Sex Hormone-Binding Globulin (SHBG)

SHBG is a homodimeric glycoprotein made by the liver, with one high-affinity steroid site per dimer. It binds dihydrotestosterone most tightly, then testosterone, then estradiol, tightly enough that only a low single-digit percentage of circulating testosterone is free. A much larger fraction rides on albumin, which binds weakly and dissociates readily. The free hormone hypothesis holds that only the unbound portion, and arguably the albumin-bound portion, is available to tissues.

SHBG concentration is not a constant. It rises with estrogen exposure, thyroid hormone excess, ageing, liver disease and some anticonvulsants; it falls with insulin resistance, obesity, androgens, glucocorticoids, hypothyroidism and growth hormone. The swing is wide enough that two men with the same free testosterone can differ substantially in total testosterone purely through SHBG, so an identical total means different things in a lean 25-year-old and a 55-year-old with type 2 diabetes.

That is what makes total testosterone unreliable at the margins. Where SHBG is likely to be abnormal, free testosterone is the more informative measurement, either by equilibrium dialysis or calculated from total testosterone, SHBG and albumin. Guidelines reserve that step for discordant cases, because calculated free values depend on binding constants that differ between published equations.

The trap is the direct free testosterone immunoassay - the analogue kits that report a free value with no dialysis and no calculation. They perform poorly, particularly at low concentrations, and can move in the wrong direction when SHBG changes, which is the exact situation they are ordered for. A related error is treating a low SHBG as an isolated abnormality to correct, when it is usually a marker of insulin resistance travelling with the metabolic picture rather than causing it.