What is the appropriate workup to evaluate a male patient with elevated estradiol and markedly increased testosterone for an adrenal or testicular tumor?

Workup for Adrenal or Testicular Tumor in Male with Elevated Estradiol and Markedly Increased Testosterone

In a male patient with elevated estradiol and markedly increased testosterone, perform comprehensive biochemical screening for autonomous cortisol secretion, primary aldosteronism, and pheochromocytoma, combined with testicular ultrasound and adrenal imaging with non-contrast CT to identify the source of hormone excess. 1

Initial Imaging Approach

Testicular Evaluation

• Perform testicular ultrasound immediately as the first-line imaging study, as germ cell tumors (even without Leydig cell involvement) can present with hyperandrogenism and hyperestrogenism 2, 3
• Testicular cancer with sex hormone excess is not limited to Leydig cell tumors—mixed germ cell tumors can produce both androgens and estrogens 3

Adrenal Evaluation

• Obtain non-contrast CT of the adrenals as first-line imaging to distinguish benign from indeterminate lesions 1
• If the mass remains indeterminate on non-contrast CT (>10 HU), proceed to second-line imaging with either:
  • Washout CT, or
  • Chemical-shift MRI 1
• Avoid routine adrenal mass biopsy in the workup 1

Comprehensive Biochemical Testing

Mandatory Screening (All Patients)

Given your patient's presentation with both elevated estradiol and testosterone, perform the following:

1. Autonomous Cortisol Secretion Screening

   • 1 mg dexamethasone suppression test (preferred screening test) 1
   • Even without overt Cushing's features, feminizing adrenocortical carcinomas can have mixed hormonal secretion including cortisol 4

2. Primary Aldosteronism Screening (if hypertension or hypokalemia present)

   • Aldosterone-to-renin ratio 1

3. Pheochromocytoma Screening

   • Skip this test ONLY if unenhanced CT confirms adrenocortical adenoma with <10 HU AND no adrenergic symptoms 1
   • Otherwise, measure plasma or 24-hour urinary metanephrines for any mass >10 HU 1

4. Androgen Excess Testing

   • Serum DHEA-S and testosterone (already elevated in your case, but document baseline)
   • This is specifically recommended when clinical virilization is present or adrenocortical carcinoma is suspected 1
   • Feminizing adrenocortical carcinomas often show elevated DHEA-S alongside estradiol 4, 5

Clinical Context and Pitfalls

Key Diagnostic Considerations

The combination of elevated estradiol with markedly increased testosterone in a male is highly suspicious for:

• Feminizing adrenocortical carcinoma (extremely rare, 1-2% of ACC, but almost pathognomonic when present) 4
• Germ cell testicular tumor (can occur without Leydig cell involvement) 2, 3

Critical Pitfall to Avoid

Do not assume a benign-appearing adrenal lesion excludes testicular pathology. One case report demonstrated persistent symptoms after adrenalectomy for a benign-appearing adrenal lesion, with testicular cancer ultimately identified 2. Both sites must be evaluated simultaneously.

Multidisciplinary Review Threshold

Arrange multidisciplinary review with endocrinology, urology, and radiology when 1:

• Imaging is not consistent with a benign lesion
• Evidence of hormone hypersecretion exists (as in your patient)
• Tumor grows significantly on follow-up
• Surgery is being considered

Interpretation Notes

For Testicular Masses

• If ultrasound identifies a suspicious testicular mass, orchiectomy is the primary treatment 6
• Beta-hCG and LDH may be elevated but should not be used alone for staging pure seminoma 6
• Discuss sperm banking prior to any treatment 6

For Adrenal Masses

• Feminizing adrenocortical carcinomas tend to be larger tumors with worse prognosis compared to other ACCs 4
• These tumors can present with gynecomastia and are considered almost pathognomonic of malignancy in the context of an adrenal mass 4
• Estrogen-secreting adrenal tumors in males warrant aggressive surgical evaluation

Timing Considerations

Delayed hormonal assessment is associated with delayed treatment 7. Complete the biochemical workup expeditiously while imaging studies are being obtained to avoid treatment delays.