In a premenopausal woman with adrenal insufficiency (low cortisol), an ovarian mass, markedly elevated estradiol, and suppressed follicle‑stimulating hormone (FSH) and luteinizing hormone (LH), what is the most likely diagnosis and the recommended diagnostic and therapeutic approach?

Estrogen-Secreting Ovarian Sex Cord-Stromal Tumor (Granulosa Cell Tumor)

In a premenopausal woman presenting with low cortisol, markedly elevated estradiol, suppressed FSH and LH, and an ovarian mass, the most likely diagnosis is an estrogen-secreting sex cord-stromal tumor—specifically a granulosa cell tumor—and the patient requires urgent surgical evaluation with unilateral oophorectomy as definitive treatment. 1

Diagnostic Reasoning

Why This Hormonal Pattern Points to an Estrogen-Secreting Ovarian Tumor

The constellation of markedly elevated estradiol with suppressed FSH and LH is pathognomonic for autonomous estrogen production by an ovarian tumor, as the excess estrogen provides negative feedback to the hypothalamic-pituitary axis, suppressing gonadotropin secretion. 1

• Granulosa cell tumors are the most common estrogen-secreting ovarian neoplasms within the sex cord-stromal tumor category, accounting for the majority of hormonally active ovarian tumors in premenopausal women. 1
• These tumors secrete inhibin in addition to estrogen, which further suppresses FSH through direct pituitary feedback. 1
• The presence of an ovarian mass in this hormonal context makes a functional ovarian cyst extremely unlikely, as functional cysts do not produce the degree of estrogen elevation sufficient to completely suppress gonadotropins. 2

Distinguishing From Other Diagnoses

This is NOT functional hypothalamic amenorrhea (FHA):

• FHA presents with low-normal FSH/LH and LOW estradiol due to hypothalamic suppression of GnRH pulsatility. 3, 4
• The markedly elevated estradiol in this case directly contradicts FHA, where hypoestrogenism is the defining feature. 3, 4
• FHA patients have no ovarian mass on imaging. 3

This is NOT polycystic ovary syndrome (PCOS):

• PCOS typically shows elevated LH with normal or elevated FSH (LH:FSH ratio >2), not suppressed gonadotropins. 3
• PCOS presents with normal or mildly elevated estradiol, not the marked elevation seen with estrogen-secreting tumors. 3

This is NOT primary ovarian insufficiency (POI):

• POI demonstrates elevated FSH and LH (both >40 IU/L) with low estradiol, the opposite pattern from this case. 3

The Adrenal Insufficiency Component

The low cortisol in this presentation warrants careful consideration:

• Primary concern: Verify whether this represents true adrenal insufficiency or is an incidental finding that requires separate evaluation with morning cortisol and ACTH levels, followed by ACTH stimulation testing if indicated. 5
• Important caveat: Adrenal insufficiency can coexist with ovarian pathology but does not explain the ovarian mass or the estrogen excess pattern. 5
• The adrenal insufficiency should be addressed concurrently but does not alter the primary diagnosis of an estrogen-secreting ovarian tumor. 5

Recommended Diagnostic Approach

Immediate Laboratory Evaluation

1. Serum inhibin A and B levels: Granulosa cell tumors characteristically secrete inhibin, which serves as both a diagnostic marker and a tool for monitoring recurrence. 1

2. Complete tumor marker panel:

   • CA-125: May be elevated in sex cord-stromal tumors, though less specific than in epithelial ovarian cancers. 1
   • AFP and hCG: Should be measured to exclude germ cell tumors, which can present with ovarian masses in premenopausal women. 1
   • LDH: Useful for germ cell tumor evaluation. 1

3. Adrenal function assessment:

   • Morning cortisol and ACTH levels to confirm adrenal insufficiency. 5
   • ACTH stimulation test if morning cortisol is borderline or if clinical suspicion for adrenal insufficiency is high. 5
   • DHEAS and testosterone to assess adrenal androgen production, as adrenal hypoandrogenism can coexist with ovarian pathology. 5

Imaging Studies

1. Abdominopelvic CT scan with contrast: Essential for surgical planning to assess tumor size, laterality, presence of ascites, peritoneal implants, and lymphadenopathy. 1

2. Chest X-ray or chest CT: Required to exclude pulmonary metastases, as sex cord-stromal tumors can metastasize, though most are diagnosed at early stage. 1

3. Pelvic ultrasound findings: Granulosa cell tumors typically appear as complex ovarian masses with both solid and cystic components, often with internal septations. 1

Pathology Considerations

• Expert pathology review is mandatory for sex cord-stromal tumors due to their rarity and the critical importance of accurate diagnosis for fertility-sparing surgery decisions. 1
• Immunohistochemical markers including inhibin, calretinin, and FOXL2 confirm the diagnosis of granulosa cell tumor. 1
• Adult-type versus juvenile-type: Adult-type granulosa cell tumors are more common in premenopausal women (average age 50 years), while juvenile-type occurs predominantly in prepubertal girls. 1, 6

Therapeutic Approach

Surgical Management

Unilateral salpingo-oophorectomy is the standard surgical treatment for stage I granulosa cell tumors in premenopausal women desiring fertility preservation. 1

• Surgical staging includes:

  • Peritoneal washings for cytology
  • Inspection and palpation of all peritoneal surfaces
  • Omentectomy (infracolic for apparent early-stage disease)
  • Selective peritoneal biopsies
  • Contralateral ovarian biopsy only if abnormal in appearance 1

• Fertility-sparing surgery is appropriate for stage IA disease (tumor confined to one ovary, intact capsule, no surface involvement, negative washings). 1

• Complete surgical staging is essential even when the tumor appears confined to one ovary, as accurate staging determines the need for adjuvant therapy. 1

Adjuvant Therapy Considerations

Most granulosa cell tumors are diagnosed at stage I and confined to the ovary; adjuvant chemotherapy is NOT routinely indicated for stage IA disease. 1

• Indications for adjuvant chemotherapy (BEP or EP regimen):

  • Ruptured ovary (stage IC)
  • Higher stage disease (stage II-IV)
  • Incompletely resected disease 1

• Carboplatin and paclitaxel are under evaluation for recurrent disease and have shown activity. 1

• Hormonal therapies (tamoxifen, progestagens, LHRH analogs, aromatase inhibitors) have been investigated for recurrent disease with variable benefit, though prolonged therapy (>12 months) may be required to see response. 1

Management of Adrenal Insufficiency

If adrenal insufficiency is confirmed:

• Initiate glucocorticoid replacement (hydrocortisone 15-25 mg daily in divided doses) prior to surgery to prevent adrenal crisis. 5
• Stress-dose steroids (hydrocortisone 100 mg IV every 8 hours) are required perioperatively. 5
• Mineralocorticoid replacement (fludrocortisone 0.05-0.2 mg daily) if primary adrenal insufficiency is confirmed. 5

Follow-Up and Prognosis

Long-Term Surveillance

Granulosa cell tumors are notoriously indolent but recur late—up to 20 years after primary diagnosis—making long-term follow-up mandatory. 1

• Surveillance schedule:

  • Clinical examination every 3-6 months for the first 5 years
  • Annual examinations thereafter, continuing for at least 20 years 1

• Tumor markers for surveillance:

  • Inhibin A and B are the most useful markers, particularly in postmenopausal or castrated patients. 1
  • Anti-Müllerian hormone (AMH) is an emerging marker that may replace inhibin due to superior sensitivity. 1
  • Estradiol, FSH, and LH can be monitored, though they are more useful in postmenopausal women. 1

• Imaging surveillance:

  • Pelvic ultrasound or CT scan every 6-12 months for the first 5 years
  • Annual imaging thereafter based on clinical suspicion 1

Prognosis

• Stage IA granulosa cell tumors have excellent prognosis with 5-year survival rates exceeding 90%. 1
• Recurrence risk is approximately 10-20% for stage I disease, with most recurrences occurring 5-10 years after initial diagnosis. 1
• Fertility outcomes: Successful pregnancies have been reported after fertility-sparing surgery for stage IA disease. 1

Critical Pitfalls to Avoid

1. Do not delay surgical evaluation while pursuing extensive endocrine workup—the ovarian mass with this hormonal pattern requires urgent surgical assessment. 1

2. Do not misdiagnose as functional hypothalamic amenorrhea based on low gonadotropins alone; the presence of elevated estradiol and an ovarian mass excludes FHA. 3, 4

3. Do not assume all sex cord-stromal tumors secrete estrogen—approximately 8% of granulosa cell tumors present with hyperandrogenism rather than hyperestrogenism, so normal or low estradiol does not exclude the diagnosis in the presence of an ovarian mass. 6, 7

4. Do not overlook the adrenal insufficiency—ensure glucocorticoid replacement is initiated before surgery to prevent perioperative adrenal crisis. 5

5. Do not perform bilateral oophorectomy in a premenopausal woman with apparent stage I disease without intraoperative frozen section confirmation and complete surgical staging. 1

6. Do not discharge the patient from follow-up after 5 years—granulosa cell tumors can recur decades after initial diagnosis, requiring lifelong surveillance. 1