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DRENAL AXIS

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Under the supervision of Miklós Jászberényi

TABLE OF CONTENTS

- Introduction-Physiology of the HPA axis

- Discussion -Hypoactivity of the HPA axis-Hyperactivity of the HPA axis

- Conclusion

STRESS SYSTEM

Stressors -> Activation of the sympathetic-adrenal-medullary axis hypothalamic-pituitary-adrenal axis

General Adaptation Syndrome (Hans Selye, 1936)1. Alarm stage

2. Resistance stage

3. Exhaustion stage

PHYSIOLOGY OF THE HPA AXIS

Cerebral cortex

STRESS

Physical EmotionalBiochemicalDiurnal rhythms

Hypothalamus

Corticotropin-releasing hormone

CRH

Parvocellular neurons in the hypothalamus synthesize and secrete

Long portal vessels carry CRH Anterior Pituitary Gland

ACTH

Adrenal Cortex

CORTISOL

Negative feedback

Negative feedback

Short Feedback

CORTISOL EFFECTS

Retrived from S. Melmet, K. S. Polonsky, P. R. Larsen, H. M. Kronenberg, Williams textbook of endocrinology, 12th edition, Elsevier Saunders, 2011

Brain/CNS: Depression Psychosis

Carbohydrate/lipid metabolism: ↑ Hepatic glycogen deposition ↑ Peripheral insulin resistance ↑ Gluconeogenesis ↑ Free fatty acid production Overall diabetogenic effec

Adipose tissue distribution: Promotes visceral obesity

Bone and calcium metabolism: ↓ Bone formation ↓ Bone mass Osteoporosis

Skin/muscle/connective tissue: Protein catabolism/collagen breakdown Skin thinning , Muscular atrophy

Endocrine system: ↓ LH, FSH release ↓ TSH release ↓ GH secretion

Eye: Glaucoma

GI tract: Peptic ulcerations

Cardiovascular/renal: Salt and water retention Hypertension

Growth and development: ↓ Linear growth

Immune system: Anti-inflammatory action Immunosuppression

STRESSOR

Activation of the HPA axis

Antireproductive Antigrowth Catabolic Immunosuppresive

effects

Essential for survival

Hazardous effects on long-term activation

Hypoactivity

Hyperactivity

DISORDERS OF THE HPA AXIS

HYPOACTI

VITY

OF HPA

AXIS

• ADRENOCORT ICAL INSUFF IC IENCY

• CONGENITAL ADRENAL HYPERPL AS IA

Primary Adrenal Insufficiency

(Adrenal Failure)

Chronic(Addison disease)

Acute

- Stress in a chronic PAI history

- Exogenous corticosteroids with acute stress

- Massive adrenal hemorrhage

- Tuberculosis- AIDS- Metastatic

cancers- Autoimmune

adrenalitis (APS1, APS2)

Secondary Adrenal

Insufficiency

Lack of production of

ACTH

Destruction by autoAB of key

enzymes involved in the

steroidogenesis for instance 21-

OH or 17-OH

CLINICAL ASPECT

Glucorticoid and

mineralocorticoid deficiency

Skin pigmentation (sun-exposed

areas and pressure points)

PAI Glucocorticoid deficiency but intact

RAA

No skin pigmentati

on

SAI

Anorexia nausea, vomiting, diarrhea, +/- abdominal pain. +/-Fever and hypoglycemia

TREATMENT- Glucocorticoid

replacement in 2 or 3 divided doses

- +/- Mineralocorticoid

ISSUES…- Mimic the

physiologic cortisol secretion rythm

- Reduce adverse effects

- Adrenal crisis

DIAGNOSIS:- ACTH stimulation test measures of plasma

cortisol level- Radioimmunoassays to detect autoantibodies

CONGENITAL ADRENAL HYPERPLASIASimple Virilizing FormSalt-

Wasting Form

Non classic Form

Mutation CYP21A2

with CYP21A1

P

Retrived from V. Kumar, A. K. Abbas, N. Fausto, J. C. Aster, Pathologic Basis of disease, Robbins and Cotran (2010), 1153

Diagnosis

Treatment- Long-term

glucocorticoid treatment

- Goal: to use the lowest dose of GCC

- Short half-life hydrocortisone preferred but single daily dose ineffective…

- to optimize the treatment and its consequences with the patient’s specificities

Measu

re o

f

eleva

ted

seru

m le

vels

of 1

7-OHP

(>10, 0

00

ng/dL)

Basal measure of 17-OHP and 60 min after Synacthen injection CYP21A2

genotyping

NOVEL TREATMENT, GENE THERAPY?

Single intra-adrenal injection of an adenoviral vector encoding CYP21A2 which may compensate for the biochemical, endocrine and histological alterations in 21OH-deficient mice

Retrieved from: http://fr.dreamstime.com/photo-stock-laboratoire-de-rat-image34061020

HYPERACTI

VITY

OF HPA

AXIS• CUSH ING ’S

SYNDROME• MULT IPLE

ENDOCRINE NEOPL AS IA TYPE 1

CAUSES OF CUSHING’S SYNDROME

Iatrogenic originGlucocorticoids are

routinely used to fight inflammatory diseases

Endogenous origin- Cushing’s disease- Ectopic corticotropin syndrome- Adrenocortical tumors

DEFINITION OF CUSHING’S SYNDROME

Cushing’s syndrome refers to the clinical manifestations induced by chronic exposure to excess glucocorticoids.

from David N. Orth, m.d., Cushing’s Syndrome The New England Journal of Medicine, 1995

CLINICAL FINDINGS• Centripetal fat distribution

• Tissue fragility• Easily scratched skin• Wide and purple striae• Wide ecchymotic lesions

• Protein wasting features• Muscle wasting, great weakness• Osteoporosis

• Immunodeficiency• High blood pressure• Disturbances of the gonadotropic

axis• Psychiatric disorders

From "Adrenal Cortex." In Williams Textbook of Endocrinology. 12th ed.

TREATMENTS

• Surgical removal of the tumor with medical treatments.

• In Cushing’s disease transsphenoidal surgery has very good outcomes

DIAGNOSIS

Cushing’s syndrome24h urinary cortisol

Late night serum or salivary samples

Suppression tests

ACTH-dependentHigh plasma ACTH

level

Cushing’s diseasePituitary

MRI shows adenoma

Ectopic ACTH

secretionLow ACTH level

in petrosal sinus blood

sample

ACTH-independent

Low plasma ACTH level

Adrenal tumorCT scan

MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

Rare autosomal dominant hereditary disease.

Tumors develop in endocrine tissues polyendocrine syndromes

• Parathyroid glands (HPT)

• Pancreatic islets (Gastrinomas)

• Anterior pituitary• Prolactinomas• ACTH adenomas: Cushing’s disease

• Adrenals glands• Cortisol adenomas: Cushing’s syndrome• Aldosterone tumors: Conn’s syndrome

Hyperactivity of HPA axis

TAKE HOME MESSAGES

• The ‘General Adaptation Syndrome’ describes the body’s reaction to a stressor

• The HPA axis mediates the stress response through a chain of hormones

• Adrenocortical insufficiency can be primary or secondary depending on the localization of the impairment.

• Congenital Adrenal Hyperplasia is caused by mutations in key enzymes involve in the steroidogenesis.

• Spontaneous Cushing’s syndrome can be either ACTH-dependent or ACTH-independent.

• MEN1 induce polyendocrine syndromes such as hyperactivity of HPA axis

Thank you for your attention