What is the appropriate management for a postmenopausal female with significantly elevated testosterone levels (hyperandrogenism)?

Elevated Testosterone in a 67-Year-Old Postmenopausal Woman

A testosterone level of 153 ng/dL (5.3 nmol/L) in a postmenopausal woman requires urgent investigation to exclude an androgen-producing tumor, as levels >5 nmol/L are associated with virilization and potential malignancy. 1

Differential Diagnosis by Severity

The testosterone level determines urgency and likely etiology:

• Testosterone >150 ng/dL (>5 nmol/L): Strongly suggests androgen-secreting tumor (ovarian or adrenal) requiring immediate imaging 1
• Testosterone 50-150 ng/dL: Consider ovarian hyperthecosis, late-onset congenital adrenal hyperplasia, or severe PCOS 2, 1
• Testosterone <50 ng/dL: Likely PCOS, relative androgen excess from menopause, or exogenous sources 2

Immediate Clinical Assessment

Examine specifically for:

• Virilization signs: Clitoromegaly, deepening voice, male-pattern baldness, increased muscle mass 2, 3
• Hirsutism: Terminal hair growth on face, chest, abdomen, back 1
• Rapidity of onset: Rapid progression (weeks to months) strongly suggests tumor 2, 1
• Metabolic features: Abdominal obesity, acanthosis nigricans suggesting insulin resistance 1

Essential Laboratory Workup

Order the following tests immediately:

• Repeat testosterone by liquid chromatography-tandem mass spectrometry (LC-MS/MS): Immunoassays can have interference; confirm with gold standard 4
• DHEAS (dehydroepiandrosterone sulfate): Elevated suggests adrenal source 2, 3
• Androstenedione: Helps localize source 2, 3
• 17-hydroxyprogesterone: Screens for late-onset congenital adrenal hyperplasia 2
• 24-hour urinary free cortisol or overnight dexamethasone suppression test: Exclude Cushing syndrome 2
• Inhibin B: May be elevated with ovarian tumors 2

Critical caveat: Normal DHEAS and androstenedione do NOT exclude an adrenal tumor, as rare pure testosterone-secreting adrenal adenomas exist 3

Imaging Strategy

Based on laboratory results:

If DHEAS Elevated (>700 μg/dL)

• CT or MRI of adrenal glands as first-line imaging 2, 1
• Adrenal tumors are less common than ovarian but include both benign adenomas and malignant carcinomas 2

If DHEAS Normal or Mildly Elevated

• Transvaginal ultrasound initially for ovaries 1
• Pelvic MRI if ultrasound inconclusive or for better characterization 2, 1
• Consider PET-CT if imaging equivocal to assess metabolic activity and exclude ectopic sources 3

Important: Image BOTH ovaries and adrenals regardless of hormone pattern, as source localization based solely on hormone levels is unreliable 3

Tumor Probability and Management

• Ovarian androgen-secreting tumors: Occur in 1-3 per 1000 patients with hirsutism, comprise <0.5% of all ovarian tumors 2
• Adrenal tumors: Less common than ovarian but must be excluded 2

If Tumor Identified

• Surgical resection is definitive treatment (adrenalectomy or oophorectomy) 2, 3, 1
• Testosterone normalizes within 24 hours post-operatively 3
• Histopathology confirms diagnosis and malignancy risk 3

If No Tumor Found

• Bilateral oophorectomy may be considered if source remains unidentified and symptoms severe 2
• GnRH agonists/antagonists for medical management in women unfit for surgery 2
• Antiandrogen therapy (spironolactone, finasteride) for mild-moderate symptoms once malignancy excluded 1

Associated Metabolic Risks

Elevated testosterone causes more than virilization:

• Hypercholesterolemia 2
• Insulin resistance and type 2 diabetes 2, 1
• Hypertension and cardiac disease 2

Monitor and treat these cardiovascular risk factors concurrently 2

Common Pitfalls to Avoid

• Do not assume ovarian source based solely on very high testosterone with normal DHEAS—pure testosterone-secreting adrenal adenomas exist 3
• Do not delay imaging for testosterone >5 nmol/L even without virilization signs, as selective tissue response can occur 4
• Do not rely on immunoassay alone—confirm with LC-MS/MS if clinical picture doesn't match, as laboratory interference occurs 4
• Do not assume benign etiology in postmenopausal women—25-43% of ovarian steroid cell tumors are malignant 4