Determining the source of androgen excess

DAST: dexamethasone androgen-suppression test; ACTH: adrenocorticotropic hormone; PCOS: polycystic ovary syndrome; SD: standard deviations; CAH: congenital adrenal hyperplasia; FAH: functional adrenal hyperandrogenism; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulfate; LH: luteinizing hormone.
* Baseline testing consists of early morning blood sample for steroid intermediates (eg, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, and androstenedione) and a 24-hour urine for glucocorticoids (ie, free cortisol and 17 alpha-hydroxycorticosteroids, as well as creatinine to control for completeness of collection).
¶ A long DAST is a definitive test. This consists of a 4-day course of dexamethasone (0.5 mg 4 times daily) prior to an early morning post-test blood sample on day 5 after the final dexamethasone dose. A short DAST (sampling blood 4 hours after a single noontime 0.5 mg dexamethasone dose) maximally suppresses total and free testosterone and 17-hydroxyprogesterone, but DHEAS and cortisol are not maximally suppressed in comparison with the 4-day DAST.
Δ Normal androgen suppression in response to the 4-day DAST is indicated in the University of Chicago laboratory (95% cutoff levels) by total testosterone <28 ng/dL (1.0 nmol/L), free testosterone <8 pg/mL (28 pmol/L), DHEAS <40 mcg/dL (1.0 micromol/L) (>75% fall), and 17-hydroxyprogesterone <26 ng/dL (0.8 nmol/L).
◊ Normal glucocorticoid suppression is indicated by serum cortisol <1.5 mcg/dL (40 nmol/L) and urinary cortisol <10 mcg (27 nmol) per 24 hours by the second day of dexamethasone administration.
§ If androgen excess is suppressed by dexamethasone, further evaluation with a cosyntropin (ACTH) stimulation test is indicated. To perform the ACTH test, cosyntropin (250 micrograms) is given and blood is drawn for steroid measurements 30 to 60 minutes later.
¥ Subnormal suppression of testosterone (as well as androstenedione and 17-hydroxyprogesterone) and a normal suppression of cortisol and DHEAS is characteristic of PCOS, but the rare virilizing tumor or adrenal rests should be considered on the basis of clinical factors.
‡ If androgen and cortisol are both not normally suppressed, Cushing syndrome and cortisol resistance should be considered. Poor suppression can also result from noncompliance with the dexamethasone regimen.
† Steroid levels are assessed 30 to 60 minutes after ACTH administration. A post-ACTH 17-hydroxyprogesterone value >1000 ng/dL (30 nmol/L) is highly suggestive, and >1500 ng/dL (45 nmol/L) is definitive for nonclassic CAH due to 21-hydroxylase deficiency. A post-ACTH value of 17-hydroxypregnenolone >4500 ng/dL (150 nmol/L) suggests nonclassic 3-beta-hydroxysteroid dehydrogenase deficiency, and a post-ACTH value of 11-deoxycortisol >4000 ng/dL (116 nmol/L) suggests nonclassic 11-beta-hydroxylase deficiency. A serum cortisol level ≥18 mcg/dL (500 nmol/L) validates the administration of ACTH.
** Primary FAH (suggested by a modest rise in DHEA, 17-hydroxypregnenolone, and/or 17-hydroxyprogesterone that does not meet the criteria for the diagnosis of CAH) is sometimes the only demonstrable source of androgen excess in PCOS. (Apparent) cortisone reductase deficiency is a rare mimic of FAH and idiopathic hyperandrogenism; baseline urinary glucocorticoids consist primarily of cortisone metabolites rather than cortisol metabolites, so baseline 17-alpha-hydroxycorticosteroid excretion is elevated, but cortisol excretion is normal.
¶¶ When the source of hyperandrogenemia remains unexplained after intensive investigation (approximately 10% of cases), it usually appears to be due to obesity. The "atypical PCOS of obesity" is characterized by mild hyperandrogenism, oligo-ovulation, and low-normal LH; the hyperandrogenemia is readily dexamethasone-suppressible. Otherwise, the diagnosis is idiopathic hyperandrogenism (distinct from idiopathic hirsutism), if (apparent) cortisone reductase deficiency has been excluded.
ΔΔ Low baseline DHEAS with mildly elevated DHEA response to ACTH indicates apparent DHEA sulfotransferase deficiency (PAPSS2 deficiency); refer to UpToDate content on uncommon congenital adrenal hyperplasias.