Decreasing Testosterone with Increasing Age: More Factors, More Questions

Many studies have now demonstrated that as men age, their serum testosterone concentrations fall. The first studies were cross-sectional. One of the earliest was in 83 healthy men, aged 20–88 yr, in New Mexico (1). The serum total testosterone concentration fell only marginally with age, but as the SHBG concentration increased with age, the free testosterone concentration fell markedly, so the mean free testosterone concentration at age 80 yr was less than one third of that at age 20 yr. Later cross-sectional studies in larger groupsofmen, conducted, amongotherplaces, inMassachusetts (2),TheNetherlands (3), and at a consortium of six sites across the United States (4), confirmed that with increasing age, the total testosterone concentration falls only slightly, but the free testosterone concentration falls to a much greater degree. These larger studies also demonstrated that adiposity and comorbid conditions were independently associated with decreases in total and free testosterone. Longitudinal studies later confirmed the fall in testosterone with increasing age. In the Baltimore Longitudinal Study of Aging, the serum total testosterone concentration decreased modestly with increasing age, and an index of the free testosterone concentration decreased even more (5). By the eighth decade of life, 28% of men had total testosterone concentrations that would be considered hypogonadal by the standards of young men, and 68% had free testosterone index values considered hypogonadal by the standards of young men. In the Massachusetts Male Aging Study, longitudinal observation also showed a decrease in total testosterone with increasing age and a greater decrease in free testosterone (6). The Massachusetts Male Aging Study results, in addition, showed a greaterdeclinewhenagingwasaccompaniedbythedevelopmentof obesity,anewcomorbidcondition,oranuntowardevent inaman’s life, such as loss of a wife. In this issue of the Journal, Wu et al. (7) describe results from 3220 men equally distributed across 4 decades from 40 to 79 yr observed cross-sectionally in the European Male Aging Study (EMAS). The results from these men confirm and extend the results of the previous studies. As in the previous studies, the EMAS data show that the serum concentration of total testosterone fell slightly, only0.4%peryear, but the free testosterone fell 1.3%peryear.The serumconcentrationof total testosteronewasalso lower thegreater the degree of obesity. Although much of the effect of obesity was explained by a decrease in SHBG, the serum-free testosterone concentration was also lower at all ages in men with a BMI 30 kg/m orgreater than inthosewithaBMIless than25kg/m butnotnearly as much as the total testosterone. Comorbidity was also associated with a lower total and, to a lesser degree, free testosterone concentration at all ages. The report from the EMAS extends the results of previous studies, suggesting different mechanisms for the different factors involved in the fall in testosterone with increasing age. Increasing age was associated with increasing serum concentration of LH, suggesting that an important factor in the fall in free testosterone with increasing age is testicular failure. Obesity and comorbidity, however, were not associated with an increase in LH, suggesting that their influence on free testosterone was exerted by a pituitary or hypothalamic mechanism. These results add to the unanswered questions about the consequences of the fall in testosterone with increasing age in men. We have not known whether the fall in testosterone with increasing age alone has adverse consequences, such as on physical, sexual, and cognitive function and vitality. Now we can also ask whether the decreases in testosterone due to obesity and comorbidity have clinical consequences different from those of age alone. We have also not known whether increasing the serum testosterone concentration of elderly men would improve physical, sexual, and cognitive function and vitality. Now we can also ask whether increasing the serum testosterone concentration when it is low because of obesity or comorbidity will be beneficial. The results of these new data from the EMAS, finally, will influence the design of future studies to test the effect of testosterone in elderly men with low testosterone concentrations. Should such studies intentionally include or exclude men with obesity or comorbidity? If men with obesity or comorbidity are included, should