SHBG's Impact on Testosterone Bioactivity
Sex Hormone-Binding Globulin (SHBG) significantly affects testosterone bioactivity by binding to testosterone and regulating its bioavailability, but contrary to traditional belief, higher SHBG levels do not necessarily reduce bioavailable testosterone in healthy individuals with an intact hypothalamic-pituitary-gonadal axis. 1, 2
Mechanisms of SHBG's Effect on Testosterone
- SHBG binds and transports testosterone in plasma, with only a small fraction of testosterone remaining in the unbound (free) form 1
- Free testosterone (FT) is the biologically active form of testosterone that is unbound to SHBG or albumin, making it a more sensitive indicator of hyperandrogenemia than total testosterone 1
- SHBG can alter both production and clearance rates of testosterone in vivo, which affects plasma testosterone levels 2
- The traditional belief that increased SHBG automatically decreases bioavailable testosterone is not consistently supported by in vivo evidence 2
Clinical Measurement and Significance
- Calculated free testosterone (cFT) can be estimated from total testosterone and SHBG measurements using formulas like the Vermeulen equation 1
- Free Androgen Index (FAI), derived from the total testosterone to SHBG ratio, is a simple tool for assessing bioavailable testosterone but can be inaccurate if SHBG concentration is <30 nmol/L 1
- In vitro androgen bioassays demonstrate that SHBG determines free and bioavailable testosterone concentrations, supporting the free hormone hypothesis 3
- Nonsteroidal compounds can bind to SHBG and displace testosterone, thereby increasing testosterone bioactivity in cell culture systems 4
Surprising In Vivo Findings
- Cross-sectional studies in healthy men show that higher SHBG levels are associated with higher total testosterone but have minimal or slightly positive effects on non-SHBG-bound testosterone 2
- In male newborns, higher SHBG is associated with higher total testosterone but not with changes in non-SHBG-bound testosterone 2
- The age-related increase in SHBG does not account for the age-related decline in non-SHBG-bound testosterone in healthy adult men 2
Factors Affecting SHBG Levels
- SHBG levels can be elevated due to medications (anticonvulsants, estrogens, thyroid hormone replacement), aging, smoking, hyperthyroidism, hepatic disease, and HIV/AIDS 5
- Testosterone administration can decrease SHBG levels, as demonstrated in both normal men and patients with Klinefelter's syndrome 6
- SHBG may be a mixture of at least two functionally different hormone-binding globulins that are affected by obesity and gender, showing different affinities for testosterone and estradiol 7
Clinical Implications
- Elevated SHBG can contribute to symptoms of hypogonadism even with normal total testosterone levels 5
- Focusing only on total testosterone can be misleading; free or bioavailable testosterone measurements provide better insight into androgen status 5, 3
- In androgen replacement therapy, monitoring both total and free testosterone is important as SHBG changes can affect bioavailable testosterone 6, 3
- Anti-androgen treatments can decrease serum bioactivity more dramatically than they decrease serum testosterone concentrations 3