What causes elevated testosterone levels in women?

Causes of Elevated Testosterone in Women

Polycystic ovary syndrome (PCOS) is by far the most common cause of elevated testosterone in women, accounting for approximately 95% of hyperandrogenism cases and affecting 10-13% of women globally. 1, 2

Primary Causes by Frequency

Most Common: PCOS (95% of cases)

• PCOS is characterized by ovarian dysfunction with elevated LH secretion, ovarian theca stromal cell hyperactivity, and increased androgen production, typically presenting with hirsutism, acne, oligomenorrhea, and infertility. 2
• The condition typically begins after menarche with persistent anovulatory cycles continuing into adult life. 3
• PCOS is associated with insulin resistance, which further aggravates hyperandrogenism and abdominal obesity. 4

Other Endocrine Disorders

• Non-classical congenital adrenal hyperplasia (NCCAH) presents similarly to PCOS with hyperandrogenism and oligomenorrhea, diagnosed by elevated basal or ACTH-stimulated 17-hydroxyprogesterone levels or significant decrease in testosterone and DHEAS with dexamethasone suppression testing. 2, 3
• Hyperprolactinemia causes menstrual irregularity and hirsutism, requiring prolactin measurement for exclusion. 2, 3
• Cushing's syndrome should be considered in women with recent-onset hyperandrogenism accompanied by signs of hypercortisolism, excluded by overnight dexamethasone suppression test or 24-hour urinary free cortisol. 2, 3
• Ovarian hyperthecosis is a consideration in postmenopausal women with hyperandrogenism. 5

Androgen-Secreting Tumors (Rare but Critical)

• Ovarian androgen-secreting tumors occur in 1-3 per 1000 patients with hirsutism and comprise less than 0.5% of all ovarian tumors, but must be excluded when testosterone levels are very high (>8.7 nmol/L or 250 ng/dL) or virilization develops rapidly. 6, 5
• Adrenal tumors (adenomas and carcinomas) are less common than ovarian tumors but cause postmenopausal virilization, suspected when DHEAS is markedly elevated (>16.3 μmol/L or 6000 ng/mL). 6, 5
• The positive predictive value of testosterone >8.7 nmol/L for detecting tumors is only 9%, but the negative predictive value is 100%, meaning normal levels effectively exclude tumors. 6

Iatrogenic and Medication-Related

• Exogenous androgen use from medications or supplements is an important reversible cause. 2
• Antiepileptic drugs (carbamazepine, phenobarbital, phenytoin) alter sex hormone metabolism by increasing SHBG production, affecting free testosterone levels. 2

Factors That Lower SHBG (Increasing Free Testosterone)

• Obesity, insulin resistance, high-dose glucocorticoids, growth hormone, and certain medications lower SHBG, resulting in higher bioavailable testosterone despite normal total testosterone. 7
• PCOS itself is associated with low SHBG levels, compounding the hyperandrogenic state. 7

Clinical Red Flags Requiring Urgent Investigation

Tumor Suspicion Criteria

• Rapid onset of severe virilization (deepening voice, clitoromegaly, male-pattern baldness, increased muscle mass) demands immediate imaging to exclude androgen-secreting tumors. 2, 8, 3
• Total testosterone >8.7 nmol/L (250 ng/dL) warrants transvaginal ultrasound for ovarian evaluation. 6
• DHEAS >16.3 μmol/L (6000 ng/mL) indicates adrenal source and requires adrenal CT or MRI. 2, 6
• Postmenopausal presentation of hyperandrogenism is particularly concerning for malignancy. 5

Diagnostic Approach

First-Line Laboratory Testing

• Measure total testosterone (TT) and free testosterone (FT) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the morning, as this method has superior accuracy with TT sensitivity 74% and specificity 86%, and FT sensitivity 89% and specificity 83%. 1, 2
• Calculate free androgen index (FAI = total testosterone/SHBG ratio) when LC-MS/MS is unavailable. 1, 2
• Measure prolactin and TSH to exclude hyperprolactinemia and thyroid disease. 2, 3

Second-Line Testing (if TT/FT not elevated but clinical suspicion high)

• Measure androstenedione (A4) and DHEAS, noting their poorer specificity (A4: 75% sensitivity, 71% specificity; DHEAS: 75% sensitivity, 67% specificity). 1, 2
• Consider 17-hydroxyprogesterone to evaluate for NCCAH. 3
• LH/FSH ratio >2 suggests PCOS. 2

Important Testing Considerations

• Avoid direct immunoassay methods for free testosterone due to poor accuracy at low serum concentrations. 2
• SHBG fluctuations from age, weight, and oral contraceptives can affect TT and FAI results. 1, 2
• Laboratory interference should be suspected when very high testosterone levels occur without virilization; diethyl ether extraction can help detect assay interference. 8

Common Pitfalls

• Attributing all hyperandrogenism to PCOS without excluding other causes, particularly in atypical presentations. 3
• Missing tumors by not investigating rapidly progressive or severe hyperandrogenism. 8, 6
• Using inaccurate direct immunoassay methods for free testosterone measurement. 2
• Failing to recognize that isolated polycystic ovaries on ultrasound without clinical/biochemical hyperandrogenism and ovulatory dysfunction is not PCOS. 2