What conditions can cause a 55-year-old woman, 10 weeks after adrenalectomy, to have a serum testosterone level of 237 ng/dL?

Elevated Testosterone After Adrenalectomy: Differential Diagnosis

A testosterone level of 237 ng/dL in a 55-year-old woman 10 weeks post-adrenalectomy indicates an ovarian source of androgen excess, most likely an androgen-secreting ovarian tumor (such as a steroid cell tumor, Leydig cell tumor, or Sertoli-Leydig cell tumor) or ovarian hyperthecosis.

Understanding the Clinical Context

This testosterone level is severely elevated—approximately 5-10 times the upper limit of normal for postmenopausal women (normal range 0.12-0.35 ng/mL or 12-35 ng/dL) 1. The fact that this persists 10 weeks after adrenalectomy definitively excludes an adrenal source and points to ovarian pathology.

Primary Differential Diagnoses

Ovarian Androgen-Secreting Tumors (Most Likely)

• Steroid cell tumors: These are rare ovarian tumors that can produce marked testosterone elevations. A recent case demonstrated bilateral ovarian steroid cell tumors causing free testosterone of 8.1 ng/mL (280 ng/dL total equivalent) with complete normalization after bilateral oophorectomy 2
• Leydig cell tumors: Extremely rare but almost always secrete androgens. One case showed testosterone of 392 ng/dL that normalized after oophorectomy despite the presence of an adrenal adenoma 3. Another case demonstrated marked testosterone elevation with a hilar-type Leydig cell tumor 4
• Sertoli-Leydig cell tumors (arrhenoblastomas): Comprise less than 0.5% of ovarian tumors but are classic causes of virilization 1

Ovarian Hyperthecosis

• Characterized by nests of luteinized theca cells throughout the ovarian stroma
• Typically LH-dependent and associated with insulin resistance 5
• Can cause severe hyperandrogenism even without a discrete mass
• One case showed persistent testosterone of 644 ng/dL from bilateral hilar cell hyperplasia 6

Residual Testosterone-Producing Tissue

• Rare but documented: ectopic testosterone-producing tissue from primitive mesenchymal cells of the urogenital ridge
• Can be gonadotropin-responsive and located in unidentified abdominal/pelvic sites 6

Critical Diagnostic Pitfalls

Ovarian tumors can be missed on initial imaging. Multiple case reports demonstrate that transvaginal ultrasound may initially appear normal, requiring repeat imaging with Doppler studies or high-resolution techniques 4. In one case, a fibrothecoma and Leydig cell tumor were not visible on initial ovarian imaging 7.

The presence of an adrenal mass does NOT mean it's the source. Several cases document patients with adrenal adenomas who actually had ovarian sources of testosterone 7, 3, 4. The adrenalectomy in your patient has already proven this point.

Recommended Diagnostic Algorithm

Immediate Laboratory Testing

1. Repeat early morning total and free testosterone to confirm persistent elevation
2. DHEAS level: Should be normal or low since adrenal source is removed. If DHEAS remains elevated (>600 µg/dL), this would suggest residual adrenal tissue or ectopic production 5
3. LH and FSH levels: To assess gonadotropin status
4. SHBG: To calculate free testosterone accurately 1

Imaging Studies

1. High-resolution transvaginal ultrasound with Doppler: Specifically looking for small ovarian masses or increased stromal vascularity
2. Pelvic MRI with contrast: Superior to ultrasound for detecting small ovarian lesions
3. Consider repeat abdominal CT: To ensure no residual adrenal tissue or ectopic adrenal rests

Specialized Testing if Imaging is Negative

Selective venous sampling: If no mass is identified but testosterone remains elevated, bilateral ovarian vein sampling can lateralize the source 3. This involves catheterization of ovarian veins with direct testosterone measurement.

GnRH agonist suppression test: Administer a GnRH agonist (such as nafarelin 200 µg intranasally daily for 6 weeks). If testosterone decreases significantly, this confirms gonadotropin-dependent ovarian production 5, 6. This can be both diagnostic and temporarily therapeutic.

Management Approach

If an ovarian mass is identified: Proceed directly to bilateral salpingo-oophorectomy. At age 55 (postmenopausal), there is no reason to preserve ovarian tissue, and bilateral removal is indicated because:

• Tumors can be bilateral 2
• Contralateral ovary may have hyperthecosis
• Complete androgen source removal is the goal

If no mass is identified but testosterone remains elevated:

• Trial of GnRH agonist therapy can confirm ovarian source 6
• If responsive, proceed to bilateral oophorectomy even without visible mass (likely hyperthecosis or microscopic tumor)
• Selective venous sampling may be needed to confirm ovarian source before surgery 3

Expected Outcomes

Testosterone should normalize within days to weeks after removal of the source. One case showed normalization within 3 days 4, another within 1 month 2. Clinical virilization symptoms (hirsutism, alopecia) improve gradually over months after testosterone normalization.

The key clinical pearl: In a postmenopausal woman with testosterone >150-200 ng/dL, an androgen-secreting tumor must be excluded, and after adrenalectomy, the ovaries are the definitive source requiring surgical removal 1, 5.