What are the possible causes of elevated total testosterone and elevated free testosterone in a 55-year-old postmenopausal female, 10 weeks after adrenalectomy for a functioning lipid‑poor atypical Cushing's syndrome, Conn's syndrome (primary aldosteronism), and MACS (mild autonomous cortisol secretion)?

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Elevated Testosterone Post-Adrenalectomy: Likely Residual or Contralateral Adrenal Tissue vs. Ovarian Source

The most likely causes of your elevated testosterone (332.86 ng/dL) and free testosterone (2.7 ng/dL) are: (1) residual functioning adrenal tissue from incomplete resection or contralateral adrenal hyperfunction, (2) ovarian hyperthecosis or an androgen-secreting ovarian tumor, or (3) a combination of both adrenal and ovarian sources given your tumor's multi-hormonal secretion pattern.

Understanding Your Specific Context

Your original tumor was particularly concerning because it was lipid-poor, atypical, and secreting multiple hormones (cortisol, aldosterone, and likely androgens given the MACS/Cushing's/Conn's combination). According to guidelines, tumors that are lipid-poor, larger than 3 cm, or secreting more than one hormone raise suspicion for malignancy 1. At 10 weeks post-adrenalectomy, these testosterone levels are abnormally elevated for a postmenopausal woman and require urgent investigation.

Immediate Diagnostic Algorithm

Step 1: Determine Adrenal vs. Ovarian Source

Measure DHEAS (dehydroepiandrosterone sulfate) immediately:

  • If DHEAS is elevated: This strongly suggests adrenal origin (residual tissue, contralateral gland hyperfunction, or missed malignancy) 2, 3
  • If DHEAS is low/normal with high testosterone: This points to ovarian source 3, 4, 5

Step 2: Imaging Based on DHEAS Results

For elevated DHEAS (adrenal source):

  • Obtain dedicated adrenal protocol CT of the surgical bed AND the contralateral adrenal gland 1
  • Look for: residual tumor, local recurrence, contralateral adenoma, or metastases
  • Critical concern: Your tumor's lipid-poor, multi-hormonal nature increases malignancy risk. Testosterone >150 ng/dL can distinguish malignant from benign causes 3. Your level of 332.86 ng/dL exceeds this threshold significantly.

For normal/low DHEAS (ovarian source):

  • Obtain pelvic MRI (superior to ultrasound for detecting small ovarian tumors) 5
  • Transvaginal ultrasound may miss small androgen-secreting tumors due to bowel gas interference 5
  • Look for: ovarian masses, hyperthecosis, or stromal tumors

Step 3: Additional Hormonal Testing

Measure simultaneously:

  • Androstenedione (helps localize source)
  • 17-hydroxyprogesterone (rules out congenital adrenal hyperplasia)
  • LH and FSH (should be elevated in menopause; suppression suggests autonomous androgen production) 6, 5
  • Morning cortisol and ACTH (assess for residual cortisol secretion or adrenal insufficiency) 7

Most Likely Scenarios in Your Case

Scenario 1: Residual/Recurrent Adrenal Disease (Most Concerning)

Given your tumor's aggressive features:

  • Incomplete resection with residual functioning tissue in the surgical bed
  • Contralateral adrenal hyperplasia or adenoma that was masked by the dominant tumor
  • Malignant transformation or metastatic disease (lipid-poor tumors secreting multiple hormones have higher malignancy risk) 1

Action: Requires immediate CT imaging of adrenals and consideration of multidisciplinary tumor board review 8, 2

Scenario 2: Ovarian Hyperthecosis or Tumor

Postmenopausal women can develop:

  • Ovarian hyperthecosis (bilateral ovarian stromal hyperplasia producing androgens) 9, 10
  • Androgen-secreting ovarian tumors (adult granulosa cell tumors, Sertoli-Leydig cell tumors) 5, 10
  • These can coexist with or be unmasked after adrenal surgery 9

Critical point: One case report describes a patient whose ovarian hyperthecosis became apparent only after adrenalectomy for a cortisol/aldosterone-secreting tumor, as the hypercortisolism had masked hyperandrogenic symptoms 9.

Scenario 3: Dual Pathology

Your tumor's multi-hormonal secretion pattern suggests both adrenal and ovarian sources may be contributing 9. The resolution of cortisol excess post-surgery may have unmasked pre-existing ovarian androgen production.

Red Flags Requiring Urgent Action

Seek immediate evaluation if you develop:

  • Progressive virilization (voice deepening, clitoromegaly, male-pattern baldness)
  • Rapid symptom onset or worsening
  • Abdominal/pelvic pain
  • Constitutional symptoms (weight loss, fatigue beyond expected post-surgical recovery)

These suggest malignant androgen-secreting tumor requiring urgent surgical intervention 3, 4, 10.

Expected Post-Adrenalectomy Course (What Should Have Happened)

After successful unilateral adrenalectomy for a functioning tumor:

  • Testosterone should normalize within weeks 4, 11
  • You should have developed temporary adrenal insufficiency requiring glucocorticoid replacement for 12-18 months 7, 1
  • Persistent elevation at 10 weeks indicates ongoing autonomous androgen production

Management Pathway

Immediate (within 1-2 weeks):

  1. Complete hormonal panel (DHEAS, androstenedione, 17-OHP, LH/FSH, cortisol/ACTH)
  2. Imaging based on DHEAS results (adrenal CT vs. pelvic MRI)
  3. Multidisciplinary review with endocrinology, surgical oncology, and radiology 8, 2

If imaging identifies source:

  • Adrenal recurrence/residual: Surgical re-exploration vs. medical management depending on resectability
  • Ovarian source: Bilateral salpingo-oophorectomy (you're postmenopausal, so ovarian preservation is not needed) 9, 5, 10
  • Malignancy: Oncologic resection with appropriate staging

If no clear source identified:

  • Consider adrenal vein sampling (if technically feasible post-surgery) to assess contralateral adrenal function
  • Consider ovarian vein sampling (rarely performed but can localize ovarian androgen production)
  • Empiric bilateral oophorectomy may be considered given age and severity of hyperandrogenism 10

Critical Pitfalls to Avoid

  1. Don't assume the adrenalectomy was curative - your tumor's characteristics (lipid-poor, multi-hormonal, atypical) carry higher recurrence/malignancy risk 1

  2. Don't rely solely on ultrasound for ovarian evaluation - MRI is superior for detecting small androgen-secreting tumors 5

  3. Don't delay imaging - testosterone >150 ng/dL warrants urgent malignancy exclusion 3

  4. Don't forget to assess for adrenal insufficiency - you should have required steroid replacement post-surgery; if you're not on steroids, verify your HPA axis function 7

  5. Don't overlook the possibility of dual pathology - adrenal and ovarian sources can coexist 9

References

1
Guideline

neuroendocrine tumors.

Journal of the National Comprehensive Cancer Network : JNCCN, 2012

7
Guideline

treatment of cushing's syndrome: an endocrine society clinical practice guideline.

The Journal of clinical endocrinology and metabolism, 2015

8
Guideline

imaging of adrenal masses.

Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologist, 2025

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