Ihp stress voice

• 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.