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syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559. Ko EY, Siddiqi K, Brannigan RE, et al. Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol. 2012;187:973-978. World Health Organization. Standard Procedures. WHO Laboratory Manual for the Examination and Processing of Human Semen. 5th ed., Chapter 2. Geneva, Switzerland: WHO Press; 2010:7-48. http://www.doctoroz.com/videos/truth-about-testosterone. Martinez G, Daniels K, Chandra A. Fertility of men and women aged 15-44 years in the United States: National Survey of Family Growth. Natl Health Stat Report. 2012;12:1-28. Samplaski MK, Loai Y, Wong K, et al. Testosterone use in the male infertility population: prescribing patterns and effects on semen and hormonal parameters. Fertil Steril. 2014;101:64-69. Sigman M, Lipshultz LI, Howards SS. Evaluation of the subfertile male. In: Lipshultz LI, Howards SS, eds. Infertility in the Male. 3rd ed. St Louis, MO: Mosby; 1997:173-193. WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996;65: 821-829. Gu Y, Liang X, Wu W, et al. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J Clin Endocrinol Metab. 2009;94:1910-1915. Liu PY, Swerdloff RS, Christnson PD, et al. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367:1412-1420. Whitten SJ, Nangia AK, Kolettis PN. Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate. Fertil Steril. 2006;86:1664-1668. Hsieh TC, Pastuszak AW, Hwang K, et al. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013; 189:647-650.
EDITORIAL COMMENT The use . and misuse . of testosterone supplementation in reproductive-aged men is addressed in this enlightening article.1 The authors1 provided a retrospective review of patients referred to them for evaluation of infertility. They identified 110 men (7%) who had been prescribed testosterone supplementation for a median duration of 24 months. Sixty-eight percent of these men were azoospermic at presentation, whereas 32% were not. What is concerning is that 21% remained azoospermic and another 8% had a sperm concentration 0.1 million/mL after stopping testosterone with a median follow-up of 4.5 months. Of possibly even greater importance, the mean sperm concentration in those who had sperm return to their ejaculate at followup was only 6.3 million/mL. Although their findings are in agreement with prior studies that demonstrated the adverse effect of testosterone on spermatogenesis,2,3 there are several limitations to their study. These limitations are primarily related to the retrospective nature of their study and that their initial contact with the patients was after cessation of testosterone supplementation. Patients did not have a semen analyses before beginning testosterone replacement or documentation of why they were started on therapy. The dose and frequency of use was not known; no hormonal testing was reported before or during to compare with after cessation of testosterone supplementation that might have given some insight into both the reason for treatment as well as the underlying testicular pathology. With the small number of patients in their study, evaluation of their use of clomiphene citrate or human chorionic gonadotropin 1072
for azoospermic men after testosterone supplementation is inconclusive. In addition, no further evaluation of men who remained azoospermic after cessation testosterone was performed, so potential coexisting genetic or iatrogenic conditions unrelated to testosterone supplementation were not evaluated. Nonetheless, in spite of these limitations, the study highlights the need for further education of physicians treating reproductive-age men for hypogonadism, as well as patients themselves. The authors’ observation that 95% of their study patients were treated with injectable testosterone and not gels, patches, or pellets is curious. Currently, most urologists experienced in treating significant hypogonadism in this population would probably begin with a selective estrogen modulator and proceed on to a testosterone gel or patch if this is not effective. According to the American Urological Association,4 70% of treated hypogonadal men use gels, with only 10% using patches. Injectable testosterone is used by 17% of treated men and although an important option is usually not preferred in men of reproductive age as it is thought to be more potent in suppression of the HPT axis than gels. The authors1 suggested that the increased use of testosterone can be “attributed to new forms of T supplementation, an increased awareness of possible symptoms associated with low T, and possibly direct to consumer marketing by pharmaceutical companies”; however, their population primarily used injectable testosterone. Does this mean that the patients referred to them were seen by practices not experienced in the contemporary treatment of hypogonadism? Or are these patients self-medicating or lured in by pernicious advertising or the omnipresent low T clinics? Unfortunately, as valuable as this study is in highlighting the consequences of testosterone use on male fertility, we are still challenged with the task of educating our colleagues and patients on the use and misuse of testosterone supplementation. Additional studies like this will continue to guide us in our role as educators. Bruce R. Gilbert, M.D., Ph.D., Hofstra North Shore LIJ School of Medicine, Smith Institute for Urology, Great Neck, NY
References 1. Kolettis PN, Purcell ML, Parker W, et al. Medical testosterone: an iatrogenic cause of male infertility and a growing problem. Urology. 2015;85:1068-1073. 2. WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996;65:821-829. 3. Gu Y, Liang X, Wu W, et al. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J Clin Endocrinol Metab. 2009;94:1910-1915. 4. Urology Care Foundation (http://www.urologyhealth.org/urology/ index.cfm?article¼132).
http://dx.doi.org/10.1016/j.urology.2014.12.053 UROLOGY 85: 1072, 2015. Published by Elsevier Inc.
REPLY We thank the editor1 for his comments. In our retrospective review, we were concerned about these reproductive-aged men taking testosterone. We speculate that many were on injectable testosterone as they did not have insurance coverage for topical UROLOGY 85 (5), 2015
4.
5. 6.
7.
8.
9.
10.
11.
12.
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syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559. Ko EY, Siddiqi K, Brannigan RE, et al. Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol. 2012;187:973-978. World Health Organization. Standard Procedures. WHO Laboratory Manual for the Examination and Processing of Human Semen. 5th ed., Chapter 2. Geneva, Switzerland: WHO Press; 2010:7-48. http://www.doctoroz.com/videos/truth-about-testosterone. Martinez G, Daniels K, Chandra A. Fertility of men and women aged 15-44 years in the United States: National Survey of Family Growth. Natl Health Stat Report. 2012;12:1-28. Samplaski MK, Loai Y, Wong K, et al. Testosterone use in the male infertility population: prescribing patterns and effects on semen and hormonal parameters. Fertil Steril. 2014;101:64-69. Sigman M, Lipshultz LI, Howards SS. Evaluation of the subfertile male. In: Lipshultz LI, Howards SS, eds. Infertility in the Male. 3rd ed. St Louis, MO: Mosby; 1997:173-193. WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996;65: 821-829. Gu Y, Liang X, Wu W, et al. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J Clin Endocrinol Metab. 2009;94:1910-1915. Liu PY, Swerdloff RS, Christnson PD, et al. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367:1412-1420. Whitten SJ, Nangia AK, Kolettis PN. Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate. Fertil Steril. 2006;86:1664-1668. Hsieh TC, Pastuszak AW, Hwang K, et al. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013; 189:647-650.
EDITORIAL COMMENT The use . and misuse . of testosterone supplementation in reproductive-aged men is addressed in this enlightening article.1 The authors1 provided a retrospective review of patients referred to them for evaluation of infertility. They identified 110 men (7%) who had been prescribed testosterone supplementation for a median duration of 24 months. Sixty-eight percent of these men were azoospermic at presentation, whereas 32% were not. What is concerning is that 21% remained azoospermic and another 8% had a sperm concentration 0.1 million/mL after stopping testosterone with a median follow-up of 4.5 months. Of possibly even greater importance, the mean sperm concentration in those who had sperm return to their ejaculate at followup was only 6.3 million/mL. Although their findings are in agreement with prior studies that demonstrated the adverse effect of testosterone on spermatogenesis,2,3 there are several limitations to their study. These limitations are primarily related to the retrospective nature of their study and that their initial contact with the patients was after cessation of testosterone supplementation. Patients did not have a semen analyses before beginning testosterone replacement or documentation of why they were started on therapy. The dose and frequency of use was not known; no hormonal testing was reported before or during to compare with after cessation of testosterone supplementation that might have given some insight into both the reason for treatment as well as the underlying testicular pathology. With the small number of patients in their study, evaluation of their use of clomiphene citrate or human chorionic gonadotropin 1072
for azoospermic men after testosterone supplementation is inconclusive. In addition, no further evaluation of men who remained azoospermic after cessation testosterone was performed, so potential coexisting genetic or iatrogenic conditions unrelated to testosterone supplementation were not evaluated. Nonetheless, in spite of these limitations, the study highlights the need for further education of physicians treating reproductive-age men for hypogonadism, as well as patients themselves. The authors’ observation that 95% of their study patients were treated with injectable testosterone and not gels, patches, or pellets is curious. Currently, most urologists experienced in treating significant hypogonadism in this population would probably begin with a selective estrogen modulator and proceed on to a testosterone gel or patch if this is not effective. According to the American Urological Association,4 70% of treated hypogonadal men use gels, with only 10% using patches. Injectable testosterone is used by 17% of treated men and although an important option is usually not preferred in men of reproductive age as it is thought to be more potent in suppression of the HPT axis than gels. The authors1 suggested that the increased use of testosterone can be “attributed to new forms of T supplementation, an increased awareness of possible symptoms associated with low T, and possibly direct to consumer marketing by pharmaceutical companies”; however, their population primarily used injectable testosterone. Does this mean that the patients referred to them were seen by practices not experienced in the contemporary treatment of hypogonadism? Or are these patients self-medicating or lured in by pernicious advertising or the omnipresent low T clinics? Unfortunately, as valuable as this study is in highlighting the consequences of testosterone use on male fertility, we are still challenged with the task of educating our colleagues and patients on the use and misuse of testosterone supplementation. Additional studies like this will continue to guide us in our role as educators. Bruce R. Gilbert, M.D., Ph.D., Hofstra North Shore LIJ School of Medicine, Smith Institute for Urology, Great Neck, NY
References 1. Kolettis PN, Purcell ML, Parker W, et al. Medical testosterone: an iatrogenic cause of male infertility and a growing problem. Urology. 2015;85:1068-1073. 2. WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996;65:821-829. 3. Gu Y, Liang X, Wu W, et al. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J Clin Endocrinol Metab. 2009;94:1910-1915. 4. Urology Care Foundation (http://www.urologyhealth.org/urology/ index.cfm?article¼132).
http://dx.doi.org/10.1016/j.urology.2014.12.053 UROLOGY 85: 1072, 2015. Published by Elsevier Inc.
REPLY We thank the editor1 for his comments. In our retrospective review, we were concerned about these reproductive-aged men taking testosterone. We speculate that many were on injectable testosterone as they did not have insurance coverage for topical UROLOGY 85 (5), 2015
