Does high Sex Hormone-Binding Globulin (SHBG) affect fertility if free testosterone (T) levels are normal?

Impact of High SHBG on Fertility with Normal Free Testosterone

High Sex Hormone-Binding Globulin (SHBG) levels generally do not negatively affect fertility when free testosterone levels remain within the normal range, as free testosterone is the biologically active form that impacts spermatogenesis. 1

Understanding SHBG and Testosterone Relationship

Sex Hormone-Binding Globulin (SHBG) is a protein that binds to testosterone in the bloodstream, making it biologically inactive. The relationship between SHBG and fertility can be understood through several key points:

• Free testosterone is the biologically active form affecting spermatogenesis, and the ratio of total testosterone to SHBG is a better indicator of androgen status than total testosterone alone 1
• A ratio of total testosterone/SHBG ≥0.3 indicates normal gonadal function, while <0.3 suggests hypogonadism 1
• When evaluating low total testosterone in men with obesity, measurement of morning serum free testosterone is essential, as obesity-related decreases in testosterone are frequently attributable to low concentrations of SHBG 2

Clinical Implications of High SHBG

When Free Testosterone is Normal:

• If free testosterone levels remain normal despite elevated SHBG, fertility is generally preserved as the biologically active hormone remains available for spermatogenesis
• The American Urological Association (AUA) and American Society for Reproductive Medicine (ASRM) guidelines recommend that management should be guided by free testosterone levels and clinical symptoms rather than total testosterone alone 1

Evaluation of High SHBG:

Elevated SHBG warrants investigation for underlying causes:

1. Medical conditions associated with high SHBG:

   • Hyperthyroidism
   • Chronic liver disease
   • Alcoholism 1

2. Recommended workup:

   • Liver function tests
   • Thyroid function tests
   • Medication review
   • Assessment of alcohol consumption 1

Fertility Management Considerations

When high SHBG is identified but free testosterone remains normal:

• Monitor semen parameters: Semen analysis is crucial for assessing fertility status, evaluating sperm concentration, motility, and morphology 1
• Avoid testosterone therapy: Testosterone monotherapy should not be prescribed for men interested in current or future fertility, as it suppresses spermatogenesis 1
• Consider specialist referral: If difficulty conceiving occurs after 12 months of unprotected intercourse despite normal free testosterone levels, referral to a reproductive specialist is recommended 1

Clinical Pitfalls to Avoid

1. Relying solely on total testosterone measurements: This can be misleading when SHBG levels are abnormal. Always assess free testosterone levels, preferably by equilibrium dialysis, which is the most accurate method 1

2. Inappropriate testosterone replacement: Administering exogenous testosterone to men with fertility concerns can worsen fertility by suppressing spermatogenesis 1

3. Overlooking underlying conditions: High SHBG may be a marker of other medical conditions that could independently affect fertility, such as thyroid disorders or liver disease 1

4. Ignoring metabolic factors: SHBG levels correlate negatively with body mass index and fasting insulin levels, potentially indicating insulin resistance that may affect reproductive function 3

In conclusion, while high SHBG affects the bioavailability of total testosterone, fertility is primarily dependent on free testosterone levels. As long as free testosterone remains within normal range, high SHBG alone is unlikely to significantly impair fertility.