What causes elevated testosterone levels in females?

Causes of Elevated Testosterone in Females

Polycystic ovary syndrome (PCOS) is the most common cause of elevated testosterone in women of reproductive age, affecting approximately 4-6% of the general female population. 1, 2

Primary Causes by Category

Ovarian Sources

• PCOS is characterized by hyperandrogenism, chronic anovulation, and ovarian dysfunction with elevated LH secretion, ovarian theca stromal cell hyperactivity, and increased androgen production 1, 3

• Ovarian androgen-secreting tumors (steroid cell tumors, Sertoli-Leydig cell tumors) should be suspected when testosterone levels exceed 150-200 ng/dL or when virilization develops rapidly 2, 4, 5

• Ovarian hyperthecosis represents severe ovarian stromal hyperplasia producing excess androgens, more common in postmenopausal women 4, 5

Adrenal Sources

• Non-classic congenital adrenal hyperplasia (NCCAH) causes elevated DHEAS and androstenedione with variable testosterone elevation 2, 5

• Adrenal tumors (adenomas or carcinomas) typically present with markedly elevated DHEAS levels and are less common than ovarian tumors but can cause severe virilization 4, 5

• Cushing syndrome produces hyperandrogenism through excess cortisol and adrenal androgen production 2, 5

Functional/Endocrine Disorders

• Hyperprolactinemia can cause menstrual irregularity and hirsutism, requiring prolactin measurement for exclusion 1, 2

• Hypothalamic amenorrhea affects approximately 12% of women with temporal lobe epilepsy versus 1.5% of the general population, though this typically presents with low rather than high androgens 1

• Thyroid disease should be excluded as it can affect sex hormone binding globulin (SHBG) levels and alter free testosterone 2

Iatrogenic and Exogenous Causes

• Exogenous androgen use from medications, supplements, or anabolic steroids must be excluded through careful medication history 2

• Antiepileptic drugs can alter sex hormone metabolism; enzyme-inducing drugs like carbamazepine, phenobarbital, and phenytoin increase SHBG production, affecting free testosterone levels 1

Age-Specific Considerations

• Postmenopausal hyperandrogenism warrants aggressive evaluation for tumors, as physiologic androgen production declines after menopause, making pathologic causes more likely 4, 5

• Adolescent hyperandrogenism presents diagnostic challenges due to overlap between normal pubertal changes and PCOS; longitudinal evaluation is often required 6

Clinical Pitfalls to Avoid

• Laboratory interference should be suspected when testosterone levels are extremely elevated (>200 ng/dL) without corresponding virilization signs; diethyl ether extraction can help identify assay interference 7

• SHBG fluctuations significantly affect total testosterone and free androgen index results; SHBG is influenced by weight, age, oral contraceptives, and liver disease 2

• Measurement methodology matters: LC-MS/MS is the gold standard for testosterone measurement in women; direct immunoassays for free testosterone should be avoided due to poor accuracy at low concentrations 2

• Isolated polycystic ovaries on ultrasound (present in 17-22% of normal women) should not be confused with PCOS, which requires both clinical/biochemical hyperandrogenism and ovulatory dysfunction 1

Diagnostic Approach

First-line testing should include total testosterone and free testosterone (measured by LC-MS/MS when available), TSH, and prolactin 2

Second-line testing (if initial testosterone normal but clinical suspicion high) should include androstenedione, DHEAS, and 17-hydroxyprogesterone for NCCAH screening 2

Urgent imaging with pelvic ultrasound or MRI and adrenal CT/MRI is indicated when testosterone exceeds 150-200 ng/dL or virilization is present to exclude tumors 4, 5