The testes in a healthy young man will produce nearly 95% of his androgens, most of which is testosterone, at a rate of roughly 10 mg per day. The other 5% of androgens are derived from adrenal-gland production of DHEA, a precursor molecule. The stimulus for production originates in the hypothalamic-pituitary axis, where gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of two hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), in the pituitary gland. Luteinizing hormone drives the production of testosterone in the testes while FSH hormone affects spermatogenesis. Testosterone is metabolized further to dihydrotestosterone (DHT) by the ever-demonized enzyme 5-alpha-reductase (DHT is considered to be responsible for prostatic hypertrophy as well as male-pattern hair loss in genetically susceptible men)6 or it undergoes transformation into estradiol via the enzyme aromatase. DHT binds with greater affinity to androgen receptors and therefore acts as a more potent activator (up to four times the strength) of testosterone receptors. Estrogens are also a factor in andropause; 25% of the estradiol (the most biologically active form of estrogen) produced in the male is derived from the testicles while the remaining 75% is produced mainly in adipose tissue, the brain, and the liver. Nearly 98% of testosterone circulates bound to plasma proteins (and is thereby "unavailable") whereas the remaining 2%, known as free testosterone, accounts for nearly all of the biologic activity of the hormone. Of the bound testosterone, 40% is tightly bound to SHBG while the remainder is relatively weakly bound to albumin and is therefore more readily available. The term bioavailable refers to both the free testosterone and that which is bound to albumin.7 The amount of testosterone that binds with SHBG increases with aging thereby decreasing the amount of free testosterone.8 As testosterone levels fall, this stimulates increased production of SHBG by the liver; the estrogens in a man's body will also increase SHBG. Increased levels of SHBG-bound testosterone lead to normal serum ranges of total testosterone, despite a relative deficiency in bioavailable testosterone.
When the body has excess androgens, SHBG will tend to be low, which results in normal levels of total testosterone but elevated levels of bioavailable testosterone.
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