全部 标题 作者
关键词 摘要


Testosterone and Its Analogs as a Male Contraceptive

DOI: 10.4236/asm.2013.33A002, PP. 10-18

Keywords: Hormonal Contraception, Suppression of Spermatogenesis, Testosterone, Androgen-Progestin Combination

Full-Text   Cite this paper   Add to My Lib

Abstract:

Male contraception by means of hormonal approach was initiated more than 60 years ago when men became azoospermic with administration of testosterone. The basic principle of male hormonal contraception is suppression of spermatogenesis. Exogenous testosterone/testosterone analogs alone or in combination with progestin have been tested for contraceptive efficacy by inhibiting gonadotropins release from pituitary gland. In this review article, advancement in different testosterone preparation tested alone or in combination for contraceptive efficacy has been focused. Administration of testosterone or testosterone analogs alone failed to provide uniform azoospermia or severe oligospermia (<1 million/ml sperm count) at lower doses regimens whereas higher doses causes side effects. Newer, androgen-progestin combination has proved better contraceptive efficacy than testosterone alone. Further, long term studies with hormonal regimens and other alternative approaches are required with fewer side effects for development of safe and reversible contraceptive.

References

[1]  L. B. Finer and M. R. Zolna, “Unintended Pregnancy in the United States: Incidence and Disparities, 2006,” Contraception, Vol. 84, No. 5, 2011, pp. 478-485. doi:10.1016/j.contraception.2011.07.013
[2]  S. K. Henshaw, “Unintended Pregnancy in the United States,” Family Planning Perspectives, Vol. 30, No. 1, 1998, pp. 24-29. doi:10.2307/2991522
[3]  N. J. Hackel, “Production of Oligospermia in Man by the Use of Testosterone Propionate,” Experimental Biology and Medicine, Vol. 40, No. 4, 1939, pp. 658-659. doi:10.3181/00379727-40-10527P
[4]  E. P. McCllagh and F. J. McGurl, “Further Observation on Clinical Use of Testosterone Propionate,” Journal of Urology, Vol. 42, 1939, pp. 1265-1267.
[5]  A. D. Coviello, A. M. Matsumoto, W. J. Bremner, K. L. Herbst, J. K. Amory and B. D. Anawalt, “Low-Dose Human Chorionic Gonadotropin Maintains Intratesticular Testosterone in Normal Men with Testosterone-Induced Gonadotropin Suppression,” The Journal of Clinical Endocrinology & Metabolism, Vol. 90, No. 5, 2005, pp. 2595-2602. doi:10.1210/jc.2004-0802
[6]  C. Wang, N. G. Berman, J. D. Veldhuis, T. Der, V. McDonald, B. Steiner and R. S. Swerdloff, “Graded Testosterone Infusions Distinguish Gonadotropin Negative-Feedback Responsiveness in Asian and White Men—A Clinical Research Center Study,” The Journal of Clinical Endocrinology & Metabolism, Vol. 83, No. 3, 1998, pp. 870-876. doi:10.1210/jc.83.3.870
[7]  S. A. P. Hikim, C. Wang, Y. Lue, L. Johnson, X. H. Wang and R. S. Swerdloff, “Spontaneous Germ Cell Apoptosis in Humans: Evidence for Ethnic Differences in the Susceptibility of Germ Cells to Programmed Cell Death,” The Journal of Clinical Endocrinology & Metabolism, Vol. 83, No. 1, 1998, pp. 152-156. doi:10.1210/jc.83.1.152
[8]  P. Aaltonen, J. K. Amory, R. A. Anderson, H. M. Behre, G. Bialy and D. Blithe, “10th Summit Meeting Consensus: Recommendations for Regulatory Approval for Hormonal Male Contraception,” Journal of Andrology, Vol. 28, No. 3, 2007, pp. 362-363. doi:10.2164/jandrol.106.002311
[9]  G. R. Cunningham, V. E. Silverman, J. Thornby and P. O. Kohler, “The Potential for an Androgen Male Contraceptive,” The Journal of Clinical Endocrinology & Metabolism, Vol. 49, No. 4, 1979, pp. 520-526. doi:10.1210/jcem-49-4-520
[10]  C. J. Bagatell, A. M. Matsumoto, R. B. Christensen, J. E. Rivier and W. J. Bremner, “Comparison of a Gonadotropin Releasing-Hormone Antagonist Plus Testosterone (T) Versus T Alone as Potential Male Contraceptive Regimens,” The Journal of Clinical Endocrinology & Metabolism, Vol. 77, No. 2, 1993, pp. 427-432. doi:10.1210/jc.77.2.427
[11]  M. Y. Roth, S. T. Page, K. Lin, B. D. Anawalt, A. M. Matsumoto, B. Marck, W. J. Bremner and J. K. Amory, “The Effect of Gonadotropin Withdrawal and Stimulation With Human Chorionic Gonadotropin on Intratesticular Androstenedione and DHEA in Normal Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 96, No. 4, 2011, pp. 1175-1181. doi:10.1210/jc.2010-2518
[12]  P. J. Snyder and D. A. Lawrence, “Treatment of Male Hypogonadism with Testosterone—Enanthate,” The Journal of Clinical Endocrinology & Metabolism, Vol. 51, No. 6, 1980, pp. 1335-1339. doi:10.1210/jcem-51-6-1335
[13]  Y. Q. Gu, X. H. Wang, D. Xu, L. Peng, L. F. Cheng, M. K. Huang, Z. J. Huang and G. Y. Zhang, “A Multicenter Contraceptive Efficacy Study of Injectable Testosterone Undecanoate in Healthy Chinese Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 88, No. 2, 2003, pp. 562-568. doi:10.1210/jc.2002-020447
[14]  F. Neumann, R. Von Bersworelt-Wallrabe, W. Elger, H. Stienbeck, J. D. Hahn and M. Kramer, “Aspects of Androgen-Dependent Events as Studied by Antiandrogens,” Recent Progress in Hormone Research, Vol. 26, 1970, pp. 337-410.
[15]  Z. Laron, G. Rumney, L. Rat and N. Naji, “Effects of 17α-hydroxy 6α-methyl-Progesterone Acetate (Depoprovera) on Urinary Gonadotrophins and Oestrogens in Man,” Acta Endocrinologica, Vol. 44, 1963, pp. 75-80.
[16]  M. R. N. Prasad and M. Rajalakshmi, “Recent Advances in the Control of Male Reproductive Functions,” In: R. O. Greep, Ed., International Review of Physiology, Reproductive Physiology II, 2nd Edition, University Park Press, Baltimore, 1977, pp. 153-159.
[17]  L.L. Ewing, L. G. Stratton and C. Desjardins, “Effect of Testosterone Polydimethyl-Siloxane Implants upon Sperm Production, Libido and Accessory Sex Organ Function in Rabbits,” Journal of the Society for Reproduction and Fertility, Vol. 25, No. 2, 1973, pp. 245-253. doi:10.1530/jrf.0.0350245
[18]  R. S. Swerdloff, A. Palacios, R. D. McClure, L. A. Campfield and S. A. Brosmen, “Clinical Evaluation of Testosterone Enanthate in the Reversible Suppression of Sperm-Atogenesis in the Human Male: Efficacy, Mechanism of Action and Adverse Effects,” In: D. J. Patanelli, Ed., Hormonal Control of Male Fertility, US DHEW (NIH), Bethesda, 1978, pp. 41-70.
[19]  D. Jayaprakash, K. Sharma, A. S. Ansari and N. K. Lohiya, “Testosterone Enanthate, Single Entity Male Contraceptive Agent in Langur Monkey,” European Archives of Biology, Vol. 105, No. 3, 1994, pp. 103-110.
[20]  World Health Organization Task Force on Methods for the Regulation of Male Fertility, “Contraceptive Efficacy of Testosterone Induced Azoospermia and Oligozoospermia in Normal Men,” Fertility and Sterility, Vol. 65, No. 4, 1996, pp. 821-829.
[21]  World Health Organization Task Force on Methods for the Regulation of Male Fertility, “Contraceptive Efficacy of Testosterone-Induced Azoospermia in Normal Men,” Lancet, Vol. 336, No. 8721, 1990, pp. 955-959. doi:10.1016/0140-6736(90)92416-F
[22]  Y. Gu, X. Liang, W. Wu, M. Liu, S. Song, L. Cheng, L. Bo, C. Xiong, X. Wang, X. Liu, L. Peng and K. Yao, “Multicenter Contraceptive Efficacy Trial of Injectable Testosterone Undecanoate in Chinese Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 94, No. 6, 2009, pp. 1910-1915. doi:10.1210/jc.2008-1846
[23]  K. Heinemann, F. Saad, M. Wiesemes, S. White and L. Heinemann, “Attitudes toward Male Fertility Control: Results of a Multinational Survey on Four Continents,” Human Reproduction, Vol. 20, No. 2, 2005, pp. 549-556. doi:10.1093/humrep/deh574
[24]  D. J. Handelsman, A. J. Conway, C. J. Howe, L. Turner and M. A. Mackey, “Establishing the Minimum Effective Dose and Additive Effects of Depot Progestin in Suppression of Human Spermatogenesis by a Testosterone Depot,” The Journal of Clinical Endocrinology & Metabolism, Vol. 81, No. 11, 1996, pp. 4113-4121. doi:10.1210/jc.81.11.4113
[25]  R. A. Anderson, D. Kinniburgh and D. T. Baird, “Suppression of Spermatogenesis by Etonogestrel Implants With Depot Testosterone: Potential for Long-Acting Male Contraception,” The Journal of Clinical Endocrinology & Metabolism, Vol. 87, No. 8, 2002, pp. 3640-3649. doi:10.1210/jc.87.8.3640
[26]  L. Turner, A. J. Conway, M. Jimenez, P. Y. Liu, E. Forbes, R. I. McLachlan and D. J. Handelsman, “Contraceptive Efficacy of a Depot Progestin and Androgen Combination in Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 88, No. 10, 2003, pp. 4659-4667. doi:10.1210/jc.2003-030107
[27]  J. K. Amory, S. T. Page, B. D. Anawalt, A. M. Matsumoto and W. J. Bremner, “Acceptability of a Combination Testosterone Gel and Depot-Medroxyprogesterone Acetate Male Contraceptive Regimen,” Contraception, Vol. 75, No. 3, 2007, pp. 218-223. doi:10.1016/j.contraception.2006.11.003
[28]  R. S. Swerdloff and C. Wang, “Three-Year Follow-Up of Androgen Treatment in Hypogonadal Men: Preliminary Report with Testosterone Gel,” Aging Male, Vol. 6, No. 3, 2003, pp. 207-211.
[29]  S. T. Page, J. K. Amory, B. D. Anawalt, M. S. Irwig, A. T. Brockenbrough, A. M. Matsumoto and W. J. Bremner, “Testosterone Gel Combined with Depomedroxy-Progesterone Acetate is an Effective Male Hormonal Contraceptive Regimen and is Not Enhanced by the Addition of a GnRH Antagonist,” The Journal of Clinical Endocrinology & Metabolism, Vol. 91, No. 11, 2006, pp. 4374-4380. doi:10.1210/jc.2006-1411
[30]  C. S. Yadav, M. Bajpai, V. Kumar, S. K. Datta, P. Gupta, R. S. Ahmed and B. D. Banerjee, “Polymorphisms in the P450 c17 (17-Hydroxylase/17, 20-Lyase) Gene: Association with Estradiol and Testosterone Concentration in Hypospadias,” Urology, Vol. 78, No. 4, 2011, pp. 902-907. doi:10.1016/j.urology.2011.04.021
[31]  C. Wang and R. S. Swerdloff, “Hormonal Approaches to Male Contraception,” Current Opinion in Urology, Vol. 20, No. 6, 2010, pp. 520-524, doi:10.1097/MOU.0b013e32833f1b4a
[32]  N. K. Lohiya and O. P. Sharma, “Effects of Cyproterone Acetate with Combination of Testosterone Enanthate on Seminal Characteristics, Androgenicity and Clinical Chemistry in Langur Monkey,” Contraception, Vol. 28, No. 6, 1983, pp. 575-586. doi:10.1016/0010-7824(83)90108-7
[33]  N. K. Lohiya, O. P. Sharma, R. C. Sharma and R. S. Sharma, “Reversible Sterility by Cyproterone Acetate Plus Testosterone Enanthate in Langur Monkey with Maintenance of Libido,” Biomedica Biochemica Acta, Vol. 46, No. 4, 1987, pp. 259-266.
[34]  M. C. Meriggiola, W. J. Bremner, C. A. Paulsen, A. Valdiserri, L. Incorvaia, R. Motta, A. Pavani, M. Capelli and Flamigni, “A Combined Regimen of Cyproterone Acetate and Testosterone Enanthate as a Potentially Highly Effective Male Contraceptive,” The Journal of Clinical Endocrinology & Metabolism, Vol. 81, No. 8, 1996, pp. 3018-3023. doi:10.1210/jc.81.8.3018
[35]  M. C. Meriggiola, A. Costantino, S. Cerpolini, W. J. Bremner, D. Huebler, A. M. Morselli Labate, B. Kirsch, A. Bertaccini, C. Pelusi and G. Pelusi, “Testosterone Undecanoate Maintains Spermatogenic Suppression Induced by Cyproteroneacetate Plus Testosterone Undecanoate in Normal Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 88, No. 12, 2003, pp. 5818-5826. doi:10.1210/jc.2003-030574
[36]  M. C. Meriggiola, W. J. Bremner, A. Costantino, G. Di Cintio and C. Flamigni, “Low Dose of Cyproterone Acetate and Testosterone Enanthate for Contraception in Men,” Human Reproduction, Vol. 13, No. 5, 1998, pp. 1225-1229. doi:10.1093/humrep/13.5.1225
[37]  N. Moeloek, D. A. Pujianto and R. Agustin, “Achieving Azoospermia by Injections of Testosterone Undecanoate Alone or Combined with Depot Medroxyprogesterone Acetate in Indonesian Men (Jakarta Center Study),” Proceeding of the 7th International Congress of Andrology, Montreal, 15-19 June 2001, Poster 1/2-133.
[38]  Y. Gu, J. S. Tong, D. Z. Ma, X. H. Wang, D. Yuan, W. H. Tang and W. J. Bremner, “Male Hormonal Contraception: Effects of Injections of Testosterone Undecanoate and Depot Medroxyprogesterone Acetate at Eight-Week Intervals in Chinese Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 89, No. 2, 2004, pp. 2254-2262. doi:10.1210/jc.2003-031307
[39]  F. C. Wu, R. Balasubramanian, T. M. Mulders and H. J. Coelingh-Bennink, “Oral Progestogen Combined with Testosterone as a Potential Male Contraceptive: Additive Effects Between Desogestrel and Testosterone Enanthate in Suppression of Spermatogenesis, Pituitary-Testicular Axis, and Lipid Metabolism,” The Journal of Clinical Endocrinology & Metabolism, Vol. 84, No. 1, 1999, pp. 112-122. doi:10.1210/jc.84.1.112
[40]  B. D. Anawalt, K. L. Herbst, A. M. Matsumoto, T. M. Mulders, H. J. Coelingh-Bennink and W. J. Bremner, “Desogestrel Plus Testosterone Effectively Suppresses Spermato-Genesis but Also Causes Modest Weight Gain and High-Density Lipoprotein Suppression,” Fertility and Sterility, Vol. 74, No. 4, 2000, pp. 707-714. doi:10.1016/S0015-0282(00)01490-4
[41]  D. Kinniburgh, H. Zhu, L. Cheng, A. T. Kicman, D. T. Baird and R. A. Anderson, “Oral Desogestrel with Testosterone Pellets Induces Consistent Suppression of Spermatogenesis to Azoospermia in both Caucasian and Chinese Men,” Human Reproduction, Vol. 17, No. 6, 2002, pp. 1490-1501. doi:10.1093/humrep/17.6.1490
[42]  M. Brady, M. Walton, N. Hollow, A. T. Kicman, D. T. Baird and R. A. Anderson, “Depot Testosterone with Etonogestrel Implants Result in Induction of Azoospermia in all Men for Long-Term Contraception,” Human Reproduction, Vol. 19, No. 6, 2004, pp. 2658-2667. doi:10.1093/humrep/deh491
[43]  J. Hay, B. M. Brady, M. Zitzmann, K. Osmanagaoglu, P. Pollanen and D. Apter, “A Multicenter Phase IIb Study of a Novel Combination of Intramuscular Androgen (Testosterone Decanoate) and Oral Progestogen (Etonogestrel) for Male Hormonal Contraception,” The Journal of Clinical Endocrinology & Metabolism, Vol. 90, No. 4, 2005, pp. 2042-2049. doi:10.1210/jc.2004-0895
[44]  A. Nelson, “New Low-Dose, Extended-Cycle Pills with Levonorgestrel and Ethinyl Estradiol: An Evolutionary Step in Birth Control,” International Journal of Women’s Health, Vol. 2, 2010, pp. 99-106. doi:10.2147/IJWH.S4886
[45]  R. A. Bebb, B. D. Anawalt, R. B. Christensen, C. A. Paulsen, W. J. Bremner and A. M. Matsumoto, “Combined Administration of Levonorgestrel and Testosterone Induces More Rapid and Effective Suppression of Spermatogenesis than Testosterone Alone: A Promising Male Contraceptive Approach,” The Journal of Clinical Endocrinology & Metabolism, Vol. 81, No. 2, 1996, pp. 757-762. doi:10.1210/jc.81.2.757
[46]  B. D. Anawalt, R. A. Bebb, W. J. Bremner and A. M. Matsumoto, “A Lower Dosage Levonorgestrel and Testosterone Combination Effectively Suppresses Spermatogenesis and Circulating Gonadotropin Levels with Fewer Metabolic Effects than Higher Dosage Combinations,” Journal of Andrology, Vol. 20, No. 3, 1999, pp. 407-414.
[47]  B. D. Anawalt, J. K. Amory, K. L. Herbst, A. D. Coviello, S. T. Page, W. J. Bremner and A. M. Matsumoto, “Intramuscular Testosterone Enanthate Plus Very Low Dosage Oral Levonorgestrel Suppresses Spermatogenesis without Causing Weight Gain in Normal Young Men: A Randomized Clinical Trial,” Journal of Andrology, Vol. 26, No. 3, 2005, pp. 405-413. doi:10.2164/jandrol.04135
[48]  A. Kamischke, D. Ploger, S. Venherm, S. von Eckardstein, A. von Eckardstein and E. Nieschlag, “Intramuscular Testosterone Undecanoate with or without Oral Levonorgestrel: A Randomized Placebo-Controlled Feasibility Study for Male Contraception,” Clinical Endocrinology, Vol. 53, No. 1, 2000, pp. 43-52. doi:10.1046/j.1365-2265.2000.01024.x
[49]  K. L. Matthiesson, J. K. Amory, R. Berger, A. Ugoni, R. I. McLachlan and W. J. Bremner, “Novel Male Hormonal Contraceptive Combinations: The Hormonal and Spermatogenic Effects of Testosterone and Levonorgestrel Combined with a 5α-Reductase Inhibitor or Gonadotropin-Releasing Hormone Antagonist,” The Journal of Clinical Endocrinology & Metabolism, Vol. 90, No. 1, 2005, pp. 91-97. doi:10.1210/jc.2004-1228
[50]  I. T. Gonzalo, R. S. Swerdloff, A. L. Nelson, B. Clevenger, R. Garcia, N. Berman and C. Wang, “Levonorgestrel Implants (Norplant II) for Male Contraception Clinical Trials: Combination with Transdermal and Injectable Testosterone,” The Journal of Clinical Endocrinology & Metabolism, Vol. 87, No. 8, 2002, pp. 3562-3572. doi:10.1210/jc.87.8.3562
[51]  A. Kamischke, T. Heuermann, K. Krüger, S. von Eckardstein, I. Schellschmidt, A. Rübig and E. Nieschlag, “An Effective Hormonal Male Contraceptive Using Testosterone Undecanoate With Oral or Injectable Norethisterone Preparations,” The Journal of Clinical Endocrinology & Metabolism, Vol. 87, No. 2, 2002, pp. 530-539. doi:10.1210/jc.87.2.530
[52]  M. C. Meriggiola, A. Costantino, F. Saad, L. D'Emidio, A. M. Morselli Labate, A. Bertaccini, W. J. Bremner, I. Rudolph, M. Ernst, B. Kirsch, G. Martorana and G. Pelusi, “Norethisterone Enanthate plus Testosterone Undecanoate for Male Contraception: Effects of Various Injection Intervals on Spermatogenesis, Reproductive Hormones, Testis, and Prostate,” The Journal of Clinical Endocrinology & Metabolism, Vol. 90, No. 4, 2005, pp. 2005-2014. doi:10.1210/jc.2004-1852
[53]  A. Qoubaitary, C. Meriggiola, C. M. Ng, L. Lumbreras, S. Cerpolini and G. Pelusi, “Pharmacokinetics of Testosterone Undecanoate Injected Alone or in Combination with Norethisterone Enanthate in Healthy Men,” Journal of Andrology, Vol. 27, No. 6, 2006, pp. 853-867. doi:10.2164/jandrol.106.000281

Full-Text

comments powered by Disqus