What is the diagnostic workup and management for a patient with hyperestrogenism (elevated estrogen levels), weight gain, breast enlargement, fatigue, and intermittent abdominal pain, without estrogen supplementation or known liver disease?

Diagnostic Workup for Hyperestrogenism with Weight Gain, Breast Enlargement, Fatigue, and Abdominal Pain

The most appropriate diagnostic workup for a patient with hyperestrogenism without supplementation or known liver disease should include adrenal and ovarian function testing, comprehensive hormone panel, and imaging studies to rule out estrogen-producing tumors.

Initial Evaluation

History and Physical Examination Focus Points

• Detailed menstrual history (if female)
• Timing of symptom onset
• Pattern of weight gain (central vs. peripheral)
• Characterization of abdominal pain (location, timing, triggers)
• Medication history (including over-the-counter supplements)
• Family history of endocrine disorders or tumors

Laboratory Workup

1. Comprehensive Hormone Panel:

   • Estradiol (E2), estrone (E1), and estriol (E3) levels
   • Testosterone (total and free)
   • Sex hormone-binding globulin (SHBG)
   • FSH and LH
   • Prolactin
   • Thyroid function tests (TSH, free T4)

2. Adrenal Function Testing:

   • Morning cortisol
   • ACTH level
   • Dexamethasone suppression test to evaluate adrenal source of hyperestrogenism 1
   • DHEA-S and androstenedione (precursors for peripheral estrogen conversion)

3. Liver Function Assessment:

   • Comprehensive liver panel (ALT, AST, alkaline phosphatase, bilirubin)
   • Albumin and protein levels
   • Prothrombin time

Imaging Studies

1. Adrenal Imaging:

   • Abdominal CT or MRI with contrast to evaluate adrenal glands for tumors or hyperplasia 2

2. Pelvic/Ovarian Imaging:

   • Transvaginal ultrasound (for females) to evaluate ovaries for tumors or polycystic changes
   • Pelvic MRI if ultrasound is inconclusive

3. Breast Imaging:

   • Mammography and breast ultrasound for patients ≥30 years 2
   • Ultrasound alone for patients <30 years 2
   • Consider breast MRI for dense breast tissue or inconclusive findings 2

4. Liver Imaging:

   • Liver ultrasound to evaluate for occult liver disease, fatty infiltration, or tumors 2

Specialized Testing

1. Hormone Challenge Tests:

   • Dexamethasone-infecundin test to determine source of hyperestrogenism (adrenal vs. ovarian) 1
   • Dexamethasone-choriogonin test to assess ovarian hormonal activity 1

2. Tissue Sampling:

   • Consider core needle biopsy of suspicious lesions identified on imaging 2
   • Avoid bone biopsies if possible due to technical limitations of biomarker detection 2

Potential Causes to Consider

1. Adrenal Sources:

   • Adrenal adenomas or carcinomas
   • Adrenal hyperplasia
   • Cushing syndrome

2. Ovarian Sources:

   • Ovarian tumors (granulosa cell tumors)
   • Polycystic ovary syndrome
   • Ovarian hyperfunction

3. Metabolic Causes:

   • Increased peripheral conversion of androgens to estrogens in adipose tissue 3, 4
   • Familial hyperestrogenism due to increased aromatase activity 3

4. Occult Liver Disease:

   • Early cirrhosis with impaired estrogen metabolism 2, 5
   • Nonalcoholic fatty liver disease 6, 5

Management Approach

Based on diagnostic findings, management may include:

1. For Adrenal Source:

   • Surgical removal of adrenal tumors if identified
   • Medical management of adrenal hyperfunction

2. For Ovarian Source:

   • Surgical intervention for ovarian tumors
   • Hormonal therapy for ovarian dysfunction

3. For Metabolic Causes:

   • Aromatase inhibitors (such as anastrozole) to reduce peripheral conversion of androgens to estrogens 7, 3
   • Weight management strategies

4. For Liver-Related Causes:

   • Management of underlying liver disease
   • Monitoring of liver function

Important Clinical Considerations

• Approximately 50% of hyperestrogenism cases originate from adrenal glands, 30% from ovaries, and 20% from combined sources 1
• Estrogen excess can cause weight gain, breast enlargement, and fatigue through multiple mechanisms
• Intermittent abdominal pain may be related to hepatic congestion, ovarian pathology, or other abdominal processes
• Elevated estrogen levels can occur in chronic liver disease even without obvious clinical signs of liver dysfunction 5

By following this systematic approach, the source of hyperestrogenism can be identified and appropriate treatment initiated to address the underlying cause and relieve symptoms.