Androgen Replacement Therapy in the Aging Male—A Critical Evaluation

Recent years have seen an increasing interest in the study of the aging male, with a particular interest in the problem of whether so-called rejuvenating hormones and, more specifically, androgens can improve quality of life, counteract progressive skeletal muscle loss and strength, prevent falls and fractures, prolong independent living, and reduce the dependence on medical care. Almost a decade has elapsed since the first studies on androgen supplementation in elderly men were published (1, 2) and, in the view of the persisting controversies concerning this problem as well as the increasing public interest for rejuvenating hormones, it may be indicated to evaluate critically the clinical relevance of the relative androgen deficiency in elderly males, the diagnostic criteria of androgen deficiency, as well as the risks and benefits of androgen supplementation in elderly men. Male hormone replacement therapy implies, of course, that elderly men have a significant deficit in male hormone. Therefore, the first question to be answered is whether the common occurrence of the age-associated decline of testosterone levels is inherent to the aging process and occurs also in healthy men or whether the observed decline is the consequence of intercurrent disease, obesity, stress, relative physical inactivity, medications, etc. After years of controversy, due to differences in the characteristics of the population studied and variation in the timing of blood sampling (morning or afternoon) or the frequently small number of elderly subjects studied, authors now agree that in healthy men also there is a clear, slow but continuous, age-dependent decline of testosterone (T) levels, which is more pronounced for free T (FT) than for total T, a consequence of the age-associated increase of the levels of sex hormone binding globulin (SHBG); at 75 yr of age mean total T level in the morning is about two thirds of the mean level at 20–30 yr of age, whereas the mean FT and bioactive T (FT plus albumin bound T) level are only 40% of the mean levels in younger males. Moreover, the circadian rhythm of plasma T levels, with higher levels in the morning than in the evening, is generally lost in elderly men (3). However, wide interindividual variations exist due to genetic factors, body mass index, diet, social habits (alcohol, tobacco), and stress, and about 20% of males over 70 yr old have T levels in the upper third of males 20–40 yr of age (4). This is in clear distinction to the situation in postmenopausal women who all have clearly decreased estradiol levels. It is important to mention that this decrease, observed in cross-sectional studies, has now been confirmed by longitudinal studies (5–9). However, the androgen deficiency in elderly men is generally moderate; therefore, some authors have suggested the term partial androgen deficiency in the aging male (PADAM). Others, in analogy with the term menopause in women, use the term andropause, although distinct from women in menopause, elderly men retain their reproductive capacity. Although the decrease in (F)T levels occurs in healthy elderly men, it is evident that sequelae of intercurrent disease (10), medication, environmental, psychosocial, and socioeconomic factors accelerate this age-associated decrease. Recently, the important role of abdominal obesity in the ageassociated decrease of T levels has been stressed (10–12).