Multiple cross-sectional and a few longitudinal studies have shown that serum T levels in men decrease with age (Deslypere et al., l984; Harman et al., 200l; Morley et al., 2000). Age-related changes in total T underestimate changes in T available to target tissues. Several cross-sectional studies have shown that an increase of sex hormone binding globulin (SHBG) with aging and a decrease in T and free T (fT) levels are independent of changes in body mass index (Deslypere et al., l984; Morley et al., 2000). Approximately 40 to 50% of circulating T in men is bound with high affinity to SHBG. This portion of the circulating total T is not readily available to target tissues, whereas T bound to albumin and fT (l-3%) are available to target tissues (Pardridge l98l). The albumin bound and the fT are referred to as the bioavailable or weakly bound T (bT). Thus, serum concentrations of T and, to a greater extent, fT and bT, are decreased in aging men.
Serum SHBG levels are affected by several conditions. SHBG levels are inversely correlated with increased total body fat, subcutaneous and visceral adiposity (Couillard et al., 2000). Levels also vary inversely with hyperinsulinism in nondiabetic subjects. They seem to be an indicator of general adiposity rather than an index of altered insulin/glucose homeostasis in morbidly obese subjects. Hyperinsulinism decreases SHBG synthesis by cultured hepatic cells. These observations have been interpreted to show that obesity causes insulin resistance and hyperinsulinism, and hyperinsulinism decreases SHBG levels. Hypothyroidism and the nephrotic syndrome also reduce SHBG levels. Estrogen, hyperthy-roidism, some anticonvulsants, a high phytoestrogen diet, hepatic cirrhosis, and aging increase SHBG levels (Anderson, l974; Kley et al., l975).
We recently reported that SHBG levels are increased in some patients with cancer, and the elevated SHBG may maintain total T levels within the normal range even though the calculated fT and bT levels are low. Thus, SHBG levels are variable in older, obese men, and this limits the value of total T levels in this age group.
Approximately 20% of men 60 to 70 years of age and 30% of men 70 to 80 years of age have T levels below that of 97.5% of healthy 20- to 45-year-old men (Harman et al., 200l). Longitudinal studies have confirmed these findings (Feldman et al., 2000; Harman et al., 200l; Morley et al., l997). Feldman and coworkers found total T levels decreased at 0.8% per year, bT fell at 2% per year, and SHBG levels increased l.6% per year (Feldman et al., 2000). This is due in part to a reduction in the number of Leydig cells in the testes that produce T.
The decline in T levels with aging when associated with symptoms and signs of androgen deficiency has been called andropause. This association also has been referred to as androgen deficiency in the aging male (ADAM), partial androgen deficiency in the aging male (PADAM), aging-associated androgen deficiency (AAAD) or late-onset hypogonadism. The term andropause is inaccurate because men do not have menses and because androgen secretion gradually decreases, and usually is
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