Causes of Elevated Testosterone in Postmenopausal Women
Elevated testosterone in postmenopausal women requires systematic evaluation to distinguish between benign functional causes and potentially malignant androgen-secreting tumors, with polycystic ovary syndrome (PCOS) being the most common etiology, followed by ovarian hyperthecosis, adrenal disorders, and rarely, androgen-producing neoplasms. 1, 2, 3
Primary Etiologies
Non-Tumorous Functional Causes
Polycystic Ovary Syndrome (PCOS)
- PCOS is the most common cause of postmenopausal hyperandrogenism, affecting 4-6% of the general population and persisting beyond menopause 4, 3
- Characterized by hyperandrogenism, chronic anovulation, and increased luteinizing hormone secretion driving ovarian androgen production 4
- Testosterone levels are typically mildly to moderately elevated (usually <5 nmol/L or <150 ng/dL) 3
Ovarian Hyperthecosis
- Represents severe end of the PCOS spectrum with diffuse ovarian stromal luteinization 1, 2
- Produces more severe hyperandrogenism than PCOS, often with virilization 2, 3
- Increased luteinizing hormone after menopause stimulates residual ovarian stromal cells to produce androgens 1
Obesity and Metabolic Dysfunction
- Peripheral conversion of androgens in adipose tissue contributes to elevated testosterone 1
- Associated with insulin resistance, which amplifies ovarian androgen production 1
Non-Classic Congenital Adrenal Hyperplasia (NCCAH)
- Mild enzyme deficiency (typically 21-hydroxylase) causing adrenal androgen overproduction 1, 2
- May become clinically apparent or worsen after menopause 2
- Characterized by elevated 17-hydroxyprogesterone levels 1
Endocrinopathies
Cushing Syndrome
- Excess cortisol production stimulates adrenal androgen secretion 1, 2
- Presents with characteristic cushingoid features plus hyperandrogenism 1
Acromegaly
- Growth hormone excess can stimulate ovarian and adrenal androgen production 1
Iatrogenic Causes
Exogenous Androgen Administration
- Testosterone supplementation (not FDA-approved for women but sometimes prescribed off-label) 5, 1
- Anabolic steroid use or abuse 1
- DHEA supplementation 1
Tumorous Causes
Ovarian Tumors
Sex Cord-Stromal Tumors
- Include Sertoli-Leydig cell tumors, granulosa-theca cell tumors, and hilar cell tumors 1, 2
- Diagnosed in 1-3 per 1000 patients with hirsutism, comprising <0.5% of all ovarian tumors 2
- Typically present with rapidly progressive virilization and markedly elevated testosterone (often >5 nmol/L or >150 ng/dL) 3, 6
Ovarian Metastases
- Metastatic disease to the ovary can produce androgens 1
Adrenal Tumors
Adrenocortical Adenomas
- Benign adenomas can rarely secrete pure testosterone without other adrenal androgens 7
- More commonly co-secrete DHEAS, androstenedione, and sometimes cortisol 1, 7
Adrenocortical Carcinomas
- Malignant tumors typically produce multiple hormones including androgens and cortisol 1, 2
- Present with rapidly progressive virilization and very high testosterone levels (often >5 nmol/L) 3
- Less common than ovarian tumors but more likely to be malignant 2
Adrenal Incidentalomas
- Incidentally discovered adrenal masses may have subclinical androgen production 1
Diagnostic Approach Algorithm
Step 1: Initial Hormonal Assessment
Measure total testosterone by tandem mass spectrometry (most accurate method) 3
- Testosterone <5 nmol/L (<150 ng/dL): suggests functional cause (PCOS, hyperthecosis, NCCAH) 3, 6
- Testosterone >5 nmol/L (>150 ng/dL): strongly suggests androgen-secreting tumor requiring urgent investigation 1, 3
- Testosterone >8.7 nmol/L (>250 ng/dL): very high specificity (98%) for neoplasm, though positive predictive value is only 9% due to rarity 6
Measure androstenedione as additional marker of ovarian vs. adrenal source 1, 2
Measure inhibin B if ovarian tumor suspected 2
Step 2: Exclude Cushing Syndrome
- Perform 24-hour urinary free cortisol or overnight dexamethasone suppression test if clinical features suggest hypercortisolism 2
Step 3: Imaging Based on Hormonal Results
If Ovarian Source Suspected (elevated testosterone with normal/low DHEAS):
- Transvaginal ultrasound as first-line imaging 3
- Pelvic MRI if ultrasound inconclusive or for better characterization 1, 3
If Adrenal Source Suspected (elevated DHEAS or clinical suspicion):
If Source Unclear:
- Image both ovaries and adrenals 7
- Consider selective venous sampling in rare cases where imaging is negative but biochemistry strongly suggests tumor 2
Step 4: Clinical Context Integration
- Rapidly progressive virilization (clitoromegaly, voice deepening, male-pattern baldness) strongly suggests tumor regardless of testosterone level 2, 3
- Gradual onset with mild symptoms more consistent with functional hyperandrogenism 3
- Postmenopausal presentation of new-onset hyperandrogenism warrants more aggressive investigation than premenopausal cases 2, 3
Critical Pitfalls to Avoid
Do not rely solely on DHEAS to localize androgen source—rare pure testosterone-secreting adrenal adenomas can present with normal DHEAS, androstenedione, and 17-hydroxyprogesterone 7
Do not assume ovarian source based only on elevated testosterone with normal adrenal androgens—always image both ovaries AND adrenals in postmenopausal women with virilization 7
Do not use testosterone >8.7 nmol/L (>250 ng/dL) as sole screening criterion for tumors—sensitivity is 100% but positive predictive value is only 9%, and clinical evaluation (rapidity of symptom onset, degree of virilization) is equally important 6
Do not dismiss PCOS as a diagnosis in postmenopausal women—it remains the most common cause and can persist or worsen after menopause 4, 3
Do not delay imaging in women with testosterone >5 nmol/L or any degree of virilization—these features mandate prompt tumor exclusion 3