In late onset hypogonadism (LOH) there is a variable decline predominantly involving non-SHBG-bound T. Several studies document that androgen levels decline with aging (for review see ). Longitudinal studies [76-78] have documented a statistical decline of serum T by approximately 30% in healthy men between the ages of 25 and 75 years. Since serum levels of SHBG increase with aging, plasma T not bound to SHBG decreases even more, by about 50%, over that period. Studies in twins have shown that genetic factors account for 63% of the variability of serum T levels, and for 30% of the variability in SHBG levels . Also systemic diseases, increasing with age, are a cause of declining serum levels of T [78,80]. While it now has been shown beyond doubt, that serum T, and in particular BT and FT, decline with aging, it remains uncertain what percentage of men actually become T-deficient with aging, in the sense that they will suffer the clinical consequences of T deficiency, and will potentially benefit from T therapy. In a study of 300 healthy men between the ages of 20 and 100 years, Vermeulen, defining their reference range of total plasma T between 11 and 40nmol/L, found one man with subnormal T in the age group 20-40 years, but more than 20% above the age of 60 years . However, 15% of men above the age of 80 years still had T values above 20nmol/L! It follows that only a certain proportion of men have lower-than-normal T values in old age.
What are the pitfalls of diagnosing LOH? There are several problems regarding LOH. For androgen deficiency it is difficult to rely on clinical symptoms, particularly in elderly men. In previously eugonadal adults, symptoms of T deficiency emerge only gradually and insidiously. Only the physical signs of longstanding T deficiency will be clinically recognized. Further, stringent criteria to diagnose T deficiency have not been formulated, neither in the young nor in the elderly male population. In the elderly population T deficiency is difficult to identify since symptoms of aging mimic symptoms of T deficiency and are also similar to growth hormone deficiency. It has not become clear whether other criteria for T deficiency in aging men should be different than those for younger men.
There are different threshold values for different biologic effects. Testosterone has a number of physiologic functions in the male. In adulthood it is responsible for maintenance of reproductive capacity and of secondary sex characteristics. T has positive effects on mood and libido, anabolic effects on bone and muscle, and affects fat distribution and the cardiovascular system. Threshold serum values of T for each of these functions are becoming established. The studies of Bhasin et al. and of Kelleher et al., analyzing the dose-response relationships between serum T and biologic effects, show that low-to-mid-normal serum levels of T suffice for most biologic actions of T [8,36]. Another consideration is whether these threshold values change over the life cycle. Theoretically, it is possible that in old age normal androgen levels suffice for some but not for all andro-gen-related functions. With regard to anabolic actions, elderly men are as responsive to T as young men . Conversely, as previously detailed in p. 228, the threshold required for libido and erectile function might increase with aging.
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