Evaluation and Management of Borderline-Low Free Testosterone with Normal Total Testosterone
Immediate Next Steps: Confirm the Diagnosis
You must repeat the free testosterone measurement using equilibrium dialysis (the gold standard method) or calculate free testosterone using a validated algorithm, because direct immunoassays for free testosterone are notoriously inaccurate and your current result may be a laboratory artifact. 1, 2, 3
Obtain a second fasting morning (8–10 AM) total testosterone measurement on a separate day to confirm whether total testosterone truly remains in the normal range, as single measurements are insufficient due to diurnal variation and assay variability. 4, 5, 3
Measure sex hormone-binding globulin (SHBG) simultaneously, because the discordance between borderline-normal total testosterone and reportedly low free testosterone strongly suggests either elevated SHBG (which would lower free testosterone despite normal total testosterone) or a faulty direct immunoassay result. 4, 1, 2
Calculate the free androgen index (FAI = [total testosterone ÷ SHBG] × 100) as an interim assessment; an FAI < 30 indicates true biochemical hypogonadism even when total testosterone appears borderline-normal. 4
If equilibrium dialysis is unavailable, use the Vermeulen equation to calculate free testosterone from total testosterone, SHBG, and albumin, as this method has been validated in large population studies and is more reliable than direct immunoassays. 1, 6, 3
Determine the Type of Hypogonadism
Once you confirm that free testosterone is genuinely low (< 1.7% or calculated free testosterone below the reference range), measure serum LH and FSH to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism, because this distinction is critical for treatment selection and fertility counseling. 4
- Low or inappropriately normal LH/FSH with low free testosterone → secondary (hypogonadotropic) hypogonadism. 4
- Elevated LH/FSH with low free testosterone → primary (testicular) hypogonadism. 4
If LH and FSH are low or low-normal, obtain a serum prolactin level to screen for hyperprolactinemia, which can cause secondary hypogonadism and may indicate a pituitary adenoma. 4
If prolactin is elevated (> 1.5 × the upper limit of normal), order a pituitary MRI to exclude a prolactinoma or other sellar mass. 4
Evaluate for Reversible Causes of Elevated SHBG or Secondary Hypogonadism
Before considering testosterone therapy, screen for and address the following reversible conditions that can elevate SHBG or suppress the hypothalamic-pituitary axis:
Obesity-associated secondary hypogonadism: Excess adipose tissue increases aromatization of testosterone to estradiol, which suppresses LH secretion via negative feedback. 4
- First-line intervention: implement a hypocaloric diet (500–750 kcal/day deficit below maintenance) and structured exercise (≥ 150 min/week moderate-intensity aerobic activity plus resistance training 2–3 times/week), as a 5–10% weight loss can markedly increase endogenous testosterone without medication. 4
Hyperthyroidism: Measure TSH; elevated thyroid hormone increases SHBG production. 4
Hepatic disease (e.g., cirrhosis): Check liver function tests and hepatitis serologies; liver disease raises SHBG. 4
Medications that elevate SHBG: Review anticonvulsants, estrogens, and thyroid hormone; discontinue or substitute when feasible. 4
Smoking: Counsel cessation, as smoking increases SHBG. 4
Metabolic syndrome/type 2 diabetes: Obtain fasting glucose, HbA1c, and lipid profile; optimize metabolic control. 4
Chronic systemic illnesses: Screen for HIV, chronic kidney or liver disease, and inflammatory conditions. 4
Hemochromatosis: Measure iron saturation and ferritin if clinically suspected. 4
Assess Symptoms to Determine Whether Treatment Is Indicated
Testosterone therapy is justified only if you confirm both biochemical hypogonadism (two morning total testosterone < 300 ng/dL or confirmed low free testosterone with low-normal total testosterone) AND the presence of specific sexual symptoms—namely, diminished libido and/or erectile dysfunction. 4
Nonspecific symptoms such as fatigue, low energy, depressed mood, poor concentration, or reduced physical strength do NOT justify testosterone therapy, because these symptoms show minimal correlation with testosterone levels and exhibit little to no improvement with replacement therapy even in confirmed hypogonadism. 4
Expected benefits of testosterone therapy are modest and confined to sexual function: small but statistically significant improvement in libido and erectile function (standardized mean difference ≈ 0.35), with little to no effect on energy, vitality, physical functioning, depressive symptoms, or cognition. 4
Treatment Algorithm
If Free Testosterone Is Confirmed Low and Symptoms Are Present
Step 1: Confirm the patient does NOT desire fertility, as exogenous testosterone suppresses spermatogenesis and causes prolonged, potentially irreversible azoospermia. 4
- If fertility preservation is desired and secondary hypogonadism is confirmed (low LH/FSH), use gonadotropin therapy (recombinant hCG plus FSH) instead of testosterone, as this stimulates endogenous testosterone production and maintains spermatogenesis. 4
Step 2: Initiate testosterone replacement therapy with transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations or one 40.5 mg packet), applied once daily in the morning to clean, dry, intact skin of the shoulders and upper arms. 4, 5
Transdermal gel is first-line because it provides more stable day-to-day testosterone levels and carries a lower risk of erythrocytosis (≈ 15%) compared with injectable testosterone (≈ 44%). 4
Alternative: intramuscular testosterone cypionate or enanthate 100–200 mg every 2 weeks is a cost-effective option (annual cost ≈ $156 vs. ≈ $2,135 for transdermal gel), but it produces greater serum testosterone variability and higher erythrocytosis risk. 4
Step 3: Target mid-normal serum testosterone concentrations (450–600 ng/dL) when monitoring therapy. 4
Monitoring and Safety
Baseline assessments before initiating therapy:
- Hematocrit/hemoglobin: Absolute contraindication if > 54%. 4
- PSA (if age > 40 years): PSA > 4.0 ng/mL requires urologic evaluation and documented negative prostate biopsy before starting therapy. 4
- Fasting glucose and HbA1c: Rule out diabetes. 4
- Lipid profile: Baseline metabolic assessment. 4
Follow-up schedule:
2–3 months after initiation: Measure total and free testosterone (midway between injections for injectables), hematocrit, and PSA; evaluate clinical response (particularly sexual function and libido) and adjust dose if symptoms persist with suboptimal levels. 4
Every 3–6 months during the first year: Repeat testosterone, hematocrit, PSA, lipid profile, and perform digital rectal examination. 4
Annually thereafter: Continue the same panel if stable. 4
Safety thresholds:
Withhold testosterone if hematocrit rises > 54%; consider therapeutic phlebotomy (500 mL every 1–2 weeks until hematocrit < 52%) in high-risk individuals. 4
Refer to urology if PSA increases > 1.0 ng/mL within the first 6 months or > 0.4 ng/mL per year thereafter. 4
Discontinue therapy at 12 months if there is no documented improvement in sexual function, to prevent unnecessary long-term exposure to potential risks without benefit. 4
Critical Pitfalls to Avoid
Do NOT diagnose hypogonadism based on a single testosterone measurement or on symptoms alone; require two fasting morning values and appropriate sexual symptoms. 4
Do NOT rely on direct immunoassays for free testosterone in men with abnormal SHBG; use equilibrium dialysis or calculate free testosterone using the Vermeulen equation. 1, 2, 3
Do NOT initiate testosterone without confirming the patient does not desire fertility, as exogenous testosterone can cause prolonged azoospermia. 4
Do NOT prescribe testosterone for weight loss, general energy enhancement, or athletic performance, as these are not evidence-based indications. 4
Do NOT ignore mild erythrocytosis (hematocrit 50–52%) in elderly patients or those with cardiovascular disease, as even modest elevations increase blood viscosity and thrombotic risk. 4