What is the best approach to manage elevated bioavailable testosterone in a post-menopausal woman?

Management of Elevated Bioavailable Testosterone in Postmenopausal Women

The priority is to exclude androgen-producing tumors through urgent biochemical and imaging evaluation, as these represent potentially life-threatening malignancies that require immediate surgical intervention. 1, 2

Initial Risk Stratification Based on Testosterone Level

The degree of testosterone elevation determines the urgency and direction of your workup:

• Testosterone >5 nmol/L (>150 ng/dL): This threshold indicates high risk for androgen-producing tumor and mandates immediate imaging to exclude malignancy before any other intervention 1, 3, 2
• Testosterone 2.5-5 nmol/L: Moderate elevation suggesting ovarian hyperthecosis, undiagnosed PCOS, or benign adenoma 4, 2
• Testosterone <2.5 nmol/L: Mild elevation consistent with relative androgen excess from menopausal transition or metabolic syndrome 4, 2

Essential Biochemical Evaluation

Measure the following androgens using liquid chromatography-tandem mass spectrometry (LC-MS/MS) when available, as immunoassays lack accuracy at these levels 5, 2:

• Total testosterone (preferably by LC-MS/MS) 2
• DHEAS (dehydroepiandrosterone sulfate) to assess adrenal contribution 1, 3
• Androstenedione to help localize source 1, 3
• 17-hydroxyprogesterone to exclude non-classic congenital adrenal hyperplasia 1, 3
• Inhibin B may help identify ovarian source 1

Critical pitfall: Do not rely solely on DHEAS and androstenedione to distinguish ovarian from adrenal source—pure testosterone-secreting adrenal adenomas can present with isolated testosterone elevation and normal DHEAS/androstenedione 6. Both ovaries AND adrenals must be imaged in all cases of postmenopausal virilization 6.

Imaging Protocol

For Suspected Ovarian Source:

• Transvaginal ultrasound as first-line imaging 2
• Pelvic MRI if ultrasound is non-diagnostic or shows abnormality 1, 2
• Note: Most virilizing ovarian tumors are <3 cm and may be below imaging resolution limits 4

For Suspected Adrenal Source:

• Adrenal CT or MRI to identify adenomas or carcinomas 1, 3, 2
• PET-CT can help distinguish benign from malignant lesions 6

When Source Remains Unclear:

• Consider bilateral ovarian vein sampling in specialized centers if imaging is negative but biochemistry strongly suggests ovarian source 4

Clinical Features Requiring Urgent Evaluation

Proceed immediately to imaging if any of the following are present:

• Virilization: clitoromegaly, voice deepening, male-pattern baldness, increased muscle mass 1, 2
• Rapid symptom progression over weeks to months 4
• Testosterone >5 nmol/L (>150 ng/dL) 1, 3, 2
• Associated hypercortisolism suggesting adrenocortical carcinoma 1

Differential Diagnosis Framework

Tumorous Causes (Require Surgical Excision):

• Ovarian tumors: Sex cord-stromal tumors (Sertoli-Leydig cell tumors, granulosa-theca cell tumors) comprise 1-3 per 1000 patients with hirsutism but <0.5% of all ovarian tumors 1, 3
• Adrenal tumors: Adenomas or carcinomas, less common than ovarian but more likely malignant 1, 3
• Malignant tumors are exceedingly rare but must be excluded 4

Non-Tumorous Causes:

• Polycystic ovary syndrome (PCOS): Most common cause of postmenopausal hyperandrogenism, with symptoms worsening due to loss of estrogen's suppressive effect 1, 3, 2
• Ovarian hyperthecosis: Strongly associated with insulin resistance and metabolic syndrome; elevated LH stimulates thecal cell hyperplasia in the absence of granulosa cell aromatase activity 4, 2
• Non-classic congenital adrenal hyperplasia (NCCAH): Check 17-hydroxyprogesterone 3
• Cushing syndrome: Perform screening tests (overnight dexamethasone suppression, 24-hour urinary free cortisol) 1, 3
• Iatrogenic: Review medications including testosterone, DHEA supplements, anabolic steroids 1, 3
• Obesity and insulin resistance: Can drive androgen production independent of other pathology 4, 3

Treatment Algorithm

If Tumor Identified:

• Surgical excision is definitive treatment 1, 4, 2
• For ovarian tumors: Laparoscopic bilateral salpingo-oophorectomy serves both diagnostic and therapeutic purposes 4
• For adrenal tumors: Adrenalectomy with histopathological confirmation 6, 2

If No Tumor Found or Patient Unfit for Surgery:

• GnRH agonists/analogues suppress gonadotropin-dependent ovarian androgen secretion 1, 4
• Oral antiandrogens (spironolactone, cyproterone acetate) for symptomatic management 4, 2
• These medical therapies are safe and well-tolerated long-term 4

For Ovarian Hyperthecosis with Metabolic Features:

• Lifestyle modification: Weight loss and exercise can significantly reduce androgens 4
• Metformin or other insulin-sensitizing drugs: Target the hyperinsulinemia driving thecal cell androgen production 4
• This approach addresses the pathophysiology directly and may avoid need for surgery 4

Monitoring and Long-Term Considerations

Beyond the virilizing effects, elevated testosterone causes:

• Hypercholesterolemia 1
• Insulin resistance 1
• Hypertension 1
• Increased cardiovascular disease risk 1

These metabolic consequences require ongoing cardiovascular risk factor management regardless of the source of hyperandrogenism 1.

Critical Pitfalls to Avoid

1. Do not assume ovarian source based solely on isolated testosterone elevation—pure testosterone-secreting adrenal adenomas exist and require adrenal imaging 6

2. Do not delay imaging in severe or rapidly progressive cases—prioritize cross-sectional imaging over exhaustive biochemical testing when malignancy is suspected 4

3. Do not rely on imaging alone to distinguish ovarian hyperthecosis from virilizing ovarian tumor—even high-resolution imaging combined with dynamic endocrine testing often cannot differentiate these conditions; definitive diagnosis typically requires histological examination 4

4. Do not reassure patients that medical therapy is equivalent to surgery without proper tumor exclusion—while long-term medical therapy is safe for confirmed benign conditions, missing a malignant tumor has catastrophic consequences 4