The Pipeline of Male Contraceptives: Shifting the Burden of Pregnancy Prevention

August 23, 2022 - Currently, there are numerous forms of effective hormonal and nonhormonal birth control on the market, such as oral contraceptives, transdermal patches, implants, vaginal rings, intrauterine devices, injections, diaphragms, sponges, and cervical caps. However, none of them was intended for use by the male population.

In the United States, given the SCOTUS’s decision to overturn Roe vs Wade, men seeking to take control of their reproductive health and family planning have severely limited options — vasectomy, condoms, and spermicide, most of which have a fairly high failure rate.

While vasectomies are almost 100% effective at preventing pregnancy after three months, only 75% of procedures are reversible if reversed within 3 years. Even though condoms have a high failure rate and spermicide alone is only 70% effective in preventing pregnancies, many men are hesitant about the outpatient procedure associated with vasectomies and the chance of becoming infertile after reversal. As a result, people capable of giving birth bear most of the burden of preventing pregnancy, but the discovery of new male contraceptives may soon shift this responsibility imbalance.

“Scientists have been trying for decades to develop an effective male oral contraceptive, but there are still no approved pills on the market,” explained Md Abdullah Al Noman, Graduate Research Assistant at the University of Minnesota, at the ACS Spring 2022 Media Briefings.

The development of male hormonal contraception began in the 1970s, using testosterone alone or combined with a gonadotropin-releasing hormone (GnRH) to suppress sperm. In the past, most attempts to create a male birth control method failed due to inefficient results or patient complaints of side effects such as weight gain, low libido, and mood swings, among others.

An average fertile sperm count ranges from 15 million to more than 200 million sperm per mL of semen. A man’s sperm count needs to be around 1–10 million sperm per mL to form an effective male contraceptive, but achieving this drastic decrease in production, at least without side effects or permanent infertility, is complicated.

Potential Male Contraception Methods

According to a Male Contraceptive Initiative consumer research study, 17 million men in the United States are seeking reliable and effective contraception that suits their lifestyle. Other data suggest a majority of males, roughly 60%, would consider taking another form of birth control if available. 

Currently, there are several hormonal and nonhormonal male birth control options in the FDA pipeline. Hormonal male birth control options contain synthetic hormones that safely and effectively stop sperm production.

Hormonal Contraception

Male hormonal contraception methods include substances that reduce sperm count. However, determining the correct chemical combination that leads to effective and temporary pregnancy prevention has proven challenging for researchers. For example, data shows that chemical compounds like gossypol and triptolide are close to 100% effective in preventing partner pregnancy but can provoke permanent sperm reduction and infertility.

Testosterone Injections

Testosterone has a variety of functions, such as treating decreased libido, mood swings, and erectile dysfunction but has a negative effect on fertility by preventing the release of hormones responsible for sperm production in the testes. In the largest hormone-based male birth control trial to date, monthly injections of testosterone were found to be 99% effective in preventing partner pregnancy. Yet other studies suggest testosterone alone is not as effective as combining it with progestin (a hormone similar to progesterone) in females.

The notable side effects of testosterone injections include acne, weight gain, injection site pain, abnormal blood lipid levels, and psychological effects.

Topical Gel (NES/T)

Using preliminary data, scientists from the University of Utah Health are currently focused on studying a topical, hormonal gel believed to decrease sperm production without reducing sex drive. This gel combines Nestorone (NES), a progesterone-like hormone that suppresses sperm production, and testosterone (T), a male hormone added to maintain sex drive.

In addition to assessing the safety and effectiveness of the gel in preventing pregnancy, the researchers are also tracking how diligent participants are at applying the gel daily while evaluating its acceptance as a contraceptive method. Most people included in the study experienced little to no side effects when the gel was used as instructed.

Combination Injections

Norethisterone enanthate (NETE), also known as norethindrone enanthate, has been used in long-acting injectable birth control formulations for women and has shown sustained suppression of sperm production in male primates and prolonged suppression of gonadotropins in men. Gonadotropins, such as follicle-stimulating hormones (FSHs) and luteinizing hormones (LHs), are hormones released to increase the production of sex hormones and trigger sperm or ova production.

According to a JCEM study, oral and injectable NETE combined with testosterone undecanoate (TU) — an anabolic steroid medication primarily used for hormone therapy, gender-affirming treatments, and restoring low testosterone levels — shows promise as an effective hormonal contraceptive.

Studies show that injections of NETE/T that were administered at 6- and 8-week intervals significantly reduced sperm production in participants. However, typical side effects include injection site and muscle pain, mood swings, and acne.

GnRH Antagonists and Testosterone

Gonadotropin-releasing hormone (GnRH) antagonists inhibit testosterone production and effectively suppress sperm production. However, long-term use alone results in androgen deficiency, meaning the body has lower levels of male sex hormones needed for optimum health. Therefore, androgen replacement is critical for maintaining testosterone levels in any GnRH antagonist regimen designed for human male contraception.

Although GnRH antagonists combined with testosterone cause little to no side effects, frequent injections are costly and inconvenient for many individuals looking for an easy and affordable birth control option.

Hormonal Male Pill

After passing the first round of clinical testing, a male hormonal birth control pill is giving hope to men looking to take responsibility for pregnancy prevention.

While oral testosterone forms are most often toxic or require multiple doses throughout the day to decrease sperm production, dimethandrolone undecanoate (DMAU) can be taken daily and orally to achieve the same result with limited side effects. Comparable to female birth control pills, this hormonal male birth control pill is roughly 95% effective and reversible.

Although 2018 data published in the Journal of Clinical Endocrinology and Metabolism indicates that men who took the highest dose of DMAU had lower levels of testosterone, FSH, and LH — hormones required for sperm production, the study did not measure sperm count to determine efficacy.

Notable medication side effects include acne, headaches, mild erectile dysfunction, weight gain, fatigue, and low libido.

Nonhormal Contraception

Nonhormonal birth control methods prevent healthy sperm from reaching ova without affecting male hormones.

Vasalgel/Reversible Inhibition of Sperm under Guidance (RISUG)

An alternative to vasectomy, Vasalgel, uses a chemical injection to block the paired tube (vas deferens) that carries sperm from the testicles to the penis, offering long-term contraception with safety, efficacy, and ease in mind. In preclinical trials, this noninvasive procedure is completely reversible with a dissolving agent but most likely won’t hit the market for a few more years.

Vasalgel’s counterpart, RISUG, has been in development for years in India and is currently in Phase III clinical trials. No serious side effects were recorded after the study volunteers received the RISUG procedure, although most participants noted mild scrotal enlargement within the first-week post-injection. Research suggests that RISUG is 99% effective for up to 10 years.

Intra Vas Device (IVD)

The implantation of an intra vas device (IVD) — small silicone devices inserted into the vas deferens — is an investigational procedure designed to accomplish sterilization similar to a vasectomy by preventing semen flow. Only minor cuts are made during the insertion process, but the vas deferens remain intact. Meanwhile, studies are ongoing to determine the safety and effectiveness of this new contraceptive device.

The release of the first FDA-approved male contraceptive and a change in social ideology may be the right combination to achieve an equal contraceptive arrangement across genders. In the meantime, men should discuss birth control options with their doctor and partner(s). Additionally, interested men can enroll in clinical trials to further the developmental progress of male contraceptives.