Keywords
Testosterone Undecanoate
Retinoic Acid Inhibitors
Vasal peristalsis blockers
How to Cite
Abstract
New male contraceptive methods would expand male and female contraceptive alternatives and enhance male contraceptive agency. Since 1969, a program for developing contraceptives has been financed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which also continues to fund the majority of hormonal male contraceptive development today. Also, the early stages of non-hormonal techniques start to develop. The hormonal male contraceptive methods, include testosterone undecanoate injection plus norethisterone enanthate injection, implants of testosterone plus depo-medroxyprogesterone acetate injection, testosterone enanthate injection, and other testosterone-based methods. The non-hormonal methods, include novel hormone-free substances such as retinoic acid inhibitors, sperm ion channel blockers, and vasal peristalsis blockers. The review provides insights into the efficacy, safety, and potential side effects of each method, and highlights the current state of research and development in the field of male contraception.
References
Aaltonen, P., Amory, J.K., Anderson, R.A., Behre, H.M., Bialy, G., Blithe, D., Zitzmann, M. (2007). 10th Summit Meeting consensus: recommendations for regulatory approval for hormonal male contraception. Journal of Andrology, 28(3), 362-363.
Attardi, B.J., Hild, S.A., Reel, J.R. (2006). Dimethandrolone undecanoate: a new potent orally active androgen with progestational activity. Endocrinology, 147(6), 3016-3026.
Attardi, B.J., Marck, B.T., Matsumoto, A.M., Koduri, S., Hild, S.A. (2011). Long?Term Effects of Dimethandrolone 17??Undecanoate and 11??Methyl?19?Nortestosterone 17??Dodecylcarbonate on Body Composition, Bone Mineral Density, Serum Gonadotropins, and Androgenic/Anabolic Activity in Castrated Male Rats. Journal of Andrology, 32(2), 183-192.
Ayoub, R., Page, S.T., Swerdloff, R.S., Liu, P.Y., Amory, J.K., Leung, A., Wang, C. (2017). Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive. Andrology, 5(2), 278-285.
Barone, M.A., Irsula, B., Chen-Mok, M., Sokal, D.C., Investigator study group (2004). Effectiveness of vasectomy using cautery. BMC Urology, 4, 1-9.
Behre, H.M., Zitzmann, M., Anderson, R.A., Handelsman, D.J., Lestari, S. W., McLachlan, R.I., Colvard, D.S. (2016). Efficacy and safety of an injectable combination hormonal contraceptive for men. The Journal of Clinical Endocrinology Metabolism, 101(12), 4779-4788.
Belker, A.M., Thomas Jr, A.J., Fuchs, E.F., Konnak, J.W., Sharlip, I.D. (1991). Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. The Journal of Urology, 145(3), 505-511.
Black, K.I., Gupta, S., Rassi, A., Kubba, A. (2010). Why do women experience untimed pregnancies? A review of contraceptive failure rates. Best Practice Research Clinical Obstetrics Gynaecology, 24(4), 443-455.
Blithe, D.L. (2016). Pipeline for contraceptive development. Fertility and Sterility, 106(6), 1295-1302.
Bryant, J.M., Berger, S.L. (2012). Low?hanging fruit: targeting Brdt in the testes. The EMBO Journal, 31(19), 3788-3789.
Campelia, G.D., Abbe, C., Nickels, L.M., McElmeel, E., Amory, J.K. (2020). “Shared risk”: Reframing risk analysis in the ethics of novel male contraceptives. Contraception, 102(2), 67-69.
Carlson, A.E., Burnett, L.A., del Camino, D., Quill, T.A., Hille, B., Chong, J.A., Babcock, D.F. (2009). Pharmacological targeting of native CatSper channels reveals a required role in maintenance of sperm hyperactivation. PloS One, 4(8), e6844.
Chávez, J.C., Ferreira, J.J., Butler, A., Beltrán, J.L.D.L.V., Treviño, C.L., Darszon, A., Santi, C.M. (2014). SLO3 K+ channels control calcium entry through CATSPER channels in sperm. Journal of Biological Chemistry, 289(46), 32266-32275.
Cheng, C.Y. (2014). Toxicants target cell junctions in the testis: insights from the indazole-carboxylic acid model. Spermatogenesis, 4(2), e981485.
Chung, S.S., Wang, X., Wolgemuth, D.J. (2005). Male sterility in mice lacking retinoic acid receptor ? involves specific abnormalities in spermiogenesis. Differentiation, 73(4), 188-198.
Chung, S.S., Wang, X., Wolgemuth, D.J. (2016). Prolonged oral administration of a pan-retinoic acid receptor antagonist inhibits spermatogenesis in mice with a rapid recovery and changes in the expression of influx and efflux transporters. Endocrinology, 157(4), 1601-1612.
Chung, S.S., Wang, X., Roberts, S.S., Griffey, S.M., Reczek, P.R., Wolgemuth, D.J. (2011). Oral administration of a retinoic acid receptor antagonist reversibly inhibits spermatogenesis in mice. Endocrinology, 152(6), 2492-2502.
Curci, L., Carvajal, G., Sulzyk, V., Gonzalez, S. N., Cuasnicú, P.S. (2021). Pharmacological inactivation of CatSper blocks sperm fertilizing ability independently of the capacitation status of the cells: implications for non-hormonal contraception. Frontiers in Cell and Developmental Biology, 9, 686461.
Dorman, E., Perry, B., Polis, C.B., Campo-Engelstein, L., Shattuck, D., Hamlin, A., Sokal, D. (2018). Modeling the impact of novel male contraceptive methods on reductions in unintended pregnancies in Nigeria, South Africa, and the United States. Contraception, 97(1), 62-69.
Finer, L.B., Zolna, M.R. (2016). Declines in unintended pregnancy in the United States, 2008–2011. New England Journal of Medicine, 374(9), 843-852.
Gao, Y., Sun, Y., Zheng, W., Lin, Y.F., Tian, T., Li, Y., Zou, H. (2022). Risk Compensation in Voluntary Medical Male Circumcision Programs. Current HIV/AIDS Reports, 19(6), 516-521.
Glasier, A. (2010). Acceptability of contraception for men: a review. Contraception, 82(5), 453-456.
Golub, S.A., Starks, T.J., Payton, G., Parsons, J.T. (2012). The critical role of intimacy in the sexual risk behaviors of gay and bisexual men. AIDS and Behavior, 16, 626-632.
Gu, Y.Q., Tong, J.S., Ma, D.Z., Wang, X.H., Yuan, D., Tang, W.H., Bremner, W. J. (2004). 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, 89(5), 2254-2262.
Gu, Y.Q., Wang, X.H., Xu, D., Peng, L., Cheng, L.F., Huang, M.K., Zhang, G.Y. (2003). A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. The Journal of Clinical Endocrinology Metabolism, 88(2), 562-568.
Gu, Y., Liang, X., Wu, W., Liu, M., Song, S., Cheng, L., Yao, K. (2009). Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. The Journal of Clinical Endocrinology Metabolism, 94(6), 1910-1915.
Hamm, M., Evans, M., Miller, E., Browne, M., Bell, D., Borrero, S. (2019). “It's her body”: low-income men's perceptions of limited reproductive agency. Contraception, 99(2), 111-117.
Heinemann, K., Saad, F., Wiesemes, M., White, S., Heinemann, L. (2005). Attitudes toward male fertility control: results of a multinational survey on four continents. Human Reproduction, 20(2), 549-556.
Heller, C.G., Moore, D.J., Paulsen, C.A. (1961). Suppression of spermatogenesis and chronic toxicity in men by a new series of bis (dichloroacetyl) diamines. Toxicology and Applied Pharmacology, 3(1), 1-11.
Hellstrom, W.J., Sikka, S.C. (2009). Effects of alfuzosin and tamsulosin on sperm parameters in healthy men: Results of a short?term, randomized, double?blind, placebo?controlled, crossover study. Journal of Andrology, 30(4), 469-474.
Hellstrom, W.J., Wang, R., Peterson, C.A., Varady, J.C., Gesundheit, N., Sikka, S.C. (1998). Effects of alprostadil and prazosin on motility, viability and membrane integrity of human sperm. The Journal of Urology, 159(5), 1559-1562.
Hild, S.A., Marshall, G.R., Attardi, B.J., Hess, R.A., Schlatt, S., Simorangkir, D.R., Plant, T.M. (2007). Development of l-CDB-4022 as a nonsteroidal male oral contraceptive: induction and recovery from severe oligospermia in the adult male cynomolgus monkey (Macaca fascicularis). Endocrinology, 148(4), 1784-1796.
Hild, S.A., Reel, J.R., Dykstra, M.J., Mann, P.C., Marshall, G.R. (2007). Acute adverse effects of the indenopyridine CDB?4022 on the ultrastructure of Sertoli cells, spermatocytes, and spermatids in rat testes: comparison to the known Sertoli cell toxicant di?n?pentylphthalate (DPP). Journal of Andrology, 28(4), 621-629.
Homonnai, Z.T., Shilon, M., Paz, G.F. (1984). Phenoxybenzamine—an effective male contraceptive pill. Contraception, 29(5), 479-491.
Ilani, N., Roth, M.Y., Amory, J.K., Swerdloff, R.S., Dart, C., Page, S.T., Wang, C. (2012). A new combination of testosterone and nestorone transdermal gels for male hormonal contraception. The Journal of Clinical Endocrinology Metabolism, 97(10), 3476-3486.
Johnson, D., Sandlow, J.I. (2017). Vasectomy: tips and tricks. Translational andrology and Urology, 6(4), 704.
Kauffenstein, G., Pelletier, J., Lavoie, E.G., Kukulski, F., Martín-Satué, M., Dufresne, S. S., Sévigny, J. (2014). Nucleoside triphosphate diphosphohydrolase-1 ectonucleotidase is required for normal vas deferens contraction and male fertility through maintaining P2X1 receptor function. Journal of Biological Chemistry, 289(41), 28629-28639.
Kavanaugh, M.L., Jerman, J. (2018). Contraceptive method use in the United States: trends and characteristics between 2008, 2012 and 2014. Contraception, 97(1), 14-21.
Kendrick, J.S., Gonzales, B., Huber, D.H., Grubb, G.S., Rubin, G.L. (1987). Complications of vasectomies in the United States. J Fam Pract, 25(3), 245-248.
Kjærgaard, N., Kjærgaard, B., Lauritsen, J.G. (1988). Prazosin, an adrenergic blocking agent inadequate as male contraceptive pill. Contraception, 37(6), 621-629.
Liu, Y., Zhang, C., Wang, S., Hu, Y., Jing, J., Ye, L., Ding, Z. (2020). Dependence of sperm structural and functional integrity on testicular calcineurin isoform PPP3R2 expression. Journal of Molecular Cell Biology, 12(7), 515-529.
Long, J.E., Lee, M.S., Blithe, D.L. (2021). Update on novel hormonal and nonhormonal male contraceptive development. The Journal of Clinical Endocrinology Metabolism, 106(6), e2381-e2392.
Majra, J.P. (2010). Use of condoms: Clarifying the message. Indian Journal of Community Medicine, 35(2), 362.
Male, M.F.T.R.O. (1990). Contraceptive efficacy of testosterone-induced azoospermia in normal men. The Lancet, 336(8721), 955-959.
Mannowetz, N., Miller, M.R., Lishko, P.V. (2017). Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids. Proceedings of the National Academy of Sciences, 114(22), 5743-5748.
Meriggiola, M.C., Costantino, A., Cerpolini, S., Bremner, W. J., Huebler, D., Morselli-Labate, A.M., Pelusi, G. (2003). Testosterone undecanoate maintains spermatogenic suppression induced by cyproterone acetate plus testosterone undecanoate in normal men. The Journal of Clinical Endocrinology Metabolism, 88(12), 5818-5826.
Miyata, H., Oura, S., Morohoshi, A., Shimada, K., Mashiko, D., Oyama, Y., Ikawa, M. (2021). SPATA33 localizes calcineurin to the mitochondria and regulates sperm motility in mice. Proceedings of the National Academy of Sciences, 118(35), e2106673118.
Miyata, H., Satouh, Y., Mashiko, D., Muto, M., Nozawa, K., Shiba, K., Ikawa, M. (2015). Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive. Science, 350(6259), 442-445.
Mok, K.W., Mruk, D.D., Lie, P.P., Lui, W.Y., Cheng, C.Y. (2011). Adjudin, a potential male contraceptive, exerts its effects locally in the seminiferous epithelium of mammalian testes. Reproduction (Cambridge, England), 141(5), 571.
Mommers, E., Kersemaekers, W.M., Elliesen, J., Kepers, M., Apter, D., Behre, H.M., Zitzmann, M. (2008). Male hormonal contraception: a double-blind, placebo-controlled study. The Journal of Clinical Endocrinology Metabolism, 93(7), 2572-2580.
Mruk, D.D., Wong, C. H., Silvestrini, B., Cheng, C.Y. (2006). A male contraceptive targeting germ cell adhesion. Nature Medicine, 12(11), 1323-1328.
Mulryan, K., Gitterman, D.P., Lewis, C.J., Vial, C., Leckie, B.J., Cobb, A.L., Evans, R.J. (2000). Reduced vas deferens contraction and male infertility in mice lacking P2X1 receptors. Nature, 403(6765), 86-89.
Nasrullah, M., Oraka, E., Chavez, P.R., Johnson, C.H., DiNenno, E. (2017). Factors associated with condom use among sexually active US adults, national survey of family growth, 2006–2010 and 2011–2013. The Journal of Sexual Medicine, 14(4), 541-550.
Nguyen, B.T., Farrant, M.T., Anawalt, B.D., Yuen, F., Thirumalai, A., Amory, J.K., Swerdloff, R.S., Bremner, W.J., Liu, P.Y., Blithe, D.L., Page, S.T. (2020). Acceptability of oral dimethandrolone undecanoate in a 28-day placebo-controlled trial of a hormonal male contraceptive prototype. Contraception. 102(1),52-7.
Nguyen, B.T. (2024). The demand for male contraception: Estimating the potential market for users of novel male contraceptive methods using United States National Survey of Family Growth data. Contraception, 110438.
Nieschlag, E. (2010). Clinical trials in male hormonal contraception. Contraception, 82(5), 457-470.
Nieschlag, E., Kumar, N., Sitruk-Ware, R. (2013). 7?-methyl-19-nortestosterone (MENTR): the population council's contribution to research on male contraception and treatment of hypogonadism. Contraception, 87(3), 288-295.
Noman, M.A.A., Kyzer, J.L., Chung, S.S., Wolgemuth, D.J., Georg, G.I. (2020). Retinoic acid receptor antagonists for male contraception: current status. Biology of Reproduction, 103(2), 390-399.
Noori, F.R., Althanoon, Z.A. (2022a). Evaluation of glycemic control in users of oral contraceptive pills in Mosul City. Azerbaijan Medical Journal 62(05).
Noori, F.R., Althanoon, Z.A. (2022b). Effects Of Estrogen and Progesterone Used in Oral Contraceptive Pills: A review. Iraqi Journal of Pharmacy, 19(1), 134-146.
O’Rand, M.G., Hamil, K.G., Adevai, T., Zelinski, M. (2018). Inhibition of sperm motility in male macaques with EP055, a potential non-hormonal male contraceptive. PLoS One, 13(4), e0195953.
O’Rand, M.G., Widgren, E.E., Hamil, K.G., Silva, E.J., Richardson, R.T. (2011). Functional studies of eppin. Biochemical Society Transactions, 39(5), 1447-1449.
Page, S.T., Amory, J.K., Anawalt, B. D., Irwig, M.S., Brockenbrough, A.T., Matsumoto, A.M., Bremner, W.J. (2006). Testosterone gel combined with depomedroxyprogesterone 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, 91(11), 4374-4380.
Paz, G.F., Shilon, M., Homonnai, Z.T. (1984). The possible use of phenoxybenzamine as a male contraceptive drug: studies on male rats. Contraception, 29(2), 189-195.
Pozor, M.A., Macpherson, M.L., McDonnell, S.M., Nollin, M., Roser, J.F., Love, C., Troedsson, M.H. (2013). Indenopyride derivative RTI-4587-073 (l): a candidate for male contraception in stallions. Theriogenology, 80(9), 1006-1016.
Qi, H., Moran, M.M., Navarro, B., Chong, J.A., Krapivinsky, G., Krapivinsky, L., Clapham, D.E. (2007). All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. Proceedings of the National Academy of Sciences, 104(4), 1219-1223.
Quill, T.A., Sugden, S.A., Rossi, K.L., Doolittle, L.K., Hammer, R.E., Garbers, D.L. (2003). Hyperactivated sperm motility driven by CatSper2 is required for fertilization. Proceedings of the National Academy of Sciences, 100(25), 14869-14874.
Reece, M., Herbenick, D., Schick, V., Sanders, S.A., Dodge, B., Fortenberry, J.D. (2010). Condom use rates in a national probability sample of males and females ages 14 to 94 in the United States. The Journal of Sexual Medicine, 7, 266-276.
Rehfeld, A. (2020). Revisiting the action of steroids and triterpenoids on the human sperm Ca2+ channel CatSper. Molecular Human Reproduction, 26(11), 816-824.
Rennhack, A., Schiffer, C., Brenker, C., Fridman, D., Nitao, E.T., Cheng, Y.M., Strünker, T. (2018). A novel cross?species inhibitor to study the function of CatSper Ca2+ channels in sperm. British Journal of Pharmacology, 175(15), 3144-3161.
Ross, J., Hardee, K. (2017). Use of male methods of contraception worldwide. Journal of Biosocial Science, 49(5), 648-663.
Roth, M.Y., Ilani, N., Wang, C., Page, S. T., Bremner, W. J., Swerdloff, R. S., Amory, J. K. (2013). Characteristics associated with suppression of spermatogenesis in a male hormonal contraceptive trial using testosterone and Nestorone® gels. Andrology, 1(6), 899-905.
Roth, M.Y., Shih, G., Ilani, N., Wang, C., Page, S.T., Bremner, W.J., Amory, J. K. (2014). Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial. Contraception, 90(4), 407-412.
Sævareid, L.O. (2022). Hormonell prevensjon for menn–UiT-studenters holdninger. En spørreundersøkelse (Master's thesis, UiT Norges arktiske universitet). Masteroppgave i profesjonsstudiet medisin MED-3950, June 2022.
Schleif, M.C., Havel, S.L., Griswold, M.D. (2022). Function of retinoic acid in development of male and female gametes. Nutrients, 14(6), 1293.
Schulze, G.E., Clay, R.J., Mezza, L.E., Bregman, C.L., Buroker, R.A., Frantz, J.D. (2001). BMS-189453, a novel retinoid receptor antagonist, is a potent testicular toxin. Toxicological Sciences, 59(2), 297-308.
Service, C.A., Puri, D., Hsieh, T.C., Patel, D.P. (2023). Emerging concepts in male contraception: a narrative review of novel, hormonal and non-hormonal options. Therapeutic Advances in Reproductive Health, 17, 26334941221138323.
Smith, M.D., Grov, C., Seal, D.W. (2009). Agency-based male sex work: A descriptive focus on physical, personal, and social space. The Journal of Men’s Studies, 16(2), 193-210.
Sun, X.H., Zhu, Y.Y., Wang, L., Liu, H.L., Ling, Y., Li, Z.L., Sun, L.B. (2017). The Catsper channel and its roles in male fertility: a systematic review. Reproductive Biology and Endocrinology, 15, 1-12.
Sundaram, A., Vaughan, B., Kost, K., Bankole, A., Finer, L., Singh, S., Trussell, J. (2017). Contraceptive failure in the United States: estimates from the 2006–2010 National Survey of Family Growth. Perspectives on Sexual and Reproductive Health, 49(1), 7-16.
Thirumalai, A., Ceponis, J., Amory, J.K., Swerdloff, R., Surampudi, V., Liu, P.Y., Page, S.T. (2019). Effects of 28 days of oral dimethandrolone undecanoate in healthy men: a prototype male pill. The Journal of Clinical Endocrinology Metabolism, 104(2), 423-432.
Thirumalai, A., Yuen, F., Amory, J.K., Hoofnagle, A.N., Swerdloff, R.S., Liu, P.Y., Page, S.T. (2021). Dimethandrolone undecanoate, a novel, nonaromatizable androgen, increases P1NP in healthy men over 28 days. The Journal of Clinical Endocrinology Metabolism, 106(1), e171-e181.
Thirumalai, K., Clemens, S.C., Partin, J.W. (2020). Methane, monsoons, and modulation of millennial?scale climate. Geophysical Research Letters, 47(9), e2020GL087613.
Trussell, J. (2004). Contraceptive failure in the United States. Contraception, 70(2), 89-96.
Turner, L., Conway, A.J., Jimenez, M., Liu, P.Y., Forbes, E., McLachlan, R. I., Handelsman, D.J. (2003). Contraceptive efficacy of a depot progestin and androgen combination in men. The Journal of Clinical Endocrinology Metabolism, 88(10), 4659-4667.
Waites, G.M. (2003). Development of methods of male contraception: impact of the World Health Organization Task Force. Fertility and Sterility, 80(1), 1-15.
Wang, C., Festin, M.P.R., Swerdloff, R.S. (2016). Male Hormonal Contraception: Where Are We Now? Current Obstetrics and Gynecology Reports, 5 (1), 38-47.
Wang, C., Wang, X.H., Nelson, A.L., Lee, K.K., Cui, Y.G., Tong, J.S., Swerdloff, R.S. (2006). Levonorgestrel implants enhanced the suppression of spermatogenesis by testosterone implants: comparison between Chinese and non-Chinese men. The Journal of Clinical Endocrinology Metabolism, 91(2), 460-470.
Wang, J., Zhao, Y., Jiang, S.B., Xia, Q.H., Wei, C.X., Wang, M.W., Jin, X.B. (2012). Assessment of tamsulosin as a potential male contraceptive in healthy volunteers. Urology, 80(3), 614-617.
Wisniewski, A., Georg, G.I. (2020). BET proteins: Investigating BRDT as a potential target for male contraception. Bioorganic Medicinal Chemistry Letters, 30(6), 126958.
Wrighton, D.C., Muench, S.P., Lippiat, J.D. (2015). Mechanism of inhibition of mouse S lo3 (K Ca5. 1) potassium channels by quinine, quinidine and barium. British Journal of Pharmacology, 172(17), 4355-4363.
Wu, F.C., Farley, T.M., Peregoudov, A., Waites, G.M. (1996). Effects of testosterone enanthate in normal men: experience from a multicenter contraceptive efficacy study. Fertility and Sterility, 65(3), 626-636.
Wu, S., Yuen, F., Swerdloff, R.S., Pak, Y., Thirumalai, A., Liu, P.Y., Wang, C. (2019). Safety and pharmacokinetics of single-dose novel oral androgen 11 ?-methyl-19-nortestosterone-17 ?-dodecylcarbonate in men. The Journal of Clinical Endocrinology Metabolism, 104(3), 629-638.
Yang, F., Li, J., Dong, L., Tan, K., Huang, X., Zhang, P., Yu, X. (2021). Review of vasectomy complications and safety concerns. The World Journal of Men's Health, 39(3), 406.
Yuen, F., Thirumalai, A., Pham, C., Swerdloff, R.S., Anawalt, B.D., Liu, P.Y., Page, S.T. (2020). Daily oral administration of the novel androgen 11?-MNTDC markedly suppresses serum gonadotropins in healthy men. The Journal of Clinical Endocrinology Metabolism, 105(3), e835-e847.
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