ESR [031] PATHOPHYSIOLOGY OF THE ADRENAL AXIS (part 1) Flashcards
Effect of STRESS on the HPA Axis ?
What causes Cushing’s Disease?
A. Chronic stress
B. Ectopic ACTH secretion
C. Functional ZF tumour
D. Glucocorticoid resistance
E. Pituitary ACTH tumor
E
Cushing’s DiseaseVSsyndrome ?
Causes of Cushing’s Syndrome ?
(Prolonged or excess exposure to cortisol)
• Long-term use of corticosteroid hormones such as cortisone or prednisone
• A tumor or abnormality of the adrenal gland, which causes the body to produce excess cortisol
• Tumors of the lungs, thyroid, pancreas or thymus gland, which can, in rare instances, produce hormones that trigger the syndrome
Symptoms of Cushing’s Syndrome ?
+
• Menstrual disorders, especially infrequent or absent periods
• Fatigue and muscle weakness
• Personality changes or mood swings
How to Diagnose Cushing’s Syndrome ?
Treatment of Cushing’s Syndrome ?
Drug
The drug ?
The drug ?
A drug that is a Somatostatin analogue, useful in controlling Cushing’s syndrome caused by ectopic ACTHsecreting tumours ?
Octeriotide
How is Radiotherapy used for Cushing’s disease ?
How are Adrenal adenomas removed ?
• Removed after pre-operative normalisation of cortisol levels using metyrapone or ketoconazole
• The usual operation is a laparoscopic adrenalectomy, although the cortisol-weakened tissues make the surgery difficult.
Effectivity of Adrenal carcinomas removal ?
• In carcinomas open operation (prognosis is poor).
• The tumor may be removed surgically, although this will not account for metastases, and so medical treatment and radiotherapy are also indicated.
treatment of choice for ectopic ACTH secreting tumors ?
• Where possible, the treatment of choice for ectopic ACTHsecreting tumors is resection of the primary tumor. The best results in carcinoid.
• In cases where the primary tumor cannot be localised, the treatment of choice is bilateral adrenalectomy
Causes of Hypocortisolaemia ?
• Decreased ACTH drive
- Decreased pituitary ACTH output
- ACTH resistance
- Decreased hypothalamic CRH drive
What causes Addison’s disease?
• Autoimmune: most often occurs when the body’s immune system kills off the part of the adrenal glands that makes cortisol and Aldosterone.
• Damage to the adrenal glands
What causes Addison’s disease?
Ans: Damage to the adrenal glands by other causes as follows ?
Addison’s disease-age ralshionship ?
People can get Addison’s disease at any age.
…. disease can also occur if you take a steroid medication for a long time and then suddenly stop using it.
Addison’s
Why must patients be “weaned off”of glucocorticoids?
How can a defect in ACTH drive to the adrenal cortex be differentiated from Addison’s disease?
Charecteristics of Congenital Adrenal Hyperplasia ?
Which gene is usually mutated in patients with salt-wasting CAH?
A. CYP11A encodes P450CSCC
B. HSD3B2 encodes 3βHSD
C. CYP17 encodes P450C17
D. CYP21 encodes P450C21
E. CYP11B1 encodes P450C11B1
F. CYP11B2 encodes P450C11B2
D. CYP21 encodes P450C21
What causes Hyperglycaemia?
(A) Mineralocorticoids
(B) Glucocorticoids
( c ) Adrenal Androgens
(B) Glucocorticoids ELEVATED
What Causes Hypokalemia?
(A) Mineralocorticoids
(B) Glucocorticoids
(c) Adrenal Androgens
(A) Mineralocorticoids – ELEVATED
(B) Glucocorticoids – ELEVATED
What Causes Increased Gluconeogenesis?
(A) Mineralocorticoids
(B) Glucocorticoids
( C ) Adrenal Androgens
(B) Glucocorticoids – ELEVATED
How does Glucocorticoids – ELEVATED cause Increased Gluconeogenesis? ?
• Increased expression of liver gluconeogenic enzymes.
• Increased availability of glycerol and gluconeogenic amino-acids
What Causes Acne?
(A) Mineralocorticoids
(B) Glucocorticoids
(C) Adrenal androgens
(C) Adrenal androgens– ELEVATED
How does Adrenal androgens– ELEVATED cause Acne ?
Through Increased production of sebaceous secretions
What Causes Immune Suppression?
(A) Mineralocorticoids
(B) Glucocorticoids
(C) Adrenal Androgens
(B) Glucocorticoids ELEVATED
How does Glucocorticoids ELEVATED Causes Immune Suppression ?
• Involution of thymus + lymphatic tissue
• Induction of lipocortin expression inhibits inflammatory mediators
What Causes Osteoporosis?
(A) Mineralocorticoids
(B) Glucocorticoids ELEVATED
(C) Adrenal Androgens
(B) Glucocorticoids ELEVATED
How does Glucocorticoids ELEVATED cause Osteoporosis ?
Through Increased bone catabolism
What Causes Anti-Natriuresis?
(A) Mineralocorticoids
(B) Glucocorticoids
(C) Adrenal Androgens
(A) Mineralocorticoids – ELEVATED
(B) Glucocorticoids – ELEVATED
What Causes Insulin Resistance?
(A) Mineralocorticoids
(B) Glucocorticoids
(C) Adrenal Androgens
(B) Glucocorticoids ELEVATED
How does Glucocorticoids ELEVATED Causes Insulin Resistance? ?
Antagonises insulin actions - directly and indirectly
What Causes Increased Bruising?
(A) Mineralocorticoids
(B) Glucocorticoids
(C) Adrenal Androgens
(B) Glucocorticoids- ELEVATED
How does Glucocorticoids- ELEVATED cause Increased Bruising? ?
• Less muscle and adipose to protect blood vessels
• Suppressed proliferation of fibroblasts
• Impaired collagen synthesis
What Causes Hirsutism?
(A) Mineralocorticoids
(B) Glucocorticoids
(C) Adrenal androgens
(C) Adrenal androgens - ELEVATED
How does Adrenal androgens - ELEVATED cause Hirsutism ?
• Increased stimulation of androgen dependent (facial) hair follicles
What Increases Gastric Ulceration?
(A) Mineralocorticoids
(B) Glucocorticoids
(C) Adrenal Androgens
(B) Glucocorticoids - ELEVATED
How does Glucocorticoids - ELEVATED Increases Gastric Ulceration?
• Acid attack on gastric mucosa inhibited by prostaglandins
• Prostaglandin synthesis inhibited by glucocorticoids (via increased lipocortin/Annexin)
What Causes Hypervolemic Hypertension?
(A) Mineralocorticoids
(B) Glucocorticoids
(C) Adrenal Androgens
(A) Mineralocorticoids - ELEVATED
(B) Glucocorticoids – ELEVATED
What Causes Cliteromegaly?
(A) Mineralocorticoids
(B) Glucocorticoids
(C) Adrenal androgens
(C) Adrenal androgens – ELEVATED
How does Adrenal androgens – ELEVATED Causes Cliteromegaly?
• Differentiation of genital tubercle into glans
• ?Labial fusion
• Requires DHEA → → Testosterone → 5αDHT
What surgery is indicated for Cushing’s disease ?
trans-sphenoidal surgery
What surgery is indicated for Cushing’s syndrome ?
- Resect ectopic site of ACTH secretion
- Adrenalectomy (& steroid replacement)
What medicine is indicated for Cushing’s syndrome ?
- Anti-glucocorticoids (e.g. RU486) & anti-androgens (e.g.flutamide)
A drug that :
- Anti-progestogen, anti-glucocorticoid and a weak anti-
androgen.
- It does not bind to the oestrogen receptor or the mineralocorticoid receptor.
RU486 (Mifepristone)
drugs that :
• Block or suppress the activity of androgens and block androgen receptors.
• Finasteride reduces androgen dependent activity by hindering 5α-reductase (isoenzymes type1&2) action and the peripheral conversion of T to DHT.
flutamide, spironolactone and cyproterone acetate
Why does glucocorticoid resistance result in hyperpigmentation?
Why does Addison’s disease result in hyperpigmentation?
Why does glucocorticoid Resistance (or a defect in cortisol synthesis) result in lack of hepatic glycogen?
• Cortisol increases plasma [glucose] via increased gluconeogenesis (enzymes + substrates)
• Cortisol increases expression of glycogen synthetase
• Cortisol increases hepatic glycogen as a glucose reserve for future use
Why does increased production of DOC in salt-sparing CAH result in malignant hypertension?
• DOC is produced in excess.
• Lack of cortisol raise ACTH drive thus more DOC is produced.
• Normal feedback mechanisms do not control DOC production
What’s Conn’s Syndrome
1ry & 2ry hyperaldosteronism the adrenal gland releases too much aldosterone
Define Secondary Conn’s Syndrome
- excess aldosterone is caused by something outside the adrenal gland that mimics the primary condition.
Symptoms & Signs of Conn’s Syndrome ?
Diagnosis of Conn’s Syndrome ?
Treatment of Conn’s Syndrome ?
Nelson’s syndrome ?
• In the past, the identification of a pituitary adenoma was more difficult, and therefore patients underwent removal of the adrenal glands in order to lower the blood levels of cortisol. Because the pituitary tumour was not removed, the tumour enlarged and excessive production of ACTH continued. The excess ACTH stimulates pigment production in the skin.
• An iatrogenic condition that occurs as a result of removal of both adrenal glands. Treatment involves trans-sphenoidal surgery to remove the pituitary tumor.
• The common signs and symptoms include muscle weakness and skin hyperpigmentation due to excess MSH. Nelson’s syndrome is now rare because bilateral adrenalectomy is only used in extreme circumstances.
