Risks of Testosterone Replacement
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Rhoden and Morgentaler1 and Snyder2 (Jan. 29 issue) assuage the anxiety of physicians who administer testosterone to older men because the men report andropause, a collection of ill-defined maladies related to male aging. Their position in this regard is very disconcerting.
More than 50 years ago, physicians began treating the "male climacteric" with testosterone.3 Since then, no standardized definition of this condition has been developed, no metric defining a therapeutic effect has been created, no randomized controlled studies have been conducted to support the widespread use of testosterone in men for this condition, and the adverse-event profile of the drug in this population has not been studied adequately. The Food and Drug Administration (FDA) has not approved testosterone for this condition. In addition, the schemes suggested by Rhoden and Morgentaler and by Snyder for managing the risk of prostate cancer, a hazard of testosterone exposure that is of great concern, are untested.
The Women's Health Initiative advanced our understanding of the risks and benefits of estrogen through randomized trials. The recent Institute of Medicine report4 advises thoughtful, well-designed research on testosterone in aging men; this should be supported.
Daniel A. Shames, M.D.
Food and Drug Administration
Rockville, MD 20857
References
Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350:482-492.
Snyder PJ. Hypogonadism in elderly men -- what to do until the evidence comes. N Engl J Med 2004;350:440-442.
Rothman SM, Rothman DJ. The pursuit of perfection: the promise and perils of medical enhancement. New York: Pantheon Books, 2003:158.
Liverman CT, Blazer DG, eds. Testosterone and aging, clinical research directions. Washington, D.C.: National Academies Press, 2004.
To the Editor: We wish to address several points made by Rhoden and Morgentaler and by Snyder, as highlighted by a recent case. A 59-year-old man with idiopathic hypogonadism who was receiving testosterone-replacement therapy was referred because of a rising prostate-specific antigen (PSA) level (4.0 ng per milliliter; total testosterone level, 202 ng per deciliter; free testosterone level, 45 pg per milliliter). Biopsy revealed adenocarcinoma of the prostate (Gleason grade, 6). A radical retropubic prostatectomy was performed. Pathological examination revealed extensive organ-confined adenocarcinoma (Gleason grade, 6; tumor–node–metastasis stage, T2N0Mx). Three and six months postoperatively, PSA was undetectable, and without testosterone replacement, his testosterone levels were 410 and 487 ng per deciliter, respectively.
Because prostate cancer can suppress the hypothalamic–pituitary–testicular axis and lower serum testosterone levels,1,2 we propose that adenocarcinoma of the prostate be considered in the differential diagnosis of hypogonadism. Furthermore, because removal of the prostate may lead to normalization of testosterone levels in hypogonadal men who have previously received testosterone-replacement therapy, we recommend measurement of testosterone before therapy is reinstated after surgery.
Edward M. Schaeffer, M.D., Ph.D.
Patrick C. Walsh, M.D.
Johns Hopkins Medical Institutions
Baltimore, MD 21287-2101
References
Miller LR, Partin AW, Chan DW, et al. Influence of radical prostatectomy on serum hormone levels. J Urol 1998;160:449-453.
Madersbacher S, Schatzl G, Bieglmayer C, et al. Impact of radical prostatectomy and TURP on the hypothalamic-pituitary-gonadal hormone axis. Urology 2002;60:869-874.
To the Editor: In reviewing the risks of testosterone replacement in older men, Rhoden and Morgentaler did not mention a safety concern specific to transdermal gels and creams: the transfer of testosterone from the patient to a partner or child through skin-to-skin contact. Reports from France describe women who had supraphysiologic testosterone levels, signs of hirsutism, or both after their partners began using a topical testosterone gel (100 mg applied daily),1,2 and a U.S. report documents precocious puberty in a two-year-old boy whose father used testosterone cream.3 A study of gel transfer between 45 men and their female partners showed that 15 minutes of vigorous skin-to-skin contact daily at the application site (of 100 mg) transiently raised the women's testosterone levels by a factor of 5 to 6; in some cases, elevations similar to those in severe polycystic ovary syndrome were reached.4 Although the incidence of testosterone-related effects due to gel transfer is unknown, physicians as well as patients and their partners should be aware of such a transfer as a possible cause of androgenic changes such as acne, hirsutism, and alopecia.
Geoffrey Redmond, M.D.
Hormone Center of New York
New York, NY 10021
gpredmond@aol.com
Editor's note: Dr. Redmond reports having served as an investigator in clinical trials for AndroGel and as a member of Watson Pharmaceuticals Scientific Advisory Board, Women's Health.
References
Delanoe D, Fougeyrollas B, Meyer L, Thonneau P. Androgenisation of female partners of men on medroxyprogesterone acetate/percutaneous testosterone contraception. Lancet 1984;1:276-276.
Moore N, Paux G, Noblet C, Andrejak M. Spouse-related drug side-effects. Lancet 1988;1:468-468.
Yu YM, Punyasavatsu N, Elder D, D'Ercole AJ. Sexual development in a two-year-old boy induced by topical exposure to testosterone. Pediatrics 1999;104:e23-e23.
Food and Drug Administration, Center for Drug Evaluation and Research. Summary basis for approval of AndroGel (testosterone) gel. NDA 20-015. Clinical PK/biopharmaceuticals section. (Accessed April 16, 2004, at http://www.fda.gov/cder/foi/nda/2000/21-015_AndroGel.htm.)
To the Editor: Testosterone therapy may soon become the next youthful panacea as baby boomers edge into their older years. Rhoden and Morgentaler give a concise overview of medical risks but minimize psychiatric side effects. The AIDS treatment community has been using testosterone and anabolic steroids for many years, often at the request of well-educated and informed patients. Increased aggressiveness, irritability, and impulsiveness are side effects that can be quite substantial over time. Subtle but insidious behavioral changes can erode relationships with family members and coworkers. Practitioners need to be mindful of these "softer" side effects of testosterone therapy as it increases in popularity.
Rosemary M. Harris, M.D.
Drexel University
Philadelphia, PA 19104
rh39@drexel.edu
The authors reply: We are grateful for the letter from Dr. Shames, which allows us the opportunity to address aspects of testosterone therapy in men that we did not mention in our article. We agree wholeheartedly that there is a great need for standardization and further research in the field. However, it is important to recognize that a substantial body of research concerning testosterone already exists, accumulated over the course of several decades, and that it involves a wide array of biologic systems.
The effects of low serum testosterone levels listed in Table 1 of our article are well established and are similar whether a man is 25 or 65 years old. For this reason, we would argue that the distinction between older and younger men in terms of these effects lacks a scientific basis, as does the use of age-adjusted reference ranges for testosterone, which rigidly assign only men with a testosterone level in the lowest 2.5 percentile to the subnormal category, without consideration of clinical features.
The well-documented benefits of testosterone include increases in libido, the hematocrit, muscle mass, and bone density and diminished body fat.1 Promising benefits in cognition2 and mood3 have been suggested by some studies but will require additional investigation and confirmation. Many men report increased energy, decreased fatigue, and a heightened sense of vitality with treatment, but these apparent benefits have not been rigorously tested.
In our review, we specifically discuss literature on the often-repeated concerns regarding testosterone and the specific risks of prostate cancer and cardiovascular disease. Although it has been considered almost axiomatic that increased testosterone levels are causative factors in these two diseases, we were unable to identify any clear and compelling evidence of such a link in the available literature. We thus believe that the underlying hypotheses about testosterone, prostate cancer, and cardiovascular disease should be reevaluated. As for indications in older men, it has not been widely appreciated that hypogonadism associated with aging usually occurs as a result of a combination of hypergonadotrophic and hypogonadotrophic hypogonadism. Both of these conditions are specifically listed in FDA-approved package inserts as indications for testosterone therapy.
The observation by Drs. Schaeffer and Walsh of a possible depressive effect of prostate cancer on serum testosterone levels involves a relationship that, in our view, merits further investigation. It has been hypothesized that this effect is particularly evident in high-grade tumors.4
Dr. Redmond rightly points out the importance of avoiding close physical contact with women and children for several hours after the application of testosterone gel. A cautionary note to this effect should be routinely incorporated in instructions given to patients.
Finally, we must make a clear distinction between the physiologic replacement of testosterone in hypogonadal men, which is most frequently associated with mood stabilization, and the illicit use of anabolic steroids, usually in markedly supraphysiologic doses, which has been anecdotally linked to aggressive, violent behavior.
Abraham Morgentaler, M.D.
Harvard Medical School
Boston, MA 02115
amorgent@caregroup.harvard.edu
Ernani Luis Rhoden, M.D.
Federal Foundation of Medical Sciences
90050-170 Porto Allegre, Brazil
References
Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000;85:2839-2853.
Cherrier MM, Plymate S, Mohan S, et al. Relationship between testosterone supplementation and insulin-like growth factor-I levels and cognition in healthy older men. Psychoneuroendocrinology 2004;29:65-82.
Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 2003;160:105-111.
Hoffman MA, DeWolf W, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol 2000;163:824-827.
More than 50 years ago, physicians began treating the "male climacteric" with testosterone.3 Since then, no standardized definition of this condition has been developed, no metric defining a therapeutic effect has been created, no randomized controlled studies have been conducted to support the widespread use of testosterone in men for this condition, and the adverse-event profile of the drug in this population has not been studied adequately. The Food and Drug Administration (FDA) has not approved testosterone for this condition. In addition, the schemes suggested by Rhoden and Morgentaler and by Snyder for managing the risk of prostate cancer, a hazard of testosterone exposure that is of great concern, are untested.
The Women's Health Initiative advanced our understanding of the risks and benefits of estrogen through randomized trials. The recent Institute of Medicine report4 advises thoughtful, well-designed research on testosterone in aging men; this should be supported.
Daniel A. Shames, M.D.
Food and Drug Administration
Rockville, MD 20857
References
Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350:482-492.
Snyder PJ. Hypogonadism in elderly men -- what to do until the evidence comes. N Engl J Med 2004;350:440-442.
Rothman SM, Rothman DJ. The pursuit of perfection: the promise and perils of medical enhancement. New York: Pantheon Books, 2003:158.
Liverman CT, Blazer DG, eds. Testosterone and aging, clinical research directions. Washington, D.C.: National Academies Press, 2004.
To the Editor: We wish to address several points made by Rhoden and Morgentaler and by Snyder, as highlighted by a recent case. A 59-year-old man with idiopathic hypogonadism who was receiving testosterone-replacement therapy was referred because of a rising prostate-specific antigen (PSA) level (4.0 ng per milliliter; total testosterone level, 202 ng per deciliter; free testosterone level, 45 pg per milliliter). Biopsy revealed adenocarcinoma of the prostate (Gleason grade, 6). A radical retropubic prostatectomy was performed. Pathological examination revealed extensive organ-confined adenocarcinoma (Gleason grade, 6; tumor–node–metastasis stage, T2N0Mx). Three and six months postoperatively, PSA was undetectable, and without testosterone replacement, his testosterone levels were 410 and 487 ng per deciliter, respectively.
Because prostate cancer can suppress the hypothalamic–pituitary–testicular axis and lower serum testosterone levels,1,2 we propose that adenocarcinoma of the prostate be considered in the differential diagnosis of hypogonadism. Furthermore, because removal of the prostate may lead to normalization of testosterone levels in hypogonadal men who have previously received testosterone-replacement therapy, we recommend measurement of testosterone before therapy is reinstated after surgery.
Edward M. Schaeffer, M.D., Ph.D.
Patrick C. Walsh, M.D.
Johns Hopkins Medical Institutions
Baltimore, MD 21287-2101
References
Miller LR, Partin AW, Chan DW, et al. Influence of radical prostatectomy on serum hormone levels. J Urol 1998;160:449-453.
Madersbacher S, Schatzl G, Bieglmayer C, et al. Impact of radical prostatectomy and TURP on the hypothalamic-pituitary-gonadal hormone axis. Urology 2002;60:869-874.
To the Editor: In reviewing the risks of testosterone replacement in older men, Rhoden and Morgentaler did not mention a safety concern specific to transdermal gels and creams: the transfer of testosterone from the patient to a partner or child through skin-to-skin contact. Reports from France describe women who had supraphysiologic testosterone levels, signs of hirsutism, or both after their partners began using a topical testosterone gel (100 mg applied daily),1,2 and a U.S. report documents precocious puberty in a two-year-old boy whose father used testosterone cream.3 A study of gel transfer between 45 men and their female partners showed that 15 minutes of vigorous skin-to-skin contact daily at the application site (of 100 mg) transiently raised the women's testosterone levels by a factor of 5 to 6; in some cases, elevations similar to those in severe polycystic ovary syndrome were reached.4 Although the incidence of testosterone-related effects due to gel transfer is unknown, physicians as well as patients and their partners should be aware of such a transfer as a possible cause of androgenic changes such as acne, hirsutism, and alopecia.
Geoffrey Redmond, M.D.
Hormone Center of New York
New York, NY 10021
gpredmond@aol.com
Editor's note: Dr. Redmond reports having served as an investigator in clinical trials for AndroGel and as a member of Watson Pharmaceuticals Scientific Advisory Board, Women's Health.
References
Delanoe D, Fougeyrollas B, Meyer L, Thonneau P. Androgenisation of female partners of men on medroxyprogesterone acetate/percutaneous testosterone contraception. Lancet 1984;1:276-276.
Moore N, Paux G, Noblet C, Andrejak M. Spouse-related drug side-effects. Lancet 1988;1:468-468.
Yu YM, Punyasavatsu N, Elder D, D'Ercole AJ. Sexual development in a two-year-old boy induced by topical exposure to testosterone. Pediatrics 1999;104:e23-e23.
Food and Drug Administration, Center for Drug Evaluation and Research. Summary basis for approval of AndroGel (testosterone) gel. NDA 20-015. Clinical PK/biopharmaceuticals section. (Accessed April 16, 2004, at http://www.fda.gov/cder/foi/nda/2000/21-015_AndroGel.htm.)
To the Editor: Testosterone therapy may soon become the next youthful panacea as baby boomers edge into their older years. Rhoden and Morgentaler give a concise overview of medical risks but minimize psychiatric side effects. The AIDS treatment community has been using testosterone and anabolic steroids for many years, often at the request of well-educated and informed patients. Increased aggressiveness, irritability, and impulsiveness are side effects that can be quite substantial over time. Subtle but insidious behavioral changes can erode relationships with family members and coworkers. Practitioners need to be mindful of these "softer" side effects of testosterone therapy as it increases in popularity.
Rosemary M. Harris, M.D.
Drexel University
Philadelphia, PA 19104
rh39@drexel.edu
The authors reply: We are grateful for the letter from Dr. Shames, which allows us the opportunity to address aspects of testosterone therapy in men that we did not mention in our article. We agree wholeheartedly that there is a great need for standardization and further research in the field. However, it is important to recognize that a substantial body of research concerning testosterone already exists, accumulated over the course of several decades, and that it involves a wide array of biologic systems.
The effects of low serum testosterone levels listed in Table 1 of our article are well established and are similar whether a man is 25 or 65 years old. For this reason, we would argue that the distinction between older and younger men in terms of these effects lacks a scientific basis, as does the use of age-adjusted reference ranges for testosterone, which rigidly assign only men with a testosterone level in the lowest 2.5 percentile to the subnormal category, without consideration of clinical features.
The well-documented benefits of testosterone include increases in libido, the hematocrit, muscle mass, and bone density and diminished body fat.1 Promising benefits in cognition2 and mood3 have been suggested by some studies but will require additional investigation and confirmation. Many men report increased energy, decreased fatigue, and a heightened sense of vitality with treatment, but these apparent benefits have not been rigorously tested.
In our review, we specifically discuss literature on the often-repeated concerns regarding testosterone and the specific risks of prostate cancer and cardiovascular disease. Although it has been considered almost axiomatic that increased testosterone levels are causative factors in these two diseases, we were unable to identify any clear and compelling evidence of such a link in the available literature. We thus believe that the underlying hypotheses about testosterone, prostate cancer, and cardiovascular disease should be reevaluated. As for indications in older men, it has not been widely appreciated that hypogonadism associated with aging usually occurs as a result of a combination of hypergonadotrophic and hypogonadotrophic hypogonadism. Both of these conditions are specifically listed in FDA-approved package inserts as indications for testosterone therapy.
The observation by Drs. Schaeffer and Walsh of a possible depressive effect of prostate cancer on serum testosterone levels involves a relationship that, in our view, merits further investigation. It has been hypothesized that this effect is particularly evident in high-grade tumors.4
Dr. Redmond rightly points out the importance of avoiding close physical contact with women and children for several hours after the application of testosterone gel. A cautionary note to this effect should be routinely incorporated in instructions given to patients.
Finally, we must make a clear distinction between the physiologic replacement of testosterone in hypogonadal men, which is most frequently associated with mood stabilization, and the illicit use of anabolic steroids, usually in markedly supraphysiologic doses, which has been anecdotally linked to aggressive, violent behavior.
Abraham Morgentaler, M.D.
Harvard Medical School
Boston, MA 02115
amorgent@caregroup.harvard.edu
Ernani Luis Rhoden, M.D.
Federal Foundation of Medical Sciences
90050-170 Porto Allegre, Brazil
References
Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000;85:2839-2853.
Cherrier MM, Plymate S, Mohan S, et al. Relationship between testosterone supplementation and insulin-like growth factor-I levels and cognition in healthy older men. Psychoneuroendocrinology 2004;29:65-82.
Pope HG Jr, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 2003;160:105-111.
Hoffman MA, DeWolf W, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol 2000;163:824-827.