What are the likely diagnoses and initial work‑up and management for an obese woman with a normal total testosterone of 44 ng/dL but elevated free testosterone and a high weakly‑bound fraction (≈29% and 13%), suggesting low sex‑hormone‑binding globulin?

Likely Diagnosis and Initial Management

This obese woman most likely has polycystic ovary syndrome (PCOS) with obesity-related low sex hormone-binding globulin (SHBG), which artificially lowers total testosterone while free testosterone remains elevated. 1, 2

Understanding the Hormonal Pattern

Why Total Testosterone Appears "Normal"

• In obesity, SHBG levels drop significantly due to insulin resistance and increased adipose tissue 3, 4
• With SHBG around 10 nmol/L (estimated from the high free fraction), most testosterone circulates unbound or albumin-bound rather than SHBG-bound 3, 5
• The total testosterone of 44 ng/dL is misleadingly low because it reflects reduced SHBG-bound testosterone, not true androgen deficiency 4, 5

Why Free Testosterone is Elevated

• Free testosterone represents the metabolically active fraction and is elevated in PCOS regardless of total testosterone 2, 5
• The weakly-bound fraction (28.9%) and calculated free testosterone (12.7 ng/dL) are both markedly elevated, confirming true hyperandrogenism 2, 4
• In PCOS with obesity, free testosterone correlates directly with metabolic abnormalities and central obesity 2

Initial Diagnostic Workup

Essential Laboratory Tests

• Repeat morning total testosterone (8-10 AM) with simultaneous SHBG measurement to calculate the free androgen index (FAI = total testosterone ÷ SHBG × 100); an FAI > 5-6 confirms hyperandrogenism in women 1, 3
• Measure LH and FSH on day 2-5 of the menstrual cycle; an LH:FSH ratio > 2:1 supports PCOS, though this is not required for diagnosis 6
• Fasting glucose, HbA1c, and 2-hour oral glucose tolerance test to screen for impaired glucose tolerance and type 2 diabetes, which occur in 30-40% of women with PCOS 7, 1
• Fasting lipid panel to assess cardiovascular risk, as PCOS is associated with dyslipidemia 7, 1
• TSH to exclude thyroid dysfunction, which can mimic PCOS symptoms 1
• 17-hydroxyprogesterone to exclude non-classic congenital adrenal hyperplasia if total testosterone were > 150 ng/dL (not needed here) 1

Clinical Assessment

• Document menstrual pattern (oligomenorrhea or amenorrhea), hirsutism using the modified Ferriman-Gallwey score, and acne 7, 1
• Measure waist circumference as it correlates more strongly with free testosterone than BMI alone 8
• Pelvic ultrasound to assess for polycystic ovarian morphology (≥ 12 follicles per ovary or ovarian volume > 10 mL), though this is not mandatory for diagnosis 7, 1

Initial Management Strategy

First-Line: Lifestyle Modification

• Implement a hypocaloric diet with 500-750 kcal/day deficit below maintenance requirements 1, 6
• Prescribe structured physical activity: minimum 150 minutes/week of moderate-intensity aerobic exercise plus resistance training 2-3 times weekly 1, 6
• Weight loss of 5-10% significantly improves testosterone levels, insulin resistance, and menstrual regularity in obesity-related PCOS 1, 6

Pharmacologic Therapy

Metabolic Management

• Metformin 1,500-2,000 mg daily is first-line pharmacotherapy for PCOS with obesity, improving insulin resistance, menstrual regularity, and modestly reducing free testosterone 7, 1
• GLP-1 receptor agonists (e.g., liraglutide, semaglutide) or exenatide produce superior weight loss compared to metformin alone and improve metabolic parameters in PCOS 7

Hyperandrogenism Management (if hirsutism or acne is present)

• Combined oral contraceptive pills (COCP) containing cyproterone acetate 2 mg/ethinylestradiol 35 μg or drospirenone 3 mg/ethinylestradiol 20 μg reduce free testosterone by increasing SHBG and suppressing ovarian androgen production 7, 1
• Spironolactone 50-100 mg twice daily can be added if hirsutism persists despite COCP 1

Expected Outcomes

Hormonal Changes with Weight Loss

• Weight loss reverses obesity-related suppression of SHBG, which will increase total testosterone while reducing free testosterone 6, 4
• LH and FSH levels may normalize as estradiol-mediated negative feedback from adipose aromatization decreases 6

Metabolic Improvements

• Free testosterone reduction correlates with improved insulin sensitivity, reduced waist circumference, and lower cardiovascular risk 2, 8
• Metformin reduces HOMA-IR, fasting glucose, and 2-hour glucose on OGTT 7

Critical Pitfalls to Avoid

• Do not diagnose androgen deficiency based on total testosterone alone in obese women; always assess free testosterone or calculate FAI when SHBG is low 3, 4, 5
• Do not start testosterone therapy; this patient has hyperandrogenism, not hypogonadism 1
• Do not rely on symptoms alone to diagnose PCOS; biochemical confirmation of hyperandrogenism and exclusion of other causes (thyroid dysfunction, hyperprolactinemia, Cushing's syndrome) are mandatory 1
• Never skip lifestyle modification as first-line therapy; pharmacologic agents are adjuncts, not replacements 7, 1, 6
• Do not assume normal fertility; counsel regarding ovulation induction options (clomiphene, letrozole) if pregnancy is desired 7, 1