Is high Sex Hormone-Binding Globulin (SHBG) with high serum testosterone but normal free testosterone associated with infertility?

High SHBG with High Total Testosterone but Normal Free Testosterone and Male Infertility

High SHBG with high total testosterone but normal free testosterone is not directly associated with male infertility, as free testosterone is the biologically active form that affects spermatogenesis. 1

Understanding the Relationship Between SHBG, Testosterone, and Fertility

Free testosterone, not total testosterone or SHBG alone, is the critical determinant of male reproductive function. When free testosterone levels are normal, even with elevated SHBG and total testosterone, spermatogenesis can proceed normally 1. The American Urological Association (AUA) guidelines emphasize that:

• Free testosterone is the biologically active form affecting spermatogenesis
• The ratio of total testosterone to SHBG is a better indicator of androgen status than total testosterone alone
• A ratio of total testosterone/SHBG ≥0.3 indicates normal gonadal function 1

Evaluation of Male Infertility with Abnormal Hormone Profiles

For men presenting with this hormonal pattern, the following evaluation is recommended:

1. Confirm free testosterone is truly normal:

   • Morning measurement is essential due to diurnal variation
   • Free testosterone by equilibrium dialysis is the most accurate method 1

2. Investigate underlying causes of high SHBG:

   • Liver function tests (chronic liver disease can elevate SHBG)
   • Thyroid function tests (hyperthyroidism increases SHBG)
   • Medication review
   • Assessment of alcohol consumption 1

3. Perform semen analysis to directly assess fertility status, evaluating:

   • Sperm concentration
   • Motility
   • Morphology 2, 1

Clinical Implications and Management

If actively trying to conceive and experiencing difficulty:

1. Avoid exogenous testosterone therapy as it suppresses spermatogenesis and can worsen fertility issues 2, 1, 3

   • The AUA/ASRM guideline clearly states: "For the male interested in current or future fertility, testosterone monotherapy should not be prescribed." 2

2. Consider treatment options if infertility is confirmed:

   • For men with normal free testosterone but abnormal semen parameters, treatment should focus on the specific cause of infertility
   • If hypogonadism is present (low free testosterone), options may include:
     • Selective estrogen receptor modulators (SERMs)
     • Aromatase inhibitors
     • Human chorionic gonadotropin (hCG) 2

3. Address any underlying conditions causing elevated SHBG:

   • Treat hyperthyroidism if present
   • Manage liver disease
   • Reduce alcohol consumption if excessive 1

Important Considerations and Caveats

• Free testosterone calculation is crucial: Total testosterone alone can be misleading in the presence of abnormal SHBG levels 1, 4
• SHBG changes with treatment: When treating hypogonadism, monitor both total and free testosterone, as SHBG levels may change with therapy 5
• FSH levels provide additional information: FSH >4.5 IU/L may be associated with abnormal semen parameters even when within the traditional "normal" range 6
• Referral to a reproductive specialist is recommended if difficulty conceiving occurs after 12 months of unprotected intercourse despite normal free testosterone levels 1

In clinical practice, the focus should be on free testosterone levels and direct assessment of fertility through semen analysis rather than making assumptions based on SHBG or total testosterone levels alone.