Testosterone and estradiol circulate in the bloodstream, bound mostly to SHBG and to some degree bound to serum albumin. Only a small fraction is unbound, or "free," and thus biologically active and able to enter a cell and activate its receptor. The SHBG inhibits the function of these hormones. Thus, bioavailability of sex hormones is influenced by the level of SHBG. SHBG has a higher affinity for Dihydrotestosterone than for Testosterone or for Estradiol, making it essential in women for regulating the bio-availability of Dihydrotestosterone.
SHBG is produced mostly by the liver and is released into the bloodstream. Other sites that produce SHBG include the brain, uterus, testes, and placenta. Testes-produced SHBG is called androgen-binding protein. The gene for SHBG is located on chromosome 17.
SHBG levels appear to be controlled by a delicate balance of enhancing and inhibiting factors. Its level is decreased by high levels of insulin and insulin-like growth factor 1 (IGF-1) (see:milk). Also, high androgen and transcortin levels decrease SHBG, whereas high growth hormone, estrogen, and thyroxine levels increase it.
However, recent evidence suggests that it is the liver's production of fats that reduces SHBG levels,[2][3] not any direct effect of insulin and specific genetic mechanisms that do this have been found.
Conditions with low SHBG include polycystic ovary syndrome, diabetes, and hypothyroidism. Conditions with high SHBG include pregnancy, hyperthyroidism, and anorexia nervosa. There has recently been research to link high SHBG levels with breast and testicular cancer as well.
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