Why is testosterone elevated in a 55‑year‑old woman?

Elevated Testosterone in a 55-Year-Old Woman

In a 55-year-old woman with elevated testosterone, the most critical step is to determine the degree of elevation: if testosterone is more than twice the upper limit of normal, immediately measure DHEAS to distinguish between adrenal and ovarian sources, as this guides urgent imaging and potential surgical intervention for androgen-secreting tumors. 1

Diagnostic Algorithm

Step 1: Verify the Elevation and Rule Out Laboratory Interference

Before pursuing extensive workup, confirm the testosterone elevation is real:

• Repeat the testosterone assay under optimal conditions—ensure the patient is not taking thyroid hormones, estrogen-containing medications, or antiepileptic drugs (like valproate) that can alter SHBG levels and affect total testosterone interpretation 1
• Consider laboratory interference, particularly heterophile antibodies, which can cause falsely elevated results 2. If clinical presentation doesn't match the laboratory values (i.e., no virilization signs despite very high testosterone), request diethyl-ether extraction prior to immunoassay or use liquid chromatography-mass spectrometry (LC-MS/MS) for confirmation 3, 2

Step 2: Assess the Degree of Elevation

The magnitude of testosterone elevation determines urgency and next steps:

If testosterone is >2× upper limit of normal:

• This demands urgent investigation for androgen-secreting tumors 1
• Proceed immediately to DHEAS measurement

If testosterone is mildly elevated:

• Consider PCOS (though less common at age 55), metabolic syndrome, or medication effects
• Measure SHBG to calculate free testosterone, as low SHBG (common with obesity, metabolic syndrome) can affect interpretation 1

Step 3: Localize the Source with DHEAS

DHEAS >600 µg/dL (16,000 nmol/L):

• Indicates adrenal source—likely androgen-secreting adrenal adenoma (often with hypercorticism)
• Perform abdominal CT scan urgently 1

DHEAS normal with markedly elevated testosterone:

• Indicates ovarian source—either ovarian hyperthecosis or androgen-secreting ovarian tumor 1
• Both are LH-dependent and can be suppressed by GnRH agonists
• Perform transvaginal ultrasound and pelvic imaging 4, 5, 6

Step 4: Additional Hormonal Testing

Consider measuring:

• 17-hydroxyprogesterone (17OHP) to exclude nonclassic 21-hydroxylase deficiency 1
• Δ4-androstenedione if there's diagnostic uncertainty, though it may be elevated independently of testosterone 1
• LH and FSH to confirm postmenopausal status (should be elevated; if suppressed, highly suspicious for tumor) 5

Step 5: Functional Testing if Source Remains Unclear

If imaging is negative but testosterone remains elevated:

• GnRH antagonist suppression test (cetrorelix) can confirm ovarian source—testosterone will suppress if ovarian in origin 6
• Low-dose dexamethasone suppression can help exclude adrenal source 6

Common Causes in This Age Group

Tumorous Causes (Most Critical)

• Ovarian Leydig cell tumors: Small (often <1 cm), may not be visible on standard imaging, cause marked virilization and cardiovascular/metabolic complications 5, 6
• Ovarian steroid cell tumors: Can present without virilization in rare cases due to selective tissue response 3
• Serous or mucinous cystadenomas: Rarely androgen-secreting but documented 4
• Adrenal adenomas: If DHEAS markedly elevated 1

Non-Tumorous Causes

• Ovarian hyperthecosis: Associated with insulin resistance, responds to hormonal suppression 1
• Metabolic syndrome/obesity: Causes low SHBG and elevated free testosterone 1
• Medication effects: Tamoxifen, raloxifene can elevate SHBG and total testosterone 1

Critical Pitfalls to Avoid

1. Don't dismiss very high testosterone without virilization signs—selective tissue response can occur, and ovarian tumors may not cause virilization initially 3

2. Don't rely solely on imaging—Leydig cell tumors can be as small as 6 mm and missed on CT/ultrasound 6. If clinical suspicion is high with negative imaging, consider functional testing or exploratory surgery

3. Don't forget to check for assay interference—heterophile antibodies can cause dramatic false elevations 2. Clinical-laboratory discordance should trigger alternative testing methods

4. Recognize the urgency—androgen-secreting tumors carry 25-43% malignancy risk for steroid cell tumors 3 and cause significant cardiovascular and metabolic complications with prolonged exposure 5

The postmenopausal state makes tumor more likely than PCOS, and the cardiovascular/metabolic risks of prolonged hyperandrogenism necessitate prompt diagnosis and treatment.