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From the Kronos Longevity Research Institute, Phoenix, Arizona.
| Correspondence to: S. Mitchell Harman, MD, PhD, Kronos Longevity Research Institute, 2222 E Highland, Suite 220, Phoenix, AZ 85016 (e-mail: Harman{at}kronosinstitute.org). |
Typical age-related changes in body composition and function include loss of lean body and muscle mass, decreased muscle strength (Kallman et al, 1990) and fitness (Fleg and Lakatta, 1988), and loss of functional capacity (Fried et al, 1998). There is also an increase in total fat mass and percent body fat (Shimokata et al, 1989) accompanied by insulin resistance and a higher risk of type 2 diabetes (Fink et al, 1983; Kohrt et al, 1993), increased low-density lipoprotein (LDL) cholesterol, triglycerides, and fatty acids (Obisesan et al, 1997). Other changes in metabolism include negative calcium balance leading to decreased bone density and osteoporotic fractures (Wark, 1996), decreased protein synthesis, slower healing, and impaired immune system function (Scordamaglia et al, 1991). Predictably, in aging men, there also occur decreased frequency of and desire for sexual activity and a reduction in the number and quality of erections (Kaiser et al, 1988; Helgason et al, 1996; Morley et al, 2000). Behavioral and psychological manifestations of aging also include slower problem solving, lapses of memory, and increasing incidence of dementing illness.
It is unclear the extent to which alterations in hormone balance contribute to the changes enumerated above. Documented age-related changes in hormones in men include a decrease in circulating total T (Bremner and Prinz, 1983) and various measures of free or bioavailable T (Vermeulen and Kaufman, 1995), the latter decline described as steeper due to increases in circulating sex hormone binding globulin with age. The decreases in T have been observed to begin in the third decade and proceed at a more-or-less constant rate into extreme old age, whether measured cross-sectionally (Tenover et al, 1987) or longitudinally in the Baltimore Longitudinal Study of Aging (BLSA) (Figure 1A and B) and other study populations (Morley et al, 1997; Harman et al, 2001). There are also reductions in circulating growth hormone and insulin-like growth factor I (Ho et al, 1987; O'Connor et al, 1998) and a tendency for increased cortisol secretion, especially in response to stress (Arnetz, 1985; Van Cauter et al, 1996).
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Each of the hormonal alterations mentioned above, occurring in young adults, can present a clinical picture having certain features in common with typical age-related changes in body composition and function. In particular, male hypogonadism is associated with loss of muscle mass and strength, increased total and (especially) truncal and visceral body fat (accompanied by mild insulin resistance), and reduced libido and erectile capacity. The relationship between impaired pituitary-gonadal axis function and diminished sexual response during aging is not fully delineated, but it has become clear recently that the decline in free/bioavailable T levels is sufficient to make a substantial fraction of men over the age of 65 hypogonadal, at least by standard criteria for serum hormone levels (Figure 2) (Harman et al, 2001).
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The decline in sexual activity levels and erectile function with aging has been well documented in a number of studies. Martin (1977) followed total self-reported male "sexual outlet," including heterosexual and homosexual intercourse, masturbation, etc, in BLSA men and documented a profound decrease in rates of sexual activity with age. This change was accompanied by an expressed decrease in desire for sexual activity and an increase in the period men reported being comfortable without sex. These same BLSA men also reported a decrease in frequency of erections such that by age 70 and above, over 50% had no erections whatsoever. In a more recent study by Panser et al (1995), approximately 80% of men ages 40 to 49 reported adequate erectile function "all the time," whereas less than 20% of men ages 70 and older did so. Conversely, fewer than 5% of men ages 40 to 49 rated their erectile function as "little/none," whereas this level of deficiency occurred in nearly 40% of men ages 70 and older. In the same study, over 70% of the younger men reported desire for sex more than once weekly, but only about 15% of men over 70 had this level of libido. The number of men ages 40 to 49 with no interest in sex was less than 5%, but approximately 35% of men ages 70 and older expressed no desire for sexual activity. The decrease in erectile function with age has also been documented in a study by Feldman et al (1994) (Figure 3), in which approximately 50% of men ages 70 to 79 reported moderate or complete erectile dysfunction (ED) compared with 25% of men ages 40 to 49.
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Although the decrease in free/bioavailable T levels with age has been shown in some studies to be correlated with the loss of muscle strength (Roy et al, 2002) and the decrease in bone mineral density (Scopacasa et al, 2000), even when age is adjusted for as a covariate, the finding of such associations does not prove causality. This is also true for the relationship of hormonal alterations to sexual function. In one study of BLSA men (Tsitouras et al, 1982) there did appear to be a weak relationship between total serum T levels and self-reported sexual activity, such that men over 60 in the lowest age-adjusted tertile for sexual outlet had lower serum T levels (P < .05) than those in the middle or upper tertiles (Figure 4). This relationship did not hold true for younger men. The concept that hormonal alterations underlie a significant fraction of age-related male sexual disability is further supported by data (Morley, personal communication) showing that the fraction of men complaining of ED who have an identifiable endocrine etiology increases from 43% in men less than 60 years of age to 83% of men more than 60 years of age.
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An important step in establishing plausibility of a causal relationship between decreased T and altered erectile function and libido is the identification of biological mechanisms by which T-action alters each of these sexual functions. In the case of libido, it has long been known that exposure to T alters both brain function, and, in some species, structure (Xiao and Jordan, 2002; Cooke et al, 2003). There are both androgen and estrogen receptors on neurons in various areas of the brain, including those known to be involved in mediation of male sexual activity. It also appears, from experiments in a number of species, that T affects sexual behavior both directly and after local aromatization to estradiol in the brain (Vagell and McGinnis, 1997; Roselli and Chambers, 1999). In addition, a direct local role for T in erectile function is suggested by recent data derived from animal studies, which have shown that exposure to T increases, and deprivation of T decreases, the activity of constitutive NO synthase in the nonadrenergic, noncholinergic autonomic vascular nerve endings of the corpora cavernosa (Chamness et al, 1995; Zvara et al, 1995; Park et al, 1999). NO is an important mediator of the erectile response and directly activates guanyl cyclase in the vascular smooth muscle cells, leading to production of cyclic guanosine monphosphate (cGMP) from guanosine triphosphate. Increased cGMP relaxes smooth muscle, allowing the sinusoids of the corpora cavernosa to dilate, causing erection. Thus, the erectile response is augmented by T and impaired in its absence (Seo et al, 1999). The relevance of the above relationships to human physiology is likely but not proven at this point in time.
Final confirmation of the importance of T in mediating changes in sexual function with age await definitive data documenting the extent to which T replacement does or does not ameliorate this deficiency. Preliminary studies appear promising. In one study (Seo et al, 1999), 80% of older men (mean age 71) perceived their libido as improved after treatment with T, compared with about 8% receiving placebo. In another trial (Kunelius et al, 2002), 150 men ages 50 to 70 years were treated with placebo or dihydrotestosterone (DHT) (which is not aromatized to estrogen and hence is less likely to have effects at the central nervous system). Early morning erections improved transiently in the DHT group at 3 months of treatment, and the ability to maintain erection improved in the DHT group compared with the placebo group.
In summary, aging is associated with changes in body composition similar to those observed in men with hypogonadism. These changes include 1) loss of libido and decreased sexual function, 2) decreases in LBM, muscle strength, and endurance, 3) decreases in bone density, and 4) increases in body fat and insulin resistance
Total and free T levels also decrease with age in men. In older men,
circulating T or free T correlate positively with sexual function, LBM, muscle
strength, 
O2max, and bone density
and correlate negatively with body fat. ED is frequently associated with low T
in older men. Relationships of endogenous androgen measures to clinical
outcome variables suggest that some deleterious age-related changes may be
caused by androgen depletion. Finally, T replacement appears to improve both
sexual desire and erectile capacity in some older men with low T levels.
Further studies of the risks and benefits of androgen replacement in aging
men, emphasizing clinical outcomes, especially ED and libido, are justified
and should further clarify these issues.
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