DHEA and Testosterone in the Elderly

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correspondence today, according to data from the United Network Dr. Buchanan reports receiving a grant from the American Society of Transplantation. Dr. Schnitzler reports receiving con- for Organ Sharing. sulting fees from Novartis Pharma, lecture fees from Genzyme, Daniel C. Brennan, M.D. and grant support from Genzyme, Novartis Pharma, Astellas, Washington University School of Medicine and TransMedics. St. Louis, MO 63110 [email protected] 1. Humar A, Johnson EM, Payne WD, et al. Effect of initial slow graft function on renal allograft rejection and survival. Clin Paula Buchanan, M.P.H. Transplant 1997;11:623-7. Mark A. Schnitzler, Ph.D. Saint Louis University Center for Outcomes Research St. Louis, MO 63104

To the Editor: In their report on the effects of Alvin M. Matsumoto, M.D. dehydroepiandrosterone (DHEA) and testosterone Veterans Affairs Puget Sound Health Care System when used as antiaging supplements, Nair et al. Seattle, WA 98108 (Oct. 19 issue)1 conclude that low-dose testoster- William J. Bremner, M.D., Ph.D. one replacement in elderly men has no “physiolog- University of Washington ically relevant beneficial effects on body composi- Seattle, WA 98195 tion, physical performance, [or] insulin sensitivity.” 1. Nair KS, Rizza RA, O’Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006; However, this conclusion is premature, since the 355:1647-59. testosterone replacement administered failed to 2. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testoster- achieve physiologic testosterone levels throughout one treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999;84:2647-53. the study period (Fig. 2 of the article). Moreover, 3. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone despite the marginal increase in testosterone lev- therapy in adult men with androgen deficiency syndromes: an els achieved, improvements in fat-free mass, fast- Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2006;91:1995-2010. [Erratum, J Clin Endocrinol Metab ing insulin levels, and bone mineral density were 2006;91:2688.] observed. 4. Page ST, Amory JK, Bowman FD, et al. Exogenous testoster- Other studies of testosterone replacement, in- one (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. cluding those cited to support the authors’ con- J Clin Endocrinol Metab 2005;90:1502-10. 2 clusions, have shown a decrease in fat mass 5. Amory JK, Watts NB, Easley KA, et al. Exogenous testoster- (12.5%) and an increase in lean mass (4%) when one or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol physiologic testosterone levels are achieved in el- Metab 2004;89:503-10. derly men. Studies of standard doses of testosterone in the treatment of testicular failure3 have shown additional positive effects on muscle To the Editor: The findings of Nair et al. can- strength, physical performance,4 and bone min- not be generalized, because the study included eral density.5 Large, long-term trials are clearly relatively healthy subjects. To investigate the ben- needed to assess the risks and benefits of testos- efits and risks of androgen-replacement therapy, terone replacement in elderly men, and caution it is essential to make judicious choices regarding should be exercised regarding the treatment of the subjects to be included in the research. In this andropause in men. However, the serum testos- study, the average baseline scores for the quality terone level achieved should be within the normal of life (on the Health Status Questionnaire [HSQ] range to assess the effect on outcome measures and the Medical Outcomes Study 36-item Short- adequately. Form General Health Survey [SF-36]) of all the Stephanie T. Page, M.D., Ph.D. subjects were above 50 for both the physical and mental components. The average score on both University of Washington 1 Seattle, WA 98195 instruments in the general U.S. population is 50. [email protected] The high scores of these subjects suggest that the

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study included healthier elderly persons than ute for antiaging uses but constitutes a market those who would be representative of the general estimated at more than $600 million per year in elderly population. the United States alone.4 Moreover, physical exercise is expected to im- Thomas T. Perls, M.D. prove and maintain physical functioning in older Boston University Medical Center people.2,3 Not only androgen administration but Boston, MA 02118 also well-designed physical training is needed to [email protected] improve the physical performance of elderly per- 1. U.S. Senate Special Committee on Aging. Swindlers, hucksters sons. The androgen level might be a mediator and snake oil salesman: hype and hope marketing anti-aging that could be elevated by exercise training, which products to seniors. 107th Congress, 1st session. Washington, DC: Government Printing Office, September 10, 2001. would then increase physical performance. The 2. Pierpaoli W, Regelson W. The melatonin miracle: nature’s administration of androgen in the absence of ex- age-reversing, disease-fighting, sex-enhancing hormone. New ercise may not be enough to improve physical York: Pocket Books, 1995. 3. Regelson W, Colman C. The superhormone promise. New performance among the elderly. York: Pocket Books, 1996. Mitsuko Yasuda, M.D., Ph.D. 4. Perls TT, Reisman NR, Olshansky SJ. Provision or distribu- tion of growth hormone for “antiaging”: clinical and legal issues. Shigeo Horie, M.D. JAMA 2005;294:2086-90. Teikyo University Tokyo 173-8605, Japan [email protected] To the Editor: The study by Nair et al. may be 1. van Hooren SA, van Boxtel MPJ, Valentijn SAM, Bosma H, misleading. One problem arises from the age of Ponds RW, Jolles J. Influence of cognitive functioning on func- the persons involved in the study. Women older tional status in an older population: 3- and 6-year follow-up of the Maastricht Aging Study. Int J Geriatr Psychiatry 2005;20: than 60 years rarely have postmenopausal symp- 883-8. toms. In the absence of symptoms, how are the 2. Mian OS, Thom JM, Ardigo LP, et al. Effect of a 12-month beneficial effects of treatment on the quality of life physical conditioning programme on the metabolic cost of walk- ing in healthy older adults. Eur J Appl Physiol (in press). to be demonstrated? Similarly, one may question 3. Tsuji I, Tamagawa A, Nagatomi R, et al. Randomized con- the use of testosterone in men older than 60 years. trolled trial of exercise training for older people (Sendai Silver The principal problem, however, is that Nair Center Trial: SSCT): study design and primary outcome. J Epide- miol 2000;10:55-64. et al. treated laboratory values (low values of DHEA and testosterone), not — as is usual medical practice — symptoms. To return to the exam To the Editor: DHEA was banned in 1985 by the ple of postmenopausal care for women older than Food and Drug Administration because clinical 60 years, such an approach could be equated with safety and efficacy data were lacking to support indiscriminately treating unselected postmeno- claims of cures for cardiovascular disease and pausal women, all of whom, of course, have low aging. After the passage of the Dietary Supple- estradiol levels, with estrogen replacement, wheth- ment Health and Education Act in 1994, DHEA, er or not they are symptomatic. Whether such an which had not previously been labeled as a drug, unselected approach to treatment would ever re- again became available. It is amazing that a pre- veal clinical benefits regarding the quality of life viously banned substance can now be sold directly is questionable. to the public, and it speaks to the lack of over- That DHEA can indeed positively affect certain sight and protection afforded by the Dietary Sup- physiological processes of aging has been sug- plement Health and Education Act. gested with regard to ovarian function.1-3 Thus, Hormones have long been equated with youth nothing in the study by Nair et al. contradicts by the public and are thus a favorite type of sub- the value of further investigation of DHEA in stance for marketing by the antiaging industry.1 specific conditions of aging. As one substance falls out of favor, another quick Norbert Gleicher, M.D. 2 ly replaces it: the miracle of melatonin was re- David Barad, M.D. placed by the superhormone promise3 of DHEA. Center for Human Reproduction The heir apparent now seems to be growth hor- New York, NY 10021 mone, which, paradoxically, is illegal to distrib- [email protected]

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Drs. Gleicher and Barad are part owners of a pending patent verse events and long-term benefits of restoring involving the use of DHEA for the improvement of ovarian function in women with diminished ovarian function. testosterone levels in older people to levels seen in young people. 1. Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. In response to Yasuda and Horie, the HSQ is Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod 2000; a measure of perceived but not actual health. On 15:2129-32. the basis of the HSQ, we cannot state whether 2. Barad DH, Gleicher N. Increased oocyte production after the persons in our sample were more or less treatment with dehydroepiandrosterone. Fertil Steril 2005;84: 756. healthy than the general population. Scores for 3. Idem. Effect of dehydroepiandrosterone on oocyte and em- both the physical and the mental components of bryo yields, embryo grade and cell number in IVF. Hum Reprod the SF-36 questionnaire derived from the HSQ are 2006;21:2845-9. only minimally different from a score of 50, and our interquartile range includes 50. We agree The authors reply: Our conclusion that “addi- with Yasuda and Horie that the interaction be- tional long-term studies of testosterone are war- tween testosterone and exercise training in older ranted to determine the risk–benefit ratio of high- people remains to be determined and warrants er doses” is in agreement with the view expressed further investigation. by Page et al.1 We showed that low-dose testos- We agree with the comments by Perls about terone significantly increased testosterone levels DHEA and the unfortunate rush to hormone but resulted in no physiologically relevant benefi- therapies to maintain youth, even though no sci- cial effects. However, unlike the investigation of entific data conclusively support such approaches. DHEA in the study, the investigation of testoster- In response to Gleicher and Barad, our study spe- one did not address the potential beneficial effects cifically addressed whether the long-term admin- of replacement therapy that would increase the istration of DHEA has any beneficial effects in plasma levels of testosterone in older people to women older than 60 years who have low levels levels found in young people. Standard testoster- of DHEA. The main outcome measures were ob- one replacement in younger men with testicular jective physiological measurements and responses failure has a profound effect on body composi- to the standard HSQ. We did not evaluate the tion,2 but the response to testosterone therapy in effect of DHEA in women who have postmeno- older men with low testosterone levels remains pausal symptoms for which estrogen therapy is uncertain. Biweekly intramuscular injection of tes- likely to be more effective than DHEA. tosterone (at a dose of 200 mg) in older people1 K. Sreekumaran Nair, M.D., Ph.D. has been shown to increase peak testosterone Glenn Smith, Ph.D. levels to values above the normal range in young Mayo Clinic people3 and improves physical performance.1 How- Rochester, MN 55905 [email protected] ever, because of adverse events, the investigators 1 1. Page ST, Amory JK, Bowman FD, et al. Exogenous testoster- had to reduce the dose in some subjects. Trans- one (T) alone or with finasteride increases physical performance, dermal administration of testosterone maintained grip strength, and lean body mass in older men with low serum testosterone levels in older people to levels with- T. J Clin Endocrinol Metab 2005;90:1502-10. 2. Brodsky IG, Balagopal P, Nair KS. Effects of testosterone in the normal range for young people for a period replacement on muscle mass and muscle protein synthesis in of 36 months but had no effect on physical per- hypogonadal men — a clinical research center study. J Clin Endo- formance,4 despite a significant increase in fat- crinol Metab 1996;81:3469-75. 3. Amory JK, Watts NB, Easley KA, et al. Exogenous testoster- free mass. We agree with Page et al. that there one or testosterone with finasteride increases bone mineral den- are tantalizing data on the effect of testosterone sity in older men with low serum testosterone. J Clin Endocrinol on bone density. The findings in the studies cited Metab 2004;89:503-10. 4. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testoster- here and in other studies highlight the importance one treatment on bone mineral density in men over 65 years of of conducting long-term studies to document ad- age. J Clin Endocrinol Metab 1999;84:1966-72.

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