Interpretation

Elevated androstenedione levels indicate increased adrenal or gonadal androgen production. Mild elevations in adults are usually idiopathic or related to conditions, such as polycystic ovarian syndrome (PCOS) in women or use of androstenedione supplements in men and women. However, levels greater than or equal to 500 ng/dL can suggest the presence of an androgen-secreting adrenal or, less commonly, a gonadal tumor. Androstenedione levels are elevated in more than 90% of patients with benign androgen-producing adrenal tumors, usually well above 500 ng/dL. Most androgen-secreting adrenal carcinomas also exhibit elevated androstenedione levels but more typically show relatively larger elevations in 17-alpha-hydroxyprogesterone (OHPG) and dehydroepiandrosterone sulfate (DHEA-S) than in androstenedione, as they have often lost the ability to produce downstream androgens.

Most androgen-secreting gonadal tumors overproduce androstenedione, often to lesser degrees than adrenal tumors. They also overproduce testosterone. In men and in women with high baseline androgen levels (eg, PCOS), the respective elevations of androstenedione and testosterone may not be high enough to allow unequivocal diagnosis of androgen-producing gonadal tumors. In these cases, an elevation of the usual ratio of testosterone to androstenedione of 1, to a ratio of greater than 1.5, is a strong indicator of neoplastic androgen production.

Diagnosis and differential diagnosis of congenital adrenal hyperplasia (CAH) always requires the measurement of several steroids. Patients with CAH due to 21-hydroxylase gene (CYP21A2) variants, the most common cause of CAH (>90% of cases), usually have very high levels of androstenedione, often 5- to 10-fold elevations. OHPG levels are usually even higher, while cortisol levels are low or undetectable. All 3 analytes should be tested.

In the much less common CYP11A1 variant, androstenedione levels are elevated to a similar extent as in the CYP21A2 variant, and cortisol is also low, but OHPG is only mildly, if at all, elevated.

Also less common, 3-beta hydroxysteroid dehydrogenase (HSD) type 2 deficiency is characterized by low cortisol and substantial elevations in DHEA-S and 17-alpha hydroxypregnenolone, while androstenedione is either low, normal, or, rarely, very mildly elevated (as a consequence of peripheral tissue androstenedione production by 3-beta HSD-1).

In the very rare STAR (steroidogenic acute regulatory protein) deficiency, all steroid hormone levels are low, and cholesterol is elevated.

In the also very rare 17-alpha-hydroxylase deficiency, androstenedione, all other androgen-precursors (17-alpha-hydroxypregnenolone, OHPG, DHEA-S), androgens (testosterone, estrone, estradiol), and cortisol are low, while production of mineral corticoid and their precursors, in particular progesterone, 11-deoxycorticosterone, corticosterone, and 18-hydroxycorticosterone, are increased.

The goal of CAH treatment is normalization of cortisol levels and, ideally, also of sex-steroid levels. Traditionally, OHPG and urinary pregnanetriol or total ketosteroid excretion are measured to guide treatment, but these tests correlate only modestly with androgen levels. Therefore, androstenedione and testosterone should also be measured and used for treatment modifications. Normal prepubertal levels may be difficult to achieve, but if testosterone levels are within the reference range, androstenedione levels up to 100 ng/dL are usually regarded as acceptable.

Girls younger than 7 to 8 years of age and boys younger than 8 to 9 years of age who present with early development of pubic hair or, in boys, penile enlargement, may be suffering from either premature adrenarche or premature puberty, or both. Measurement of DHEA-S, DHEA, and androstenedione, alongside determination of sensitive estradiol, total and bioavailable or free testosterone, sex hormone binding globulin (SHBG), and luteinizing hormone/follicle-stimulating hormone levels will allow correct diagnosis in most cases. In premature adrenarche, only the adrenal androgens, chiefly DHEA-S, and to a lesser degree, androstenedione, will be above prepubertal levels, whereas early puberty will also show a fall in SHBG levels and variable elevations of gonadotropins and gonadal sex-steroids above the prepuberty reference range.

For more information see Steroid Pathways.