Reproductive function declines as men grow older. An age-associated decline in plasma testosterone concentration occurs even in healthy men (104,105), although there is considerable variation in the age of onset (106). The level of testosterone in the blood stream declines on average by 1.2% each year for men over 40 yr of age. Because SHBG rises, the level of free (bioavailable) testosterone in the blood decreases more with age compared to total testosterone (106,107). Because clearance of testosterone does not rise with age, it is reasonable to deduce that the age-related decreases in androgen concentrations result from decreased Leydig cell androgen production (108,109).
Age-related declines in testosterone could be caused by decreased Leydig cell numbers and atrophy of their structure and/or reduced steroidogenic ability. Leydig cell numbers are inversely correlated with age, decreasing 44% by age 58 compared to 32-yr-old men (34). Leydig cell numbers decline because of degeneration rather than dedifferentiation (110). In addition, aged Leydig cells contain cytoplasmic or intranuclear crystalline inclusions, lipofuscin granules, diminished SER, and smaller and fewer mitochondria compared to young men (7,111-113). Older men with higher serum LH and low serum testosterone levels also have a large number of abnormal Leydig cells, suggesting that Leydig cell structural changes are related to changes in steroidogenic function (112). Age-related declines in steroidogenesis are caused by a global reduction in steroidogenic enzyme gene expression and by decreases in the rate of cholesterol transfer to mitochondria (114-117). In fact, the senescence of Leydig cells is involved at all aspects of the steroidogenic process, from LH binding to the steroidogenic reactions in the SER. Zirkin and colleagues report that reactive oxygen, produced as a by-product of steroidogenesis itself, may be responsible for age-related reductions testosterone production (118).
Therefore, unless Leydig stem cells can be recruited to restore the Leydig cell numbers, age-related declines in testosterone levels are unavoidable. The endocrine changes with aging in men are reviewed more thoroughly in Chapter 14.
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