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Male contraceptives, also known as male birth control, are methods of preventing pregnancy that are used by males or people who produce sperm.^[1] The main forms of male contraceptives available today are condoms, vasectomy, and withdrawal, and these methods combined make up less than one-third of global contraceptive use.^[2]^[3]^[4]^[5]

New forms of male contraception are in clinical and preclinical stages of research and development, but as of 2024, none have reached regulatory approval for widespread use.^[6]^[7]^[8]^[9] Surveys indicate that around half of men in countries across the world are interested using a novel contraceptive method, and they display interest in a wide variety of contraceptive methods including hormonal and non-hormonal pills, gels, and implants,^[10]^[11]^[12] and men in clinical trials for male contraceptives have reported high levels of satisfaction with the products.^[13]^[14] Modelling studies suggest that even limited adoption of new male contraceptives would significantly reduce unintended pregnancy rates around the globe.^[15] Despite the availability of many forms of female-controlled contraceptives, nearly half of pregnancies across the world are still unintended, even in developed countries where women have high levels of access to modern contraceptives.^[16]^[17]^[18] Unintended pregnancies are associated with negative socioeconomic, educational, and health outcomes for women, men, and the resulting children (especially in disadvantaged communities),^[19]^[20]^[21]^[22]^[23]^[24]^[25] and so the development of new male contraceptives has the potential to improve racial, economic, and gender equality across the world.

Currently available methods

Vasectomy

Vasectomy is surgical procedure for permanent male sterilization usually performed in a physician's office in an outpatient procedure.^[26] During the procedure, the vasa deferentia of a patient are severed, and then tied or sealed to prevent sperm from being released during ejaculation.^[27] Vasectomy is an effective procedure, with less than 0.15% of partners becoming pregnant within the first 12 months after the procedure.^[28] Vasectomy is also a widely reliable and safe method of contraception, and complications are both rare and minor.^[29]^[30] Vasectomies can be reversed, though rates of successful reversal are variable, and the procedure is often costly.^[26]^[27]

Condoms

A condom is a barrier device made of latex or thin plastic film that is rolled onto an erect penis before intercourse and retains ejaculated semen, thereby preventing pregnancy.^[31] Condoms are less effective at preventing pregnancy than vasectomy or modern methods of female contraception, with a real-world failure rate of 13%.^[28] However, condoms have the advantage of providing protection against some sexually transmitted infections such as HIV/AIDS.^[32]^[33] Condoms may be combined with other forms of contraception (such as spermicide) for greater protection.^[34]

Withdrawal

The withdrawal method, also known as coitus interruptus or pulling out, is a behavior that involves halting penile-vaginal intercourse to remove the penis out and away from the vagina prior to ejaculation.^[35]^[36] Withdrawal is considered an less-effective contraceptive method, with typical-use failure rates around 20%.^[26]^[28] However, it requires no equipment or medical procedures.^[35]

Contraceptive Failure Rate^[28]^{[note 1]}
Method	Typical use	Perfect use
Vasectomy	0.15%	0.10%
Condoms	13%	2%
Withdrawal	20%	4%

Research into new methods

Researchers are currently working to generate novel male contraceptives with diverse mechanisms of action and possible delivery methods, including long-acting reversible contraceptives (LARCs), daily transdermal gels, daily and on-demand oral pills, monthly injectables, and implants.^[37]^[38]^[39] Efforts to develop male contraceptives have been ongoing for many decades, but progress has been slowed by a lack of funding and industry involvement. As of 2024, most funding for male contraceptive research is derived from government or philanthropic sources.^[40]^[41]^[42]^[43]

Male contraceptives can work by blocking various steps of the sperm development process, blocking sperm release, or interfering with any of the sperm functions necessary to reach and fertilize an egg in the female reproductive tract.^[44] Advantages and disadvantages of each of these approaches will be discussed below, along with relevant examples of products in development.

Male contraceptives that block or interfere with sperm production

These methods work by preventing the testes from producing sperm, or interfering with sperm production in a way that leads to the production of nonfunctional sperm.^[45] This approach can be accomplished by either hormonal or nonhormonal small-molecule drugs, or potentially by thermal methods. The effectiveness of contraceptives in this group can be easily assessed microscopically, by measuring sperm count or abnormalities in sperm shape, but because spermatogenesis takes approximately 70 days to complete,^[46] these methods are likely to require approximately three months of use before they become effective, and approaches that halt sperm production may result in reduced testicular size^{[citation needed]}.

Hormonal contraceptives for men

Hormonal contraceptives for men work similarly to hormonal female methods, using steroids to interrupt the hypothalamic-pituitary-gonadal axis and thereby block sperm production. Administering external androgens and progestogens suppresses secretion of the gonadotropins LH and FSH, which impairs testosterone production and sperm generation in the testes, leading to reduced sperm counts in ejaculates within 4–12 weeks of use.^[47] However, since the contraceptives contain testosterone or related androgens, the levels of androgens in the blood remain relatively constant, thereby limiting side effects and maintaining masculine secondary sex characteristics like muscle mass and hair growth.^[47]

Multiple methods of male hormonal contraception have been tested in clinical trials, and although one trial was halted early, leading to a large amount of press attention,^[48]^[49]^[50]^[51]^[52] most hormonal male contraceptives have been found to be effective, reversible, and well-tolerated.^[53]^[54]^[55]^[56]^[57]^[58]

Hormonal male contraceptives in clinical trials as of 2024

NES/T (Nesterone/Testosterone gel) is a transdermal gel that users apply to the upper arms and shoulders once daily.^[59]^[60] Developed as a collaboration between the NICHD and Population Council, NES/T is in a phase II clinical trial (ClinicalTrials.gov), where it is being evaluated for safety and efficacy, with healthy couples relying on it as their only means of birth control.^[61]^[62]^[63]^[64]
DMAU (Dimethandrolone undecanoate) is a steroid-based contraceptive molecule with both androgenic and progestational activities, which allows it to be used as a single agent. DMAU has been tested in clinical trials in both oral^[65]^[66] and injectable (NCT02927210) forms.
11β-MNTDC is another dual-function molecule (progestogenic androgen) in clinical development as an oral contraceptive for men.^[67]

Some anabolic steroids may exhibit suppressive effects on spermatogenesis, but none are being investigated for use as a male contraceptive.^[68]

Non-hormonal pharmaceutical contraceptives for men

Non-hormonal contraceptives for men are a diverse group of molecules that act by inhibiting any of the many proteins involved in sperm production, release, or function. Because sperm cells are highly specialized, they express many proteins that are rare in the rest of the human body.^[69]^[70]^[71] This suggests the possibility that non-hormonal contraceptives that specifically block these sperm proteins could have fewer side effects than hormonal contraceptives, since sex steroid receptors are found in tissues throughout the body.^[72] Non-hormonal contraceptives can work by blocking spermatogenesis, sperm release, or mature sperm function, resulting in products with a wide variety of usage patterns, from slow onset to on-demand usage.^[73] Contraceptives targeting mature sperm functions could even be taken by both sperm-producing and egg producing people.^[74]^[75] Challenges of non-hormonal contraceptive development include bioavailability and delivery past the blood-testis barrier.^[76]

Non-hormonal spermatogenesis-blocking male contraceptives in clinical trials as of 2024

YCT529, a retinoic acid receptor antagonist, began a Phase 1 clinical trial in 2023 (NCT06094283) organized by the US startup YourChoice Pharmaceuticals.^[77]^[78]^[79] It has been known since the late 1950s that blocking the retinoic acid/Vitamin A signalling pathway inhibits spermatogenesis in rodents and humans, and various attempts have been made to develop male contraceptives that use this approach.^[80]^[81]^[82] Development success of these earlier molecules has been limited by off-target effects.^[83]

Non-hormonal spermatogenesis-blocking male contraceptives in preclinical development as of 2024

Triptonide, a derivative of Tripterygium wilfordii, a plant used in traditional Chinese medicine,^[84] has been shown to safely, effectively, and reversibly block sperm production in laboratory mice and monkeys.^[85]
JQ1, a pharmacological inhibitor of chromatin remodeling by BRDT, has been shown to produce reversible sterility in male mice.^[86]^[87]^[88]

Thermal male contraceptive approaches

Heat-based contraception causes thermal dysregulation of spermatogenesis and is a well-established means of producing a contraceptive effect in men.^[89]^[90]^[91]^[92] Normally, the testis are held at a temperature approximately 2 °C below that of basal body temperature, and are thermoregulated by smooth muscle tissue in the scrotum. Increases in testicular temperature of as little as 2 °C are associated with decreased sperm count and decreased sperm quality, and the effect has been shown to be directly related to heat intensity and frequency.^{[citation needed]}

Various approaches have been taken to induce hyperthermia in the testes, including the application of simple heat via exogenous “wet” means, such as a heated water bath, and “dry” means such as insulated or externally-heated underwear.^[93]^[94] Other thermal methods utilize endogenous body temperature to halt spermatogenesis, usually by holding the testes in the inguinal canal for an extended period through the use of a wearable device such as underwear or a silicone ring.^[95] Currently, no thermal male methods of contraception have been approved by a regulatory agency for use as a contraceptive method.

The mechanism by which hyperthermia disrupts spermatogenesis is still not fully understood, though generally, these methods are thought of as safe.^[96] In the many human studies, no severe consequences or side effects have been reported, though there are some safety concerns, generally related to genetic risks of increasing testicular temperature, either from a testicular cancer risk, drawing a parallel to the increased cancer rates seen in cryptorchidism, or from alteration of sperm DNA, resulting in reproductive harm to potential offspring.^[94]

Another approach to heat the testes involves conducting electromagnetic energy via ultrasound to the testes through immersion in liquid baths or direct application of a transducer probe.^[97] Ultrasonic methods may also have a non-thermal component to their mechanism.^[98]

In 2021, a design of a water bath based ultrasonic male contraceptive product called COSO was a finalist for the James Dyson Award.^[99]

Other methods in basic science studies include magnetic targeting and magnetic hyperthermia^{[citation needed]}.

Male contraceptives that block sperm release

These approaches work by either physically or pharmaceutically preventing the emission of sperm during ejaculation, and are likely to be effective on-demand.

Vas-occlusive male contraceptive approaches

Vas-occlusive contraception provides a contraceptive effect through physical blockage of the vas deferens, the portion of the male reproductive system connecting the epididymis to the urethra. While a vasectomy excises, or removes, a piece of each vas deferens and occludes the remaining open ends of the tissue, reversible vas-occlusive methods provide partial or total blockage of the tissue while leaving it intact. In vasectomy, fascial interposition, electrocautery, clips, and sutures are often used to occlude the open ends of the vas deferentia after excision, but these methods are still used for permanent sterilization.^[100]^[101] Novel surgical methods for vas-occlusive male contraception are largely focused on creating long-acting reversible options, and reversibility of most vas-occlusive devices consist of a second procedure that removes the blockage.^[102]

ADAM is a hydrogel-based male contraceptive implant in clinical development (NCT05134428) by Contraline, Inc.^[103] Previously known as Echo-VR, the implant is administered to a user in a procedure similar to a no-scalpel vasectomy, and is proposed to provide protection from pregnancy for approximately two years, after which the hydrogel degrades, thereby restoring fertility.^[104] Results from an exploratory trial in humans were published in 2023.^[105]
Reversible inhibition of sperm under guidance (RISUG) is an injectable male contraceptive implant composed of the polymer styrene maleic anhydride (SMA) and is proposed to provide protection from pregnancy for more than ten years.^[106]^[107] RISUG has been in development in India since the 1970s and has been studied in rats, rabbits, non-human primates, and most recently, men.^[108]^[109] To reverse RISUG, a second injection of bicarbonate is proposed to dissolve the substance and be fully flushed from the tissue to restore fertility, though reversibility has not yet been demonstrated in humans.^[110] RISUG may act through both chemical and occlusive mechanisms. RISUG is in human testing in India and has been patented in India, China, Bangladesh and the United States.^{[citation needed]}
Plan A, formerly known as Vasalgel, is a brand name of polymer gel injection based on the same SMA platform as RISUG. Licensed by the Parsemus Foundation and developed by NEXT Life Sciences, Plan A is currently in preclinical studies.^[111]^[112]^[113]^[114]^[115]^[116]^[117]

Other methods have been proposed that use ultrasound treatment to reverse the blockage, though these methods are largely in basic science studies.^[118]^[119]

The Bimek SLV is researching a valve designed for the spermatic duct, controlling the movement of sperm cells within the ducts. Users have the ability to independently open and close the valve. Its closed position serves as a safeguard against unintended pregnancies. Remarkably, the materials employed in its construction are entirely devoid of any adverse effects on the body, and the SLV operates without the need for supplementary hormones or medications. ^[120]

Pharmaceutical approaches that block sperm release

Phenoxybenzamine has been found to block ejaculation, which gives it the potential to be an effective contraceptive.^[121]

Barrier methods in development

Research into new designs of condoms is ongoing.^[122]

Approaches that block necessary functions of mature sperm

These approaches work by blocking functions that mature sperm need in order to reach and fertilize an egg in the female reproductive tract, such as motility, capacitation, semen liquification, or fertilization. Drugs or devices that target mature sperm are likely to be effective on-demand, and could even be delivered either in sperm-producing or egg-producing bodies, leading to truly unisex contraceptives.^[74]^[75]

Non-hormonal pharmaceutical approaches

An enzyme called soluble adenylyl cyclase (sAC) which is used to trigger the behavior of fertilization can be de-activated to prevent the regular cellular process.^[123] Soluble adenylyl cyclase inhibition has been demonstrated to temporarily reduce male fertility in mice.^[124]^[125]^[126]^[127]^[128]
EP055 is a non-hormonal contraceptive in preclinical development by Eppin Pharma, Inc.^[129]^[130]^[131]
Immunocontraception targeting sperm antigens has been found to be effective in male primates.^[132]
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.^[133]^[134]
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, targeting the sperm-specific isoform of sodium-potassium ATPase.^[135]

Impact

It is predicted that the introduction of a long-acting reversible contraception for males could decrease the rate of unintended pregnancy and women's burden of birth control responsibility in a sexual relationship.^[136]^[39] Family planning has been found to be associated with overall well-being and is one of the most efficient tools for human empowerment.^[137]^[138]^[139] Positive outcomes of effective birth control include but are not limited to one's self-agency, education, labor force participation, financial stability, future childbearing, etc.^[140]

Acceptability

Men consistently report high levels of interest in novel forms of male contraception. Men's willingness to use novel male contraception is linked to gender-equitable attitudes in an online survey.^[141]^[10]^[63]

Multiple small-scale acceptability questionnaires also indicate high levels of interest in male contraception.^[142]^[143]

Acceptability of some thermal methods has been reported in the literature.^[144]^[145]

History

Contraceptives for use by men have been described in the writings of Antiqiuty. 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.^[146] One test in rats (20 milligrams of the 80% ethanol extract) found that these reduced sperm count by more than half.^[147] In medieval Persia (and in other traditions as cited) these herbs were used for male contraception, as well as Gossypium herbaceum (Malvaceae),^[148] Cyperus longus (Cyperaceae), Vitex pseudonegundo (Verbenaceae), Chenopodium ambrosioides (Chenopodiaceae),^[105]^[149] Aristolochia indica (Aristolochiaceae),^[7] Punica granatum (Punicaceae),^[67] and Sarcostemma acidum (Asclepiadaceae).^[99] 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.^[150]^[151]

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.^[47]

Past research efforts

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.^[152]
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.^[153]
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.^[154]^[155]
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.^[156]
Adjudin, a non-toxic analog of lonidamine has been shown to cause reversible infertility in rats.^[157] 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.^[158]
The intra-vas device (IVD) is a rod-shaped device intended to be inserted into the vasal lumen via a small incision. The outer shell of the intra‐vas device (IVD) is mainly urethane, and filled with medical grade nylon thread.^[100]^[159] Two grooves near the head and tail are intended to fix the device within the vas and to prevent sperm transport between the device and the vas wall.
The “Shug” is a noninjectable device consisting of 2 silicone plugs with nylon tails to help anchor the plug to the vas, and is inserted via the no-scalpel method.^[160]
Injectable medical polyurethane (MPU)
Trestolone (MENT) has been formulated as a contraceptive implant.^[161]
Researchers in 2010 fed extracts from the papaya seeds to monkeys. Subsequently, the monkeys had no sperm in their ejaculate, with no apparent ill effects on the testes or other organs.^[162]

notes

^ The percentage of users of each method who will experience an unintended pregnancy in the first year of use of the method.

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@@ Line 53: / Line 53: @@
 ===== Hormonal male contraceptives in clinical trials as of 2024 =====
-*NES/T ([[Segesterone acetate|Nesterone]]/Testosterone gel) is a transdermal gel that users apply to the upper arms and shoulders once daily.<ref name="Yahoo News_2023">{{Cite web |date=2023-03-01 |title=With a New Gel, the Future of Male Birth Control Looks Bright |url=https://news.yahoo.com/gel-future-male-birth-control-140000146.html |access-date=2023-10-09 |website=Yahoo News |language=en-US}}</ref><ref>{{Cite web |date=2022-02-22 |title=What Happens When Men Take Hormonal Birth Control? |url=https://www.cosmopolitan.com/health-fitness/a38954452/male-contraceptive-gel-trial/ |access-date=2023-10-12 |website=Cosmopolitan |language=en-US}}</ref> Developed as a collaboration between the [[Eunice Kennedy Shriver National Institute of Child Health and Human Development|NICHD]] and [[Population Council]], NES/T is in a phase II clinical trial ([https://clinicaltrials.gov/study/NCT03452111 ClinicalTrials.gov]), where it is being evaluated for safety and efficacy, with healthy couples relying on it as their only means of birth control.<ref name="Amory_2023">{{cite journal | vauthors = Amory JK, Blithe DL, Sitruk-Ware R, Swerdloff RS, Bremner WJ, Dart C, Liu PY, Thirumalai A, Nguyen BT, Anawalt BD, Lee MS, Page ST, Wang C | display-authors = 6 | title = Design of an international male contraceptive efficacy trial using a self-administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone) | journal = Contraception | volume = 124 | pages = 110064 | date = August 2023 | pmid = 37210024 | doi = 10.1016/j.contraception.2023.110064 | s2cid = 258800752 }}</ref><ref>{{cite journal | vauthors = Ilani N, Roth MY, Amory JK, Swerdloff RS, Dart C, Page ST, Bremner WJ, Sitruk-Ware R, Kumar N, Blithe DL, Wang C | display-authors = 6 | title = A new combination of testosterone and nestorone transdermal gels for male hormonal contraception | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 97 | issue = 10 | pages = 3476–3486 | date = October 2012 | pmid = 22791756 | pmc = 3462927 | doi = 10.1210/jc.2012-1384 }}</ref><ref name="Roth_2014">{{cite journal | vauthors = Roth MY, Shih G, Ilani N, Wang C, Page ST, Bremner WJ, Swerdloff RS, Sitruk-Ware R, Blithe DL, Amory JK | display-authors = 6 | title = Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial | journal = Contraception | volume = 90 | issue = 4 | pages = 407–412 | date = October 2014 | pmid = 24981149 | pmc = 4269220 | doi = 10.1016/j.contraception.2014.05.013 }}</ref><ref>{{cite journal | vauthors = Anawalt BD, Roth MY, Ceponis J, Surampudi V, Amory JK, Swerdloff RS, Liu PY, Dart C, Bremner WJ, Sitruk-Ware R, Kumar N, Blithe DL, Page ST, Wang C | display-authors = 6 | title = Combined nestorone-testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men | journal = Andrology | volume = 7 | issue = 6 | pages = 878–887 | date = November 2019 | pmid = 30969032 | pmc = 6768743 | doi = 10.1111/andr.12603 }}</ref>
+*NES/T ([[Segesterone acetate|Nesterone]]/Testosterone gel) is a transdermal gel that users apply to the upper arms and shoulders once daily.<ref name="Yahoo News_2023">{{Cite web |date=2023-03-01 |title=With a New Gel, the Future of Male Birth Control Looks Bright |url=https://news.yahoo.com/gel-future-male-birth-control-140000146.html |access-date=2023-10-09 |website=Yahoo News |language=en-US}}</ref><ref>{{Cite web |date=2022-02-22 |title=What Happens When Men Take Hormonal Birth Control? |url=https://www.cosmopolitan.com/health-fitness/a38954452/male-contraceptive-gel-trial/ |access-date=2023-10-12 |website=Cosmopolitan |language=en-US}}</ref> Developed as a collaboration between the [[Eunice Kennedy Shriver National Institute of Child Health and Human Development|NICHD]] and [[Population Council]], NES/T is in a [[Phases of clinical research|phase II]] clinical trial ([https://clinicaltrials.gov/study/NCT03452111 ClinicalTrials.gov]), where it is being evaluated for safety and efficacy, with healthy couples relying on it as their only means of birth control.<ref name="Amory_2023">{{cite journal | vauthors = Amory JK, Blithe DL, Sitruk-Ware R, Swerdloff RS, Bremner WJ, Dart C, Liu PY, Thirumalai A, Nguyen BT, Anawalt BD, Lee MS, Page ST, Wang C | display-authors = 6 | title = Design of an international male contraceptive efficacy trial using a self-administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone) | journal = Contraception | volume = 124 | pages = 110064 | date = August 2023 | pmid = 37210024 | doi = 10.1016/j.contraception.2023.110064 | s2cid = 258800752 }}</ref><ref>{{cite journal | vauthors = Ilani N, Roth MY, Amory JK, Swerdloff RS, Dart C, Page ST, Bremner WJ, Sitruk-Ware R, Kumar N, Blithe DL, Wang C | display-authors = 6 | title = A new combination of testosterone and nestorone transdermal gels for male hormonal contraception | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 97 | issue = 10 | pages = 3476–3486 | date = October 2012 | pmid = 22791756 | pmc = 3462927 | doi = 10.1210/jc.2012-1384 }}</ref><ref name="Roth_2014">{{cite journal | vauthors = Roth MY, Shih G, Ilani N, Wang C, Page ST, Bremner WJ, Swerdloff RS, Sitruk-Ware R, Blithe DL, Amory JK | display-authors = 6 | title = Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial | journal = Contraception | volume = 90 | issue = 4 | pages = 407–412 | date = October 2014 | pmid = 24981149 | pmc = 4269220 | doi = 10.1016/j.contraception.2014.05.013 }}</ref><ref>{{cite journal | vauthors = Anawalt BD, Roth MY, Ceponis J, Surampudi V, Amory JK, Swerdloff RS, Liu PY, Dart C, Bremner WJ, Sitruk-Ware R, Kumar N, Blithe DL, Page ST, Wang C | display-authors = 6 | title = Combined nestorone-testosterone gel suppresses serum gonadotropins to concentrations associated with effective hormonal contraception in men | journal = Andrology | volume = 7 | issue = 6 | pages = 878–887 | date = November 2019 | pmid = 30969032 | pmc = 6768743 | doi = 10.1111/andr.12603 }}</ref>
 *[[Dimethandrolone undecanoate|DMAU]] (Dimethandrolone undecanoate) is a steroid-based contraceptive molecule with both [[androgen]]ic and [[Progestogen|progestational]] activities, which allows it to be used as a single agent. DMAU has been tested in clinical trials in both oral<ref>{{Cite journal |last=Jacobsohn |first=Tamar |last2=Nguyen |first2=Brian |last3=Fernando |first3=Frances |last4=Brown |first4=Jill |last5=Blithe |first5=Diana |last6=Lee |first6=Min |last7=Yuen |first7=Fiona |last8=Swerdloff |first8=Ronald |last9=Liu |first9=Peter |last10=Wang |first10=Christina |last11=Farrant |first11=Maritza |last12=Anawalt |first12=Bradley |last13=Thirumalai |first13=Arthi |last14=Bremner |first14=William |last15=Page |first15=Stephanie |date=2022-11-01 |title=ODP644 Oral Dosing of Progestogenic Androgens for Male Contraception Show Low Serum Testosterone and High Acceptability in Placebo-Controlled Trials |url=https://academic.oup.com/jes/article/6/Supplement_1/A676/6786697 |journal=Journal of the Endocrine Society |language=en |volume=6 |issue=Supplement_1 |pages=A676–A676 |doi=10.1210/jendso/bvac150.1398 |issn=2472-1972}}</ref><ref>{{Cite journal |last=Nguyen |first=Brian T. |last2=Farrant |first2=Maritza T. |last3=Anawalt |first3=Bradley D. |last4=Yuen |first4=Fiona |last5=Thirumalai |first5=Arthi |last6=Amory |first6=John K. |last7=Swerdloff |first7=Ronald S. |last8=Bremner |first8=William J. |last9=Liu |first9=Peter Y. |last10=Blithe |first10=Diana L. |last11=Page |first11=Stephanie T. |last12=Wang |first12=Christina |date=2020 |title=Acceptability of oral dimethandrolone undecanoate in a 28-day placebo-controlled trial of a hormonal male contraceptive prototype |url=https://linkinghub.elsevier.com/retrieve/pii/S0010782420301098 |journal=Contraception |language=en |volume=102 |issue=1 |pages=52–57 |doi=10.1016/j.contraception.2020.04.006}}</ref> and injectable ([https://clinicaltrials.gov/study/NCT02927210 NCT02927210]) forms.
 *[[11β-Methyl-19-nortestosterone dodecylcarbonate|11β-MNTDC]] is another dual-function molecule (progestogenic androgen) in clinical development as an oral contraceptive for men.<ref name="Nguyen_2021">{{cite journal | vauthors = Nguyen BT, Yuen F, Farrant M, Thirumalai A, Fernando F, Amory JK, Swerdloff RS, Anawalt BD, Blithe DL, Long JE, Liu PY, Page ST, Wang C | display-authors = 6 | title = Acceptability of the oral hormonal male contraceptive prototype, 11β-methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC), in a 28-day placebo-controlled trial | journal = Contraception | volume = 104 | issue = 5 | pages = 531–537 | date = November 2021 | pmid = 34153318 | pmc = 8995005 | doi = 10.1016/j.contraception.2021.06.009 }}</ref>
 Some anabolic steroids may exhibit suppressive effects on spermatogenesis, but none are being investigated for use as a male contraceptive.<ref>{{cite journal | vauthors = El Osta R, Almont T, Diligent C, Hubert N, Eschwège P, Hubert J | title = Anabolic steroids abuse and male infertility | journal = Basic and Clinical Andrology | volume = 26 | pages = 2 | date = 2016 | pmid = 26855782 | pmc = 4744441 | doi = 10.1186/s12610-016-0029-4 | doi-access = free }}</ref>
-==== Non-hormonal pharmaceutical contraceptives in development for men ====
+==== Non-hormonal pharmaceutical contraceptives for men ====
+Non-hormonal contraceptives for men are a diverse group of molecules that act by inhibiting any of the many [[Protein|proteins]] involved in sperm production, release, or function.  Because sperm cells are highly specialized, they express many proteins that are rare in the rest of the human body.<ref>{{Cite journal |last=Chen |first=Su-Ren |last2=Batool |first2=Aalia |last3=Wang |first3=Yu-Qian |last4=Hao |first4=Xiao-Xia |last5=Chang |first5=Chawn-Shang |last6=Cheng |first6=C Yan |last7=Liu |first7=Yi-Xun |date=2016-11-10 |title=The control of male fertility by spermatid-specific factors: searching for contraceptive targets from spermatozoon’s head to tail |url=https://www.nature.com/articles/cddis2016344 |journal=Cell Death & Disease |language=en |volume=7 |issue=11 |pages=e2472–e2472 |doi=10.1038/cddis.2016.344 |issn=2041-4889}}</ref><ref>{{Cite journal |last=Zheng |first=Li-Ping |last2=Wang |first2=Hua-Feng |last3=Li |first3=Bao-Ming |last4=Zeng |first4=Xu-Hui |date=2013 |title=Sperm-specific ion channels: targets holding the most potential for male contraceptives in development |url=https://linkinghub.elsevier.com/retrieve/pii/S0010782413003053 |journal=Contraception |language=en |volume=88 |issue=4 |pages=485–491 |doi=10.1016/j.contraception.2013.06.002}}</ref><ref>{{Cite journal |last=Robertson |first=Matthew J. |last2=Kent |first2=Katarzyna |last3=Tharp |first3=Nathan |last4=Nozawa |first4=Kaori |last5=Dean |first5=Laura |last6=Mathew |first6=Michelle |last7=Grimm |first7=Sandra L. |last8=Yu |first8=Zhifeng |last9=Légaré |first9=Christine |last10=Fujihara |first10=Yoshitaka |last11=Ikawa |first11=Masahito |last12=Sullivan |first12=Robert |last13=Coarfa |first13=Cristian |last14=Matzuk |first14=Martin M. |last15=Garcia |first15=Thomas X. |date=2020 |title=Large-scale discovery of male reproductive tract-specific genes through analysis of RNA-seq datasets |url=https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-020-00826-z |journal=BMC Biology |language=en |volume=18 |issue=1 |doi=10.1186/s12915-020-00826-z |issn=1741-7007}}</ref>  This suggests the possibility that non-hormonal contraceptives that specifically block these sperm proteins could have fewer side effects than hormonal contraceptives, since sex steroid receptors are found in tissues throughout the body.<ref>{{Cite journal |last=Johnston |first=Daniel S |last2=Goldberg |first2=Erwin |date=2020-08-04 |title=Preclinical contraceptive development for men and women |url=https://academic.oup.com/biolreprod/article/103/2/147/5837011 |journal=Biology of Reproduction |language=en |volume=103 |issue=2 |pages=147–156 |doi=10.1093/biolre/ioaa076 |issn=0006-3363}}</ref>  Non-hormonal contraceptives can work by blocking spermatogenesis, sperm release, or mature sperm function, resulting in products with a wide variety of usage patterns, from slow onset to on-demand usage.<ref>{{Cite web |title=Mechanisms of Male Contraception |url=https://www.malecontraceptive.org/mechanisms-of-male-contraception.html |access-date=2024-01-30 |website=Male Contraceptive Initiative |language=en}}</ref>  Contraceptives targeting mature sperm functions could even be taken by both sperm-producing and egg producing people.<ref name=":4" /><ref name=":5" />  Challenges of non-hormonal contraceptive development include [[bioavailability]] and delivery past the [[Blood–testis barrier|blood-testis barrier]].<ref>{{Cite journal |last=Cheng |first=C. Yan |last2=Mruk |first2=Dolores D. |date=2012 |editor-last=Sibley |editor-first=David R. |title=The Blood-Testis Barrier and Its Implications for Male Contraception |url=http://pharmrev.aspetjournals.org/lookup/doi/10.1124/pr.110.002790 |journal=Pharmacological Reviews |language=en |volume=64 |issue=1 |pages=16–64 |doi=10.1124/pr.110.002790 |issn=0031-6997}}</ref>
-*[[YCT529]], a Vitamin A receptor antagonist, entered early clinical development in 2023 ([https://clinicaltrials.gov/study/NCT06094283 NCT06094283]) as a male contraceptive by the US startup YourChoice Pharmaceuticals. The clinical test on humans is done by the UK company Quotient Sciences.<ref>[https://www.acs.org/content/acs/en/pressroom/newsreleases/2022/march/non-hormonal-pill-could-soon-expand-mens-birth-control-options.html A non-hormonal pill could soon expand men’s birth control options. ''ACS News'' 23 March 2022]</ref><ref>{{Cite web |date=13 December 2023 |title=YourChoice Therapeutics begins first-in-human trial for male birth control pill |url=https://www.pharmacy.umn.edu/news/yourchoice-therapeutics-begins-first-human-trial-male-birth-control-pill |access-date=2023-12-18 |website=University of Minnesota College of Pharmacy |language=en}}</ref> The clinical test was originally planned in 2022 instead of 2023, with an expected marketing date 5 years later.<ref>{{cite web|url=https://www.biotechniques.com/drug-discovery-development/is-that-an-oral-male-contraceptive-on-the-horizon/|title=Is that an oral male contraceptive on the horizon?}}</ref>
-*Non-hormonal oral medications based on extracts and derivatives of ''[[Tripterygium wilfordii]]'' ([[wikt:雷|雷]][[wikt:公|公]][[wikt:籐|籐]], lei gong teng), a plant used in Traditional Chinese Medicine, were studied clinically from the mid-1980s to mid-1990s.<ref name="Zhen_1995">{{cite journal |vauthors=Zhen QS, Ye X, Wei ZJ |date=February 1995 |title=Recent progress in research on Tripterygium: a male antifertility plant |journal=Contraception |volume=51 |issue=2 |pages=121–129 |doi=10.1016/0010-7824(94)00018-R |pmid=7750290}}</ref> In 2021, a trial published in ''Nature Communications'' showed that one derivative, [[triptonide]], was safe, effective, and reversible in laboratory mice and monkeys.<ref>{{cite journal |display-authors=6 |vauthors=Chang Z, Qin W, Zheng H, Schegg K, Han L, Liu X, Wang Y, Wang Z, McSwiggin H, Peng H, Yuan S, Wu J, Wang Y, Zhu S, Jiang Y, Nie H, Tang Y, Zhou Y, Hitchcock MJ, Tang Y, Yan W |date=February 2021 |title=Triptonide is a reversible non-hormonal male contraceptive agent in mice and non-human primates |journal=Nature Communications |volume=12 |issue=1 |pages=1253 |bibcode=2021NatCo..12.1253C |doi=10.1038/s41467-021-21517-5 |pmc=7902613 |pmid=33623031}}</ref>
-*Pharmacological inhibition of [[chromatin remodeling]] by the pan-inhibitor [[JQ1]] on the target [[BRDT]] has been shown to produce reversible sterility in male mice.<ref>{{cite web |title=A male contraceptive pill in the making? |url=http://www.eurekalert.org/pub_releases/2012-08/dci-amc081412.php |access-date=17 August 2012}}</ref><ref name="pmid22901802">{{cite journal |display-authors=6 |vauthors=Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE |date=August 2012 |title=Small-molecule inhibition of BRDT for male contraception |journal=Cell |volume=150 |issue=4 |pages=673–684 |doi=10.1016/j.cell.2012.06.045 |pmc=3420011 |pmid=22901802}}</ref><ref>{{Cite journal |last1=Wisniewski |first1=Andrea |last2=Georg |first2=Gunda I. |date=2020-03-15 |title=BET proteins: Investigating BRDT as a potential target for male contraception |journal=Bioorganic & Medicinal Chemistry Letters |volume=30 |issue=6 |pages=126958 |doi=10.1016/j.bmcl.2020.126958 |issn=1464-3405 |pmc=7023680 |pmid=32019712}}</ref>
-*[[BMS-189453]], 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.<ref name="livescience">{{cite news |date=4 June 2011 |title=New Male Birth Control Concept Shows Promise |url=https://www.livescience.com/14440-male-birth-control-pill-sperm-vitamin.html |work=LiveScience |vauthors=Parry W}}</ref><ref>{{cite journal |vauthors=Chung SS, Wang X, Roberts SS, Griffey SM, Reczek PR, Wolgemuth DJ |date=June 2011 |title=Oral administration of a retinoic Acid receptor antagonist reversibly inhibits spermatogenesis in mice |journal=Endocrinology |volume=152 |issue=6 |pages=2492–2502 |doi=10.1210/en.2010-0941 |pmc=3100616 |pmid=21505053}}</ref> 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.<ref name="Science2012">{{cite journal |vauthors=Kean S |date=October 2012 |title=Contraception research. Reinventing the pill: male birth control |journal=Science |volume=338 |issue=6105 |pages=318–320 |bibcode=2012Sci...338..318K |doi=10.1126/science.338.6105.318 |pmid=23087225}}</ref> Another way is blocking retionic receptors themselves, although it can also have serious side effects.<ref name="livescience" />
-*In 2002, researchers fed extracts from the seeds of papaya fruits (''[[Carica papaya]]'') to monkeys. Subsequently, the monkeys had no sperm in their ejaculate.<ref name="www.nichd.nih.gov_2022">{{Cite web |date=2022-02-16 |title=CDP Research: Developing Hormonal Contraception Methods for Men {{!}} NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development |url=https://www.nichd.nih.gov/about/org/dir/dph/officebranch/cdp/research/contraception_men |access-date=2023-10-10 |website=www.nichd.nih.gov |language=en}}</ref> 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.<ref>{{cite journal |vauthors=Goyal S, Manivannan B, Ansari AS, Jain SC, Lohiya NK |date=February 2010 |title=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=Journal of Ethnopharmacology |volume=127 |issue=2 |pages=286–291 |doi=10.1016/j.jep.2009.11.007 |pmid=19914367}}</ref>
+===== Non-hormonal spermatogenesis-blocking male contraceptives in clinical trials as of 2024 =====
-==== Thermal male contraceptive approaches ====
+*[[YCT529]], a [[Retinoic acid receptor alpha|retinoic acid receptor]] [[Receptor antagonist|antagonist]], began a [[Phases of clinical research|Phase 1]] clinical trial in 2023 ([https://clinicaltrials.gov/study/NCT06094283 NCT06094283]) organized by the US startup YourChoice Pharmaceuticals.<ref>[https://www.acs.org/content/acs/en/pressroom/newsreleases/2022/march/non-hormonal-pill-could-soon-expand-mens-birth-control-options.html A non-hormonal pill could soon expand men’s birth control options. ''ACS News'' 23 March 2022]</ref><ref>{{Cite web |date=13 December 2023 |title=YourChoice Therapeutics begins first-in-human trial for male birth control pill |url=https://www.pharmacy.umn.edu/news/yourchoice-therapeutics-begins-first-human-trial-male-birth-control-pill |access-date=2023-12-18 |website=University of Minnesota College of Pharmacy |language=en}}</ref><ref>{{cite web|url=https://www.biotechniques.com/drug-discovery-development/is-that-an-oral-male-contraceptive-on-the-horizon/|title=Is that an oral male contraceptive on the horizon?}}</ref>  It has been known since the late 1950s that blocking the retinoic acid/Vitamin A signalling pathway inhibits spermatogenesis in rodents and humans, and various attempts have been made to develop male contraceptives that use this approach.<ref>{{Cite journal |last=Kean |first=Sam |date=2012-10-19 |title=Reinventing the Pill: Male Birth Control |url=https://www.science.org/doi/10.1126/science.338.6105.318 |journal=Science |language=en |volume=338 |issue=6105 |pages=318–320 |doi=10.1126/science.338.6105.318 |issn=0036-8075}}</ref><ref>{{Cite journal |last=Noman |first=Md Abdullah Al |last2=Kyzer |first2=Jillian L |last3=Chung |first3=Sanny S W |last4=Wolgemuth |first4=Debra J |last5=Georg |first5=Gunda I |date=2020-08-04 |title=Retinoic acid receptor antagonists for male contraception: current status† |url=https://academic.oup.com/biolreprod/article/103/2/390/5871846 |journal=Biology of Reproduction |language=en |volume=103 |issue=2 |pages=390–399 |doi=10.1093/biolre/ioaa122 |issn=0006-3363}}</ref><ref>{{Cite journal |last=Chung |first=Sanny S. W. |last2=Wang |first2=Xiangyuan |last3=Roberts |first3=Shelby S. |last4=Griffey |first4=Stephen M. |last5=Reczek |first5=Peter R. |last6=Wolgemuth |first6=Debra J. |date=2011-06-01 |title=Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice |url=https://academic.oup.com/endo/article/152/6/2492/2457398 |journal=Endocrinology |language=en |volume=152 |issue=6 |pages=2492–2502 |doi=10.1210/en.2010-0941 |issn=0013-7227}}</ref>  Development success of these earlier molecules has been limited by off-target effects.<ref>{{Cite journal |last=Thirumalai |first=Arthi |last2=Amory |first2=John K. |date=2021 |title=Emerging approaches to male contraception |url=https://doi.org/10.1016/j.fertnstert.2021.03.047 |journal=Fertility and Sterility |volume=115 |issue=6 |pages=1369–1376 |doi=10.1016/j.fertnstert.2021.03.047 |issn=0015-0282 |pmc=PMC8169637 |pmid=33931201}}</ref>
+===== Non-hormonal spermatogenesis-blocking male contraceptives in preclinical development as of 2024 =====
+*[[Triptonide]], a derivative of ''[[Tripterygium wilfordii]]'', a plant used in [[traditional Chinese medicine]],<ref name="Zhen_1995">{{cite journal |vauthors=Zhen QS, Ye X, Wei ZJ |date=February 1995 |title=Recent progress in research on Tripterygium: a male antifertility plant |journal=Contraception |volume=51 |issue=2 |pages=121–129 |doi=10.1016/0010-7824(94)00018-R |pmid=7750290}}</ref> has been shown to safely, effectively, and reversibly block sperm production in laboratory mice and monkeys.<ref>{{cite journal |display-authors=6 |vauthors=Chang Z, Qin W, Zheng H, Schegg K, Han L, Liu X, Wang Y, Wang Z, McSwiggin H, Peng H, Yuan S, Wu J, Wang Y, Zhu S, Jiang Y, Nie H, Tang Y, Zhou Y, Hitchcock MJ, Tang Y, Yan W |date=February 2021 |title=Triptonide is a reversible non-hormonal male contraceptive agent in mice and non-human primates |journal=Nature Communications |volume=12 |issue=1 |pages=1253 |bibcode=2021NatCo..12.1253C |doi=10.1038/s41467-021-21517-5 |pmc=7902613 |pmid=33623031}}</ref>
+*[[JQ1]], a pharmacological inhibitor of [[chromatin remodeling]] by [[BRDT]], has been shown to produce reversible sterility in male mice.<ref>{{cite web |title=A male contraceptive pill in the making? |url=http://www.eurekalert.org/pub_releases/2012-08/dci-amc081412.php |access-date=17 August 2012}}</ref><ref name="pmid22901802">{{cite journal |display-authors=6 |vauthors=Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE |date=August 2012 |title=Small-molecule inhibition of BRDT for male contraception |journal=Cell |volume=150 |issue=4 |pages=673–684 |doi=10.1016/j.cell.2012.06.045 |pmc=3420011 |pmid=22901802}}</ref><ref>{{Cite journal |last1=Wisniewski |first1=Andrea |last2=Georg |first2=Gunda I. |date=2020-03-15 |title=BET proteins: Investigating BRDT as a potential target for male contraception |journal=Bioorganic & Medicinal Chemistry Letters |volume=30 |issue=6 |pages=126958 |doi=10.1016/j.bmcl.2020.126958 |issn=1464-3405 |pmc=7023680 |pmid=32019712}}</ref>
+===== Thermal male contraceptive approaches =====
 {{Main|Heat-based contraception}}
 [[File:Anneaux Samuel.png|thumb|Silicone rings, worn by users for male contraceptive purposes.]][[Heat-based contraception]] causes thermal dysregulation of spermatogenesis and is a well-established means of producing a contraceptive effect in men.<ref>{{Cite journal |last1=Macleod |first1=John |last2=Hotchkiss |first2=Robert S. |date=1941-05-01 |title=The Effect of Hyperpyrexia Upon Spermatozoa Counts in Men |url=https://academic.oup.com/endo/article-lookup/doi/10.1210/endo-28-5-780 |journal=Endocrinology |language=en |volume=28 |issue=5 |pages=780–784 |doi=10.1210/endo-28-5-780 |issn=0013-7227}}</ref><ref>{{Cite journal |last1=Wallach |first1=Edward E. |last2=Kandeel |first2=Fouad R. |last3=Swerdloff |first3=Ronald S. |date=1988-01-01 |title=Role of temperature in regulation of spermatogenesis and the use of heating as a method for contraception |journal=Fertility and Sterility |volume=49 |issue=1 |pages=1–23 |doi=10.1016/S0015-0282(16)59640-X |issn=0015-0282 |pmid=3275550 |doi-access=free}}</ref><ref>{{Cite journal |last=Robinson |first=Derek |date=1968-04-22 |title=Control of Human Spermatogenesis Intrascrotal Temperature |url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.1968.03140170006002 |journal=JAMA: The Journal of the American Medical Association |language=en |volume=204 |issue=4 |pages=290 |doi=10.1001/jama.1968.03140170006002 |issn=0098-7484}}</ref><ref>{{Cite journal |last1=Fahim |first1=M. S. |last2=Fahim |first2=Z. |last3=Harman |first3=J. |last4=Thompson |first4=I. |last5=Montie |first5=J. |last6=Hall |first6=D. G. |date=August 1977 |title=Ultrasound as a new method of male contraception |url=https://pubmed.ncbi.nlm.nih.gov/407106 |journal=Fertility and Sterility |volume=28 |issue=8 |pages=823–831 |doi=10.1016/S0015-0282(16)42735-4 |issn=0015-0282 |pmid=407106}}</ref> Normally, the [[Testicle|testis]] are held at a temperature approximately 2&nbsp;°C below that of basal body temperature, and are [[thermoregulated]] by smooth muscle tissue in the [[scrotum]]. Increases in testicular temperature of as little as 2&nbsp;°C are associated with decreased sperm count and decreased sperm quality, and the effect has been shown to be directly related to heat intensity and frequency.{{Citation needed|date=October 2023}}
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 === Approaches that block necessary functions of mature sperm ===
-These approaches work by blocking functions that mature sperm need in order to reach and fertilize an egg in the female reproductive tract, such as [[Sperm motility|motility]], [[capacitation]], semen liquification, or [[Fertilisation|fertilization]].  Drugs or devices that target mature sperm are likely to be effective on-demand, and could even be delivered either in sperm-producing or egg-producing bodies, leading to truly unisex contraceptives.<ref>{{Cite web |title=Investigating Sperm-Specific Proteins and Physiology to Inform Development of Non-Hormonal, Unisex Contraception - ProQuest |url=https://www.proquest.com/openview/87a41aefc3eaa903a8bae6cb60ab5316/1?pq-origsite=gscholar&cbl=18750&diss=y |access-date=2024-01-27 |website=www.proquest.com |language=en}}</ref><ref>{{Cite journal |last=Lishko |first=Polina V. |date=2016 |title=Contraception: Search for an Ideal Unisex Mechanism by Targeting Ion Channels |url=https://doi.org/10.1016/j.tibs.2016.08.002 |journal=Trends in Biochemical Sciences |volume=41 |issue=10 |pages=816–818 |doi=10.1016/j.tibs.2016.08.002 |issn=0968-0004 |pmc=5364274 |pmid=27545067}}</ref>
+These approaches work by blocking functions that mature sperm need in order to reach and fertilize an egg in the female reproductive tract, such as [[Sperm motility|motility]], [[capacitation]], semen liquification, or [[Fertilisation|fertilization]].  Drugs or devices that target mature sperm are likely to be effective on-demand, and could even be delivered either in sperm-producing or egg-producing bodies, leading to truly unisex contraceptives.<ref name=":4">{{Cite web |title=Investigating Sperm-Specific Proteins and Physiology to Inform Development of Non-Hormonal, Unisex Contraception - ProQuest |url=https://www.proquest.com/openview/87a41aefc3eaa903a8bae6cb60ab5316/1?pq-origsite=gscholar&cbl=18750&diss=y |access-date=2024-01-27 |website=www.proquest.com |language=en}}</ref><ref name=":5">{{Cite journal |last=Lishko |first=Polina V. |date=2016 |title=Contraception: Search for an Ideal Unisex Mechanism by Targeting Ion Channels |url=https://doi.org/10.1016/j.tibs.2016.08.002 |journal=Trends in Biochemical Sciences |volume=41 |issue=10 |pages=816–818 |doi=10.1016/j.tibs.2016.08.002 |issn=0968-0004 |pmc=5364274 |pmid=27545067}}</ref>
 ==== Non-hormonal pharmaceutical approaches ====
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 * Injectable medical [[polyurethane]] (MPU)
 * [[Trestolone]] (MENT) has been formulated as a contraceptive implant.<ref>{{cite journal |vauthors=Nieschlag E, Kumar N, Sitruk-Ware R |date=March 2013 |title=7α-methyl-19-nortestosterone (MENTR): the population council's contribution to research on male contraception and treatment of hypogonadism |journal=Contraception |volume=87 |issue=3 |pages=288–295 |doi=10.1016/j.contraception.2012.08.036 |pmid=23063338}}</ref>
+* Researchers in 2010 fed extracts from the [[papaya]] seeds to monkeys. Subsequently, the monkeys had no sperm in their ejaculate, with no apparent ill effects on the testes or other organs.<ref>{{cite journal |vauthors=Goyal S, Manivannan B, Ansari AS, Jain SC, Lohiya NK |date=February 2010 |title=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=Journal of Ethnopharmacology |volume=127 |issue=2 |pages=286–291 |doi=10.1016/j.jep.2009.11.007 |pmid=19914367}}</ref>
 ==notes==