ihp stress voice
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• Lightheadness• Low blood pressure• Rapid heart rate• Salt craving• High blood potassium• Low blood sugar• Poor appetite• Weight loss • Tanned• Death if untreated
• Low blood pressure• Rapid heart rate • High blood potassium• Low blood sugar• Poor appetite• Weight loss • Ambiguous genitalia• Death if untreated
Newborn Child
• Lightheadness• Low blood pressure• Rapid heart rate• Salt craving• High blood potassium• Low blood sugar• Poor appetite• Weight loss • Tanned• Death if untreated
Child
• Lightheadness• Low blood pressure• Rapid heart rate• Salt craving• High blood potassium• Low blood sugar• Poor appetite• Weight loss • Tanned• Death if untreated
• Low blood pressure• Rapid heart rate • High blood potassium• Low blood sugar• Poor appetite• Weight loss • Ambiguous genitalia• Death if untreated
Newborn
• High blood pressure
• Low blood potassium• High blood sugar• Increased appetite• Weight gain• Poor growth• Death if untreated
Adolescent
Circadian Rhythm in ACTH and Cortisol
6am 6pm 6am
ACTH(pg/mL)
Cortisol(g/dL)
1
15
5
20
The Stress AxisHormonal[Hypothalamic-Pituitary-Adrenal]
• Maintain blood pressure• Prevent ahypoglycemia• Loss of areproductive abehavior and fxn• Loss of growth
Behavioral
Acute• Fear• Clarity of thought• Anorexia• Loss of libido• Fight or flight
Chronic• Loss of reproductive behavior
RAPID SLO
W
HARDW
IRED
DIFFUS
E
Autonomic[Sympathetic NervousSystem]• Dilate eyes• Raise heart rate• Raise cardiac output• Maintain blood pressure• Raise breathing rate• Bronchodilate• Prevent hypoglycemia• Increase blood to brain, muscle• Decrease blood to skin gut
The Stress Axis
Amygdala
Stress-inducedbehaviors
Behavioral
Brainstem
Catecholamines
AutonomicSympatheticNervousSystem
effects
HormonalHypothalamic-Pituitary-Adrenal
CRHVP III
CRH
PVN
PituitaryACTH
CortisolEpinephrine effects
pregangionic
postgangionic
CRHVP III
CRH
PVN
Ant PitACTH
The Hypothalamic-Pituitary-Adrenal Axis
Mineralocorticoid Effects
Suppress GrowthSuppress Fertility
Glucocorticoid Effects
StressLulu Wang, PhD
Cortisol inhibits reproductive function by blocking kisspeptin gene expression
Unstressed 5h restraint
Kisspeptin mRNA
CRHVP III
CRH
PVN
Ant PitACTH
The Hypothalamic-Pituitary-Adrenal Axis
Mineralocorticoid Effects
Suppress GrowthSuppress Fertility
Glucocorticoid Effects
N-terminalGlycopeptide
(1-76)
JoiningPeptide(79-108)
-MSH(112-124)
CLIP(130-150)
-LPH(153-207)
-END(210-240)
ACTH(112-150)
-LPH(153-240)
- KR
- KR
- KK
RR
- KR
- KR
Pro-opiomelanocortin (POMC)
Anterior PituitaryPC1
PC = proconvertase
N-terminalGlycopeptide
(1-76)
JoiningPeptide(79-108)
-MSH(112-124)
CLIP(130-150)
-LPH(153-207)
-END(210-240)
ACTH(112-150)
-LPH(153-240)
- KR
- KR
- KK
RR
- KR
- KR
Pro-opiomelanocortin (POMC)Hypothalamus
PC1
PC2
PC = proconvertase
MC1R MC4R MC2R skin hypothalamus adrenal
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
Epinephrine
CRHVP III
CRH VP
PVHpc
Ant PitACTH
Glucocorticoid Effects
The Hypothalamic-Pituitary-Adrenal Axis
Development
Metabolism
Immune
Vascular
Mineralocorticoid Effects
Suppress GrowthSuppress Fertility
Fetal Lung Development Requires Glucocorticoid
Normal Crh KO Crh KO + Glucocorticoid
CRHVP III
CRH VP
PVHpc
Ant PitACTH
Glucocorticoid Effects
The Hypothalamic-Pituitary-Adrenal Axis
Development
Metabolism
Immune
Vascular
Mineralocorticoid Effects
Suppress GrowthSuppress Fertility
Cortisol Maintains Blood Sugar during Fasting
FAT
LIVERMUSCLE
Amino Acids
Fatty Acids, Glycerol
Glycog
enGly
cogen
GLUCOSE
Glycogen-olysis
Cortisol
Adrenal Insufficiency
• Lightheadness• Hypotension• Tachycardia• Salt craving• Hyperkalemia• Hypoglycemia• Anorexia• Weight loss • Hyperpigmentation• Death if untreated
IIICRH
PVN
Pituitary
ACTHGlucocorticoid
• Abnormal lytes 90• Hypotension 90
• Salt craving 50
• Weakness 100• Anorexia 100• Weight loss 100• Hyperpigmentation
95%• Death (untreated) 100
Clinical Findings in Addison’s Disease
Anterior PituitaryACTH
Cortisol,Aldosterone
Types of Adrenal InsufficiencyHypothalamus
Adrenal
Primary•Autoimmune•Genetic (Adrenoleuko- dystrophy, DAX-1, CAH)• Hemorrhage•Infectious
Secondary•Steroid Rx-Withdrawal•Structural•Genetic (POMC, MCR2)
Tertiary•Steroid Rx-Withdrawal•Structural
CRH
AII K+
• Hypotension• Tachycardia • Hyperkalemia• Hypoglycemia• Anorexia• Weight loss • Ambiguous genitalia• Death if untreated
Newborn
HO
HO
=O
HO
=OOH
=O
O=
HOHO
=O
HO
=O
O=
=OOH
O=
=OOH
HO =O
O=
HOHO OH
O=
=O
zonaglomerulosa
zonafasciculata
zonareticularis
medulla
HO
OH
CHO
HCH
2
NH
-CH
3
PNMT
Testosterone
Cholesterol
Pregnenolone
17OH-Pregnenolone
Dehydroepiandrosterone
17OH-Progesterone
Androstenedione
Corticosterone Aldosterone
11Deoxy-Cortisol
Cortisol
Norepi-nephrine Epinephrine
DeoxycorticosteroneProgesterone
3ßHSD 21OHase
17-OHase
17-20Lyase
11ßOHase
O=
HOO--C
HO
Aldosterone Synthase(11ßOHase, 18OHase,18HSD)
O=
HO =O
O=
20-22Desmolase
=O
O=
OH17ßKetosteroidReductase
HO
OH CH
OH
CH2
NH
2
OH
HOEstradiol
Aromatase
GO
NAD
Adrenal Hormone Synthesis
Anterior PituitaryACTH
Cortisol,Aldosterone
Primary Adrenal Insufficiency in CAHHypothalamus
Adrenal
Adrenal Androgen Excess•Females: virilization•Males: ??
Aldosterone Deficiency•Hyperkalemia•Hypotension•Tachycardia
Cortisol Deficiency•Hypotension•Tachycardia•Hypoglycemia•Anorexia?•Weight loss?
CRH
AdrenalAndrogens
Cushing Syndrome
• Hypertension• Hypokalemia• Hyperglycemia• Hyperphagia• Obesity• Poor growth• Death if untreated
Joe EK. Dermatology Online J. 9:16, 2003
Cushing Syndrome: Violaceous Striae
• 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
Clinical Findings in Cushing Syndrome
CRH
AnteriorPituitary ACTH
Cortisol,Aldosterone
Types of Cushing SyndromeHypothalamus
Adrenal
ACTH-Independent
ACTH-Dependent
• Steroid Rx• Adrenal Tumors
• Cushing’s Disease• Ectopic ACTH
Diagnostic studies?• Cushing
syndrome• ACTH-dependent
vs. -independent
Anterior PituitaryACTH
Steroid Treatment: Cushing Syndrome + Adrenal Insufficiency
Hypothalamus
Adrenal
CRH
Prednisonefrom CVS
Cushing syndrome
cortisol
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 MedicalAssociation, May 18, 1957, vol. 164, No. 3, pp. 261-265.
Nichols, John, M.D., "President Kennedy's Adrenals," Journalof the American Medical Association, July 10, 1967, vol. 201, No.2, pp. 115-116.
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