Variants of Congenital Adrenal Hyperplasia

Variant Gene Impact on Steroid Synthesis Diagnostic Marker Steroids in Serum (and Urine) 21-Hydroxylase deficiency (21OHD) CYP21A2  Glucocorticoid deficiency, mineralocorticoid deficiency, adrenal androgen excess 17-Hydroxyprogesterone, 21-deoxycortisol (pregnanetriol, 17-hydroxypregnanolone, pregnanetriolone) 11beta-Hydroxylase deficiency (11OHD) CYP11B1  Glucocorticoid deficiency, mineralocorticoid excess, adrenal androgen excess 11-Deoxycortisol, 11-deoxycorticosterone (tetrahydro-11-deoxycortisol, tetrahydro-11-deoxycorticosterone) 17alpha-Hydroxylase deficiency (17OHD) CYP17A1  (Glucocorticoid deficiency), mineralocorticoid excess, androgen deficiency 11-Deoxycorticosterone, corticosterone, pregnenolone, progesterone (tetrahydro-11-deoxycorticosterone, tetrahydrocorticosterone, pregnenediol, pregnanediol) 3beta-Hydroxysteroid dehydrogenase deficiency (3bHSDD) HSD3B2  Glucocorticoid deficiency, (mineralocorticoid deficiency), adrenal androgen excess 17-Hydroxypregnanolone (pregnanetriol) P450 oxidoreductase deficiency (ORD) POR  Glucocorticoid deficiency, (mineralocorticoid excess), androgen deficiency, skeletal malformations Pregnenolone, progesterone, 17-hydroxyprogesterone (pregnanediol, pregnanetriol)

Signs and Symptoms of Adrenal Insufficiency

Signs and Symptoms Caused by Glucocorticoid Deficiency  Fatigue, lack of energy Weight loss, anorexia Myalgia, joint pain Fever Anemia, lymphocytosis, eosinophilia Slightly increased TSH (due to loss of feedback inhibition of TSH release) Hypoglycemia (more frequent in children) Low blood pressure, postural hypotension Hyponatremia (due to loss of feedback inhibition of AVP release) Signs and Symptoms Caused by Mineralocorticoid Deficiency (Primary AI Only)  Abdominal pain, nausea, vomiting Dizziness, postural hypotension Salt craving Low blood pressure, postural hypotension Increased serum creatinine (due to volume depletion) Hyponatremia Hyperkalemia Signs and Symptoms Caused by Adrenal Androgen Deficiency  Lack of energy Dry and itchy skin (in women) Loss of libido (in women) Loss of axillary and pubic hair (in women) Other Signs and Symptoms  Hyperpigmentation (primary AI only) [due to excess of pro-opiomelanocortin (POMC)–derived peptides] Alabaster-colored pale skin (secondary AI only) (due to deficiency of POMC-derived peptides)

Cushing's - medical therapy

Oral agents with established efficacy in Cushing's syndrome are metyrapone and ketoconazole. 


Metyrapone inhibits cortisol synthesis at the level of 11 beta-hydroxylase , whereas the antimycotic drug ketoconazole inhibits the early steps of steroidogenesis. Typical starting doses are 500 mg/tid for metyrapone (maximum dose, 6 g) and 200 mg/tid for ketoconazole (maximum dose, 1200 mg). 


Mitotane, a derivative of the insecticide o,p'DDD, is an adrenolytic agent that is also effective for reducing cortisol. Because of its side effect profile, it is most commonly used in the context of adrenocortical carcinoma, but low-dose treatment (500–1000 mg per day) has also been used in benign Cushing's. 


In severe cases of cortisol excess, etomidate can be used to lower cortisol. It is administered by continuous IV infusion in low, nonanesthetic doses.

HPA axis tests

Diagnostic tests assessing the HPA axis make use of the fact that it is regulated by negative feedback. 

Glucocorticoid excess is diagnosed by employing a dexamethasone suppression test. Dexamethasone, a potent glucocorticoid, suppresses CRH/ACTH and, therefore, endogenous cortisol.  If cortisol production is autonomous (e.g., adrenal nodule), ACTH is already suppressed and dexamethasone has little additional effect. If cortisol production is driven by an ACTH-producing pituitary adenoma, dexamethasone suppression is ineffective at low doses but usually induces suppression at high doses. If cortisol production is driven by an ectopic source of ACTH, the tumors are usually resistant to dexamethasone suppression. Thus, the dexamethasone suppression test is useful to establish the diagnosis of Cushing's syndrome and to assist with the differential diagnosis of cortisol excess.

Conversely, to assess glucocorticoid deficiency, ACTH stimulation of cortisol production is used. The ACTH peptide contains 39 amino acids but the first 24 are sufficient to elicit a physiologic response. The standard ACTH stimulation test involves administration of cosyntropin (ACTH 1-24), 0.25 mg IM or IV, and collection of blood samples at 0, 30, and 60 minutes for cortisol. A normal response is defined as a cortisol level >20 ug/dL or an increment of >10 ug/dL over baseline. A low-dose (1 ug cosyntropin IV) version of this test has been advocated to avoid overstimulation of the adrenal gland. 

Alternatively, an insulin tolerance test (ITT) can be used to assess adrenal insufficiency. It involves injection of insulin to induce hypoglycemia, which represents a strong stress signal that triggers hypothalamic CRH release and activation of the entire HPA axis. The ITT involves administration of regular insulin 0.1 U/kg IV (dose should be lower if hypopituitarism is likely) and collection of blood samples at 0, 30, 60, and 120 minutes for glucose, cortisol, and growth hormone (GH), if also assessing the GH axis. Oral or IV glucose is administered after the patient has achieved symptomatic hypoglycemia (usually glucose <40 mg/dL). A normal response is defined as a cortisol >20 ug/dL and GH >5.1 ug/L. The ITT requires careful clinical monitoring and sequential measurements of glucose. It is contraindicated in patients with coronary disease, cerebrovascular disease, or seizure disorders, which has made the short cosyntropin test the commonly accepted first-line test.

Mineralocorticoid production is controlled by the RAA regulatory cycle, which is initiated by the release of renin from the juxtaglomerular cells in the kidney, resulting in cleavage of angiotensinogen to angiotensin I in the liver . Angiotensin-converting enzyme (ACE) cleaves angiotensin I to angiotensin II, which binds and activates the angiotensin II receptor type 1 (AT1 receptor), resulting in increased aldosterone production and vasoconstriction. Aldosterone enhances sodium retention and potassium excretion, and increases the arterial perfusion pressure, which in turn regulates renin release. Because mineralocorticoid synthesis is primarily under the control of the RAA system, hypothalamic-pituitary damage does not significantly impact the capacity of the adrenal to synthesize aldosterone.

Similar to the HPA axis, the assessment of the RAA system can be used for diagnostic purposes. If mineralocorticoid excess is present, there is a counter-regulatory downregulation of plasma renin . Conversely, in mineralocorticoid deficiency, plasma renin is markedly increased. Physiologically, oral or IV sodium loading results in suppression of aldosterone, a response that is attenuated or absent in patients with autonomous mineralocorticoid excess.