Andropause: Clinical Implications of the Decline in Serum Testosterone Levels With Aging in Men

Abstract

IT is now well accepted that serum testosterone (T) levels decline progressively with aging in men (1)(2)(3)(4)(5). This decline is associated with alterations in body composition; diminished energy, muscle strength, and physical function; reduced sexual function; depressed mood; and decreased cognitive function. Similar changes occur in young men with androgen deficiency and are improved with T replacement therapy. However, the physiological and clinical significance of the aging-associated decline in serum T levels in men is unclear, particularly because T levels may remain within the normal range for young men. From a practical clinical standpoint, it is most appropriate to define “andropause” as an age-related decline in serum T levels in older men to below the normal range in young men that is associated with a clinical syndrome (i.e., symptoms and signs) consistent with androgen deficiency. The decline in T levels is a consequence both of aging per se and age-associated comorbid illnesses and medications that are used to treat them (6)(7)(8)(9)(10)(11)(12)(13). However, regardless of the etiology, androgen deficiency may contribute, at least in part, to age-related decrements in physiological function and may be associated with a clinical syndrome. Andropause has also been referred to by some as “androgen deficiency in the aging male (ADAM),” “partial androgen deficiency in the aging male (PADAM),” or “aging-associated androgen deficiency (AAAD).” The term “male menopause” is inappropriate because there is no interruption or cessation of menses, and “viropause” is inaccurate because there is no loss of virilization. “Male climacteric” refers to the syndrome of endocrine, somatic, and psychic changes that occur in normal men with aging. This term emphasizes the multidimensional nature of age-related changes, including decreases in other hormones such as growth hormone (GH), insulin-like growth factor-1 (IGF-1), dehydroepiandrosterone (DHEA), and melatonin (1)(14)(15)(16)(17), but it does not relate aspects of the male aging syndrome specifically with androgen levels. The term “andropause” is not completely accurate because androgen secretion does not cease altogether. However, because it is the only term that relates the syndrome of age-related physiological changes with the gradual and progressive decline in T levels that occurs with aging, andropause will be used in this review. Andropause is a term also used commonly by experts in the field and by lay persons because it retains some analogy to menopause in women. In both cross-sectional (5)(6)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) and longitudinal studies (39)(40)(41)(42), beginning in the third decade, aging is associated with a gradual and progressive decline in serum T levels at a rate of approximately 1% per year. As a result, ∼20% of men older than 60 and ∼50% of men older than 80 years of age have serum total T levels below the normal range for young men (39)(43)(44). Circulating T is approximately 98% bound to serum proteins, predominantly to sex hormone-binding globulin (SHBG), the major binding protein for T in blood, and albumin (45)(46)(47). Only 1% to 2% of T in circulation is completely unbound or free. Because T is bound with high affinity (i.e., tightly) to SHBG, SHBG-bound T is not available to most tissues for action. In contrast, T is bound with low affinity (weakly) to albumin, so both albumin-bound and free T are bioavailable to most tissues for action. Because the of with aging, T and bioavailable T albumin-bound decline than total T levels with aging a of older men have levels of of T below the normal range for young men and other alterations in have practical clinical in the of androgen deficiency. Because total T both free T and T bound to and albumin, alterations in albumin in changes in total T levels in the of bioavailable or free T are not by alterations in a of T in blood, in clinical such as aging in or in decreases Because levels with aging, older men with total T levels have free or bioavailable T levels that are below the normal range for young men. of bioavailable or free T or or of total T and are to androgen deficiency in older men. of free and bioavailable T are not in and are only available free T a free T this with by than an of in by or SHBG, and with alterations in levels free T may not clinical that of total T levels. to older men with androgen deficiency and androgen deficiency in men with low levels T levels a not be used in levels may be older The decline in serum T levels with aging is both to of T and secretion of hormone in of hormone secretion by the men a in the of the of the that in T and decreased in T secretion by the in to by of an hormone The of reduced T T levels is by the in of T that also occurs with aging The normal in serum T levels with in the is in older men to young men an in the function. Because of age-related of the normal in T serum T lev