What are the possible causes of elevated testosterone and dihydrotestosterone in a postmenopausal woman who is not receiving hormone replacement therapy?

Elevated Testosterone and DHT in Postmenopausal Women Not on HRT

The most critical priority is to exclude an androgen-secreting tumor—either ovarian or adrenal—because more than 50% of these tumors are malignant. 1

Immediate Risk Stratification

When evaluating elevated testosterone and DHT in a postmenopausal woman, the following features demand urgent imaging:

• Testosterone >200 ng/dL strongly suggests an androgen-secreting neoplasm and requires immediate pelvic ultrasound and adrenal CT 1
• Rapid onset or progression of hyperandrogenic symptoms over weeks to months signals high tumor probability 1, 2
• Virilization signs—clitoromegaly, voice deepening, increased muscle mass, male-pattern baldness, or breast atrophy—indicate massive androgen production and mandate urgent work-up 1, 2
• DHEAS >600 µg/dL points to an adrenal adenoma and requires urgent high-resolution adrenal CT 1

Differential Diagnosis: Tumoral Causes (Priority Evaluation)

Ovarian Tumors

• Steroid-cell tumors and Leydig-cell tumors occur in approximately 0.2% of hyperandrogenic women, with >50% being malignant 1
• Typically present with testosterone >200 ng/dL with normal or mildly elevated DHEAS 1
• Pelvic ultrasound is mandatory to detect these tumors 1

Adrenal Tumors

• Adrenal adenomas and adrenocortical carcinomas are less common than ovarian tumors but cause postmenopausal virilization 3
• Characterized by DHEAS >600 µg/dL or testosterone ≥200 ng/dL 1
• High-resolution adrenal CT is indicated when these thresholds are met 1

Critical Diagnostic Pitfall

• Do not assume ovarian origin solely because testosterone is high with normal DHEAS; rare pure testosterone-secreting adrenal adenomas exist 1
• Do not assume adrenal origin solely because DHEAS is elevated; ovarian tumors can co-secrete DHEAS 1

Differential Diagnosis: Non-Tumoral Causes

Ovarian Hyperthecosis

• Presents with testosterone more than twice the upper limit of normal while DHEAS remains normal 1
• Typically associated with insulin resistance 1, 2
• Diagnosed by pelvic ultrasound showing characteristic ovarian changes 1

Non-Classic Congenital Adrenal Hyperplasia

• Screen with early-morning 17-hydroxyprogesterone (follicular phase timing if still cycling) 1
• More prevalent in Ashkenazi Jews (≈1:27), Hispanics (≈1:40), and Slavic populations (≈1:50) 1
• If 17-OHP >200 ng/dL, perform ACTH stimulation test; stimulated level >1,000 ng/dL confirms diagnosis 4
• CYP21A2 genotyping provides definitive diagnosis 4

Cushing Syndrome

• Should be considered when hypercortisolism accompanies androgen excess 1, 2
• Screen with 24-hour urinary free cortisol or overnight dexamethasone suppression test 1

Hyperprolactinemia

• Can produce androgen excess with menstrual disturbances 1, 2
• Measure serum prolactin to exclude this diagnosis 1

Exogenous Androgen Exposure

• Systematic inquiry for anabolic steroids, androgenic supplements, or testosterone-containing products is essential 1, 2
• Standard laboratory assays do not detect exogenous androgens, making detailed medication history crucial 2
• Danazol is a known androgenic medication that can cause virilization 1, 2
• Valproic acid is the only anticonvulsant documented to raise testosterone levels 1, 2

Polycystic Ovary Syndrome (PCOS) – Postmenopausal Persistence

• Androgen levels decline with age, but hyperandrogenic women may maintain relatively higher circulating androgens after menopause 5
• The postmenopausal ovary remains an androgen-secreting organ, and testosterone levels are not directly influenced by menopause 6
• Women with prior PCOS may have a low estrogen/androgen ratio postmenopausally 5

Smoking

• Postmenopausal smokers demonstrate significantly elevated testosterone, DHT, androstenedione, 17-hydroxyprogesterone, and cortisol compared to nonsmokers 7
• This represents a physiologic but pathologic elevation 7

Essential Laboratory Evaluation

Obtain early-morning (≈8 AM) fasting blood tests for optimal accuracy: 1

• Total and free testosterone measured in a specialized reference laboratory (routine assays lack accuracy for female ranges) 1
• DHEAS to evaluate adrenal contribution 1
• 17-hydroxyprogesterone (early-morning) to rule out congenital adrenal hyperplasia 1
• Prolactin to exclude hyperprolactinemia 1
• TSH and free T4 to exclude thyroid dysfunction 1
• 24-hour urinary free cortisol or overnight dexamethasone suppression test if Cushing syndrome is suspected 1
• Fasting glucose and insulin (glucose/insulin ratio <4.5 indicates insulin resistance) 1, 2
• Lipid profile (low HDL and elevated triglycerides common in hyperandrogenism) 1

Mandatory Imaging Studies

• Pelvic ultrasound is mandatory to detect ovarian steroid-cell tumors, assess ovarian morphology, and evaluate endometrial thickness 1
• High-resolution adrenal CT is indicated when testosterone ≥200 ng/dL, DHEAS >6,600 ng/mL, or clinical suspicion points to an adrenal source 1

Diagnostic Algorithm

If Testosterone >200 ng/dL or Virilization Present:

• Perform both pelvic ultrasound and adrenal CT immediately 1
• Urgent referral to endocrinology and surgical oncology 2
• >50% of androgen-secreting tumors are malignant, making rapid identification essential 1, 2

If Testosterone 50–200 ng/dL with Moderate Elevation:

• Measure DHEAS to differentiate ovarian from adrenal source 1
• If DHEAS normal and testosterone >2× upper limit, suspect ovarian hyperthecosis 1
• If DHEAS >600 µg/dL, suspect adrenal adenoma and obtain adrenal CT 1
• Perform pelvic ultrasound regardless 1

If Mild Elevation or Normal Testosterone with Clinical Hyperandrogenism:

• Repeat total and free testosterone in a specialty laboratory 1
• Consider dynamic endocrine testing (ACTH stimulation for adrenal source, GnRH agonist challenge for ovarian source) 1, 4
• Measure 17-hydroxyprogesterone and perform ACTH stimulation test if elevated 1, 4

Management After Tumor Exclusion

Glucocorticoid-Suppressible Adrenal Hyperandrogenism:

• Low-dose glucocorticoids (dexamethasone 0.25–0.5 mg nightly or prednisone 5–7.5 mg nightly) for 2–3 months 1, 2
• Taper after normalization and monitor every 3–4 months for one year 1, 2

Ovarian Hyperthecosis or PCOS-Related:

• GnRH agonists/analogues or antagonists for women unfit for surgery or when source is unidentified 3
• Anti-androgens (spironolactone 50–200 mg daily) for persistent hirsutism 1, 4
• Metformin 1,500–2,000 mg daily targets insulin resistance 1, 4

Surgical Management:

• Adrenalectomy is indicated for biochemically active adrenal tumors 1
• Minimally-invasive approach (laparoscopic or robotic) is preferred when feasible 1
• Open adrenalectomy for large adrenocortical carcinomas or tumors with local invasion 1

Long-Term Monitoring

• Initial 3-month follow-up to reassess androgen levels, cutaneous signs, and symptoms 1, 4
• Every 3–4 months for one year after therapy cessation to detect recurrence 1, 4
• Annual metabolic screening (fasting glucose, lipids, blood pressure) given increased cardiovascular and metabolic risk 1, 4