What is the workup for a male with elevated testosterone and progesterone not due to exogenous (external) or iatrogenic (caused by medical treatment) causes?

Workup for Elevated Testosterone and Progesterone in Males

The workup for a male with elevated testosterone and progesterone that is not exogenous or iatrogenic should include comprehensive endocrine evaluation, imaging studies, and genetic testing to rule out adrenal, testicular, or neoplastic causes.

Initial Evaluation

Laboratory Assessment

1. Confirm elevated hormone levels

   • Repeat morning total testosterone and progesterone measurements to confirm elevation
   • Measure free testosterone using equilibrium dialysis or accurate calculation formula 1
   • Assess bioavailable testosterone

2. Basic hormonal workup

   • Luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
     • Low or suppressed LH/FSH with elevated testosterone suggests autonomous production 1
     • Normal/elevated LH/FSH may indicate receptor insensitivity
   • Estradiol levels (testosterone can be aromatized to estrogen) 2
   • Prolactin (to rule out hyperprolactinemia) 1
   • Human chorionic gonadotropin (hCG) (marker for certain tumors)
   • Alpha-fetoprotein (AFP) (marker for certain tumors) 1

3. Additional hormone testing

   • Adrenal hormone panel:
     • DHEA-sulfate
     • 17-hydroxyprogesterone
     • Androstenedione
     • Cortisol (morning and evening)
   • 24-hour urinary steroid profile

Imaging Studies

1. Testicular ultrasound

   • To evaluate for testicular tumors (Leydig cell tumors can produce both testosterone and progesterone)

2. Adrenal imaging

   • CT or MRI of adrenal glands to evaluate for adrenal tumors or hyperplasia

3. Pituitary MRI

   • If LH/FSH levels are inappropriately normal or elevated despite high testosterone

4. Whole-body imaging

   • Consider FDG-PET/CT if malignancy is suspected 1

Differential Diagnosis

Testicular Causes

• Leydig cell tumors (can produce both testosterone and progesterone)
• Testicular adrenal rest tumors (in congenital adrenal hyperplasia)

Adrenal Causes

• Adrenal tumors (adenoma or carcinoma)
• Congenital adrenal hyperplasia (particularly late-onset forms)
• Adrenal hyperplasia

Neoplastic Causes

• Ectopic hCG-producing tumors (lung, liver, kidney)
• Paraneoplastic syndromes

Genetic/Enzymatic Disorders

• Enzyme deficiencies in steroidogenesis pathway
• Androgen receptor mutations

Specialized Testing

1. Genetic testing

   • Karyotype analysis if chromosomal abnormality is suspected 1
   • Testing for congenital adrenal hyperplasia genes (CYP21A2, CYP11B1)

2. Stimulation/Suppression tests

   • ACTH stimulation test to evaluate adrenal function
   • Dexamethasone suppression test to differentiate between adrenal and other sources

3. Tissue biopsy

   • If imaging identifies a suspicious mass

Clinical Implications and Monitoring

Potential Health Consequences

• Monitor for polycythemia (hematocrit >50%) 1, 3
• Assess cardiovascular risk factors 1, 3
• Evaluate for gynecomastia (from estrogen conversion) 2
• Monitor prostate health with PSA and digital rectal examination 1
• Assess for sleep apnea 3
• Evaluate fertility status (elevated testosterone can suppress spermatogenesis) 4, 5

Follow-up

• Regular monitoring of hormone levels
• Periodic imaging based on initial findings
• Monitoring of symptoms and potential complications

Treatment Considerations

Treatment should be directed at the underlying cause:

• Surgical removal for tumors
• Medical management for enzymatic disorders
• Symptomatic treatment for complications

Common Pitfalls

1. Failing to confirm elevated levels - Testosterone has diurnal variation; morning samples are essential 6

2. Missing exogenous sources - Thoroughly investigate supplements, topical exposures, and environmental contamination

3. Overlooking partial enzyme deficiencies - These can present in adulthood with subtle symptoms

4. Focusing only on testosterone - The elevated progesterone is a key diagnostic clue that may point to specific enzyme deficiencies or tumors 7

5. Inadequate imaging - Small adrenal or testicular tumors can be missed without proper protocols

Remember that elevated testosterone and progesterone in males is uncommon and warrants thorough investigation, as it may indicate serious underlying pathology including tumors or enzymatic disorders.