IntroductionThe adrenal cortex produces three classes ofcorticosteroid hormones: glucocorticoids(e.g., cortisol), mineralocorticoids(e.g., aldosterone), and adrenal androgenprecursors (e.g., dehydroepiandrosterone, DHEA).Glucocorticoids and mineralocorticoids act throughspecific nuclear receptors, regulating aspects ofthe physiologic stress response as well as bloodpressure and electrolyte homeostasis. Adrenalandrogen precursors are converted in the gonadsand peripheral target cells to sex steroids that actvia nuclear androgen and estrogen receptors.
Regulatory Control ofSteroidogenesisProduction of glucocorticoids and adrenalandrogens is under the control of thehypothalamic-pituitary-adrenal (HPA)axis, whereas mineralocorticoids are regulated bythe renin-angiotensin-aldosterone (RAA) system.Glucocorticoid synthesis is under inhibitoryfeedback control by the hypothalamus and thepituitary. Hypothalamic release of corticotropin-releasing hormone (CRH) occurs in response toendogenous or exogenous stress.
Regulation of the renin-angiotensin-aldosterone (RAA) system
Thin and brittle skin in anelderly patient with Cushings
Hyperpigmentation of the knuckles in apatient with ectopic ACTH excess.
Ectopic ACTHAll the previous symptoms but….. Ectopic dominated by : Hypokalemic alkalosis (dominant feature) Fluid retention HTN Glucose intolerance Steroid psychosis Absence of other features may be explained bymore sudden onset by acquired ACTH fromtumor.
Other Test That May be Useful Midnight serum cortisol >7.5micrograms/dL (same time zone for 3days, NPO for 3 hours) Midnight saliva cortisol >550nanograms/dL, 93% sensitive
False Positives Severe depression Severe stress Phenytoin/phenobarbital/rifampin(accelerated metabolism of dex) Estrogen (pregnancy or OCP) Morbid obesity
Confirmatory TestLow dose dexamethasone suppression test Dexamethasone 0.5 mg q 6 x 48 hours Measure urine cortisol during the last 24 hours(urine free cortisol >20 micrograms/dL or urine17-hydroxycorticosteroid >4.5 mg/d)Or plasma cortisol (failure to fall to <5micrograms/dL)
Pituitary Tumor vs. EctopicACTH levels may distinguish: ACTH independent (adrenal or exogenousglucocorticoids)from ACTH dependent (pituitary, ectopic ACTH) ACTH independent- low or undetectable ACTH ACTH dependent-ACTH elevated In addition ectopic ACTH levels are usu 8xhigher than pituitary caused ACTH secretingadenomas
Treatment Cushing’s Disease: Transphenoidalresection of pituitary adenoma Adrenal neoplasms: resection Ectopic ACTH: resection if possible Bilateral adrenal hyperplasia: may needadrenalectomies (lifelong glucocorticoidand mineralcorticoid replacement)
‘Medical’ AdrenalectomyMedications that inhibit steroidogenesis Ketoconazole (600 to 1200 mg/day) metyrapone (exacerbates female virilization) (2-3 g/day) Mitotane(2-3 G/day)- slow onset Aminoglutethinide (1g/day) Ocreotide can work in 1/3 of patients.Major side affect is adrenal insufficiency, thereforestart at lowest dose and titrate
Prognosis Benign adrenal adenoma- 95% 5 yearsurvival, 90% 10 year Cushing’s disease (pituitary adenoma) samesurvival, but 10-20% transphenoidal resectionfailure rate over 10 years. Ectopic ACTH survival depends on malignancy Unknown cause of elevated ACTH- 65% 5 yearsurvival, 55% 10 year survival Adrenal carcinoma- median survival 7 months