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The proportion of individuals older than 65 years is expected to rise significantly over the next 25 years. According to US census data, the number of Americans older than 65 years will rise to nearly 55 million in 2020 (16.3% of total), and nearly 87 million in 2050 (20.7% of total). Consequently, the healthcare system will likely experience a dramatic increase in age-related health problems, such as cancer, cerebrovascular and ischemic heart disease, and hypogonadism. A substantial body of literature supports the assertion that hormonal changes in the aging male can be associated with significant health problems. This chapter reviews the epidemiology of age-related hypogonadism; alterations in testis biology that occur with age; and the effects that these changes may have on semen quality, fertility, birth defects in offspring, and on the overall health of older men.


Hypogonadism is a clinical syndrome in men with symptoms and signs of testosterone deficiency and low serum testosterone concentration. From a population standpoint, the effect of aging on circulating testosterone levels is highly significant. The Baltimore Longitudinal Study of Aging (BLSA) found that 12%, 20%, 30%, and 50%, respectively, of men in their fifties, sixties, seventies, and eighties were hypogonadal using a total serum testosterone threshold of 325 ng/dL. More recently, testosterone trials of men aged ≥65 years used a more stringent serum testosterone threshold of 275 ng/dL, and screened 51,085 men to enroll 790, for an inclusion rate by testosterone level of 14.7%. Age has been shown to be an independent risk factor for hypogonadism even after adjustment for chronic medical conditions, such as obesity, diabetes mellitus, and hyperthyroidism.


Endocrine Testis

A. Leydig Cells

The quest to understand the underlying mechanism behind the epidemiological and clinical observation that aging men experience a gradual decline in testosterone levels led to the analysis of Leydig cell populations in human testes. Leydig cells produce 95% of adult male testosterone and are found in the interstitial space between seminiferous tubules. Kaler and Neaves (1978), in a study of testes retrieved at autopsy after sudden death among men aged 18–87, noted that total Leydig cell volume declines significantly with age and that decline is directly proportional to a fall in the total number of Leydig cells. From such studies, it is estimated that a pair of young testes (20-year-old) contains 700 million Leydig cells and undergoes an attrition of about 80 million cells per decade of life. Other studies have also shown that serum luteinizing hormone (LH) levels are significantly higher in older men compared with younger men, providing physiologic corroboration of the Leydig cell studies.

B. Testosterone

Although the decline of testosterone levels in older males has been described by the terms andropause, male climacteric, male ...

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