Where Is The Male Contraceptive Pill?

In most countries around the world, there are only two available male contraceptive methods: condoms, the most common barrier method of contraception, and vasectomy, which is a minimally invasive surgical procedure and permanent contraceptive method.

Vasectomies are presented as reversible, but the results of a reversal procedure are not guaranteed. Some medical sources suggest that while the reversal procedure itself has up to a 95% success rate, pregnancy rates following a vasectomy reversal range between 30–70%.

So, while vasectomies are quick, easy, and very safe procedures, they may not leave much space for a change of heart regarding reproductive choices.

When it comes to 100% reversible male contraception, the only option is condoms, but many men — and indeed, in many cases, their partners — dislike this method for various reasons. Research has shown that a top reason for men rejecting condoms is that the ones that are commercially available, by and large, are not the right fit, size-wise.

Furthermore, both penis-havers and their partners can have allergies to latex, the material that many condoms are made of, or to some substances in the lubricants or spermicides coating some condoms.

This indicates that there is a stringent need for new male contraceptive methods. Indeed, men around the world have overwhelmingly attested that they would be open and even keen to try out new birth-control methods, according to a large survey conducted by Steve Kretschmer, founder and executive director of DesireLine, a consultancy firm serving the health development sector.

‘Very high’ demand for new contraceptive methods

Kretschmer’s survey addressed 15,678 men and 9,122 female partners from eight countries: the United States, Côte d’Ivoire, the Democratic Republic of Congo, Kenya, Nigeria, Bangladesh, India and Vietnam.

The research — whose findings Kretschmer presented at a World Health Organization (WHO) webinar series in September 2022 — was co-funded by The Bill & Melinda Gates Foundation and the Male Contraceptive Initiative.

Kretschmer told Medical News Today that “[t]he research included samples of [approximately] 2,000 men in the [low- and middle-income country] markets and 3,000 men in the U.S., sampled to be representative of men aged 18–60, who have had sex with a woman within the past year.”

The survey also included female partners to assess their level of trust in their male partners’ contraceptive use, as well as their willingness to shift the burden of contraceptive care to their partners.

According to Kretschmer, this survey found that the “Demand for [novel] male [contraceptive technologies] is very high, with [the] form of administration, e.g., pill versus gel on shoulder, etc. dominating what drives preference.”

Respondents in some low- and middle-income countries said they would prefer a contraceptive in gel form. “Do note that the ‘gel on shoulder’ preference seen in the African countries […] is for the ‘administrative form’ of a gel only, not for the specific current hormonal product in development (Nestorone/Testosterone Transdermal Gel) which is a gel on shoulder application,” noted Kretschmer.

In the U.S., men seemed to be a lot keener on a potential male contraceptive pill. MNT also conducted brief social media surveys asking male MNT and Healthline readers whether they would be open to taking a contraceptive pill in the future.

Of 44 MNT respondents engaging on Twitter, 59.1% said that yes, they would consider taking male contraceptive pills. Of 376 HL respondents engaging on Instagram, 54% responded in the affirmative.

So if the demand is there, why is a male contraceptive pill yet to make its appearance on the market?

The first clinical trials for male hormonal contraceptives hail back to the 1970s. Male hormonal contraceptives have the aim of interfering with testosterone production and ultimately stopping the production of sperm.

Without sperm in the semen or seminal fluid, the fluid that typically comes out of the penis at ejaculation, and which acts as a carrier vehicle for the sperm, there is no danger of fertilizing ovules, or eggs, produced by the ovaries, which results in pregnancy.

The first male hormonal contraceptives to be tested were injection-based, they appeared to be ultimately safe and effective, and the trial participants were able to produce sperm again once they stopped receiving the injections.

Yet several participants discontinued their involvement in these early trials due to the fact that it took a long time for the injections to take full effect and stop the production of sperm, and because they had a “dislike of the injection schedule.”

Later trials — in the early 2000s — tested the efficacy of hormonal contraceptive implants, though often they still required an additional injection protocol.

Studies showed that the participants did not experience any serious side effects, and the contraceptive method appeared effective, yet many of the male participants dropped out, reportedly due to study “protocol-related reasons” and “altered personal circumstances.”

While all this research provided key information about what might be effective and what not, none of them got very far, as the frequency of the required injections put off many of the study participants.

Data from one of the more recent studies that promised an effective contraceptive for males were reported in The Journal of Clinical Endocrinology & Metabolism in 2016. This phase 2 clinical trial tested an injectable combination hormonal contraceptive in a group of 320 healthy volunteers aged 18–45 years.

An injection with too frequent side effects

The injection — administered once every 8 weeks — contained norethisterone enanthate and testosterone undecanoate, and its aim was to suppress sperm production.

The study concluded that the contraceptive was effective in reducing sperm production almost to nil, and confirmed that this effect was reversible — all of which was good news. However, it also issued an important caution: Among the participants, there was a high “frequency of reported moderate and severe mood disorders including depression” linked to the use of the injectable contraceptive.

Despite the promising results on efficacy and overall safety, this male contraceptive candidate never made it to the market. Why? The obvious answer seems to be that the participants were uncomfortable and unwilling to put up with the reported side effects — indeed, 20 of the original 320 participants dropped out of the trial for this reason.

Yet the answer may not be as simple: Reportedly, around 75% of the volunteers said they would be happy to continue on the contraceptive at the end of the trial. So if the participants themselves were willing to continue, why did the researchers put an end to the trials? The answer is in the study paper itself.

The WHO Department of Reproductive Health and Research had established an independent Data Safety and Monitoring Committee to assess the trial results, as the WHO was one of the co-sponsors of the study.

In the study paper, the authors note that, in 2011, the external monitoring committee determined that “for safety reasons, recruitment [of further participants for the clinical trials] should be stopped and enrolled participants should discontinue receiving injections and be transitioned to the recovery phase” because, in their estimation, “the risks to the study participants outweighed the potential benefits.”

Since then, several studies on both hormonal and nonhormonal contraceptive candidates have made the headlines, all promising the imminent advent of a commercially available male contraceptive.

Oral hormonal contraceptive candidates

In June 2022, researchers from New York University presented the results of preliminary animal studies and a phase 1 clinical trial testing two oral hormonal contraceptives at the Endocrine Society annual conference in Atlanta, GA.

The drug candidates — dimethandrolone undecanoate (DMAU) and 11 beta-methyl-19-nortestosterone-17 beta-dodecylcarbonate (MNTDC) — are progestogenic androgens that have the potential to suppress sperm production. They also have another benefit, according to the researchers: They could help maintain healthy muscle, bone, and sexual function.

The phase 1 study results suggested that the candidates had potential and that they were overall well tolerated by the participants. However, it remained unclear what the best dosage would be, and further studies are due.

MNT contacted one of the study authors for more information on the current study development, but as of the date of this article’s publication, we have not had a response.

Nonhormonal contraceptive candidates

Also in 2022, researchers from the University of Minnesota presented the results of a preliminary animal study testing a nonhormonal oral contraceptive candidate at the American Chemical Society spring meeting. Their drug candidate, YCT529, works by targeting the retinoic acid receptor alpha, which plays a role in sperm formation.

In theory, by not using hormones, the drug should also have fewer and less serious cases of the side effects associated with hormonal contraceptives.

The same research team also investigated another potential non-hormonal candidate, EF-4-177, which targets a cyclin-dependent kinase (CDK), a type of protein involved in regulating the cell cycle.

In a study in mice — whose findings appeared in The Journal of Medicinal Chemistry in January 2023 — the researchers found that EF-4-177 was able to bind well to a CDK called CDK2, which is implicated in sperm production.

This approach seemed effective in the rodent model — the researchers reported that after 28 days on the contraceptive candidate, the sperm count of the mice decreased by approximately 45%.

MNT reached out to the senior author of these studies, Prof. Gunda Georg, who is a professor of medicinal chemistry at the University of Minnesota, to find out more about her and her research team’s progress on the contraceptive candidates.

Prof. Georg told us that, while she and her team are working on several potential candidates, “the project that is the furthest along” involves the selective retinoic acid receptor alpha inhibitor YCT525. This compound, she noted, is now licensed to the pharmaceutical company Your Choice Therapeutics (YCT).

“The next step, which is imminent, is the submission of an IND (Investigational New Drug) application by YCT to the Food and Drug Administration (FDA). After submission of the IND, the FDA has 30 days to respond and either allow or not allow the clinical trial to go forward,” the researcher noted.

“We have had the female pill for about 60 years and it is about time a male pill was developed so that men would be able to better participate in preventing pregnancies. It also would provide men with reproductive autonomy that is better than condoms and vasectomy, the only choices for men right now,” said Prof. Georg.

She also noted that one of the main challenges in getting any potential male contraceptive approved for market distribution is making sure that any side effects are negligible.

“It is a very interesting challenge to work on contraception because a contraceptive will not cure a disease and therefore the bar for safety is much higher than if you develop a drug for cancer or Alzheimer’s disease treatment,” she explained.

Earlier in 2023, yet another experimental male contraceptive made the headlines. Its developers, from Weill Cornell Medicine, said they are looking to create an “on-demand”, nonhormonal oral contraceptive that can be taken half an hour before penetrative intercourse and be effective.

They also believe that their contraceptive candidate may come with no or very few side effects thanks to the nature of the drug they are developing.

They tested the drug, called TDI-11861, in mice, and published their findings in February 2023 in Nature Communications.

TDI-11861 works by targeting soluble adenylyl cyclase (sAC), a cellular signaling protein implicated in sperm production. In this study, a single dose of TDI-11861 halted sperm motility (movement) in male mice for at least 2 hours, which prevented pregnancy in their female partners without fail.

MNT has spoken to two of the study’s senior authors, Prof. Jochen Buck and Prof. Lonny Levin, about their research and drug development processes.

“This [form] of on-demand male contraception […] was never done before, so there are no guidelines […] Essentially, [it’s like] we have to climb one of the mountains in the Himalayas, which nobody has climbed before,” said Prof. Buck of the drug development process.

Their “on demand” concept is based, in a way, on Viagra, said Prof. Levin, that is, a pill that is effective almost immediately, its effect lasts for a few hours, then dissipates, so that the person does not need a long-term course of medication, as is the case with the female contraceptive pills.

The idea with the end product, he explained, is that:

“[People] would take this a half hour or so before they want to have sexual intercourse, [and] they will be protected. So one of the things we want is longer coverage [than what we presented] in the paper. We have 100% efficacy in mice for 2 hours [at the moment].”

In their next step, in tests on male rabbits, this window seems to be increasing, he added, so they are hopeful they can find a formulation that will hit all their targets.

Why men prefer on-demand versus long-term contraceptives

This kind of on-demand pill seems to be precisely what male consumers want. MNT‘s and HL‘s own social media surveys indicated that, while most of the male respondents would be happy to take a contraceptive pill, they would be less likely to take it on a daily basis.

“Interestingly, we’re seeing a similar preference among women for [an] on-demand female pill for contraception in a second research study that is just completed among women,” he told us.

“[There] seems to be a key gap in the market — [a] demand for a nonintrusive method (e.g., pill), but which can be used only when needed. This also seems to align with an experience or understanding on the female side that chronic medication taken for an intermittent risk (of pregnancy) often results in experiences of side effects that may not otherwise be experienced if a product can be used acutely, only when needed, to address that intermittent risk.”

– Steve Kretschmer

Is it possible to have a pill with few to no side effects?

Like Prof. Georg, Profs Levin and Buck noted that it is very difficult to obtain approval for a potential male contraceptive unless it has negligible side effects. But how easy and feasible is it to hit this target?

According to Prof. Buck, they may be on to something very promising with their contraceptive candidate. “We have very [few] side effects in the knockout mice,” he told us, and the researchers hope that this may hold true for humans once they reach the clinical trial stage.

Both Prof. Levin and Prof. Buck acknowledged that female birth control pills, if they were being reviewed for approval in the present day, would be unlikely to receive it due to their ever-increasing list of side effects, which include mood swings, increased breast cancer risk, and blood clots.

In Prof. Levin’s opinion, female hormonal birth control continues on the market “just because society has come to accept it” by now, but “the side effect bar for a healthy person to take a drug is really high, and it should be,” he emphasized.

For their current on-demand pill candidate, the two researchers said that the most likely side effect might be the formation of kidney stones in some individuals, though they felt this was not a significant concern, as kidney stones often clear organically, without the need for surgical intervention.

Still, their goal remains to create a pill with “zero side effects,” they said. Currently, the researchers have gone “back to the drawing board” to not only perfect their current compound but also to come up with possible alternatives.

“The next steps [after that] get to be incredibly expensive,” said Prof. Levin, “for FDA and regulatory approval throughout the world.”

“We’d like to have regulatory approval everywhere, not just [from] the FDA, but those steps are incredibly expensive, and before we embark on that kind of journey we want to be sure we have the best possible compound we can,” he told us.

In the meantime, they have started a biotech company with the ultimate goal of bringing their end-product male contraceptive to the market.

The most recent study to have made the headlines at the time of this article’s publication looked at the possibility of using gene editing as a contraceptive method in males.

The research — published in Nature Communications in April 2023 — found that Arrdc5, a gene expressed in the testicular tissue of several mammals, could influence sperm count, shape, and motility.

Knocking out, or blocking, the expression of Arrdc5 in male mice led to the production of 28% less sperm than in regular mice, and these sperm also moved more slowly. Additionally, around 98% of these sperm had unusual shapes. All of this meant that the mice’s fertility was reduced.

The research team that spearheaded this study now wants to look for a contraceptive candidate that would disrupt the production or function of the protein encoded by this gene, while ensuring that the disruption remains reversible.

MNT spoke to Prof. Jon Oatley, from the College of Veterinary Medicine at Washington State University, one of the study’s senior authors, about the team’s hopes and concerns going forward with this research.

He said that, since this gene is only expressed in testes, they are not concerned that knocking it out would affect other parts of the body. In mice, this genetic editing process only resulted in sterility.

The team is already developing potential drug candidates, and the next step from here, said Prof. Oatley, is to test them in further animal studies for “specificity and potential side effects.”

“There are potential obstacles,” he admitted, “including the ability to design a drug that is specific for Arrdc5 and does not impair the function of other protein members of the Arrdc family.”

Nevertheless, “this concern is mitigated somewhat because Arrdc5 has a distinct molecular structure compared to the other Arrdc molecules produced by mammalian genomes,” he pointed out.

“A second potential obstacle is [the] delivery of a drug compound that we develop to be a selective inhibitor of Arrdc5. We will need to devise the right delivery method (for example, pill, injectable, slow-release implant, etc.) to effectively have the drug reach the target cells in testicular tissue. We believe that all of these potential limitations are addressable,” said Prof. Oatley.

At the end of the day, while several different compounds are being tested by different research teams with the aim of ultimately creating a novel male contraceptive, all of these research projects are in the early stages.

All the researchers noted that they will have to conduct more animal studies to ensure proof of concept — that their compounds are potentially viable — before they are able to take the experimental candidates to clinical trials in humans.

And even then, the potential products will have to undergo several stages of testing, to demonstrate that they are effective in human participants, and well tolerated by the volunteers.

“There are a lot of different boxes that need to be checked in order to advance the discovery to the marketplace,” Prof. Oatley told MNT.

So how long would it take to actually bring a new male contraceptive to the market? Even the most optimistic estimates suggest that such a product is still many years away.

Speaking of his and his colleagues’ own potential drug candidate, Prof. Oatley noted that “given sufficient resources (funding and tools), I am optimistic that we could have a male contraceptive available for the marketplace in 10 years’ time.”

It is early days still, and any headlines wondering “Will we have a male contraceptive pill soon?” may, for now, be premature.