Male contraceptive

Male contraceptives, also known as male birth control, are methods of preventing pregnancy by leveraging male physiology. Globally, the most common forms of male contraceptives include condoms, vasectomy, and withdrawal. Men are largely limited to these forms of contraception, and combined, male contraceptives make up less than one-third of total contraceptive use.
Novel forms of male contraception are in clinical and nonclinical stages of research and development, however, none have reached regulatory approval for widespread use. Studies of men indicate that around half of survey populations 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.
Currently available methods
Vasectomy
Vasectomy is surgical procedure for permanent male sterilization usually performed in a physician's office in an outpatient procedure. During the procedure, the vasa deferentia of a patient are severed, and then tied or sealed to prevent the transport of sperm through the reproductive tract and thereby causing a pregnancy. Vasectomy is an effective procedure, with less than 0.15% of partners becoming pregnant within the first 12 months after the procedure. Vasectomy is also a widely reliable and safe method of contraception, and complications are both rare and minor. However, due to the presence of sperm retained beyond the blocked vasa deferentia, vasectomies are not initially effective and the remaining sperm must be cleared through ejaculation and / or time. Vasectomies can be reversed, though rates of successful reversal are variable, and the procedure is often costly.
Condoms
A condom is a sheathed barrier device that is rolled onto an erect penis before intercourse and retains ejaculated semen, thereby preventing pregnancy. Condoms are marginally effective when compared to vasectomy or modern methods of contraception for women, and have a typical-use failure rate of 18%. However, condoms have the advantage of providing protection against some sexually transmitted infections such as HIV/AIDS. Condoms may be combined with other forms of contraception (such as spermicide) for greater protection.
Withdrawal
The withdrawal method, or 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. Withdrawal is considered an ineffective contraceptive method, with typical use failure rates of around 22%.
Other currently available methods for men include abstinence, outercourse, and other non-vaginal means of ejaculation.
Research into new methods
Research is ongoing to generate novel male contraceptive products based on drugs and medical devices. Products in development currently include long-acting reversible contraceptives (LARCs), daily transdermal gels, daily oral pills, injectables, implants, and oral on-demand contraceptives. Development of novel male contraceptive methods has ongoing for many decades, but progress been stymied by a lack of industry involvement. Most funding for male contraceptive research is derived from government or philanthropic sources.
Because of the nature of the male reproductive system, many stages of sperm development, and complex regulatory and signaling pathways involved in maturation steps such as capacitation and fertilization, a contraceptive effect in men can be elicited through multiple mechanisms of action. For example, a potential drug product leveraging a mechanism that targets spermatogenesis will likely also result in a reduction in sperm count and testis weight for the user, as well as some measure of an onset time, similar to a vasectomy, where the product is not effective immediately after administration. Other mechanisms that target later steps of the sperm life cycle could have unique characteristics such as near on-demand contraceptive efficacy through oral administration or topical administration in a female user. Many research programs are also early in development and have yet to consider delivery modality. Application of diverse dosage forms and innovative drug delivery platforms such as controlled release formulations and microneedles could generate further diversity in male contraceptive products.
Sperm targets can also be leveraged in the female reproductive system, potentially generating new female or unisex contraceptives.
Drug-based male contraceptive approaches
Hormonal Contraceptives
Hormonal contraceptives for men, similar to hormonal female methods, use exogenous steroids to interrupt physiologic hypothalamic-pituitary-gonadal pathways. These exogenous steroids suppress secretion of the gonadotropins LH and FSH, which further impairs testosterone production and sperm generation in the testes. This reduced sperm output manifests 4–12 weeks following initiation of the contraceptive method.
Multiple methods of male hormonal contraception have been tested in clinical trials and found to be effective and reversible. Currently, there are contraceptive products in development through the NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Contraceptive Clinical Trials Network (CCTN).
Nestorone®/Testosterone (Nes/T) Gel is a transdermal gel that users apply to the upper arms and shoulders once daily. Developed as a collaboration between the NICHD and Population Council, Nes/T is currently in clinical trials (ClinicalTrials.gov ID NCT03452111) being evaluated for safety and efficacy.
Dimethandrolone undecanoate (DMAU) is a novel progestogenic androgen which contains both androgenic and progestational activities that facilitate contraceptive activity while maintaining libido and other androgen-dependent functions. DMAU is currently being tested in clinical trials in both oral (NCT01382069 & NCT03455075) and injectable (NCT02927210) forms.
11β -Methyl Nortestosterone Dodecylcarbonate (11β-MNTDC) is another progestogenic androgen in clinical development (NCT03298373) as an oral contraceptive for men.
7-Alpha-methyl-19-nortestosterone (MENT) has been formulated as a contraceptive implant.
Some hormonal contraceptives for men such as testosterone undecanoate have faced criticism for their side effect profiles and the perceived tolerability of users.
Some anabolic steroids may exhibit suppressive effects on spermatogenesis, but none are currently approved for use as a male contraceptive.
Non-hormonal Contraceptives
Non-hormonal oral medications based on extracts and derivatives of Tripterygium wilfordii (雷公籐, lei gong teng), a plant used in Traditional Chinese Medicine, were studied clinically from the mid-1980s to mid-1990s. In 2021, a trial published in Nature Communications showed that one derivative, triptonide, was safe, effective, and reversible in laboratory mice and monkeys.
Pharmacological inhibition of chromatin remodeling by the pan-inhibitor JQ1 on the target BRDT has been shown to produce reversible sterility in male mice.
Immunocontraception targeting sperm antigens has been found to be effective in male primates.
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. 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.
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. 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. Another way is blocking retionic receptors themselves, although it can also have serious side effects.
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.
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.
YCT529, a Vitamin A receptor antagonist, is in development by the startup YourChoice Pharmaceuticals as a male contraceptive.
Soluble adenylyl cyclase inhibition has been demonstrated to temporarily reduce male fertility in mice.
EP055
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. 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.
ADAM is a hydrogel-based male contraceptive implant in clinical development (NCT05134428) by Contraline, Inc. 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. Results from an exploratory trial in humans were published in 2023.
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. RISUG has been in development in India since the 1970s and has been studied in rats, rabbits, non-human primates, and most recently, men. 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. 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.
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.
Other methods have been proposed that use ultrasound treatment to reverse the blockage, though these methods are largely in basic science studies.
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. 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.
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. 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. 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. 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.
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. Ultrasonic methods may also have a non-thermal component to their mechanism.
In 2021, a design of a water bath based ultrasonic male contraceptive product called COSO was a finalist for the James Dyson Award.
Other methods in basic science studies include magnetic targeting and magnetic hyperthermia.
Other approaches
In 2002, researchers fed extracts from the seeds of papaya fruits (Carica papaya) to monkeys. Subsequently, the monkeys had no sperm in their ejaculate. 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.
Innovative condom approaches
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.
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.
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.
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.
Adjudin, a non-toxic analog of lonidamine has been shown to cause reversible infertility in rats. 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.
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. 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.
Injectable medical polyurethane (MPU)
Impact
It is predicted that introduction of a long-acting reversible contraception for males could decrease the rate of unintended pregnancy.
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.
Multiple small-scale acceptability questionnaires also indicate high levels of interest in male contraception.
Acceptability of some thermal methods has been reported in the literature.
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. One test in rats (20 milligrams of the 80% ethanol extract) found that these reduced sperm count by more than half. In medieval Persia (and in other traditions as cited) these herbs were used for male contraception, as well as Gossypium herbaceum (Malvaceae), Cyperus longus (Cyperaceae), Vitex pseudonegundo (Verbenaceae), Chenopodium ambrosioides (Chenopodiaceae), Aristolochia indica (Aristolochiaceae), Punica granatum (Punicaceae), and Sarcostemma acidum (Asclepiadaceae). 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.
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.
References
External links
Male Contraceptive Initiative