What are the causes of hyperandrogenism (elevated testosterone) in women?

Causes of Elevated Testosterone in Females

Polycystic ovary syndrome (PCOS) is the overwhelming cause of elevated testosterone in women, accounting for approximately 95% of all hyperandrogenism cases and affecting 10-13% of women globally. 1

Primary Causes by Prevalence

Most Common: Polycystic Ovary Syndrome (PCOS)

• PCOS drives hyperandrogenism through accelerated GnRH pulsatility, which increases LH secretion and stimulates ovarian theca cells to overproduce testosterone, while the FSH-granulosa cell axis becomes dysfunctional. 2
• Hyperinsulinemia directly amplifies androgen production by stimulating ovarian theca cells independent of LH and suppresses hepatic SHBG production, increasing free testosterone levels. 2
• PCOS presents with gradual-onset hirsutism, acne, oligomenorrhea/amenorrhea, and infertility without severe virilization. 1
• Weight gain is a major trigger for PCOS development and worsening in genetically susceptible women. 2

Androgen-Secreting Tumors (Ovarian or Adrenal)

• Rapid-onset or severe hirsutism with virilization (clitoromegaly, deepening voice, male-pattern baldness) demands immediate aggressive workup for androgen-secreting tumors. 2, 3
• Ovarian androgen-secreting tumors occur in 1-3 per 1000 patients with hirsutism and comprise less than 0.5% of all ovarian tumors. 4
• Adrenal tumors (adenomas or carcinomas) are less common than ovarian tumors but cause postmenopausal virilization. 4
• Testosterone levels >5 nmol/L (>144 ng/dL) or more than twice the upper limit of normal strongly suggest tumor and require urgent imaging. 5, 6
• Pure testosterone-secreting adrenal adenomas can present with markedly elevated testosterone but normal DHEAS, androstenedione, and 17-hydroxyprogesterone, mimicking ovarian pathology. 7

Non-Classical Congenital Adrenal Hyperplasia (NCCAH)

• NCCAH must be systematically excluded before attributing symptoms solely to PCOS. 3
• Screen with early morning 17-hydroxyprogesterone levels; elevated levels warrant ACTH stimulation testing. 3

Ovarian Hyperthecosis

• Ovarian hyperthecosis presents with severe hyperandrogenism, virilization, and is normally associated with insulin resistance. 5
• Distinguished from PCOS by more severe androgen elevation and virilization symptoms. 6

Cushing's Syndrome

• Consider Cushing's syndrome in any woman with recent-onset hyperandrogenism accompanied by buffalo hump, moon facies, hypertension, abdominal striae, centripetal fat distribution, easy bruising, or proximal myopathy. 3
• Screen with overnight dexamethasone suppression test or 24-hour urinary free cortisol measurement. 3

Hyperprolactinemia

• Hyperprolactinemia causes oligomenorrhea, amenorrhea, subfertility, galactorrhea, and hirsutism. 8
• Measure prolactin levels to exclude this diagnosis in all women with hyperandrogenism. 1, 3

Drug-Induced Hyperandrogenism

• Exogenous androgen use (anabolic steroids, testosterone supplements, DHEA) is a critical cause to identify through detailed medication and supplement history. 1, 3
• Valproate (antiepileptic drug) can trigger or exacerbate PCOS-like symptoms including hirsutism. 2, 3
• Enzyme-inducing antiepileptic drugs (carbamazepine, phenobarbital, phenytoin) increase SHBG production, altering free testosterone levels. 1

Thyroid Disease

• Hyperthyroidism can cause elevated SHBG and alter testosterone metabolism. 5
• Measure TSH in all women with suspected hyperandrogenism to rule out thyroid disease. 1, 3

Postmenopausal-Specific Causes

• Relative androgen excess occurs during menopausal transition as estrogen levels decline while androgen production continues. 6
• Postmenopausal hyperandrogenism may represent worsening of previously undiagnosed PCOS, NCCAH, or ovarian hyperthecosis. 4

Diagnostic Algorithm

First-Line Laboratory Testing

• Measure total testosterone (TT) and free testosterone (FT) using LC-MS/MS methodology in the morning (8-10 AM) as first-line tests. 1
• TT has 74% sensitivity and 86% specificity; FT has 89% sensitivity and 83% specificity for hyperandrogenism. 1
• Calculate free androgen index (FAI = total testosterone/SHBG ratio) when LC-MS/MS is unavailable. 1
• Avoid direct immunoassay methods for free testosterone due to poor accuracy at low female concentrations. 1

Second-Line Testing (if TT/FT normal but clinical suspicion high)

• Measure androstenedione (A4): 75% sensitivity, 71% specificity. 1
• Measure DHEAS: 75% sensitivity, 67% specificity. 1
• DHEAS >600 μg/dL indicates adrenal source and raises concern for adrenocortical carcinoma. 1, 5
• Only 8-33% of PCOS patients have elevated DHEAS; it is not a first-line marker. 1

Additional Essential Testing

• Measure 17-hydroxyprogesterone to screen for NCCAH. 3
• Measure prolactin to exclude hyperprolactinemia. 1, 3
• Measure TSH to rule out thyroid disease. 1, 3
• Perform fasting glucose and 2-hour oral glucose tolerance test (75g load) to screen for diabetes and insulin resistance. 1
• Obtain fasting lipid panel to assess cardiovascular risk. 1

Imaging Studies

• If testosterone >5 nmol/L or rapid virilization, perform transvaginal ultrasound or pelvic MRI for ovaries and CT or MRI for adrenal glands. 4, 6
• Pelvic examination may reveal ovarian enlargement suggesting tumor. 3
• PET-CT can help differentiate benign from malignant lesions and exclude ectopic tumors. 7

Critical Clinical Pitfalls

• Recent, rapid onset of severe hyperandrogenism suggests tumor or Cushing's syndrome rather than PCOS and requires urgent evaluation. 3
• Clitoromegaly strongly suggests virilizing tumor. 3
• Palpable ovarian enlargement on pelvic exam suggests possible tumor. 3
• Normal testosterone with clear clinical hyperandrogenism (hirsutism, severe acne) may reflect low SHBG from obesity, metabolic syndrome, or familial diabetes history. 5
• Laboratory interference can cause falsely elevated testosterone; if clinical picture doesn't match, consider diethyl ether extraction prior to immunoassay. 9
• Source identification based solely on testosterone, DHEAS, and androstenedione levels is limited; evaluate both ovaries and adrenals in all women with virilization, even if DHEAS is normal. 7