In a 55-year-old postmenopausal woman 10 weeks after adrenalectomy for a lipid‑poor atypical adrenal tumor with elevated total testosterone and elevated free testosterone, what is the appropriate next step in management?

Persistent Hyperandrogenism Post-Adrenalectomy: Urgent Evaluation for Residual or Alternative Androgen Source

This patient requires immediate investigation for a residual or alternative source of androgen excess, most likely ovarian hyperthecosis or a missed androgen-secreting tumor, given the persistently elevated testosterone 10 weeks after removal of an atypical adrenal tumor.

Critical Context

The testosterone level of 332.86 ng/dL (approximately 11.5 nmol/L) and free testosterone of 2.7 ng/dL are markedly elevated for a postmenopausal woman and should have normalized within weeks after successful removal of an androgen-secreting adrenal tumor. This persistent elevation is a red flag indicating either:

• Incomplete tumor removal or metastatic disease
• A coexisting ovarian source (hyperthecosis or tumor)
• Bilateral disease that was not fully addressed

Immediate Diagnostic Steps

1. Repeat Androgen Panel with DHEAS

• Measure DHEAS immediately 1, 2
• If DHEAS remains elevated (>600 µg/dL or 16,000 nmol/L), this suggests residual adrenal pathology 1
• If DHEAS is normal or suppressed but testosterone remains high, the source is likely ovarian 1, 3

2. Comprehensive Imaging

• Abdominal/pelvic CT with contrast to evaluate:
  • The contralateral (right) adrenal gland for occult tumor
  • Surgical bed for residual tumor or local recurrence
  • Both ovaries for masses or enlargement 4, 5
• Transvaginal ultrasound if CT is inconclusive for ovarian pathology 6

3. Review Original Pathology

The "lipid-poor, atypical" designation is concerning. Request urgent pathology review focusing on:

• Weiss score (≥3 indicates adrenocortical carcinoma) 7
• Ki-67 index for risk stratification 7
• Margin status (R0 vs R1/R2 resection) 7
• Immunohistochemistry for steroidogenic markers 8, 9

Differential Diagnosis Priority

Most Likely: Ovarian Hyperthecosis

• Accounts for persistent hyperandrogenism despite adrenal insufficiency post-adrenalectomy 3
• Common in postmenopausal women with insulin resistance 3
• Testosterone elevation is LH-dependent and can be suppressed by GnRH agonists 1
• May coexist with adrenal pathology, with cortisol excess masking hyperandrogenic symptoms preoperatively 3

Second Most Likely: Malignant Adrenal Tumor

• Lipid-poor lesions (>10 HU) raise concern for adrenocortical carcinoma 10, 11
• "Atypical" features warrant aggressive follow-up 7
• Persistent androgen elevation suggests incomplete resection or metastatic disease 8
• Pure androgen-secreting adrenal tumors have 26% malignancy rate in case series 8

Less Likely but Must Exclude: Ovarian Tumor

• Rare in postmenopausal women but can present with isolated testosterone elevation 6
• Steroid cell tumors can be bilateral and small, easily missed on imaging 6

Management Algorithm

If DHEAS is elevated (>600 µg/dL):

1. Urgent abdominal CT to evaluate for adrenal malignancy or residual disease
2. Consider PET-CT if metastatic disease suspected 7
3. Multidisciplinary review with endocrine surgery and oncology 11
4. If malignancy confirmed, open re-resection with en bloc technique 10, 7

If DHEAS is normal/low but testosterone remains elevated:

1. Pelvic imaging (CT + transvaginal ultrasound) to evaluate ovaries
2. Trial of GnRH agonist (leuprolide) to suppress ovarian androgen production 1
   • If testosterone normalizes, confirms ovarian source
3. Consider bilateral salpingo-oophorectomy if:
   • Imaging shows ovarian masses
   • GnRH agonist trial confirms ovarian source
   • Patient desires definitive treatment 3, 6

If imaging is negative:

1. Dynamic testing with HCG stimulation may help localize source 8
2. Consider adrenal/ovarian venous sampling in specialized centers (rarely needed)
3. Close surveillance with repeat imaging in 3 months 10

Critical Pitfalls to Avoid

1. Assuming successful tumor removal based on surgery alone - Persistent biochemical abnormalities trump surgical reports 3, 8

2. Missing ovarian hyperthecosis - This can coexist with adrenal pathology and become unmasked after adrenalectomy when cortisol excess resolves 3

3. Delaying malignancy workup - Adrenocortical carcinoma has poor prognosis; median survival is 15 months in metastatic disease 7. Early detection of recurrence is critical.

4. Using inadequate testosterone assays - Ensure laboratory uses mass spectrometry or validated immunoassay for women 2. Many automated assays are inaccurate at female ranges.

5. Overlooking cortisol co-secretion - 28% of androgen-secreting adenomas also produce cortisol 12, 9. Check if patient developed adrenal insufficiency post-op, which would confirm the removed tumor was functional.

Monitoring Post-Diagnosis

• If ovarian source confirmed and managed surgically: Check testosterone at 1 month, then every 3-6 months for 2 years 13
• If adrenal malignancy: Intensive surveillance per oncology protocols with tumor markers every 3 months 7
• Annual screening for metabolic complications (diabetes, hypertension, dyslipidemia) given prior androgen excess 14

The 10-week timeframe is sufficient for testosterone to normalize if the source was completely removed. Persistent elevation mandates urgent investigation - this is not a "wait and see" situation 8, 15, 13, 9.