Circulating testosterone is reversibly bound to two major plasma proteins, albumin and gamma globulin. Binding to albumin is a relatively nonspecific low-affinity and high-capacity association. In contrast, binding to the specific ^-globulin fraction, called sex hormone-binding globulin (SHBG), is a high-affinity steroid-specific interaction. Under physiological conditions, 98% of testosterone is protein bound, 40% to albumin and 58% to SHBG. Thus, 2% or less of circulating testosterone is unbound or free. Free testosterone reflects the amount that is biologically active and available for interaction with peripheral target cells.
SHBG levels are known to be influenced by a variety of clinical conditions. In females, the high estrogen levels of pregnancy or the use of oral contraceptives result in increased SHBG concentrations. In males, elevated levels of SHBG are seen most commonly in individuals with liver cirrhosis or during normal aging. Elevated SHBG levels are also seen in hyperthyroidism and hypogonadism. All of these conditions are associated with elevated estrogen levels, which result in increased hepatic SHBG synthesis. SHBG levels are suppressed by androgen replacement or chronic glucocorticoid therapy. Elevations of SHBG do not necessarily result in a fall in free testosterone levels. When assessing the androgenic status of an individual, whether male or female, it is necessary to measure both total and free testosterone plasma levels.
Plasma testosterone levels also exhibit age-associated changes. The levels of the hormone are very low throughout childhood and until early adolescence, when increasing testicular steroidogenesis precedes the onset of puberty in boys. Levels peak in the early 20s, and beginning at about age 30, testicular production of testosterone begins to decline. Urinary 17-ketosteroid excretion declines slowly as a result of a concomitant decrease in the metabolic clearance rate of testosterone. Therefore, there is a relatively constant serum testosterone concentration that often does not decline significantly until after age 70. After the fifth decade, free testosterone levels do decrease as a result of increased SHBG levels. In females, testosterone levels also decline with age; however, at menopause the decline in female hormones is so much greater that many postmenopausal women have higher androgen to estrogen ratios, resulting frequently in significant hirsutism.
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