How should I evaluate and manage a 22‑year‑old woman with hirsutism, elevated free testosterone, normal total testosterone, and low sex hormone‑binding globulin?

Evaluation and Management of Hirsutism with Elevated Free Testosterone, Normal Total Testosterone, and Low SHBG

Direct Answer

Your patient's biochemical profile—elevated free testosterone (4.4) with normal total testosterone (38) and low SHBG (21.9)—represents classic biochemical hyperandrogenism that is frequently missed when only total testosterone is measured, and this pattern strongly suggests polycystic ovary syndrome (PCOS) as the underlying diagnosis. 1, 2

Understanding the Biochemical Pattern

Your patient demonstrates a critical diagnostic scenario where low SHBG unmasks hyperandrogenism that would otherwise be hidden by a normal total testosterone level. 1, 2

• Low SHBG (21.9 nmol/L, reference >30 nmol/L) increases the bioavailable fraction of testosterone, resulting in elevated free testosterone despite normal total levels. 3, 1
• The Free Androgen Index (FAI = total testosterone/SHBG × 100) in this patient would be approximately 174, which is markedly elevated (normal <5%). 1, 2
• Calculated free testosterone and FAI detect hyperandrogenism in 89-95% of PCOS patients, compared to only 36-74% detection when using total testosterone alone. 4, 5

Essential Diagnostic Workup

First-Line Laboratory Tests (All Required)

Order these tests immediately to establish the diagnosis and exclude dangerous mimics: 3, 1, 2

• Thyroid-stimulating hormone (TSH) – to exclude thyroid disease as a cause of menstrual irregularity 3, 1
• Prolactin (morning, resting sample) – values >20 μg/L indicate hyperprolactinemia, which can mimic PCOS 3, 1
• 2-hour oral glucose tolerance test with 75g glucose load – PCOS patients have substantially increased diabetes risk 3, 1, 2
• Fasting lipid panel (total cholesterol, LDL, HDL, triglycerides) – to assess cardiovascular risk from insulin resistance 3, 1, 2

Second-Line Tests (If Clinical Suspicion for Alternative Diagnoses)

• DHEAS – age-adjusted thresholds (>3800 ng/mL for ages 20-29) suggest non-classical congenital adrenal hyperplasia or adrenal tumor 3, 1, 2
• Androstenedione – values >10 nmol/L raise concern for androgen-secreting tumor 3, 1, 2
• 17-hydroxyprogesterone (morning sample) – if DHEAS elevated, to screen for non-classical CAH 3, 1

When to Suspect Dangerous Conditions Requiring Urgent Evaluation

Screen for Cushing's syndrome if the patient has: 3, 1

• Buffalo hump, moon facies, or centripetal fat distribution
• Hypertension with abdominal striae
• Easy bruising or proximal muscle weakness

Consider androgen-secreting tumor if: 3, 1

• Rapid onset of virilization (over weeks to months rather than years)
• Very high testosterone (>5-7 nmol/L or >150 ng/dL)
• Clitoromegaly or voice deepening
• DHEAS >600 μg/dL

Clinical Assessment Details

History Elements That Matter

Document the following to guide diagnosis and exclude mimics: 3, 1

• Onset and progression – gradual onset over years favors PCOS; rapid onset (<6 months) suggests tumor
• Menstrual pattern – oligomenorrhea (cycles >35 days) or amenorrhea (>6 months without bleeding) indicates anovulation
• Medication history – exogenous androgens, valproate (increases PCOS risk), or enzyme-inducing antiepileptics (alter SHBG)
• Family history – diabetes, cardiovascular disease, or PCOS in first-degree relatives

Physical Examination Priorities

• Ferriman-Gallwey score – quantify hirsutism severity (score ≥6 confirms clinical hyperandrogenism) 1, 5
• Acanthosis nigricans – velvety, hyperpigmented skin in neck folds, axillae, or groin indicates insulin resistance 3, 1
• Body mass index and waist-hip ratio – WHR >0.9 indicates truncal obesity and heightened metabolic risk 3, 1, 2
• Signs of severe virilization – clitoromegaly, temporal balding, or voice deepening warrant urgent tumor evaluation 3, 1

Diagnostic Interpretation

Most Likely Diagnosis: PCOS

Your patient meets diagnostic criteria for PCOS if she has irregular menstrual cycles (oligo/anovulation) plus the documented biochemical hyperandrogenism. 1, 2

• PCOS accounts for 95% of hyperandrogenism cases in reproductive-age women 1
• The Rotterdam criteria require only two of three features: oligo/anovulation, clinical/biochemical hyperandrogenism, or polycystic ovarian morphology on ultrasound 1, 2
• Ultrasound is NOT necessary for diagnosis if both menstrual irregularity and hyperandrogenism are present 2

Critical Diagnostic Pitfall to Avoid

Do NOT dismiss hyperandrogenism based on normal total testosterone alone—this misses 30% of PCOS cases. 2, 4

• Total testosterone is abnormal in only 70% of confirmed PCOS patients 2
• Free testosterone and FAI have superior sensitivity (89% vs. 74%) and detect cases missed by total testosterone 1, 4
• Low SHBG is itself a marker of insulin resistance and metabolic dysfunction in PCOS 3, 1

Management Approach

First-Line Treatment

Combined oral contraceptives (COCs) are the first-line treatment for hyperandrogenism in PCOS, effectively regulating menstrual cycles and reducing androgen levels. 1

• COCs suppress ovarian androgen production and increase SHBG, thereby lowering free testosterone 1
• Choose formulations with low androgenic progestins (norgestimate, desogestrel, drospirenone) 1

Metabolic Management (Mandatory for All PCOS Patients)

Address insulin resistance and metabolic risk factors aggressively, as these drive long-term morbidity: 3, 1, 2

• Lifestyle modification – weight loss of 5-10% improves insulin sensitivity, menstrual regularity, and androgen levels 1
• Metformin – consider if glucose intolerance, prediabetes, or obesity with insulin resistance 1
• Monitor cardiovascular risk factors every 6-12 months – weight, blood pressure, lipids, glucose 2

Additional Antiandrogen Therapy (If COCs Insufficient)

• Spironolactone 50-200 mg daily – blocks androgen receptors and reduces hirsutism (requires contraception due to teratogenicity) 1
• Finasteride 2.5-5 mg daily – inhibits 5α-reductase, reducing DHT formation (also requires contraception) 1

Long-Term Monitoring

Screen for metabolic complications annually: 3, 1, 2

• Repeat 2-hour OGTT every 1-2 years (PCOS patients have 8% cumulative incidence of non-surgical premature ovarian failure vs. 0.8% in controls) 3
• Annual fasting lipid panel and blood pressure monitoring 1, 2
• Assess for endometrial hyperplasia if prolonged amenorrhea (>3-6 months) due to unopposed estrogen 3

When to Refer

Refer to endocrinology or reproductive endocrinology if: 3, 1

• Rapid virilization or very high androgens suggesting tumor
• Abnormal screening tests (elevated prolactin, abnormal TSH, elevated DHEAS)
• Infertility or desire for pregnancy (requires ovulation induction)
• Inadequate response to first-line therapy after 6 months