Management of High SHBG with Normal Free Testosterone in Symptomatic Patients
If free testosterone is truly normal by accurate measurement (equilibrium dialysis or calculated from total testosterone, SHBG, and albumin), testosterone replacement therapy is not indicated, and symptoms should be attributed to other causes. 1
Diagnostic Verification First
The critical first step is confirming that free testosterone is genuinely normal, as measurement methodology profoundly affects accuracy:
- Measure morning (8-10 AM) total testosterone on at least two separate occasions to account for diurnal variation and biological variability 1, 2
- Calculate free testosterone using total testosterone, SHBG, and albumin concentrations rather than relying on direct immunoassays, which are unreliable 1, 3
- Free testosterone calculated from immunoassayed SHBG is nearly identical to equilibrium dialysis values and represents the gold standard for clinical practice 3
- Direct analog immunoassays for free testosterone are inaccurate and should be avoided, as values vary substantially with SHBG levels 3
Common pitfall: Many laboratories use direct free testosterone immunoassays that significantly underestimate true free testosterone, particularly when SHBG is elevated 3. This can lead to false diagnoses of hypogonadism in patients with normal bioavailable testosterone.
When Free Testosterone is Confirmed Normal
If calculated free testosterone is truly within the normal range despite elevated SHBG:
- Do not initiate testosterone replacement therapy 1
- The elevated SHBG with normal free testosterone indicates adequate bioavailable testosterone for tissue effects 1, 4
- Symptoms must be investigated for alternative etiologies unrelated to testosterone deficiency 1
Investigate Alternative Causes of Symptoms
Measure LH and FSH levels to characterize the hypothalamic-pituitary-gonadal axis 1:
- Normal or elevated LH with normal free testosterone confirms eugonadal status
- Low LH might suggest evolving secondary hypogonadism requiring closer monitoring
Screen for conditions that elevate SHBG and may cause symptoms independently 4:
- Thyroid function tests (hyperthyroidism increases SHBG) 1, 4
- Liver function tests (hepatic cirrhosis elevates SHBG) 1, 4
- Medication review (anticonvulsants, estrogens increase SHBG) 4
Evaluate for common comorbidities causing hypogonadal-like symptoms 1:
- Depression and mood disorders
- Sleep apnea
- Metabolic syndrome and diabetes
- Cardiovascular disease risk factors
Special Consideration: Aging Men
In men over 60 years, elevated SHBG is extremely common (52.5% prevalence), and the discordance between total and free testosterone increases substantially 5:
- Age-related SHBG elevation can mask true hypogonadism when only total testosterone is measured 5
- However, if free testosterone remains normal despite high SHBG, this represents successful compensation and does not warrant treatment 1
- The 26.3% of men over 60 with normal total testosterone but low free testosterone require treatment; those with normal free testosterone do not 5
Monitoring Strategy
For symptomatic patients with confirmed normal free testosterone:
- Repeat testosterone assessment (total, SHBG, calculated free) in 6-12 months to ensure stability 1
- Address modifiable factors affecting SHBG: weight management, thyroid optimization, medication adjustments 1, 4
- Pursue targeted treatment for identified alternative causes of symptoms 1
Critical distinction: The ratio of total testosterone to SHBG (free testosterone index) below 0.3 indicates hypogonadism 1, but this applies when free testosterone is actually low. When calculated free testosterone is normal, this ratio becomes less relevant for treatment decisions.