Male Reproductive Aging

Spermatogenesis and Semen Parameters

Spermatogenesis continues throughout the lifespan but declines gradually with increasing age. Testicular volume, which largely reflects seminiferous tubular volume, averaged 20.6 mL as determined by ultrasound in 114 elderly men, compared to 29.7 mL in 42 young men. Sperm production was studied in an autopsy study of 89 men aged 21 to 50 years old and 43 men aged 51 to 80 years old who died suddenly. The older men had a daily sperm production rate per testis that was approximately 30% less than that in the younger men ( Fig. 15.1 ). Ejaculated sperm were studied in 20 fathers aged 24 to 37 years old and 22 grandfathers aged 60 to 88 years old. Sperm density was somewhat higher in the older men, and the percentage of sperm motility was somewhat lower in the older men, so the total number of motile sperm was similar between the two groups. In 189 ambulatory men, the serum concentration of inhibin B, a reflection of Sertoli cell function, in men over 70 years old was about 75% of that in men younger than 35 years old ( P = 0.002). In the same study, the serum follicle-stimulating hormone (FSH) concentration was more than three times as high in men over 70 years old than in men under 35 years old ( P < 0.001). From these data, it appears that sperm production declines with age, but marginally.

Semen quality, however, does appear to decrease with increasing age, as shown by a meta-analysis using data from 90 studies comprising 93,839 men. Age-related decreases were noted in percentage motility, progressive motility, normal morphology, and unfragmented cells.

Sex Steroid Hormone and Gonadotropin Concentrations

Serum Testosterone Concentration

The serum testosterone concentration decreases gradually with age beginning in the third decade of life.

In a cross-sectional study in 302 healthy men in Belgium, the mean (± standard deviation [SD]) total testosterone concentration in 70 men, 20 to 39 years old, was 683 ± 289 ng/dL, and that in 51 men, 70 to 79 years old, was 428 ± 128 ng/dL. The calculated free testosterone concentration fell by a relatively greater amount; in 70- to 79-year-old men it was approximately half of that in 20- to 39-year-old men. In a study of 4263 men aged 70 to 85 years and older, total serum testosterone remained stable with age, but sex hormone binding globulin (SHBG) increased and free testosterone decreased. In the European Male Aging Study of 3200 community dwelling men aged 40 to 79 years old, total serum testosterone was not associated with increasing age, but free testosterone was lower and luteinizing hormone (LH) higher ( Fig. 15.2 ), suggesting that primary hypogonadism was the cause of the fall of the free testosterone with age. Comorbid conditions and obesity (see Fig. 15.2 ) were also correlated with lower free testosterone concentrations but not higher LH, suggesting that these conditions cause secondary hypogonadism.

Longitudinal studies also show a decrease in testosterone with increasing age. In the Baltimore Longitudinal Study of Aging, the serum total testosterone concentration and a calculated free testosterone index fell from the third to the ninth decades in 890 men. By the eighth decade, approximately 30% of men were hypogonadal using the total testosterone concentration, and 70% were hypogonadal by the free testosterone index. In the Massachusetts Male Aging Study—a population-based, random sample cohort of men aged 40 to 70 at baseline—1156 men were followed for 7 to 10 years. The serum concentration of total testosterone fell at a rate of 0.8% per year cross-sectionally, but 1.6% per year longitudinally.

The decrease in serum testosterone concentration with increasing age appears to be primarily the result of a decrease in the morning peak that younger men experience ( Fig. 15.3 ). The decrease in serum testosterone concentration with increasing age in longitudinal studies also appears to be affected by other health factors. In the Massachusetts Male Aging Study, a decrease in body mass index of 4 to 5 kg/m ² or a loss of a spouse resulted in a similar decrease in testosterone as 10 years of aging.

Bone

The bone mineral density (BMD) of hypogonadal men is lower than that of eugonadal men. ^, Men who are made severely hypogonadal by GnRH agonist treatment for prostate cancer experience a significant decrease in BMD during the first year of treatment, more in the spine than the hip. Men who are made hypogonadal to treat prostate cancer also are at greater risk for bone fracture, as shown in data from the Surveillance, Epidemiology, and End Results program and the Medicare database, in which the prevalence of fractures was determined in 50,613 men age 66 years or older with prostate cancer who had been made hypogonadal by a GnRH agonist or bilateral orchiectomy. Men who had been made hypogonadal had a significantly higher prevalence of fracture (19.4%) than men not made hypogonadal (12.6%; P < 0.001).

As men age, BMD also decreases. In a study of normal men who had no history of hip fracture, BMD of the spine and hip decreased linearly from age 20 to more than 80 years ( Fig. 15.4 ); the decline was less than that in women, similar to the findings of other cross-sectional studies. ^, A cross-sectional study in which bone density was measured by quantitated computed tomography (QCT) showed a greater rate of bone loss, reflecting the greater sensitivity of QCT than densitometry in detecting changes in trabecular bone. A longitudinal study showed as rapid a loss of bone density in men as in women. Within the 2908 men of an average age of 75.4 years in the Swedish Osteoporotic Fractures in Men (MrOS) study, serum free testosterone was a modest predictor of bone density and prevalent osteoporotic fractures. In 728 men at two sites in the European Male Aging Study, increased age was associated with decreased cortical BMD by peripheral QCT. The association of the decrease in cortical bone with the serum concentrations of estradiol and testosterone was less clear.

Replacement of testosterone in unequivocally hypogonadal men greatly increases BMD. Administration of 100 mg of testosterone enanthate once a week for 18 months to 29 men with previously untreated hypogonadism resulted in a 5% increase in BMD in the lumbar spine as determined by dual-energy x-ray absorptiometry (DEXA). Trabecular BMD, as measured by QCT, increased by 14%. Administration of testosterone transdermally for 3 years to 18 hypogonadal men who had previously untreated hypogonadism resulted in increases in BMD, as determined by DEXA of 7.7% at the lumbar spine and 4.0% at the trochanter.

Body Composition

When men become hypogonadal as the result of hypothalamic-pituitary or testicular disease, they experience a decrease in lean body mass and an increase in fat mass, and testosterone treatment of hypogonadal men usually reverses those changes. The same changes occur as men age. Appendicular skeletal muscle mass in one study was 16% less in men over 75 years old than in men 18 to 34 years old. The percentage of body fat was 26% in 36 hypogonadal men compared to 19% in 44 eugonadal men. When six normal young men were made hypogonadal for 10 weeks by the administration of the GnRH agonist leuprolide, their fat-free mass decreased from 56.5 to 54.4 kg and their fat mass increased from 15.8 to 16.9 kg.

Administration of testosterone reverses these changes in body composition. Administration of 100 mg of testosterone enanthate once a week for 18 months to previously untreated hypogonadal men resulted in a 14% decrease in total body fat, 12% decrease in subcutaneous fat, and 6.8% increase in lean muscle mass. When testosterone was administered transdermally to 18 previously untreated hypogonadal men, lean body mass increased.

Muscle Strength

Muscle strength has long been known to decrease with increasing age, but demonstrating that hypogonadism leads to decreased muscle strength, and that testosterone treatment improves strength, has been much more difficult. In a study of 72 normal men in three age groups aged 20 to 86, the strength of knee extension, both isometric and isokinetic, decreased with increasing age. In another study of 114 men aged 11 to 70 years old, quadriceps strength increased up to the third decade, was stable until age 50, then declined with increasing age. The only clear demonstration that hypogonadal men have lower muscle strength than eugonadal men was provided by the study described earlier in this chapter, in which six healthy young men were made severely hypogonadal for 10 weeks by the administration of leuprolide. At the end of the 10 weeks, their strength of knee extension was 6% less than prior to treatment when measured isokinetically at 60 degrees angular velocity, but was not significantly different during treatment than before when measured isokinetically at 180 degrees angular velocity or isometrically at either angular velocity.

Administration of testosterone transdermally to 18 previously untreated hypogonadal men did not increase their strength of knee extension or flexion or handgrip strength. Administration of 100 mg testosterone enanthate once a week to men with wasting secondary to human immunodeficiency virus (HIV) infection resulted in a 16% increase in leg press strength compared to no significant change in those treated with placebo, whereas men who were treated with testosterone and resistance exercise did not exhibit a greater increase than those treated with placebo and exercise. In short, it is clear that muscle strength decreases with increasing age, but it is not clear how much, if any, the decline in testosterone contributes to the decrease in muscle strength.