Effects of Age on Testicular Function and Consequences of Testosterone Treatment1

Peter J. Snyder

Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6149

Address all correspondence and requests for reprints to: Peter J. Snyder, M.D., 415 Curie Boulevard, Philadelphia, Pennsylvania 19104-6149

As men age, testicular function declines gradually and moderately. The similarities between the consequences of hypogonadism due to known disease and those of hypogonadism due to aging alone suggest that the decline of testicular function with aging does have consequences.

Decline in testicular function with age

Testosterone and gonadotropins. Several studies demonstrate that the serum testosterone concentration declines with increasing age. In one cross-sectional study of 83 healthy men, the free testosterone concentration declined by age 80 to approximately 40% of that at age 20, but because the serum concentration of sex hormone binding globulin (SHBG) increased during this age span, the serum concentration of total testosterone declined only to approximately 80% of that at age 20 (1). In another cross-sectional study of 71 healthy men, aged 26–90 yr, living in similar circumstances, the 33 younger men had a mean free testosterone concentration of 10.7 ± 3.4 ng/dL (SD) and the 38 older men had a mean free testosterone concentration of 5.8 ng/dL (P < 0.01) (2). Total serum testosterone concentrations in the two groups were 659 ± 201 ng/dL and 490 ± 160 ng/dL, respectively (P < 0.01). In a third cross-sectional study in 810 healthy men mostly between 50 and 84 yr old, the serum bioavailable testosterone concentration declined by approximately 55–60%, but the serum total testosterone concentration did not decline at all (3).

In one longitudinal study, 39 healthy men whose mean serum total testosterone concentration was 633 ± 22 ng/dL (SE) when they enrolled in a study of aging in 1980 had a mean value of 464 ± 33 ng/dL in 1994 (4). In another longitudinal study of 890 men, both total testosterone and the ratio of testosterone to SHBG decreased with age (Fig. 1Go) (5).



View larger version (32K):
[in this window]
[in a new window]
 
Figure 1. Decline in serum testosterone concentrations with increasing age. Shown are linear segment plots for the serum total testosterone concentration and the free testosterone index (serum testosterone concentration/serum SHBG concentration) for cohorts of men by decade from the second to the ninth. Numbers in parentheses represent the number of men in each decade. From Ref. 5.

 
The decline in testicular function appears to involve a combination of primary and secondary hypogonadism. A gradual increase in the serum concentration of LH indicates a degree of primary hypogonadism. In a cross-sectional study, the mean serum LH concentration in 33 men of an average age of 37 yr was 1.9 ± 0.6 ng/mL and in 38 men of an average age of 71 yr was 2.2 ± 0.6 ng/mL (2). In a longitudinal study, 39 men whose mean LH was 9.4 ± 0.4 (SE) mIU/mL when they enrolled in 1980 had a mean value of 13.7 ± 1.3 mIU/mL in 1994 (4). However, the findings that LH secretory burst amplitude decreases with increasing age and that this decrease was the most prominent determinant of decreased testosterone secretion indicates a degree of secondary hypogonadism (6). This conclusion is supported by the failure of LH secretion to respond to drug-induced reduction of the serum testosterone concentration in old men as well as in young men (7).

Spermatogenesis. Some studies show a preservation of spermatogenesis with increasing age, and others show a decline. In one study, spermatogenesis, as judged by ejaculated sperm, in 23 men 60–88 yr old who had fathered children earlier in life was compared to 20 men 24–37 yr old who had fathered children (8). The older men had higher sperm density than the younger men and equal results to the younger men in the hamster ova penetration test. However, the period of abstinence before ejaculation was much longer in the older men than in the younger men. Similarly, in a study of 189 elderly men, 51 middle aged men, and 50 young men, the serum concentration of inhibin B, a marker of Sertoli cell function and spermatogenesis, correlated negatively with age, but only weakly (Spearman correlation coefficient, -0.17) (9). However, in a histologic study of spermatogenesis in 30 men who died of trauma or myocardial infarction, spermatogenesis, as defined by spermatid nuclei, decreased with increasing age (10).

Possible consequences of the decline in testicular function

The decline in serum testosterone concentration with aging might have several consequences, based on a comparison with the consequences that occur in response to frank hypogonadism due to known disease. Men who become hypogonadal due to known disease experience a decrease in libido, energy, muscle mass, muscle strength, and bone density, and testosterone treatment reverses these effects. Because elderly men also experience the same effects, it is possible that the decrease in testosterone is a cause.

Libido. A study of 220 men ages 41–93 yr old demonstrated a clear association between age and several parameters of sexual function, including sexual thoughts, enjoyment, and morning erections (11). The same investigators also demonstrated that testosterone treatment of frankly hypogonadal men with testosterone markedly improved the same parameters of sexual function (12). A more recent study confirmed that physiologic testosterone treatment markedly improves sexual function in frankly hypogonadal men within 3 months and maintains the effect for 3 yr (13).

Sarcopenia. Both cross-sectional (14) and longitudinal (15) studies document the loss of muscle mass, and concomitant increase in fat mass, as a part of the normal aging process. In the New Mexico Elder Health Survey, the prevalence of sarcopenia, defined as appendicular skeletal mass less than 2 SD below the mean in a young reference group, increased from 13.5% in non-Hispanic white men less than 70 yr of age to 52.6% in those more than 80 yr old (16). The prevalence of sarcopenia in the elderly of Olmstead County, MN, was similar (17). Hypogonadism has the same effect, and testosterone treatment reverses it. In a study of six healthy young men, treatment with two doses of leuprolide 3 weeks apart lowered the serum testosterone concentration from 535 ± 141 ng/dL to 31.0 ± 9.0 ng/mL, decreased fat-free mass from 56.5 ± 2.9 kg to 54.4 ± 2.5 kg (P < 0.005), and increased fat mass from 15.8 ± 1.9 kg to 16.9 ± 2.0 kg (P < 0.05) (18). Treatment of men who had hypogonadism due to known disease increased fat-free mass in two studies (13, 19).

Muscle strength. Muscle strength in men also decreases with increasing age. A recent study of 346 men aged 20–93 in the Baltimore Longitudinal Study of Aging showed a decrease in the strength of knee extensors with increasing age (20). Another recent study showed that muscle power similarly decreases with increasing age (21). An effect of hypogonadism on muscle strength has been demonstrated less consistently. Decreasing the serum testosterone concentration drastically by treating normal young men with leuprolide (18), as described above, did decrease muscle strength, and increasing the serum testosterone concentration to normal in men with acquired immunodeficiency syndrome wasting and hypogonadism increased muscle strength (22). However, treating men with testosterone who were hypogonadal due to other etiologies did not increase their muscle strength (13).

Osteoporosis. Bone mineral density decreases gradually with increasing age in men (Fig. 2Go) (23). However, cross-sectional studies in elderly men do not show a correlation between the serum testosterone concentration and bone mineral density (24) or bone fractures (25), but do show a direct correlation between the serum estradiol concentration and these two parameters (24, 25). However, lowering the serum testosterone concentration by castration, which also lowers the estradiol, does lead to a decrease in bone mineral density (26). Moreover, testosterone treatment of men who are hypogonadal due to known disease is accompanied by a clear increase in bone mineral density. In one study, 29 hypogonadal men who were treated with 100 mg testosterone enanthate once a week for 18 months experienced an increase in bone mineral density of the lumbar spine by 5% (19). In another study, 18 men who were treated with testosterone transdermally for 3 yr experienced a 7.7% increase in bone mineral density of the spine and a 4.0% increase in that of the femoral trochanter (13).



View larger version (19K):
[in this window]
[in a new window]
 
Figure 2. Decline in bone mineral density of the hip in men with increasing age. Shown is the regression of bone mineral density for the intertrochanteric region of the proximal femur as determined by dual photon absorptiometry in 52 normal men without a history of hip fracture. From Ref. 23.

 
A study attempting to reverse the effects of the decline in testosterone

To test the hypothesis that increasing the serum testosterone concentration of elderly men to that of young men would reverse some of the effects described above, 108 men more than 65 yr old whose serum testosterone concentrations were less than mean - SD for young men were randomized to receive either testosterone or placebo transdermally for 3 yr. Men in the testosterone-treated group had a mean serum testosterone concentration of 625 ± 249 (SD) ng/dL during treatment, and those in the placebo-treated group had a value of 369 ± 75 ng/dL (27). Bone mineral density of the lumbar spine increased significantly (P < 0.001) in both groups, 2.5 ± 0.6% in the placebo-treated group and 4.2 ± 0.8% in the testosterone-treated group. Although the difference between the 2 groups was not statistically significant overall, linear regression analysis demonstrated a significant (P = 0.02) negative relationship between the pretreatment serum testosterone concentration and the testosterone treatment effect on lumbar spine bone mineral density (Fig. 3Go). That is, the lower the pretreatment serum testosterone, the greater the testosterone treatment effect on bone mineral density.



View larger version (25K):
[in this window]
[in a new window]
 
Figure 3. Inverse correlation between the pretreatment serum testosterone concentration and the testosterone treatment effect on percent change in lumbar spine bone mineral density in 108 men more than 65 yr old who received testosterone or placebo for 3 yr. The lower the pretreatment serum testosterone concentration, the greater the testosterone treatment effect (effect in the testosterone-treated men minus that in the placebo-treated men). From Ref. 27.

 
Testosterone treatment had significant effects on body composition. Testosterone-treated men experienced a 3.0 ± 3.7 kg loss in fat mass (P < 0.001) and a 1.9 ± 2.0 kg gain in fat-free mass (P < 0.001), whereas placebo-treated men experienced no significant change in either (Fig. 4Go) (28). However, strength of knee extension and flexion, measured by Biodex dynamometer (Biodex Corp., Shirley, NY) did not change in response to either treatment.



View larger version (18K):
[in this window]
[in a new window]
 
Figure 4. Decrease in fat mass, expressed as change from baseline (mean ± SE), and increase in lean (fat-free) mass in 108 men more than 65 yr old who were treated with testosterone or placebo for 3 yr. From Ref. 28.

 
Testosterone treatment improved perception of physical function, as measured by the MOS-SF 21, but did not affect actual physical function, including walking and stair climbing.

Several parameters were monitored because they reflect potential deleterious effects of testosterone (27). Men treated with testosterone experienced 16 prostate events (such as a persistent increase in prostate-specific antigen, prostate cancer, urinary obstruction) during the 3 yr of treatment, compared with 11 experienced by the men treated with placebo. This difference was not statistically significant, but the lack of statistical significance needs to be interpreted cautiously, because the study was not designed to have adequate statistical power to assess this parameter. Prostate-specific antigen increased significantly, but within the normal range, in the testosterone-treated group but not in the placebo-treated group. Hematocrit also increased significantly, but within the normal range, in the testosterone-treated group. There was no difference between the two treatment groups in the respiratory distress index or any lipid or apolipoprotein parameter.

These results suggest that physiologic testosterone replacement of elderly men does increase bone mineral density of the spine, but only in men who are hypogonadal by the same standards used for young men, and does increase fat-free mass and decrease fat mass. It is still unclear whether testosterone replacement will increase muscle strength. Furthermore, it is unknown at this time whether testosterone replacement of elderly, hypogonadal men will increase the frequency of testosterone-dependent diseases, such as prostate cancer and benign prostatic hyperplasia.

Conclusions

Even though testosterone treatment of elderly men who are hypogonadal appears to improve bone density and body composition, the risks of this treatment are not yet known. Consequently, physicians should be cautious in treating such men with testosterone. At this time, treatment should be reserved for men who are severely hypogonadal, and men who are treated should be monitored carefully for potential deleterious effects.

Footnotes

1 Supported by grants from the NIH (AR41425 and AG10954 to P.J.S. and RR040 to the General Clinical Research Center of the University of Pennsylvania). Back

Received February 16, 2001.

Revised March 18, 2001.

Accepted March 19, 2001.

References

  1. Purifoy FE, Koopmans LH, and Mayes DM. 1981 Age differences in serum androgen levels in normal adult males. Human Biol. 53:499–511.[Medline]
  2. Deslypere JP, and Vermeulen A. 1984 Leydig cell function in normal men: effect of age, life-style, residence, diet, and activity. J Clin Endocrinol Metab. 59:955–962.[Abstract]
  3. Ferrini RL, Barrett-Connor E. 1998 Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am J Epidemiol. 147:750–754.[Abstract]
  4. Morley JE, Kaiser FE, Perry III HM, et al. 1997 Longitudinal changes in testosterone, luteinizing hormone, and follicle stimulating hormone in healthy older men. Metab Clin Exp. 46:410–413.[Medline]
  5. Harman SM, Metter EJ, Tobin JD, Pearson J, and Blackman MR. 2001 Longitudial effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab. 86:724–731.[Abstract/Free Full Text]
  6. Veldhuis JD, Urban RJ, Lizarralde G, Johnson ML, and Iranmanesh A. 1992 Attenuation of luteinizing hormone secretory burst amplitude as a proximate basis for the hypoandrogenism of healthy aging in men. J Clin Endocrinol Metab. 75:707–712.[Abstract]
  7. Veldhuis JD, Zwart A, Mulligan T, and Iranmanesh A. 2001 Muting of androgen negative feedback unveils impoverished gonadotropin-releasing hormone/luteinizing hormine secretory reactivity in healthy older men. J Clin Endocrinol Metab. 86:529–535.[Abstract/Free Full Text]
  8. Nieschlag E, Lammers U, Freischem CW, Langer K, and Wickings EJ. 1982 Reproductive functions in young fathers and grandfathers. J Clin Endocrinol Metab. 55:676–680.[Abstract]
  9. Mahmoud AM, Goemaere S, De Bacquer D, Comhaire FH, and Kaufman JM. 2000 Serum inhibin B levels in community dwelling elderly men. Clin Endocrinol. 53:141–147.[CrossRef][Medline]
  10. Neaves WB, Johnson L, Porter JC, Parker CR, and Petty C. 1984 Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. J Clin Endocrinol Metab. 59:756–763.[Abstract]
  11. Davidson JM, Chen JJ, Crapo L, Gray GD, Greenlead WJ, and Catania JA. 1983 Hormonal changes and sexual function in aging men. J Clin Endocrinol Metab. 57:71–77.[Abstract]
  12. Kwan M, Greenleaf WJ, Mann J, Crapo L, and Davidson JM. 1983 The nature of androgen action on male sexuality: a combined laboratory-self-report study on hypogonadal men. J Clin Endocrinol Metab. 57:557–562.[Abstract]
  13. Snyder PJ, Peachey H, Hannoush P, et al. 2000 Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 85:2670–2677.[Abstract/Free Full Text]
  14. Borkan GA. 1983 Age changes in body composition revealed by computed tomography. J Gerontology. 38:673–677.
  15. Steen B. 1988 Body composition and aging. Nutr Rev. 46:45–51.[Medline]
  16. Baumgartner RN, Koehler KM, Gallagher D, et al. 1998. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol. 147:755–763.
  17. Melton LJI, Khosla S, and Riggs BL. 2000 Epidemiology of sarcopenia. Mayo Clin Proc. 75(Suppl.):S10–S13.
  18. Mauras N, Hayes V, Welch S, et al. 1998 Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. J Clin Endocrinol Metab. 83:1886–1892.[Abstract/Free Full Text]
  19. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, and Klibanski A. 1996 Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab. 81:4358–4365.[Abstract]
  20. Lindle RS, Metter EJ, Lynch NA, et al. 1997 Age and gender comparisons of muscle strength in 654 women and men aged 20–93 yr. J Appl Physiol. 83:1581–1587.[Abstract/Free Full Text]
  21. Martin JC, Farrar RP, Wagner BM, and Spirduso WW. 2000 Maximal power across the lifespan. J Gerontol. 55A:M311–M316 (Abstr).
  22. Bhasin S, Storer TW, Javanbakht M, et al. 2000 Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA. 283:763–770.[Abstract/Free Full Text]
  23. Riggs BL, Wahner HW, Seeman E, et al. 1982 Changes in bone mineral density of the proximal femur and spine with aging. J Clin Invest. 70:716–723.[Medline]
  24. Siemenda CW, Longcope C, Zhou L, Hui SL, Peacock M, Johnston CC. 1997 Sex steroids and bone mass in older men. J Clin Invest. 100:1755–1759.[Abstract/Free Full Text]
  25. Barrett-Connor E, Mueller JE, Von Muhlen DG, Laughlin GA, Schneider DL, and Sartoris DJ. 2000 Low levels of estradiol are associated with vertebral fractures in older men, but not women: The Rancho Bernardo Study. J Clin Endocrinol Metab. 85:219–223.[Abstract/Free Full Text]
  26. Stepan JJ, Lachman M, Zverina J, Pacovsky V, Baylink DJ. 1989 Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. J Clin Endocrinol Metab. 69:523–526.[Abstract]
  27. Snyder PJ, Peachey H, Hannoush P, et al. 1999 Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab. 84:1966–1972.[Abstract/Free Full Text]
  28. Snyder PJ, Peachey H, Hannoush P, et al. 1999 Effect of testosterone treatment on body composition and muscle strength in men over 65. J Clin Endocrinol Metab. 84:2647–2453.[Abstract/Free Full Text]