In a woman with hirsutism and elevated free testosterone and sex hormone‑binding globulin, how should we evaluate the source of androgen excess and what is the first‑line treatment?

Evaluation and Management of Hirsutism with Elevated Free Testosterone and SHBG

Initial Assessment and Diagnostic Interpretation

The combination of elevated free testosterone with elevated SHBG in a hirsute woman is unusual and requires careful evaluation to exclude androgen-secreting tumors, non-classic congenital adrenal hyperplasia, and other serious causes before attributing symptoms to PCOS. 1

This hormonal pattern is atypical because SHBG is typically low in hyperandrogenic states—androgens suppress hepatic SHBG production, and conditions like PCOS, obesity, and insulin resistance all reduce SHBG levels. 2, 3 When both free testosterone and SHBG are elevated simultaneously, you must consider:

• Androgen-secreting tumors (ovarian or adrenal)—these produce massive androgen excess that overwhelms the usual SHBG suppression, and they present with rapid-onset, severe virilization (voice deepening, clitoromegaly, marked temporal balding). 1, 4
• Exogenous androgen use—supplements or medications can elevate both parameters. 1
• Thyroid disease—hyperthyroidism raises SHBG independent of androgen status. 1, 2
• Hepatic disease—cirrhosis can elevate SHBG. 2
• Medications—oral estrogens (including combined oral contraceptives) and anticonvulsants alter SHBG levels. 2

Mandatory Exclusion Testing

Before proceeding with PCOS evaluation, immediately obtain the following to rule out life-threatening or rapidly progressive conditions:

• Total testosterone by LC-MS/MS—if >150–200 ng/dL, strongly suspect an androgen-secreting tumor and proceed urgently to imaging (pelvic ultrasound and adrenal CT). 1, 4
• DHEAS—if >600 μg/dL, suspect adrenocortical carcinoma and obtain adrenal imaging. 1
• Morning 8 AM cortisol or 24-hour urinary free cortisol—to exclude Cushing's syndrome, especially if the patient has central obesity, striae, hypertension, or moon facies. 1, 4
• 17-hydroxyprogesterone (early follicular phase or random if anovulatory)—to exclude non-classic congenital adrenal hyperplasia; if >200 ng/dL, perform ACTH stimulation test. 1
• TSH—to exclude hyperthyroidism (which elevates SHBG) or hypothyroidism (which can cause menstrual irregularity). 1, 4
• Prolactin (morning, resting)—women with PCOS have a 3.15-fold increased risk of hyperprolactinemia, and prolactinomas can cause both hirsutism and menstrual dysfunction. 1, 4

Determining the Source of Androgen Excess

Once tumors, Cushing's syndrome, and non-classic CAH are excluded, PCOS accounts for 95% of hyperandrogenism cases in reproductive-age women. 1 The diagnosis requires two of three Rotterdam criteria:

1. Oligo- or anovulation (menstrual cycles >35 days or <8 cycles per year). 4
2. Clinical or biochemical hyperandrogenism—hirsutism (modified Ferriman-Gallwey score ≥6), acne, or elevated androgens. 1, 4
3. Polycystic ovarian morphology on ultrasound—≥20 follicles (2–9 mm) per ovary or ovarian volume >10 mL using transvaginal ultrasound with ≥8 MHz transducer. 5, 4

Key Diagnostic Pitfalls

• Do not rely on ultrasound alone—up to one-third of normal women have polycystic-appearing ovaries, and the finding is non-specific. 4
• Avoid ultrasound in adolescents (<8 years post-menarche or <20 years old)—multifollicular ovaries are physiologic in this age group, yielding high false-positive rates. 5, 4
• Repeat testosterone measurement in the morning (8–10 AM) using LC-MS/MS—androgen secretion is pulsatile, and afternoon samples may miss subtle hyperandrogenism. 1, 6
• Calculate free androgen index (FAI = total testosterone/SHBG × 100) or use the Vermeulen equation to calculate free testosterone—direct immunoassays for free testosterone are inaccurate at low female concentrations and should never be used. 1, 5

Understanding the Elevated SHBG

If SHBG is truly elevated (not just high-normal) in the setting of hyperandrogenism, investigate:

• Oral estrogen use—combined oral contraceptives raise SHBG and can mask hyperandrogenism; discontinue for 3 months before retesting. 4, 2
• Hyperthyroidism—check TSH and free T4. 1, 2
• Hepatic dysfunction—check liver function tests. 2
• Anticonvulsant use (phenytoin, carbamazepine, phenobarbital)—these induce hepatic SHBG production. 1

If none of these factors are present and SHBG remains elevated, the elevated free testosterone may reflect increased androgen production that has not yet suppressed SHBG, or there may be a mixed picture (e.g., early PCOS in a patient with concurrent hyperthyroidism).

First-Line Treatment

Combined oral contraceptives (COCs) are the first-line pharmacologic treatment for hirsutism and menstrual irregularity in women with PCOS who do not desire pregnancy. 1, 4

COCs work by:

• Suppressing LH-driven ovarian androgen production. 4
• Increasing hepatic SHBG synthesis, which lowers free testosterone. 2, 3
• Providing regular withdrawal bleeding and endometrial protection. 4

Additional Treatment Considerations

• Lifestyle modification is mandatory for all PCOS patients, regardless of BMI—insulin resistance occurs independent of body weight, and even 5% weight loss improves metabolic and reproductive outcomes. 4
• Metformin improves insulin sensitivity, glucose tolerance, and ovulation frequency; consider adding it to COCs in women with impaired glucose tolerance or diabetes. 4
• Spironolactone (50–200 mg daily) is an androgen receptor blocker that reduces hirsutism when combined with COCs; it requires contraception due to teratogenicity. 4
• Mechanical hair removal (laser, electrolysis) is an important adjunct—pharmacologic therapy slows new hair growth but does not remove existing terminal hairs. 4

Metabolic Screening

All women with PCOS require metabolic screening at diagnosis, regardless of BMI or symptom severity:

• 2-hour 75-gram oral glucose tolerance test—to detect impaired glucose tolerance or diabetes. 1, 4
• Fasting lipid panel (total cholesterol, LDL, HDL, triglycerides)—to assess cardiovascular risk. 1, 4
• Blood pressure measurement—hypertension is more common in PCOS. 4

Repeat metabolic screening every 1–2 years or sooner if weight gain occurs. 4

Clinical Algorithm Summary

1. Confirm hyperandrogenism: Repeat total testosterone (LC-MS/MS) and calculate FAI or free testosterone in the morning. 1, 5
2. Exclude dangerous causes: Check total testosterone (if >150–200 ng/dL → imaging), DHEAS (if >600 μg/dL → adrenal CT), 17-OHP, TSH, prolactin, and consider Cushing's screening if clinical features present. 1, 4
3. Investigate elevated SHBG: Review medications (oral estrogens, anticonvulsants), check TSH and liver function tests. 1, 2
4. Diagnose PCOS: Apply Rotterdam criteria (two of three: anovulation, hyperandrogenism, polycystic ovaries on ultrasound). 5, 4
5. Initiate treatment: Start COCs for menstrual regulation and hirsutism; add spironolactone if hirsutism is severe; prescribe lifestyle modification for all patients. 1, 4
6. Screen for metabolic complications: Perform 2-hour OGTT, fasting lipids, and blood pressure measurement at baseline and periodically. 1, 4