Male contraceptive

Male contraceptives, also known as male birth control, are methods of preventing pregnancy that solely involve the male physiology. The most common kinds of male contraception include condoms, outercourse,[1] and vasectomy.[2] In domestic animals, castration is commonly used for contraception. Other forms of male contraception are in various stages of research and development.[3] These include methods like RISUG/VasalGel (which has completed a small phase II clinical trial in humans in India)[4] and ultrasound (with results so far obtained in experimental animals).[5][6]

Male contraceptive
A rolled-up condom

Methods

Surgery

Vasectomy is a surgical procedure for male sterilization or permanent birth control. During the procedure, the vasa deferentia of a man are severed, and then tied or sealed to prevent sperm from entering into the seminal stream (ejaculate). Vasectomies are usually performed in a physician's office or medical clinic. CDC research has estimated there is a probability of 11 failures per 1,000 procedures over 2 years; half of the failures occurred in the first three months after the vasectomy, and no failures occurred after 72 weeks. Due to the presence of sperm retained beyond the blocked vasa deferentia, vasectomies only become effective about three months following the operation.[7]

Condoms

A condom is a sheath-shaped barrier device that may be used during sexual intercourse to reduce the probability of pregnancy. It is rolled onto an erect penis before intercourse and blocks ejaculated semen from entering the sexual partner's reproductive system.[8] With perfect use, the pregnancy rate of condoms is 2%.[9][10] Condoms may be combined with other forms of contraception (such as spermicide) for greater protection.[10] The typical use pregnancy rate among condom users varies depending on the population being studied, ranging from 10 to 18%.[11]

Withdrawal

The withdrawal method is a behavior that involves halting penile-vaginal intercourse to remove the penis out and away from the vagina prior to ejaculation.[12] Pulling out is a popular contraceptive behavior that may couples use because of convenience, dissatisfaction with other methods, it’s free of expense, and has constant availability.[13] Failure rate varies with population studied, but withdrawal is overall not considered to be efficacious enough to be the sole method of pregnancy prevention being utilized. The accepted rate of failure is about 4% with perfect use at every act of intercourse,[14] but the failure rate with typical use ranges in between 18%[15] and 27%[16][12]

Retrograde ejaculation

Intentional retrograde ejaculation (coitus saxonicus) is a primitive form of male birth control.[17] It involves squeezing the urethra at the base or applying pressure to the perineum during orgasm. However, the practice is not considered a reliable method compared to most modern types of birth control.

History

Dioscorides, ca. 40 A.D., described the contraceptive property of hemp seeds (Cannabis sativa) and rue (Ruta graveolens) in De Materia Medica, a text widely used into medieval times.[18] One test in rats (20 milligrams of the 80% ethanol extract) found that these reduced sperm count by more than half.[19] In medieval Persia (and in other traditions as cited) these herbs were used for male contraception, as well as Gossypium herbaceum (Malvaceae),[20] Cyperus longus (Cyperaceae), Vitex pseudonegundo (Verbenaceae), Chenopodium ambrosioides (Chenopodiaceae),[21][22] Aristolochia indica (Aristolochiaceae),[23] Punica granatum (Punicaceae),[24] and Sarcostemma acidum (Asclepiadaceae).[25] However, the compound isolated from Gossypium, as well as other cotton seeds and okra (gossypol) has been abandoned for contraceptive use because it was found to cause permanent infertility in ten to twenty percent of users.[26]

In Indian traditional medicine, uses of the neem tree were described in Ayurvedic medicine, by Sushruta and in the Rasarathasamucchaya, Sarangadhara, Bhavaprakasha and Bhisagya Ratnavali. Held traditionally to have antifertility effects, its leaves were demonstrated to reduce pregnancy rate and litter size in a test of male rats.[27]

In 1995, researchers isolated compounds from a plant used in Chinese herbal medicine called Tripterygium wilfordii (雷公籐, lei gong teng).[28]

In 2002, researchers fed extracts from the seeds of papaya fruits (Carica papaya) to monkeys. Subsequently, the monkeys had no sperm in their ejaculate.[29] Traditionally used for contraception, papaya seeds had no apparent ill effects on the testes or other organs of rats tested with a long-term treatment.[30]

Heat-based contraception, dating in concept to the writings of Hippocrates, involves heating the testicles to prevent the formation of sperm. Requiring the maintenance of testes at 116 °F (47 °C) (just below the threshold of pain) for 45 minutes, it is not a widely appealing technique, but a variant employing ultrasound has been under investigation.[31]

Research

A goal of research is to develop a reversible male contraceptive, either pharmaceutical, surgical or other.

Medications

Two delivery methods are currently under active study: male hormonal contraceptives that can be taken in pill form by mouth, similar to the existing birth control pill for women[32] and male hormonal injections.[33]

  • Gossypol, an extract of cotton, has been studied as a male contraceptive pill. It decreased sperm production; however this is permanent in 20% of people.[34]
  • Inhibition of chromatin remodeling by binding to a pocket on BRDT has been shown to produce reversible sterility in male mice.[35] JQ1, a selective BRDT inhibitor which acts in this manner, is currently under development as a non-hormonal male contraceptive drug. It effectively blocks the production of sperm by the testes, and lacks the adverse effects of previously researched hormonal contraceptives for men.[36]
  • Immunocontraception targeting sperm antigens has been found to be effective in male primates.[37]
  • Calcium channel blockers such as nifedipine may cause reversible infertility by altering the lipid metabolism of sperm so that they are not able to fertilize an egg.[38] Recent Research at Israel's Bar-Ilan University show that as of June 2010, such a pill may be five years away. Testing it on mice has been found to be effective, with no side effects.[39]
  • A compound that interferes with the vitamin A pathway has been shown to render male mice sterile for the course of the treatment without affecting libido. Once taken off the compound, the mice continued to make sperm. The mechanism of action includes blocking the conversion of vitamin A into its active form retinoic acid which binds to retinoic receptors which is needed to initiate sperm production.[40][41] This can be done, for instance, by blocking an aldehyde dehydrogenase called RALDH3 (ALDH1A2), which converts retinaldehyde into retionic acid in testes. Past attempts to do this failed because the blocking compounds were not sufficiently specific and also blocked other aldehyde dehydrogenases, such as those responsible for the alcohol metabolism, causing serious side effects.[42] Another way is blocking retionic receptors themselves, although it can also have serious side effects.[40]
  • Adjudin, a non-toxic analog of lonidamine has been shown to cause reversible infertility in rats.[43] The drug disrupts the junctions between nurse cells (Sertoli cells) in the testes and forming spermatids. The sperm are released prematurely and never become functional gametes. A new targeted delivery mechanism has made Adjudin much more effective.[44]
  • Gamendazole, a derivative of lonidamine, shows semi-reversible infertility in rats. The mechanism of action is thought to be disruption of Sertoli cell function, resulting in decreased levels of inhibin B.[45]
  • Multiple male hormonal contraceptive protocols have been developed. One is a combination protocol, involving injections of Depo-Provera to prevent spermatogenesis, combined with the topical application of testosterone gel to provide hormonal support.[46][47] A similar proposal consists of yearly subdermal implant administering a synthetic testosterone compound (7α-methyl-19-nortestosterone) combined with regular injections of Depo-Provera.[48] The implant alone (without Depo-Provera injections) has been shown to already sufficiently reduce sperm count in most of the subjects given the highest tested dosage in a Phase II trial.[49] Another is a monthly injection of testosterone undecanoate, which recently performed very well in a Phase III trial in China.[50][51]
  • Phenoxybenzamine has been found to block ejaculation, which gives it the potential to be an effective contraceptive. Studies have found that the quality of the semen is unaffected and the results are reversible by simply discontinuing the treatment.[52]
  • Trestolone is an anabolic steroid that has been shown to significantly reduce sperm count.[53]
  • A male birth control pill based on ouabain, a plant extract used by traditional African hunters to stop the hearts of game, has been shown to reduce sperm motility sufficiently for effective contraception in rats. [54]
  • Dimethandrolone undecanoate, or DMAU is currently being tested as a new male birth control pill. This experimental male oral contraceptive is a male hormone like testosterone, and a progestin. Currently conducting research on this new medication is Stephanie Page, M.D., PhD, professor of medicine at the University of Washington, Seattle, Wash and co-author Christina Wang, M.D. Their study consists of 100 healthy men between the ages 18 to 50 years. They tested three different doses of DMAU (100, 200, and 400 milligrams) for 28 days. Each dosage group included five participants who receive an inactive placebo and 12 to 15 men who received DMAU. The results of the study were reported promising by Stephanie Page, M.D., PhD and co-author Christina Wang, M.D. A total of 83 men completed the study and successfully provided the researchers with blood and cholesterol samples. The participants in the dosage group with the highest dose of DMAU tested, 400 mg, showed "marked suppression" of testosterone levels and two hormones involved in sperm production. "Despite having low levels of circulating testosterone, very few subjects reported symptoms consistent with testosterone deficiency or excess," Page reported. Overall, all participants in their study experienced weight gain and a decrease in HDL cholesterol. All subjects passed safety tests involving liver and kidney function. "These promising results are unprecedented in the development of a prototype male pill," Page said. "Longer term studies are currently under way to confirm that DMAU taken every day blocks sperm production."[55]

Surgical methods
  • RISUG consists of injecting a polymer gel, styrene maleic anhydride in dimethyl sulfoxide, into the vas deferens. The polymer has a positive charge, and when negatively charged sperm pass through the vas deferens, the charge differential severely damages the sperm.[5] A second injection washes out the substance and restores fertility. As of 2011, RISUG is in Phase III of human testing in India and has been patented in India, China, Bangladesh and the United States. Vasalgel is a brand name of polymer gel injection that is being tested in the United States. Testing on rabbits and primates showed positive results. [56][57]
  • Vas-occlusive contraception consists of partially or completely blocking the vas deferens, the tubes connecting the epididymis to the urethra. While a vasectomy removes a piece of each vas deferens, the intra vas device (IVD) and other injectable plugs only block the tubes until the devices are removed. The U.S. Food and Drug Administration (FDA) approved human clinical trials for the intra-vas device in 2006.[58]

Other
  • Research on the safety and effectiveness of using ultrasound treatments to kill sperm has undergone since the idea originally came about following experiments in the 1970s by Mostafa S. Fahim who noticed ultrasound killed microbes and decreased fertility.[59] As of 2012 a study conducted on rats found that two 15-minute treatments of ultrasound delivered 2 days apart in a warm salt bath effectively lowered their sperm count to below fertile levels.[6][59] Another small study involved dogs, and found that after three ultrasound applications the dogs' ejaculate contained no sperm.[5] Further experiments on its effectiveness on humans, the longevity of the results, and its safety have yet to be conducted.[59]
  • Keeping testicles in a higher temperature. One method involves wearing special underwear. A group in France called Collectif Thomas Bouloù have been testing it intensively for a few years.

Abandoned research
  • Miglustat (Zavesca or NB-DNJ) is a drug approved for treatment of several rare lipid storage disorder diseases. In mice, it provided effective and fully reversible contraception. But it seems this effect was only true for several genetically related strains of laboratory mice. Miglustat showed no contraceptive effect in other mammals.[60]
  • Silodosin, an α1-adrenoceptor antagonist with high uroselectivity, approved by the FDA to treat Benign Prostatic Hyperplasia (BPH), has been shown to decrease sperm count when taken in at 5 times normal doses.[61]

Impact

It is predicted that introduction of a long-acting reversible contraception for males could decrease the rate of unintended pregnancy.[62]

References
  1. "Birth Control for Men - How Can Men Prevent Pregnancy?". Retrieved 13 March 2017.
  2. Glasier A (November 2010). "Acceptability of contraception for men: a review". Contraception. 82 (5): 453–6. doi:10.1016/j.contraception.2010.03.016. PMID 20933119.
  3. "Male birth control pill soon a reality". 26 November 2003. Retrieved 13 March 2017.
  4. Guha, Sujoy; Singh G; Ansari S; Kumar S; Srivastava A; Koul V; Das HC; Malhotra RL; Das SK. (Oct 1997). "Phase II clinical trial of a vas deferens injectable contraceptive for the male". Contraception. 56 (4): 245–50. doi:10.1016/s0010-7824(97)00142-x. PMID 9408706.
  5. Expanding Options for Male Contraception. Planned Parenthood Advocates of Arizona. August 8, 2011. Retrieved April 1, 2012.
  6. Tsuruta, James K.; Dayton PA, Gallippi CM, O'Rand MG, Streicker MA, Gessner RC, Gregory TS, Silva EJ, Hamil KG, Moser GJ, Sokal DC. (30 January 2012). "Therapeutic ultrasound as a potential male contraceptive: power, frequency and temperature required to deplete rat testes of meiotic cells and epididymides of sperm determined using a commercially available system". Reprod. Biol. Endocrinol. 10 (7): 7. doi:10.1186/1477-7827-10-7. PMC 3340307. PMID 22289508.CS1 maint: multiple names: authors list (link)
  7. <http://www.plannedparenthood.org/health-topics/birth-control-4211.htm >.
  8. "Condom | Definition of Condom by Merriam-Webster". Merriam-webster.com. Retrieved 2016-05-14.
  9. Hatcher, RA; Trussel, J; Nelson, AL; et al. (2007). "Contraceptive Technology (19th ed.)". Archived from the original on 2008-05-31. Retrieved 2016-10-10.CS1 maint: BOT: original-url status unknown (link)
  10. Kestelman, P; Trussell, J (1991). "Efficacy of the simultaneous use of condoms and spermicides". Fam Plann Perspect. 23 (5): 226–7, 232. doi:10.2307/2135759. JSTOR 2135759. PMID 1743276.
  11. Kippley, John; Sheila Kippley (1996). The Art of Natural Family Planning (4th addition ed.). Cincinnati, OH: The Couple to Couple League. p. 146. ISBN 978-0-926412-13-2., which cites:
    Guttmacher Institute (1992). "Choice of Contraceptives". The Medical Letter on Drugs and Therapeutics. 34 (885): 111–114. PMID 1448019.
  12. "Withdrawal | Student Health and Counseling Services". shcs.ucdavis.edu. Retrieved 2019-11-08.
  13. Carroll, Janell L. (2012-01-01). Sexuality Now: Embracing Diversity. Cengage Learning. ISBN 9781111835811.
  14. Hatcher RA, Trussel J, et al. (2000). Contraceptive Technology (18th ed.). New York: Ardent Media. ISBN 978-0-9664902-6-8.
  15. Jones, Rachel K.; Fennell, Julie; Higgins, Jenny A.; Blanchard, Kelly (2009-06-01). "Better than nothing or savvy risk-reduction practice? The importance of withdrawal". Contraception. 79 (6): 407–410. doi:10.1016/j.contraception.2008.12.008. ISSN 0010-7824. PMID 19442773.
  16. Smoley, Brian A.; Robinson, Christa M. (2012-11-15). "Natural Family Planning". American Family Physician. 86 (10): 924–928. ISSN 0002-838X.
  17. Francoeur, Robert T. (1991). A Descriptive Dictionary and Atlas of Sexology. Westport, Connecticut: Greenwood Press. pp. 114, 547. ISBN 0313259437.
  18. Dioscorides (ca. 40 A.D). De Materia Medica. Archived from the original on 2011-07-28. Check date values in: |year= (help) (translated by Goodyer (1655), modified and published 1933 by Robert Gunther). The herbs are said to "extinguish conception".
  19. Sailani MR, Moeini H; Moeini (July 2007). "Effect of Ruta graveolens and Cannabis sativa alcoholic extract on spermatogenesis in the adult wistar male rats". Indian Journal of Urology. 23 (3): 257–60. doi:10.4103/0970-1591.33720. PMC 2721602. PMID 19718326.
  20. Hadley MA, Lin YC, Dym M (1981). "Effects of gossypol on the reproductive system of male rats". J. Androl. 2 (4): 190–9. doi:10.1002/j.1939-4640.1981.tb00615.x.
  21. Khaleghi Ghadiri M, Gorji A; Gorji (February 2004). "Natural remedies for impotence in medieval Persia". International Journal of Impotence Research. 16 (1): 80–3. doi:10.1038/sj.ijir.3901153. PMID 14963476.
  22. Conway GA, Slocumb JC; Slocumb (October 1979). "Plants used as abortifacients and emmenagogues by Spanish New Mexicans". Journal of Ethnopharmacology. 1 (3): 241–61. doi:10.1016/S0378-8741(79)80014-8. PMID 232204.
  23. Pakrashi A, Pakrasi PL; Pakrasi (April 1977). "Antispermatogenic effect of the extract of Aristolochia indica Linn on male mice". Indian Journal of Experimental Biology. 15 (4): 256–9. PMID 914334.
  24. Prakash AO, Saxena V, Shukla S, et al. (1985). "Anti-implantation activity of some indigenous plants in rats". Acta Europaea Fertilitatis. 16 (6): 441–8. PMID 3832714.
  25. Venma PK, Sharma A, Mathur A, et al. (March 2002). "Effect of Sarcostemma acidum stem extract on spermatogenesis in male albino rats". Asian Journal of Andrology. 4 (1): 43–7. PMID 11907627.
  26. Coutinho EM (Apr 2002). "Gossypol: a contraceptive for men". Contraception. 65 (4): 259–63. doi:10.1016/S0010-7824(02)00294-9. PMID 12020773.
  27. Deshpande VY, Mendulkar KN, Sadre NL; Mendulkar; Sadre (July 1980). "Male antifertility activity of Azadirachta Indica in mice". Journal of Postgraduate Medicine. 26 (3): 167–70. PMID 7205685.CS1 maint: multiple names: authors list (link)
  28. Zhen QS, Ye X, Wei ZJ; Ye; Wei (February 1995). "Recent progress in research on Tripterygium: a male antifertility plant". Contraception. 51 (2): 121–9. doi:10.1016/0010-7824(94)00018-R. PMID 7750290.CS1 maint: multiple names: authors list (link)
  29. Lohiya NK, Manivannan B, Mishra PK, et al. (Mar 2002). "Chloroform extract of Carica papaya seeds induces long-term reversible azoospermia in langur monkey". Asian J. Androl. 4 (1): 17–26. PMID 11907624.
  30. Goyal, S.; Manivannan, B.; Ansari, A.; Jain, S.; Lohiya, N. (2010). "Safety evaluation of long term oral treatment of methanol sub-fraction of the seeds of Carica papaya as a male contraceptive in albino rats". Journal of Ethnopharmacology. 127 (2): 286–291. doi:10.1016/j.jep.2009.11.007. PMID 19914367.
  31. "Heat Methods of Male Contraception". Male Conception Information Project.
  32. "Finally, the promise of male birth control in a pill: Compound makes mice reversibly infertile". ScienceDaily. Retrieved 2018-03-09.
  33. Wang, C; Swerdloff, R. S. (Apr 2004). "Male hormonal contraception". Am. J. Obstet. Gynecol. 190 (4 Suppl): S60–8. doi:10.1016/j.ajog.2004.01.057. PMID 15105800.
  34. Coutinho, EM (Apr 2002). "Gossypol: a contraceptive for men". Contraception. 65 (4): 259–63. doi:10.1016/s0010-7824(02)00294-9. PMID 12020773.
  35. "A male contraceptive pill in the making?". Retrieved 17 August 2012.
  36. Matzuk MM, McKeown MR, Filippakopoulos P, et al. (August 2012). "Small-Molecule Inhibition of BRDT for Male Contraception". Cell. 150 (4): 673–684. doi:10.1016/j.cell.2012.06.045. PMC 3420011. PMID 22901802.
  37. O'Rand, MG; EE Widgren; P Sivashanmugam; RT Richardson; SH Hall; FS French; CA Vande Voort; SG Ramachandra; V Ramesh; A Jagannadha Roa (2004). "Reversible immunocontraception in male monkeys immunized with Eppin" (PDF). Science. 306 (5699): 1189–90. Bibcode:2004Sci...306.1189O. doi:10.1126/science.1099743. PMID 15539605.
  38. Hershlag A, Cooper GW, Benoff S; Cooper; Benoff (March 1995). "Pregnancy following discontinuation of a calcium channel blocker in the male partner". Human Reproduction. 10 (3): 599–606. doi:10.1093/oxfordjournals.humrep.a135996. PMID 7782439.CS1 maint: multiple names: authors list (link)
  39. http://msmagazine.com/blog/blog/2010/07/02/a-pill-for-men-still-five-years-away/
  40. Parry, Wynne "New Male Birth Control Concept Shows Promise", LiveScience, June 4, 2011, accessed June 6, 2011.
  41. Chung, SS; Wang, X; Roberts, SS; Griffey, SM; Reczek, PR; Wolgemuth, DJ (2011). "Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice". Endocrinology. 152 (6): 2492–2502. doi:10.1210/en.2010-0941. PMC 3100616. PMID 21505053.
  42. Sam Kean (2012). "Reinventing the Pill: Male Birth Control". Science. 338 (6105): 318–320. doi:10.1126/science.338.6105.318. PMID 23087225.
  43. Mruk DD, Cheng CY; Cheng (October 2004). "Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis". Endocrine Reviews. 25 (5): 747–806. doi:10.1210/er.2003-0022. PMID 15466940.
  44. Mruk DD, Wong CH, Silvestrini B, Cheng CY; Wong; Silvestrini; Cheng (November 2006). "A male contraceptive targeting germ cell adhesion". Nature Medicine. 12 (11): 1323–8. doi:10.1038/nm1420. PMID 17072312.CS1 maint: multiple names: authors list (link)
  45. Tash, Joseph; Attardi, B; Hild, SA; Chakrasali, R; Jakkaraj, SR; Georg, GI (July 2008). "A Novel Potent Indazole Carboxylic Acid Derivative Blocks Spermatogenesis and Is Contraceptive in Rats after a Single Oral Dose". Biology of Reproduction. 78 (6): 1127–1138. doi:10.1095/biolreprod.106.057810. PMID 18218612.
  46. Finn, Robert (May 2007). "Male Contraceptive Methods Are in the Pipeline". Ob. Gyn. News. 42 (9): 8. doi:10.1016/S0029-7437(07)70395-6 (inactive 2019-12-12).
  47. Nuzzo R (2006) Beyond condoms: male hormonal contraceptives may finally be on track. Los Angeles Times, 16 October.
  48. "MENT®: Subdermal Implants for Men - Population Council". Retrieved 13 March 2017.
  49. Sigrid von Eckardstein; Gabriela Noe; Vivian Brache; et al. (November 2003). "A clinical trial of 7α-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men". The Journal of Clinical Endocrinology and Metabolism. 88 (11): 5232–9. doi:10.1210/jc.2002-022043. PMID 14602755.
  50. Gu YQ, Wang XH, Xu D, et al. (February 2003). "A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men". The Journal of Clinical Endocrinology and Metabolism. 88 (2): 562–8. doi:10.1210/jc.2002-020447. PMID 12574181.
  51. Gu Y, Liang X, Wu W, et al. (June 2009). "Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men". The Journal of Clinical Endocrinology and Metabolism. 94 (6): 1910–5. doi:10.1210/jc.2008-1846. PMID 19293262.
  52. Kjaergaard N, Kjaergaard B, Lauritsen JG; Kjaergaard; Lauritsen (June 1988). "Prazosin, an adrenergic blocking agent inadequate as male contraceptive pill". Contraception. 37 (6): 621–9. doi:10.1016/0010-7824(88)90008-X. PMID 2899490.CS1 maint: multiple names: authors list (link)
  53. "MENT®: Subdermal Implants for Men | Population Council". www.popcouncil.org. Retrieved 23 January 2017.
  54. "Heart-Stopping Arrow Poison Could be Key to Male Birth Control".
  55. "Dimethandrolone undecanoate shows promise as a male birth control pill | Endocrine Society". www.endocrine.org. Retrieved 2018-11-29.
  56. "Male Contraception Information Project " Vasalgel". Retrieved 13 March 2017.
  57. "Vasalgel, a Multi-year Contraceptive". Retrieved 19 Feb 2018.
  58. Finn, Robert (May 1, 2007). "Male Contraceptive Methods Are in the Pipeline" (PDF). Ob. Gyn. News. 42 (9): 28.
  59. Murray, Rheana (30 January 2012). "Ultrasound kills sperm, could be the future of male birth control: study". Daily News. Retrieved 30 January 2012.
  60. Amory JK, Muller CH, Page ST, et al. (March 2007). "Miglustat has no apparent effect on spermatogenesis in normal men". Human Reproduction. 22 (3): 702–7. doi:10.1093/humrep/del414. PMID 17067996.
  61. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001209/WC500074188.pdf
  62. Dorman, Emily; Perry, Brian; Polis, Chelsea B.; Campo-Engelstein, Lisa; Shattuck, Dominick; Hamlin, Aaron; Aiken, Abigail; Trussell, James; Sokal, David (2018). "Modeling the impact of novel male contraceptive methods on reductions in unintended pregnancies in Nigeria, South Africa, and the United States". Contraception. 0 (1): 62–69. doi:10.1016/j.contraception.2017.08.015. ISSN 0010-7824. PMC 5732079. PMID 28887053.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.