{"paper_id":"40eb0479-aeeb-424c-bfe1-4a00552f37d8","body_text":"Global Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | PB Global Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 1\nis is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others \nto remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.\n©2023 Published by Scientific Scholar on behalf of Global Journal of Medical, Pharmaceutical, and Biomedical Update\nReview Article\nInnovation and Challenges in Male Contraception\nAastha Sahu1 , Research Scholar, Harish Sharma2 , PhD., Dean, Rajesh Kumar Nema1, Gyanesh Kumar Sahu2 , PhD.\n1Department of Pharmacy, Rungta Institute of Pharmaceutical Sciences, 2Department of Pharmacy, Rungta Institute of Pharmaceutical Sciences and Research, \nKohka, Bhilai, Chhattisgarh, India. \n *Corresponding author: \nDr. Gyanesh Kumar Sahu, \nProfessor and Dean, \nDepartment of Pharmacy, \nRungta Institute of \nPharmaceutical Sciences and \nResearch,  Kohka, Bhilai, \nChhattisgarh, India.\ngyanesh.sahu23@gmail.com \nReceived : 19 October 2022 \nAccepted : 13 June 2023 \nPublished : 20 November 2023\nDOI \n10.25259/GJMPBU_113_2022\nQuick Response Code:\nINTRODUCTION\nOne of the crucial concerns addressed as a Public Global Health Issue is unintended/unwanted \npregnancies. According to an estimate, countries that are developing or underdeveloped, \nhave around 74 million unwanted pregnancies annually, out of which 25 million are aborted \nand 47,000 result in maternal death every year. [1] In India, with a rate of 70.1 pregnancies \noccurring per 1000 women aged 15–49, nearly half of them have unplanned pregnancies and \none-third of them have an abortion. [1] One of the reasons for unplanned pregnancies is the \nfailure of the method of contraception used, so this demands the use of better methods of \ncontraception.\nContraception, in simple words, means birth control designed to prevent pregnancy. It is \naxiomatic that after reaching the age of puberty, men are fertile their entire age whereas women, \nafter reaching puberty are fertile for only 3–4 days in a month/36–48 days in a year, approximately \n1600  days in their entire fertile years until menopause occurs. While numerous options for \ncontraception exist for women, methods for male contraception are limited to condoms and \nvasectomy. Furthermore, with the options available in women’s contraceptives, the drawbacks are \nmore and get intense with time causing hormonal disbalance, heavy periods, and endometriosis. \nis evaluation gives rise to developing male contraception with better access and acceptability. \nSince the last few decades, extensive research has been undertaken to improve and advance the \nfemale contraceptives, yet the need for the development of male contraceptives arises more, as \ntheir availability could provide the male partner a stable relationship with an opportunity to share \nthe family planning responsibility and give men in general the opportunity to regain control over \ntheir fertility.\nABSTRACT\n e unwanted cases of pregnancy have increased resulting in improper family planning and cases of depression \nor stillbirth.  e decision regarding reproduction is shared equivalently by men and women. Although  the \ncontraception methods result in effectiveness, they have more complications than effective results. Hormonal \ndisbalance and endometriosis are a few such examples. Contraception for males is limited, yet has more effective \nresults and fewer complications.  e development of male contraception is vastly researched over the past few \ndecades. Various hormonal and non-hormonal methods are being developed to provide better contraception with \nminimum or no disadvantage.  e basic advantage of developing a male contraceptive includes its availability, low \ncost, no side effects, and ease of use.\nKeywords: Experimental male contraception, Hormonal, Vas-occlusion methods\nwww.gjmpbu.org\nGlobal Journal of Medical, \nPharmaceutical, and Biomedical Update\n\n\nSahu, et al.: Innovation and Challenges in Male Contraception\nGlobal Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 2 Global Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 3\nTo develop an ideal male contraceptive, the basic needs \nto be achieved are availability, accessibility, and few/no \nside effects from its use and budget-friendliness. With the \napproaches taken for ongoing research on male contraceptives, \nhormonal methods are potentially closest to a possible clinical \napplication.[2] With the object of developing a hormonal \ncontraceptive long-lasting delivery system, intramuscular (IM) \ninjections of testosterone undecanoate and transdermal patches \nand gels containing androgens, a combination of testosterone, \nand nestorone are on the verge of being developed. [3] Non-\nhormonal methods such as vas-occlusion device Vasalgel, a \nsolution of styrene maleic anhydrate is injected into both vas \ndeferens leading to blockage of the deferens, and preventing \nthe passage of sperm are also close to being approved.[3]\nBACKGROUND LITERATURE\nContraceptive mechanisms\n e mechanism of contraceptives is either hormonal or non-\nhormonal.  e mechanism of action of female hormonal \ncontraception includes: Suppression of luteinizing hormone \n(LH) which leads to inhibition of ovulation, eventual \nthickening of cervical mucus, hindering the transport of sperm, \nand no development of endometrium. [4] Usually, hormonal \ncontraceptives are primarily the combination of hormones, \nprogestins, estrogen, or either of those.[5,6] Progestins primarily \nsuppress LH and ovulation as a mechanism cursor of \ncontraceptives.[7,8]  ey find their way in oral pills, transdermal \npatches, implants, etc. In oral contraceptives, they are derived \nfrom 19 nor-testosterone and include norethindrone, \nnorethindrone acetate, ethynodiol diacetate, norgestrel, \nlevonorgestrel, norethynodrel, desogestrel, norgestimate, \nand gestodene.[7,9]  e primary function of estrogen in a \ncontraceptive is to regulate bleeding, along with inhibiting \nanother ovarian hormone, that is, follicle-stimulating hormone \n(FSH), and preventing the formation of the dominant follicle.[10] \nIn contrast to the long list of progestin formulations, only a few \nestrogenic compounds are used in hormonal contraceptives: \nEthinyl estradiol, mestranol, and estradiol valerate.[11]\nNon-hormonal contraceptives do not involve the use of any \nhormones. Instead, they block the invasion of sperm, their \nmotility, or the fusion with ovum. [12,13] Various methods \ninclude condoms for both, males and females, intrauterine \ndevices, spermicide, surgical methods for both men and \nwomen and withdrawal.[14]\n e methods available for the contraception of females are \ndescribed in [Table 1 ].\nAvailable male contraceptive\nCondoms and vasectomy are the only two methods of \ncontraception available for use by men.\nCondoms\nCondoms are the oldest method used to date, which is \nreliably reversible.  ey serve as an exterior barrier blocking \nfertilization.[15] Although an overall estimate of 9.5% of men \nin India use condoms, the vast difference lies in urban and \nrural parts of India. Only 7.6% of men in rural India use \ncondoms, and the percentage rises to 13.6% when urban \nparts of India are considered, showing better knowledge and \nawareness of contraceptives in the urban parts of India.[16]\nSince condoms provide an exterior barrier; they performs \nthe dual function of protecting against sexually transmitted \ndiseases and preventing pregnancies without interfering with \nhormonal parts of the body. Y et, the failure rates of its typical \nuse are very high, that is, 18% raising a concern about its \nuse.[17]\nVa s ec tomy\nWidely accepted by both developed and developing \ncountries, the no-scalpel technique developed by China \nuses a single midline puncture in the scrotal raphe using \nscissors.[18-20] Vasectomy, with advancement in medical \ntechnique and tools, can be easily performed surgically and \nmainly involves ligation of the vas deferens through a small \nscrotal incision.[21]\nAlthough the method is widely accepted, its drawback has \nawoken concern for its use.  e main and major drawback \nlies in its delay in the onset of azoospermia, which means \na complete absence of sperm from the semen. is delay \nlowers its efficacy, as the sperm still appears in the ejaculate \neven after surgery for 3–4  months. [19] After going through \nvasectomy, 10–15% of men experience chronic testicular \ndiscomfort.[8]\nPreviously, the method was considered irreversible, though, \nnow it is considered reversible as the surgical procedure \ncalled vasovasostomy can re-join the ligated deferens. \nUnfortunately, the rates of pregnancy after vasovasostomy \nvary from 50% to 75% in previously fertile men. [19] Although \nthere are many advantages, the major disadvantage of both \nprocedures is the time.  e earlier the surgery done, the \nlesser is the chance of reversal.[22,23]\nOver the world, Asia accounts for approximately three-\nfourths of 32 million couples going through vasectomy, out \nof which India and China account for 20 million vasectomy \nusers.[24] Only a 2% prevalence of vasectomy is seen in \nLatin America and the Caribbean. [24] Puerto Rico, with a \nprevalence of 5.3%, has the highest rate in the region. In sub-\nSaharan Africa, less than one-tenth of 1% of married women \nrely on a partner’s vasectomy for contraception.[25] Vasectomy \nis a highly effective method of male contraception. It has a \nfailure rate of <1% with few or no serious complications.[26]\n\nSahu, et al.: Innovation and Challenges in Male Contraception\nGlobal Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 2 Global Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 3\nNeed for male contraception\nAlthough the population is increasing the contraceptives \nof a male are limited to only two methods, condoms, and \nvasectomy. Condoms and vasectomy, although they provide \na huge success rate, come with complications. [13,27] e \nformer hinders the sexual pleasure and has a hig failure rate, \nwhereas, the latter even with low failure rates, irreversibility \nis itself a huge complication, along with other risks that \ninclude bleeding, infection, chronic orchialgia, granuloma \nformation, and recanalization.[13]  e need to develop a male \ncontraceptive should focus on overcoming the drawbacks of \navailable methods of male conception:  e limited efficacy \nand compliance problems associated with condoms, and \nthe irreversibility of male vasectomy need to be addressed. \n ere are various ongoing researches as in figure 1 on \nboth hormonal and non-hormonal methods of male \ncontraceptives.\nTable 1: Available contraceptives for women, their mechanism, and failure rates.\nContraceptives Mechanism Failure % Reference\nHormonal contraceptives\nOral contraceptive  ey are combinations of progestins and estrogen or consist either of those, \npreventing pregnancy by preventing ovulation.\n9 [41]\nHormonal implants A thin, tiny rod, and size similar to matchstick’s size is implanted in the arm releases \nhormones to prevent pregnancy.\n0.05 [42]\nDepo-Provera \ncontraceptive injection\nIt is a shot of hormone consisting progestin, given once in every 3 months, prevents \npregnancy by thickening of cervical mucus.\n6 [43]\nOrtho-Evra patch A transdermal patch, releases combination of hormones, progestin, and estrogen to \nprevent pregnancy.\n9 [44]\nHormonal IUDs A small piece of flexible plastic shaped like T, which releases a tiny amount of \nprogestin in body, preventing pregnancy by making mucus of the cervix thick, and \nblocking the entry of sperm.\n0.1–0.4 [45]\nNon hormonal\nCondom (female) A latex rubber sheath placed in the vagina to block the sperm’s passage 21 [15]\nCervical cap A rubber soft barrier that blocks the cervix to prevent sperm from entering into the \nmucus.\n12 [46]\nIUDs-Copper IUDs  e IU is a T-shaped device inserted into the uterus to alter the movement of sperm \ncells and to prevent them from fertilizing an egg.\n0.2–0.8 [45]\nDiaphragm A dome-shaped barrier, which covers the cervix hindering the sperm passage. 12 [47,48]\nSpermicide (only) Spermicide contains chemicals that prevent sperm from fertilizing an egg when put \nin the vagina before sex.\n28 [47]\nSponge Contraceptive sponge uses spermicidal and barrier methods to prevent pregnancy 20–40 [49]\nVaginal ring A small flexible ring placed in the vagina, once a month, prevents conception. 9 [50]\nIUDs: Intrauterine device\nFigure 1: Experimental novel male contraceptives ongoing research.\n\nSahu, et al.: Innovation and Challenges in Male Contraception\nGlobal Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 4 Global Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 5\nExperimental male contraceptives\nHormonal\n e main aim of the ongoing research on hormonal \ncontraceptives for males is to improve the suppression of \nsperm and reduce the side effects occurring in androgens. [28] \n e mechanism of action of hormonal contraceptives is similar \nto that of female hormonal contraceptives. It is based on \nthe suppression of gonadotrophins, that is, LH and FSH \nsecretion and release from the pituitary. [8]  e suppression \nof gonadotrophins from exogenous sex steroids or \ngonadotrophin-releasing hormone results in (1) suppression \nof production of sperms from immature male sperm cells, \nthat is, spermatogenesis and (2) decrease in intratesticular \ntestosterone.[8] is profound suppression of sperm output \ninhibits fertility in men providing an effective male-directed \ncontraceptive method. [20,28,29] Various regimens studies \ninclude the use of testosterone enanthate and androgen-\nprogestin combinations that suppress the gonadotrophins \n(pituitary hormones) which block sperm production.[28]\nTestosterone ethanoate\nFor the replacement of testosterone in hypogonadal men, \nnew researches are being done on the testosterone delivery \nsystem as shown in figure 2. [30] One such research found \ntestosterone undecanoate, given as IM injection was found \npotentially long-lasting hormonal male contraceptive agent.\n[31,32]\nIn one such study, 308 men volunteered for the research \ntrial. During the suppression phase, nine out of 308 men \nshowed a decrease in sperm concentration which was \n<3 million/mL and 296 men entered the efficacy of 6 months. \nNo pregnancy was observed when men had azoospermia or \nsevere oligo-zoospermia.[32] In 2.3% of men, sperm rebound \nto levels, above the threshold during treatment, and also \none pregnancy occurred during the same. [32] Based on \nthese results, phase 3 trials were done across ten centers in \nChina, volunteered by 1045 men given the dosage of 500 mg \ntestosterone undecanoate injection.  e result showed 1% \nand 1.1% failure rate at the end of 12–24  months. [29]  us, \nthe study showed that it can be a formulation that is safe \nand effective, along with the property of reversibility as a \ncontraception formulation for men.[29]\n e common side effects are acne, weight gain, oiliness of the \nskin, increase in hematocrit and hemoglobin decrease in high-\ndensity lipoprotein cholesterol, and sleep-related breathing \ndisorders.[32]  ese adverse effects may be dependent on the \ndose and methods of testosterone administration.[29,31]\nGossypol\nShanghai Pharmaceutical Company (Shanghai, China) \nprepared a yellow pigment extracted from seeds of \nGossypium barbadense known as Gossypol.  e gossypol was \nstudied as a drug that can be used as a constituent for male \ncontraceptive pills as it showcased some qualities similar \nto contraceptives. [33,34] During the 1970s and 1980s, China \ndid an extreme study, in which gossypol suppressed sperm \nproduction along with sperm motility. Along with these, it \nslightly changed the morphology of the sperm, of which the \nmechanism is still unknown. [19]  e study was done in two \nlarge phases that enrolled over 8000.[19,20]\nDevelopment of azoospermia was seen in the majority of \nmen after prolonged treatment. Although 90% efficiency was \nshown for gossypol in preventing pregnancy, approximately \n1% of men developed hypokalemia and almost 20% did not \nregain fertility after treatment.[19]\nAnother research done by Coutinho et al . concluded and \nshowed the potential of developing gossypol into a useful \ncontraceptive pill for men. In this study, the dose regimens \nFigure 2: Action of testosterone undecanoate.\n\nSahu, et al.: Innovation and Challenges in Male Contraception\nGlobal Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 4 Global Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 5\nused showed efficacy achieved by 60% of men. [33] On the \npositive part, this study showed no side effects, and in 51% \nof men, reversibility occurred within 1  year of stopping \nthe treatment. [33] However, in 19% of men azoospermia \npersisted.[33]  e research potential shows that it would give \nmen an additional alternative to vasectomy and barrier \nmethods.[33,34]\n7-Alpha-methyl-19nortesterone (MENT)\n e development focus of male contraceptives as mentioned \nearlier has been on developing a contraceptive that is more \npotent than testosterone and suppresses gonadotrophins with \nno or fewer side effects. [29,32] MENT is one such compound \nthat cannot be reduced to dihydrotestosterone like steroids \nand has fewer stimulating effects on the prostate gland.[29]\nIn a study performed in rats, MENT showed 10 times more \npotent action than the testosterone present in muscles, \n4  times more potent in the prostate gland but has lesser \neffects on the prostate gland, which was confirmed in a \nstudy with monkeys.[29] MENT was initially developed as an \nimplant. When the study was done in men, it effectively the \nshowed suppression of spermatogenesis given the condition \nof four implants that were used and released a total of \n1600 mcg/day.  e MENT implants are under development \nand being optimized to 1-year implant.[32]\nNon-hormonal: Vas-occlusion method\nReversible inhibition of sperm under guidance (RISUG)\nAlong with hormonal methods of male contraceptives, non-\nhormonal methods have also been a part of research since \nthe 1970s. Researchers in India and China have been working \nto develop a method that could temporarily block the vas \ndeferens.[19] A vas-occlusion method should be be removable \nat a later stage for reversibility.[19]\nIndia develops a vas-occlusion method known as RISUG. It \nuses styrene maleic anhydride (SMA) product that lines the \nvas deferens, administered through intra-vas injection. [35] \n e RISUG, when present in the vas, creates a pH level that \ngenerates a positive charge, which results in the disruption \nof the acrosomal membrane and obstructs normal sperm \ntransport through the female reproductive tract. [36] e \nstudy of RISUG done on non-human primates was found to \nbe an effective contraceptive. It also showed reversibility in \nprimates with vibratory massage, hence returning fertility.[19] \nFor over a tenure of 1 year, the study has shown successful \nand effective contraceptive efficiency. [19] Although various \ncompositions of RISUG have been studied in India for several \ndecades, no product has yet been launched in the market.[19]\nVasalgel\n e United States is now developing another vas-occlusion \nproduct for men which is an intra-vas injection like \nVasalgel.[37] is intra-vas injection consists of a high \nmolecular weight polymer, that is, SMA polymer dissolved \nin dimethyl sulfoxide (DMSO). [38,39] Unlike RISUG, Vasalgel \ndoes not claim any pharmaceutical effect and is understood \nto work by occluding the vasa differentia. When injected into \nthe vas deferens, the hydrogel formed by SMA acid acts as \ntissue adherent, which forms the mechanical barrier by filling \nthe lumen and blocking the passage of sperm.[37] Studies done \non rabbits for 12 months of treatment proved Vasalgel to be \nreliable, showing azoospermia. [3] Furthermore, reversibility \nwas achieved in the rabbits.[3]\nAnother research was done by Colagross-Schouten et al ., \nin which 16 adult male rhesus monkeys were given intra-\nvas injections of Vasalgel consisting of 25% styrene-maleic \nacid in DMSO. [40] After 1  week of recovery, the males were \nreturned to outdoor group housing, which included at least \n3 and up to 9 intact, breeding females with a successful \nhistory.[40]\nResults: After Vasalgel was administered in the males, they \nwere housed with intact females ,; the treated males had no \nconception. All 16  male rhesus monkeys were housed with \nTable 2:  e ongoing experimental novel male contraceptives and their trials done with their complications.\nContraceptives Successful models Complications Reference\nTestosterone undecanoate Human males Decrease in HDL polymer.\nIncreased hematocrit and hemoglobin.\n[29,31]\nGossypol Human males Fertility did not return after the treatment. [19]\nMENT (implants) Rats and human males Decrease in HDL polymer.\nIncreased hematocrit and hemoglobin.\nPain and bruising at removal.\nOne in five men showed impotency.\n[32,51]\nRISUG Non-human primates (rhesus and langur monkeys), \nrats, rabbits and human males.\nNo such complications were observed [19,52]\nVasalgel Non-human primates, and human males Granulomas developed [29]\nMENT: Alpha-methyl-19nortesterone, RISUG: Reversible inhibition of sperm under guidance, HDL: High-density lipoprotein\n\nSahu, et al.: Innovation and Challenges in Male Contraception\nGlobal Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 6 Global Journal of Medical, Pharmaceutical, and Biomedical Update • 2023 • 18(30) | 7\nintact females for at least one breeding season and showed \nno conception and out of 16  males, nine were continually \nhoused with females for 2 years. [40]\nComplication: Minor complications were observed:\n•\t Incorrect placement of Vasalgel into the vas-deferens\n•\t Development of granuloma\n•\t ree unilateral vasectomies were performed. One was \nfor the correction of placement and the other two were \nelective.[32]\n e conclusion of the study found Vasalgel to be an effective \nmethod in adult male rhesus macaques. [29]  e Vasalgel \nwas well tolerated and showed minimal complication. \nFurthermore, flushing out Vasalgel is warranted.[40]\nExperiments of the novel methods of male contraceptives that \nare beings developed have been successfully performed in \ntheir chosen models and their details are shown in [Table 2 ].\nCONCLUSION\nConventionally, women have been burdened with the cause of \nreproduction, hence, contraceptives for females have been a \nfocused area of research. However, for reproduction decisions \nand outcomes both men and women now agree to share the \nresponsibility equally. To prevent an unwanted pregnancy, \ncontraception is the best tool available. Acknowledging the \nfact that male contraceptives are limited to only two options, \nthat is, condoms and vasectomy, the need to develop a male \ncontraceptive that is easier to use, accessible, efficient, and \nproduces no side effects is very crucial.  e developing \nmethods of novel male contraceptives will have an important \nimpact on the interaction between men and women in the \ncommunity/society. Various hormonal and non-hormonal \napproaches have been developed for decades; yet, there is \nno promising product ready for use. Despite this delay, the \nnovel non-hormonal devices developed for males have \nshown better results than hormonal ones in their preclinical \ntrials. Furthermore, for advancement and better knowledge \nof contraceptives that are available and are to be released, \nchanges that should be made to improve reproductive health \nservices are the healthcare system, schools, and communities. \nPublic policies should be improved to broaden the range \nof reproductive health clinics that reach deeper into the \ncommunities. To remove the negative stereotypes regarding \nmale reproductive health and to motivate them to use \ncontraceptives, targeted community-led programs should be \nimplemented to make men aware that they should share the \nresponsibility of reproduction equally with female partners.\nDeclaration of patient consent\nPatient’s consent not required as there are no patients in this \nstudy.\nFinancial support and sponsorship\nNil.\nConflicts of interest\n ere are no conflicts of interest.\nREFERENCES\n1. 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Basic Clin \nAndrol 2020;30:2.\nHow to cite this article: Sahu A, Sharma H, Nema RK, Sahu GK. \nInnovation and challenges in male contraception. Glob J Med Pharm \nBiomed Update 2023;18:30.","source_license":"CC0","license_restricted":false}