What does emerging research say about the benefits and limitations of novel male contraceptives? Photo credit: Reproductive Health Supplies Coalition via Unsplash
The introduction of the female contraceptive pill (“the pill”) in the early 1960s wasn’t just a scientific breakthrough; by giving women control over their fertility, the pill challenged traditional gender roles and religious beliefs, sparking a myriad of changes and societal progression. More than six decades later, the responsibility of contraception still falls mostly on women. Whilst the pill and other hormonal contraceptives have been game-changers, they are not without their limitations, including headaches, nausea, mood changes, and weight gain. Given the huge advancements in medical research since the 1960s, why isn’t contraception more evenly shared between women and men?
Male contraception is limited to condoms, which have high failure rates with typical use. Condoms have a 2% failure rate when used properly, but with typical use this rises to 18%. Furthermore, whilst vasectomy (a surgical procedure that makes a man infertile) is effective at preventing pregnancy, it is not reliably reversible.
Nearly half of pregnancies worldwide are unplanned, and with safe abortion not globally accessible, there is a real need for new male contraceptives that are both effective and reversible. Many men wish to be actively involved in contraception and up to 75% of men report that they would use a novel male contraceptive if it was available. So, what are the types of novel male contraceptive, how do they work, and what are the promising developments?
…up to 75% of men report that they would use a novel male contraceptive if it was available.
There are lots of novel approaches to male contraception, which work in a variety of ways. Broadly speaking there are two main categories: hormonal and non-hormonal. Hormonal male contraceptives use hormones (a similar principle to hormonal female contraceptives) to inhibit sperm production in the testes. Non-hormonal approaches are more diverse—some suppress sperm production, others hinder the ability of sperm to swim, whilst others prevent sperm entering semen. Men produce around 1000 sperm per second, and though the ideal result of male contraception is zero sperm in semen, reduced sperm concentration is still good for contraception. For example, <2 million sperm/ml semen is associated with 1.6% conception rate (which is comparable to female contraceptives), but ≤1 million sperm/ml is the goal for male contraceptive clinical trials. To put this into context, ≥15 million sperm/ml is considered a normal concentration.
Hormonal contraceptives
Hormonal male contraceptives are the most well-researched, with studies dating back to 1977. These regimens involve the administration of hormones such as androgens and progestins. These hormones act in the pituitary and hypothalamus in the brain to reduce the release of gonadotrophins, which are hormones that are vital for sperm and testosterone production in the testes. Hence, reducing gonadotrophin release has a contraceptive effect.
Small-scale studies in the 1970s looked at the effect of androgens on male fertility and found that androgens given by injection or taken orally could inhibit sperm production, but this didn’t work in everyone. The World Health Organisation (WHO) later conducted studies in 1990 and 1996 looking at the effect of weekly androgen injections on sperm production and contraceptive efficacy in larger groups of men. These regimens greatly reduced sperm production and were effective contraceptives in most men, although a proportion of men did not adequately suppress sperm production. The 1996 WHO study also found that there were differences between ethnic groups, with better suppression of sperm production in Asian men compared to non-Asian men (95% vs 68% men with zero sperm in semen). Aside from the variable effectiveness, the frequent injection schedule (weekly) is neither desirable nor practical.
With the aim of reducing sperm production more consistently, androgen plus progestin combinations were trialled next. When given as weekly injection plus pills or implants, the combination was better at reducing sperm production than just androgen. Another combination trial (implants plus injections) showed contraceptive efficacy higher than that of condoms, however, there was a delay of several months before sperm production was adequately suppressed. Because sperm production occurs continuously and takes around 72 days in humans, this delay is expected—the onset of full contraceptive effect takes time. Several side effects of the hormonal regimens were noted, including mood changes, acne, injection site pain, muscle pain, changes in libido, and smaller testes. Concerningly, a 2016 trial was terminated early by a safety committee due to high rates of mood changes, depression and a case of intentional paracetamol overdose (non-fatal).
Because sperm production occurs continuously and takes around 72 days in humans, this delay is expected—the onset of full contraceptive effect takes time.
Fortunately, despite the challenges encountered, research into hormonal male contraceptives is still underway, and several novel agents have been researched and are in clinical trials. One example is a drug called DMAU that has dual androgen and progestin activity, which is a potential male contraceptive pill. In a phase I clinical trial, oral DMAU taken daily was well tolerated and effectively reduced gonadotrophins. 80% of men were satisfied with this method and 54% would use it as a main contraceptive if available. DMAU is reportedly in the next stage of clinical trials (phase II trials) to determine whether it reduces sperm production.
Another method of hormonal male contraception is the use of hormone gels. These gels are rubbed into the skin, and the hormones are absorbed. A key advantage of this is that it avoids the injections required in many other regimens. A combined Nestorone® (progestin) and testosterone (NES-T) gel has been developed, and use of NES-T gel daily suppressed serum gonadotrophins, which would hopefully inhibit sperm production. Promisingly, few adverse effects were reported with the gel, and a phase II clinical trial is underway to determine whether NES-T is effective at reducing sperm concentration in semen and to monitor side effects. 86% of men reached ≤1 million/mL sperm by 15 weeks of daily NES-T, with many men reaching this threshold sooner, according to mid-trial results. Though there is still a delay, this faster sperm suppression is promising—we will be able to be more certain when the trial is completed and the results published.
Non-hormonal methods
Unlike the hormonal male contraceptive approaches, non-hormonal methods don’t use hormones to suppress sperm production. Molecules needed for fertility, which are specific to sperm, are ideal targets. This is because inhibiting these should have less off-target effects, which should lead to less side effects. Additionally, non-hormonal methods may be faster acting than hormonal methods.
Inhibiting sperm production
Whilst hormones (e.g. gonadotrophins) are needed for sperm production, there are lots of other non-hormonal factors that are also needed. One such example is a molecule called retinoic acid (RA). Mice engineered to lack RA receptor-α (RAR-α) are sterile, so this was seen as a potential target for contraception. YCT529, a drug that inhibits RAR-α, had excellent contraceptive effect in mice: when taken orally for 4 weeks, YCT529 reduced sperm counts and prevented 99% of pregnancy with no observable side effects. Importantly, fertility returned four to six weeks after treatment. A first-in-humans study testing the safety of YCT529 ended in June 2024, and found that YCT529 is safe. A larger phase II trial to investigate safety and side effects started in September 2024 and is now active/recruiting. YCT529 is a potential non-hormonal male contraceptive pill and is the first of its kind to enter human trials, so it is an exciting development that shows great promise.
Inhibiting sperm motility
Another non-hormonal approach is to inhibit the ability of sperm to swim, which reduces the likelihood of fertilisation. An enzyme that is needed for sperm motility, called soluble adenylyl cyclase (sAC) has been investigated as a potential target. sAC levels are high in sperm but low in other tissues, so the hope is that it could be targeted without too many adverse effects. TDI-10229 is a drug that inhibits sAC and showed great results in a recent pre-clinical study. Mice treated with TDI-11861 were infertile: their sperm showed minimal motility, and TDI-11861 showed excellent efficacy in mating studies. More preclinical studies are needed before trials in humans can be considered, so this is a long way from clinical approval. Nonetheless, it is an early finding that (with extensive further research) could translate into a new type of “on-demand” contraception, where men take a pill shortly before sex.
Preventing sperm entering semen
Another approach to non-hormonal male contraception is preventing sperm entering semen. In vasectomy each vas deferens (the tube which carries sperm from the testes to the penis) is cut, separated and sealed off, preventing sperm entering semen. Nevertheless, the key limitation is that this procedure is not reliably reversible. In light of this, there are several regimens that are in testing, which involve blocking the vas deferens and in principle allow for reversal.
Reversible Inhibition of Sperm Under Guidance (RISUG®) involves injection of a co-polymer into the vas deferens, to block it. Subsequent injection of a reversal agent unblocks the vas deferens. RISUG® is the only novel male contraceptive to have reached phase III clinical trials. It was >99% effective in preventing pregnancy in 303 couples, indicating excellent contraceptive efficacy. However local inflammation, pain or swelling occurred in >40% of participants, which took several months to resolve. These adverse effects are not likely to be acceptable.
ADAMTM is another regimen that blocks sperm entering semen. This involves injection of a hydrogel into the vas deferens. In a preliminary study of four men, ADAMTM was safe, and drastically reduced sperm counts in semen. A larger clinical trial to assess the safety and effectiveness of ADAMTM is in progress. We are yet to see the results from this trial, but the preliminary results are promising.
In summary, lots of novel male contraceptive methods have been explored, and there have been some really exciting findings. These novel contraceptives work by suppressing sperm production, inhibiting sperm movement/function, or preventing sperm entering semen.
Many of the side effects deemed unacceptable in male contraceptives are the same as those experienced by women taking the pill, so people may rightly point out a double-standard here, raising the question of whether misogyny is the real reason we have yet to see new contraceptives for men. Whilst that can’t be ruled out, there is more to the story—scientific hurdles, such as challenges with effectiveness, onset, and reversibility, have definitely slowed progress. Another consideration is that contraception for women doesn’t just prevent pregnancy, it also reduces health risks linked to it, such as gestational diabetes and pre-eclampsia. Since men don’t face these same risks, the safety standards for male contraceptives are potentially stricter when evaluating risks versus benefits.
…scientific hurdles, such as challenges with effectiveness, onset, and reversibility, have definitely slowed progress.
Though these issues have slowed progress, there remains hope that the regimens currently in clinical trials, whether hormonal, non-hormonal, gel, or pill, will overcome these challenges and achieve clinical approval. Approval would have a hugely positive impact by increasing contraceptive options for couples and facilitating the sharing of contraceptive responsibility. Male contraception is an active research area, so watch this space—hopefully we will see some new contraceptives approved in the not-too-distant future.
