I am a man with elevated sex hormone‑binding globulin and low free testosterone (symptoms include low libido, fatigue, and reduced muscle mass); what investigations should I request before considering testosterone replacement therapy?

Investigations for Elevated SHBG and Low Free Testosterone Before Considering Testosterone Replacement

Confirm True Biochemical Hypogonadism First

You must obtain two separate fasting morning (8–10 AM) total testosterone measurements before proceeding with any workup. Both values should be below 300 ng/dL to establish hypogonadism, as single measurements are unreliable due to diurnal variation and assay differences. 1, 2 Your current single value of 370 ng/dL is actually above the diagnostic threshold and does not confirm hypogonadism by current guideline standards. 2

However, in men with elevated SHBG, total testosterone can be misleadingly normal while free testosterone remains frankly low—a condition termed "functional hypogonadism." 3, 4 This discordance is particularly common in men over 60 years, where 26.3% have normal total testosterone with low free testosterone, and these men experience genuine symptomatic hypogonadism that would be missed by screening with total testosterone alone. 3

Essential Hormone Panel

• Free testosterone by equilibrium dialysis is the gold standard measurement; direct immunoassays are inaccurate when SHBG is abnormal. 1, 2, 4 If equilibrium dialysis is unavailable, calculate the free androgen index (FAI) using the formula: (total testosterone ÷ SHBG) × 100. An FAI < 30 indicates true hypogonadism even when total testosterone appears borderline-normal. 2

• LH and FSH levels are mandatory after confirming low testosterone to differentiate primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism. 1, 2 Low or inappropriately normal LH/FSH with low testosterone indicates secondary hypogonadism, which has critical treatment implications including potential fertility preservation with gonadotropin therapy rather than testosterone replacement. 1, 2

• Repeat your morning total testosterone on at least one additional occasion between 8–10 AM to confirm persistent levels, as required by all major guidelines. 1, 2

Investigate Reversible Causes of Elevated SHBG

Before considering testosterone therapy, you must systematically exclude treatable conditions that elevate SHBG and cause functional hypogonadism. 1, 2

Primary Causes to Screen

• Thyroid function (TSH): Hyperthyroidism markedly increases SHBG production and can cause secondary hypogonadism. 2, 5 This is a readily treatable cause that must be excluded first.

• Liver disease: Obtain liver function tests (ALT, AST, bilirubin, albumin) and hepatitis serologies. Cirrhosis is a well-recognized cause of elevated SHBG. 2, 5 In men with liver disease, use the free testosterone index (total testosterone ÷ SHBG ratio < 0.3) to define hypogonadism rather than total testosterone alone. 2

• HIV status: If risk factors are present, HIV testing is indicated as HIV/AIDS elevates SHBG. 2, 5

• Medication review: Anticonvulsants (phenytoin, carbamazepine), estrogens, and thyroid hormone replacement all increase SHBG. 2, 5 Discontinue or substitute these medications when feasible.

• Smoking status: Smoking raises SHBG levels; counsel cessation. 2

Evaluate for Secondary Hypogonadism Causes

If LH/FSH are low or low-normal, investigate these reversible contributors:

• Serum prolactin: Hyperprolactinemia suppresses the hypothalamic-pituitary axis. 1, 2, 6 If prolactin exceeds 1.5 × the upper limit of normal, repeat the test to confirm, then order pituitary MRI to exclude prolactinoma. 2, 6

• Fasting glucose and HbA1c: Type 2 diabetes and metabolic syndrome cause secondary hypogonadism through increased aromatization of testosterone to estradiol in adipose tissue, creating estradiol-mediated negative feedback that suppresses LH secretion. 1, 2

• Iron studies (serum ferritin, transferrin saturation): Hemochromatosis is a recognized cause of secondary hypogonadism. 2

• Pituitary MRI: Order imaging if testosterone < 150 ng/dL with LH/FSH < 1.5 IU/L (regardless of prolactin level), or if visual field defects or anosmia are present. 2, 6 Non-functioning pituitary adenomas can present with isolated hypogonadism.

Address Obesity-Related Hypogonadism First

If you have obesity (BMI ≥ 30 or elevated waist circumference), weight loss through lifestyle modification is the mandatory first-line intervention before considering testosterone therapy. 1, 2

• Implement a hypocaloric diet with 500–750 kcal/day deficit below maintenance requirements. 2

• Prescribe structured physical activity: minimum 150 minutes/week of moderate-intensity aerobic exercise plus resistance training 2–3 times weekly. 1, 2

• A 5–10% weight loss can significantly increase endogenous testosterone production in obese men with secondary hypogonadism by reducing aromatization and normalizing gonadotropins. 1, 2 Meta-analyses confirm that weight loss reverses obesity-associated secondary hypogonadism, with testosterone increases of 1–2 nmol/L. 1

Never start testosterone without first attempting lifestyle modification in obesity-associated hypogonadism, as the condition is potentially reversible. 2

Pre-Treatment Safety Screening

If hypogonadism is confirmed and reversible causes have been addressed, obtain these baseline tests before initiating therapy:

• Hematocrit/hemoglobin: Testosterone therapy is absolutely contraindicated if hematocrit > 50% at baseline; values > 54% during treatment require immediate discontinuation. 1, 6

• PSA and digital rectal examination (if age > 40 years): PSA > 4.0 ng/mL mandates urologic evaluation and documented negative prostate biopsy before starting therapy. 1, 6

• Lipid profile: Assess cardiovascular risk factors as part of baseline metabolic evaluation. 1, 2

Critical Fertility Counseling

Testosterone therapy is absolutely contraindicated if you desire future fertility, as it causes prolonged and potentially irreversible azoospermia by suppressing spermatogenesis. 1, 2 If you have secondary hypogonadism and wish to preserve fertility, gonadotropin therapy (recombinant hCG plus FSH) is mandatory instead of testosterone replacement, as it stimulates the testes directly and restores both testosterone production and sperm counts. 1, 2 Combined hCG + FSH therapy provides optimal outcomes for fertility preservation. 1, 2

Set Realistic Expectations About Treatment Benefits

Even if hypogonadism is confirmed, testosterone therapy produces only small improvements in sexual function and libido (standardized mean difference ≈ 0.35), with little to no effect on energy, vitality, physical functioning, depressive symptoms, or cognition. 1, 2 Your primary complaints of fatigue and reduced muscle mass show minimal correlation with testosterone levels and do not improve reliably with replacement therapy. 2 The primary evidence-based indication for testosterone therapy is diminished libido and erectile dysfunction—not fatigue, low energy, or body composition changes. 1, 2

Common Pitfalls to Avoid

• Do not diagnose hypogonadism on a single testosterone measurement or on symptoms alone; require two fasting morning values < 300 ng/dL plus specific sexual symptoms. 1, 2

• Never omit LH/FSH testing after confirming low testosterone, as the primary vs. secondary distinction directs therapy and fertility counseling. 1, 2

• Avoid direct immunoassays for free testosterone in men with abnormal SHBG; use equilibrium dialysis or calculate the free androgen index. 2, 4

• Do not prescribe testosterone for weight loss, general energy enhancement, or athletic performance, as these are not evidence-based indications. 1, 2

• Approximately 25–30% of men receiving testosterone therapy do not meet diagnostic criteria for hypogonadism, highlighting the need for strict adherence to testing protocols. 2