What does a normal total testosterone level with a low free testosterone level indicate?

Understanding Normal Total Testosterone with Low Free Testosterone

When total testosterone is normal but free testosterone is low, this typically indicates elevated sex hormone-binding globulin (SHBG) is binding most of your testosterone, leaving less biologically active (free) hormone available to your tissues—a condition called "functional hypogonadism." 1, 2

What This Biochemical Pattern Means

The Binding Protein Problem

• Approximately 98% of circulating testosterone is bound to proteins—primarily SHBG and albumin—while only about 2% circulates as free testosterone, which is the metabolically active fraction 3, 4
• SHBG binds testosterone tightly, rendering it biologically unavailable, whereas albumin-bound testosterone is weakly bound and considered part of the "bioavailable" pool 4
• When SHBG is elevated, total testosterone may appear normal or even borderline-normal, but free testosterone can be frankly low because most hormone is sequestered in the bound form 1, 5

Clinical Significance

• Free testosterone by equilibrium dialysis is the gold standard for assessing true androgen status when total testosterone is borderline or discordant with clinical presentation 2, 4
• Men with normal total testosterone but low free testosterone have symptomatic hypogonadism that would be missed by screening with total testosterone alone—this occurs in approximately 17.2% of men presenting with erectile dysfunction and 26.3% of men over 60 years 5
• This discordance is most common in older men and those with conditions that elevate SHBG, including aging itself, obesity, liver disease, hyperthyroidism, and HIV infection 1, 5

Diagnostic Approach

Essential Laboratory Tests

• Measure free testosterone by equilibrium dialysis (not analog immunoassay methods, which are unreliable) or calculate free testosterone using validated formulas (Vermeulen equation) that incorporate total testosterone, SHBG, and albumin 1, 2, 4, 6
• Measure SHBG to calculate the free androgen index (total testosterone ÷ SHBG × 100), which estimates bioavailable testosterone when equilibrium dialysis is unavailable 1, 2
• An FAI < 30 indicates true hypogonadism even when total testosterone is in the borderline-normal range 1
• Measure LH and FSH to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism 1

Interpretation Algorithm

1. If total testosterone is 231–346 ng/dL (gray zone) and FAI < 30: functional hypogonadism due to elevated SHBG is likely 1
2. If total testosterone > 350 ng/dL but FAI < 30 together with low libido: SHBG-mediated functional hypogonadism may be present and could justify treatment 1
3. Total testosterone must exceed 350–400 ng/dL to reliably predict normal free testosterone; values between 280–350 ng/dL are not sensitive enough to exclude hypogonadism 7

Common Causes of Elevated SHBG

• Aging: SHBG increases steeply after the sixth decade, with 52.5% of men over 60 years having elevated SHBG 5
• Liver disease (e.g., cirrhosis) markedly increases SHBG production 1
• Hyperthyroidism elevates SHBG 1
• Obesity: paradoxically, while obesity typically lowers SHBG, excessive aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback suppressing pituitary LH secretion, creating secondary hypogonadism 1

Treatment Considerations

When Testosterone Therapy May Be Appropriate

• In men with borderline total testosterone (231–346 ng/dL) and FAI < 30 with specific symptoms (diminished libido, erectile dysfunction), a 4–6 month trial of testosterone therapy may be considered after careful discussion of risks and benefits 1
• Primary symptoms warranting treatment include diminished libido and erectile dysfunction, not non-specific complaints like fatigue or low energy 1
• Testosterone therapy produces small but significant improvements in sexual function (standardized mean difference 0.35) but little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition 1, 2

When Testosterone Therapy Is NOT Indicated

• When free testosterone is normal despite low-normal total testosterone, testosterone replacement therapy is generally not indicated, as the normal free testosterone level indicates adequate bioavailable androgen activity and these patients are functionally eugonadal 2
• The European Association of Urology explicitly recommends against testosterone therapy in eugonadal men, even for complaints of weight loss, fatigue, low energy, or diminished vitality 1, 2
• Never use testosterone therapy to treat non-specific symptoms like fatigue, low energy, or depressed mood in eugonadal men 2

Alternative Treatment Approaches

• For obesity-associated changes: Weight loss through low-calorie diets and regular exercise can improve the testosterone-to-SHBG ratio and normalize testosterone levels without medication 1, 2
• For erectile dysfunction: PDE5 inhibitors (sildenafil, tadalafil) are first-line therapy and do not require testosterone supplementation when free testosterone is normal 2
• For diminished libido: Investigate other causes including depression, relationship factors, and sleep disorders before attributing symptoms to borderline testosterone 2
• For men with secondary hypogonadism who desire fertility: Consider clomiphene citrate off-label (25–50 mg three times weekly) to stimulate endogenous testosterone production, or letrozole if estradiol is elevated, rather than exogenous testosterone which suppresses spermatogenesis 1

Critical Pitfalls to Avoid

• Do not diagnose hypogonadism based on total testosterone alone, especially in men over 60 years or those with conditions affecting SHBG 5, 7
• Do not rely on direct immunoassay measurements of free testosterone; use equilibrium dialysis or calculated values (Vermeulen formula) to ensure accuracy 1, 2, 4
• Do not use screening questionnaires or symptoms alone to diagnose hypogonadism due to lack of specificity 1, 2
• Current guidelines for hypogonadism screening in erectile dysfunction should be amended to include free testosterone assessment, particularly in patients over 60 years, as total testosterone cannot solely be relied upon to exclude biochemical hypogonadism 5