What is the appropriate workup for a patient presenting with primary hypergonadism (excessive production of sex hormones)?

Workup for Primary Hypergonadism

Primary hypergonadism (excessive sex hormone production from the gonads) requires a systematic evaluation to identify the underlying cause, with initial focus on distinguishing between androgen-secreting tumors, estrogen-secreting tumors, and functional disorders.

Initial Clinical Assessment

Begin by determining the sex of the patient and specific clinical manifestations, as this fundamentally directs the diagnostic approach.

In Women with Hyperandrogenism

• Assess for signs of virilization (clitoral hypertrophy, deepening voice, increased muscle mass, male-pattern baldness), which suggests an androgen-secreting tumor and requires urgent evaluation 1, 2
• Evaluate hirsutism severity using the Ferriman-Gallwey scoring system, with scores ≥6 indicating clinical hyperandrogenism in Caucasian populations 3
• Document timing of symptom onset: rapid progression with recent onset strongly suggests neoplasm rather than functional disorder 4, 3
• Examine for acne, seborrhea, and androgenic alopecia, which may occur with or without hirsutism 5, 2
• Assess menstrual history for oligomenorrhea or amenorrhea 1, 4

In Men with Hypergonadism

• Examine for gynecomastia and testicular atrophy, which indicate estrogen-secreting tumors 1
• Perform thorough testicular examination including measurement and palpation of testes, checking for masses 1
• Assess for signs of androgen excess if androgen-secreting tumor suspected 1

Laboratory Evaluation

First-Line Hormonal Testing

For women with suspected hyperandrogenism:

• Measure morning total testosterone (8-10 AM) using an accurate assay 6
• Measure serum 17-hydroxyprogesterone (17-OHP) to exclude non-classical congenital adrenal hyperplasia (NCCAH), with elevated basal or ACTH-stimulated levels confirming diagnosis 4
• Measure DHEA-S to assess adrenal androgen contribution 4
• Check serum prolactin if oligomenorrhea with mild hyperandrogenism is present, as hyperprolactinemia can mimic this presentation 4

For men with suspected estrogen excess:

• Measure serum testosterone and estradiol levels to confirm hormonal imbalance 1
• Measure LH and FSH to distinguish primary from secondary causes 6

Confirmatory and Specialized Testing

• Perform ACTH stimulation test if 17-OHP is borderline elevated to confirm or exclude NCCAH 4
• Conduct two-day dexamethasone suppression test showing significant decrease in testosterone and DHEA-S supports NCCAH diagnosis 4
• Measure 24-hour urinary free cortisol or perform overnight dexamethasone suppression test if Cushing's disease suspected (recent onset hyperandrogenism with signs of hypercortisolism) 4

Imaging Studies

When to Obtain Imaging

Obtain imaging immediately if:

• Very high serum androgen levels (testosterone typically >150-200 ng/dL in women) suggest androgen-secreting tumor 4
• Rapid onset of severe virilization indicates likely neoplasm 4, 5
• Palpable adrenal or ovarian mass on physical examination 1

Imaging Modalities

• Pelvic ultrasonography as first-line imaging for suspected ovarian source 3
• Contrast-enhanced CT of abdomen and pelvis to evaluate adrenal glands, with attention to tumor characteristics: irregular morphology, lipid-poor appearance, lack of contrast washout, size >3 cm, or multi-hormone secretion suggest malignancy 1
• Scrotal ultrasonography in men when testicular mass suspected or physical examination inadequate 1

Differential Diagnosis Algorithm

Exclude Neoplastic Causes First

Androgen-secreting tumors (ovarian or adrenal) must be ruled out when:

• Virilization is present 4, 5
• Recent onset with rapid progression 4, 3
• Testosterone levels markedly elevated 4
• If tumor suspected on imaging with irregular morphology or size >3 cm, open adrenalectomy is recommended due to rupture risk 1

Functional Causes (After Excluding Tumors)

• Polycystic ovary syndrome (PCOS) is the most common cause (70% of cases) but remains a diagnosis of exclusion 4, 3
• NCCAH diagnosed by elevated 17-OHP with or without ACTH stimulation 4
• Cushing's disease confirmed by failure to suppress cortisol on dexamethasone test or elevated 24-hour urinary free cortisol 4
• Hyperprolactinemia identified by elevated serum prolactin 4

Critical Pitfalls to Avoid

• Never dismiss rapid onset or progressive symptoms as functional disorder—this pattern demands immediate tumor evaluation 4, 3
• Never rely on single testosterone measurement—confirm with repeat testing due to assay variability 6
• Never assume PCOS without excluding other causes—it must remain a diagnosis of exclusion despite being most common 4, 3
• Never delay imaging when virilization is present—this is a red flag for androgen-secreting tumor requiring urgent evaluation 4, 5, 2