7/30/2019 IHP StressVoice

1/40

Lightheadness

Low blood pressure

Rapid heart rate

Salt craving

High blood potassium

Low blood sugar

Poor appetite

Weight loss

Tanned

Death if untreated

7/30/2019 IHP StressVoice

2/40

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

7/30/2019 IHP StressVoice

3/40

7/30/2019 IHP StressVoice

4/40

Circadian Rhythm in ACTH and

Cortisol

6am 6pm 6am

ACTH(pg/mL)

Cortisol( g/dL)

1

15

5

20

7/30/2019 IHP StressVoice

5/40

7/30/2019 IHP StressVoice

6/40

The Stress AxisHormonal[Hypothalamic-Pituitary-Adrenal]

Maintain bloodpressure

Preventahypoglycemia

Loss ofareproductiveabehavior and fxn

Loss of growth

Behavioral

Acute Fear Clarity of thought

Anorexia

Loss of libido

Fight or flight

Chronic Loss of reproductive

behavior

Autonomic[Sympathetic NervousSystem]

Dilate eyes

Raise heart rate Raise cardiac output

Maintain bloodpressure

Raise breathing rate Bronchodilate

Prevent hypoglycemia

Increase blood to brain,muscle

Decrease blood to skin

gut

7/30/2019 IHP StressVoice

7/40

The Stress Axis

Amygdala

Stress-inducedbehaviors

Behavioral

Brainstem

Catecholamines

AutonomicSympatheticNervous

System

effects

HormonalHypothalamic-Pituitary-Adrenal

CRHVP III

CRH

PVN

Pituitary

ACTH

CortisolEpinephrine effects

pregangionic

postgangionic

7/30/2019 IHP StressVoice

8/40

CRH

VP III

CRH

PVN

Ant PitACTH

The Hypothalamic-Pituitary-Adrenal Axis

Mineralocorticoid

Effects

Suppress Growth

Suppress Fertility

GlucocorticoidEffects

C i l i hibi d i f i b bl ki

7/30/2019 IHP StressVoice

9/40

Stress

Lulu Wang,PhD

01020304050

Unstressed 5h restraintCorticosterone(ug

/dL) Corticosterone after

5h restraint

Cortisol inhibits reproductive function by blocking

kisspeptin gene expression

0

2

4

68

Unstressed 5h restraint

T(ng/mL)

Testosterone after 5h

restraintUnstressed 5h restraint

Kisspeptin mRNA

7/30/2019 IHP StressVoice

10/40

CRH

VP III

CRH

PVN

Ant PitACTH

The Hypothalamic-Pituitary-Adrenal Axis

Mineralocorticoid

Effects

Suppress Growth

Suppress Fertility

GlucocorticoidEffects

7/30/2019 IHP StressVoice

11/40

N-terminal

Glycopeptide

(1-76)

Joining

Peptide

(79-108)

-MSH

(112-124)

CLIP

(130-150)

-LPH

(153-207)

-END

(210-240)

ACTH(112-150)

-LPH

(153-240)

-KR

-KR

-KKRR

-KR

-KR

Pro-opiomelanocortin (POMC)

Anterior Pituitary

PC1 PC = proconvertase

7/30/2019 IHP StressVoice

12/40

7/30/2019 IHP StressVoice

13/40

Genetic Deficiency of Human POMC

Krude and Gruters Nat Genetics 19:155, 1998

7/30/2019 IHP StressVoice

14/40

Human Adrenal from Organ Transplant Donor

7/30/2019 IHP StressVoice

15/40

Structure of Adrenal Cortex

Aldosterone

Cortisol

Adrenal Androgens

Epinephrine

7/30/2019 IHP StressVoice

16/40

CRH

VP III

CRH

VP

PVHpc

Ant PitACTH

GlucocorticoidEffects

The Hypothalamic-Pituitary-Adrenal Axis

Development

Metabolism

Immune

Vascular

Mineralocorticoid

Effects

Suppress GrowthSuppress Fertility

7/30/2019 IHP StressVoice

17/40

Fetal Lung Development Requires Glucocorticoid

Normal Crh KO Crh KO +

Glucocorticoid

7/30/2019 IHP StressVoice

18/40

CRH

VP III

CRH

VP

PVHpc

Ant PitACTH

GlucocorticoidEffects

The Hypothalamic-Pituitary-Adrenal Axis

Development

Metabolism

Immune

Vascular

Mineralocorticoid

Effects

Suppress GrowthSuppress Fertility

7/30/2019 IHP StressVoice

19/40

Cortisol Maintains Blood Sugar

during Fasting

FAT

LIVER

MUSCLE

Amino Acids

Fatty Acids, Glycerol GLUCOSE

Cortisol

7/30/2019 IHP StressVoice

20/40

Adrenal Insufficiency

7/30/2019 IHP StressVoice

21/40

Lightheadness Hypotension

Tachycardia

Salt craving

Hyperkalemia Hypoglycemia

Anorexia

Weight loss

Hyperpigmentation

Death if untreated

7/30/2019 IHP StressVoice

22/40

III

CRH

PVN

Pituitary

ACTH

Glucocorticoid

7/30/2019 IHP StressVoice

23/40

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

??????

Aldosterone

ACTH

T f Ad l I ffi i

7/30/2019 IHP StressVoice

24/40

Anterior Pituitary

ACTH

Cortisol,Aldosterone

Types of Adrenal Insufficiency

Hypothalamus

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+

7/30/2019 IHP StressVoice

25/40

Hypotension

Tachycardia

Hyperkalemia Hypoglycemia

Anorexia

Weight loss

Ambiguous genitalia

Death if untreated

Newborn

7/30/2019 IHP StressVoice

26/40

HO

HO

HO

OH

HO

O

OH OHOH

O

zonaglomerulosa

zonafasciculata

zonareticularis

medulla

OH

CHOH

CH2

NH-CH3

PNMT

Testosterone

Cholesterol

Pregnenolone

17OH-Pregnenolone

Dehydroepiandrosterone

17OH-Progesterone

Androstenedione

Corticosterone Aldosterone

11Deoxy-Cortisol

Cortisol

Norepi-nephrine

Epinephrine

DeoxycorticosteroneProgesterone

3HSD 21OHase

17-

OHase

17-20

Lyase

11OHase

Aldosterone Synthase

(11OHase, 18OHase,

18HSD)

20-22

Desmolase

OH17Ketosteroid

Reductase

OH

CHOH

CH2

NH2

OH

HOEstradiol

Aromatase

GONAD

Adrenal Hormone Synthesis

P i Ad l I ffi i i CAH

7/30/2019 IHP StressVoice

27/40

Anterior Pituitary

ACTH

Cortisol,Aldosterone

Primary Adrenal Insufficiency in CAH

Hypothalamus

Adrenal

Adrenal Androgen Excess Females: virilization

Males: ??

Aldosterone Deficiency Hyperkalemia

Hypotension

Tachycardia

Cortisol Deficiency Hypotension

Tachycardia Hypoglycemia

Anorexia?

Weight loss?

CRH

AdrenalAndrogens

7/30/2019 IHP StressVoice

28/40

Cushing Syndrome

7/30/2019 IHP StressVoice

29/40

Hypertension

Hypokalemia Hyperglycemia

Hyperphagia

Obesity

Poor growth

Death if untreated

Cushing Syndrome: Violaceous Striae

7/30/2019 IHP StressVoice

30/40

Joe EK. Dermatology Online J.9:16, 2003

Cushing Syndrome: Violaceous Striae

7/30/2019 IHP StressVoice

31/40

7/30/2019 IHP StressVoice

32/40

7/30/2019 IHP StressVoice

33/40

7/30/2019 IHP StressVoice

34/40

Cli i l Fi di i C hi S d

7/30/2019 IHP StressVoice

35/40

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

7/30/2019 IHP StressVoice

36/40

CRH

AnteriorPituitaryACTH

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

7/30/2019 IHP StressVoice

37/40

Anterior Pituitary

ACTH

Steroid Treatment:Cushing Syndrome + Adrenal Insufficiency

Hypothalamus

Adrenal

CRH

Prednisone

from CVS

Cushing syndrome

cortisol

7/30/2019 IHP StressVoice

38/40

7/30/2019 IHP StressVoice

39/40

7/30/2019 IHP StressVoice

40/40

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.