epinephrine HO HO nephrine
  26. 26. 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: ??
  27. 27. Cushing Syndrome
  28. 28. • Hypertension• Hypokalemia• Hyperglycemia• Hyperphagia• Obesity• Poor growth• Death if untreated
  29. 29. Cushing Syndrome: Violaceous Striae Joe EK. Dermatology Online J. 9:16, 2003
  30. 30. 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
  31. 31. Types of Cushing SyndromeHypothalamus 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
  32. 32. Steroid Treatment: Cushing Syndrome + Adrenal Hypothalamus CRH InsufficiencyAnterior Pituitary ACTH Adrenal cortisol Prednisone from CVS Cushing syndrome
  33. 33. Nicholas, James A., M.D., Philip D. Wilson, M.D., and Charles J.Umberger, Ph. D., "Induced Hypoadrenalism in PatientsRequiring Orthopedic Surgery," Journal of the American MedicalAssociation, May 18, 1957, vol. 164, No. 3, pp. 261-265.Nichols, John, M.D., "President Kennedys Adrenals," Journalof the American Medical Association, July 10, 1967, vol. 201,No.2, pp. 115-116.

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