If you’re a female and you want to use a contraceptive pill, patch, injection, or device, you have over 250 options. But if you’re a male and you want a contraceptive, you have three options. You can get a vasectomy, you can use condoms, which can have up to a 18% failure rate, or you can use what sex researchers politely call “the withdrawal method,” which is highly unreliable. But there could be another male contraceptive very soon. So what took so long?
Transcript of this Episode
Deboki: If you’re a woman and you want to use a contraceptive pill, patch, injection, or device, you have 263 options, according to drugs.com.
Sam: But If you’re a man and you want a contraceptive, you have three. You can get a vasectomy, you can use condoms, which can have up to a 18% failure rate.
Deboki: Or you can use what sex researchers politely call “the withdrawal method” which is, uh, not really that reliable.
Sam: But there could be another option for men pretty soon.
John Reynolds-Wright: In the Edinburgh site alone, when we had the initial advertisement for the study for people to participate, we had 1,500 contacts in a very short period of time, like people expressing a desire to enroll in the study, the phone was literally ringing off the hook in the office. We were in there until nine o'clock at night every night answering calls, ringing people back because people were so interested in taking part in the study.
Sam: That’s John Reynolds-Wright, a researcher at the University of Edinburgh who is both a practicing vasectomy surgeon and a doctor for the NES/T trial — a clinical male contraception study evaluating the effectiveness of a topical gel containing Nestorone and Testosterone — hence the name NES/T. The most recent study involved 462 couples at 17 sites around the world. When we’re recording this episode, we’re still waiting on the data but…
Gunda George: I have a really good feeling about that clinical trial that might actually make it to market.
Deboki: That’s Gunda Georg, professor of medicinal chemistry at the University of Minnesota. The NES/T trial is the furthest along a male contraceptive has gotten down the drug approval pipeline…. ever.
Welcome to Tiny Matters, a science podcast about the little things that have a big impact on our society, past and present. I’m Deboki Chakravarti and I’m joined by my co-host Sam Jones. And Sam, there are a lot of options for women, but sometimes they suck, and also it would be nice to have some options for men
Sam: Let’s start by talking about the 3 options men currently have for birth control. Option 1 is a vasectomy. A vasectomy is a roughly 20-minute outpatient surgery in which the tubes that carry sperm from where they’re produced in the testes to the urethra are cut, cauterized, and tucked away in a fatty layer of skin. A few months after the procedure, once you’ve had your sperm count tested, the chances of conceiving are…
John Reynolds-Wright: About one in 2,000, probably a little bit less than that, which makes it the most effective method of contraception overall, it's about tenfold more effective than a female sterilization.
Sam: By “female sterilization,” John is referring to tubal ligation, in which the fallopian tubes are cut and tied off.
Deboki: That sounds… very permanent.
Sam: Yeah, It is intended to be permanent. If you change your mind down the road, you can try to have it reversed, but it doesn’t always work
But going back to vasectomies, one thing that’s important to know is that it doesn’t stop the body from making sperm. So a lot of people wonder, where does the sperm go?
John Amory: The sperm continue to be made at a thousand a second, and then they're stored in the epididymis, which is this worm-like structure on the posterior aspect of the testis. So they don't have anywhere to go. So what happens? Over time, the epididymis sort of dilates and there's constantly in the testis, you're making a thousand sperm a second, but your body is also absorbing dead ones. The process is called apoptosis, which is this programmed cell death that's also going on at high rates in the testis.
Sam: That’s John Amory. He’s a professor of medicine and attending physician at the University of Washington who specializes in family planning. He helped design the NES/T study. And he’s also a history buff, but we’ll get back to that later.
Deboki: I truly never thought about dead sperm until this episode, but apparently this is similar to what happens when a man doesn’t ejaculate for a long time. During those periods, sperm production doesn’t slow down, so the body has to do something with all the extra sperm that are building up, so it goes ahead and breaks them down.
Sam: Right, but a vasectomy isn’t exactly like this, because after you cut that tube, some sperm can leak out of the reproductive system, at which point they meet something that has never seen them before, and that they’ve never seen before: the immune system!
John Amory: So sperm are made in this sort of immune privileged site within the testes, and they're kept in the epididymis and then they're ejaculated out of the body. If you do a vasectomy, you've sort of violated the integrity of that sanctuary, and men will develop anti-sperm antibodies over time after a vasectomy. And that's why when we counsel men about a vasectomy, we say, we consider this a form of permanent contraception, so only get this if you're pretty sure you don't want to have kids in the future.
Sam: OK, so that’s option 1. Now let’s briefly touch on the least effective option for contraception, which is withdrawal, also known as the pullout method.
Deboki: Vasectomies are roughly 99.95% effective. Withdrawal is about 78% effective, so you’re kinda playing with fire if that’s the only method you’re relying on.
And option 3, of course, are condoms. Condoms are not nearly as effective as a vasectomy – they have a 13-18% failure rate, but interestingly, it’s a failure rate that you have quite a bit of control over.
Sam: Hmmm… You’re gonna need to elaborate on that.
Deboki: Yeah so to understand that you have to know how these failure rates are calculated. Scientists aren’t getting these numbers by doing a bunch of experiments on condoms in a lab – they’re calculating them by conducting surveys of people who have unintended pregnancies and asking them, essentially, what happened? And what you discover when you do that is that…
John Amory: Couples who are quote-unquote using condoms are not always using them. And it's important to, so when someone goes around on a survey and says, what are you using for contraception? And people will say, condoms, but the next question is, are you using them every single time you have sex and are you using a new one that's not expired, and are you putting it on correctly and on and on. There's a million ways to mess up.
Deboki: So basically, if a couple generally uses condoms but didn’t have one on hand one time and ended up pregnant… that counts as a condom failure.
Sam: Right, that also makes sense because when condoms are used perfectly, which really only happens in the context of a clinical trial, the failure rate goes down to about 2%.
Deboki: OK now let’s contrast those 3 options with the options women or ovulating people have.
Sam: Two hundred and sixty three options, apparently.
Deboki: Yes, and crucially, many of those options are far more convenient.
Sam: Right, and there are also lots of options for women that you just get done once and then you can forget about for 5 or 10 years.
Deboki: So, some people might reasonably ask why we should bother with male contraception when we have 263 options for female contraception? Gunda put it very succinctly:
Gunda Georg: Whatever we can provide, made hormonally, regulated, or non-hormonal, we should have options.
Deboki: More options for contraception are always better. Not to get too personal, but I think like a lot of people, I’ve found contraception to be a journey. There was one pill that really affected my mood, so I switched to a different pill. And eventually when I started getting annoyed by having to take a pill every day, I switched a hormonal intrauterine device, an IUD. And some people might switch to a non-hormonal version based on preference or other medical conditions.
Sam: Here’s another reason to give men lots of contraceptive options: Math. Mathematically we’d expect that if both partners are using contraception, it would be significantly more effective – if each partner is using a method of contraception that’s 90% effective, the combined efficacy of using both is 99%.
Deboki: That’s because you’re multiplying the probability of failure of each method, which in our case here is 10% – so the chances that both fail is 10% times 10% which is 1%.
Sam: And if each partner uses a method that’s 95% effective, the combined efficacy is 99.75%.
Deboki: A vasectomy is 99.95% effective, so 99.75% is really impressive!
Sam: Exactly! I hadn’t thought about it mathematically before but it does make a lot of sense.
Deboki: And there’s a third reason why more contraceptive options are better. Here in the U.S. there are about 6.5 million pregnancies per year. Of those, only 55% or so are planned, which means that 45% are unplanned. And, just to clarify, unplanned doesn’t necessarily mean unwanted. That’s an important distinction.
John Amory: Sometimes pregnancies happen and people are like, I wasn't expecting this, but turns out it's okay, or I'm delighted, or whatever. I didn't think I could get pregnant, and now I am. So that all counts as unplanned. So the unplanned pregnancies are both unintended and happy little accidents. I guess as Bob Ross would say.
Sam: OK I did not expect a Bob Ross reference to make an appearance in a male contraceptives episode, but I’m here for it.
Deboki: But there’s of course another side to that coin.
John Amory: About half of those unintended pregnancies end in abortion. And so overall, that's how we end up with one to one and a half million abortions a year. With contraception, the goal is to get that number as low as possible.
Sam: That means people who want to get pregnant are able to get pregnant, but people who /don’t/ want to get pregnant are not getting pregnant. And, important to note, the 1.5 million abortions per year that John mentioned are in the United States. According to the WHO, 73 million abortions take place worldwide each year, although of course not all are due to unintended pregnancy.
So why have decades of research into female contraception produced 263 available options but decades of research on male contraception hasn’t given us really anything beyond what we already had.
Deboki: Because male contraception is, annoyingly, harder than female contraception. And I’m not being facetious, there are differences in biology that make it a harder scientific puzzle to solve.
Sam: The most obvious difference is that women have a built-in system that stops egg production. Progesterone is a hormone that’s produced during every menstrual cycle, and if an egg is fertilized, a woman’s body continues to produce progesterone throughout the entire pregnancy. Progesterone does lots of stuff, including sending signals to the ovaries saying that there’s already an embryo implanted in the uterus, so please stop making eggs right now because we’re preggo, okay?! At least, that’s exactly what my anthropomorphized progesterone was saying when I was pregnant.
Deboki: It’s a direct quote.
Sam: Direct quote.
John Amory: Most hormonal contraceptives are progesterone dominant. So a woman takes them, the woman's brain doesn't know where the progesterone's coming from. It says, oh, we must be pregnant. Let's turn off ovulation.
Deboki: Men, on the other hand, do not have any kind of built-in fertility master switch.
John Amory: Men start making sperm when they go through puberty. And some of 'em make sperm till the day they die. And so they don't have this sort of natural backdoor to turning off egg or sperm production the way women do.
Deboki: And there’s another difference. Women make one egg every month, but remember what John said earlier:
John Amory: Men make a thousand sperm every second.
Sam: OK now I’m actually just wondering how it’s even possible that we have a candidate for a male contraceptive drug that’s anywhere in the pipeline. I mean, if you have to take sperm production from one thousand per second all the way down to zero… that sounds… not just hard but impossible.
Deboki: Well, the good news is that you don’t actually have to get to zero.
John Amory: You have to get men down to a very low level of sperm production for them to really be contraceptive. The sort of standard in the field now is to less than a million sperm per milliliter ejaculate. That sounds like a lot to women, but that's actually, we know that the fertility there is probably around 1% or less.
Sam: And there is one final, much more subtle reason that male contraception is harder.
John Reynolds-Wright: The design of the studies is more challenging because when you have a female contraceptive study, well any contraceptive study you are testing a intervention to prevent a pregnancy and a female contraceptive study, you're testing an intervention in the same participant in whom you would then see a pregnancy if it did not work.
Sam: That’s John Reynolds-Wright again.
John Reynolds-Wright: So with a male contraceptive study, you are testing an intervention in one participant and then you are looking for an outcome in a different participant. So because of that, you're immediately doubling the complexity if not more, of whatever study design that you have. So that makes the studies bigger, it makes 'em longer, it makes them more expensive.
Sam: Alright so now we’re gonna talk about two new potential options for male contraception, one that’s getting a lot of news already and will probably get a whole lot more when the full study is released, and another that’s earlier in the pipeline that you probably haven’t heard of yet.
Deboki: So the first one is the one we mentioned at the top of the show and it’s the farthest along a male contraceptive has ever gotten through the drug development pipeline.
Sam: The drug is called NES/T and it’s a mixture of segesterone acetate, also known as nestorone, and testosterone, and right here we have to stop and explain something that always confused me about male contraception, which is this: Testosterone, the primary male sex hormone, is absolutely necessary for sperm production. You can’t make sperm without it. But if you inject a man with enough testosterone, sperm production goes down to the point where you could make that man infertile.
Deboki: We’re going to call this the “testosterone paradox.”
Sam: Yes, it does sound confusing on its surface, but here’s what's going on. Sperm production is controlled at the highest level by two hormones – Luteinizing hormone, also known as LH, and Follicle Stimulating hormone, also known as FSH. LH tells testicles to make testosterone. Most of that testosterone stays in the testicles, but some of it ends up in the bloodstream.
Deboki: Where it influences things like mood, sex drive, etc.
Sam: Yes, exactly. And testosterone levels in the testicles are tens, sometimes even a hundred times higher than in the blood, which is necessary for regular sperm production.
But to keep testosterone levels from getting too high, your body has a negative feedback loop, where, if it senses that blood testosterone levels are getting too high, it’ll tell your testicles to tone down testosterone production.
Deboki: So if you were to inject a man with enough testosterone, his body would be like “whoa there’s already so much testosterone here – testicles, stand down.” So in theory, you could actually use testosterone as a contraceptive. But in practice, it can take super high doses to suppress sperm production enough, and that can make a man’s blood testosterone high enough to cause annoying and potentially dangerous side effects including increased risk of blood clots and heart attack.
Sam: This is where Nestorone comes in – Nestorone seems to inhibit the function of both LH and FSH, which slows down sperm production a lot.
Deboki: But, if you do that, blood testosterone plummets, which is also not good.
Sam: Yes – and that’s why the drug being tested right now includes both Nestorone and testosterone. The testosterone is there mostly to keep a person’s blood testosterone levels normal. It’s basically compensating for the fact that his testicles aren’t making nearly as much testosterone anymore.
Deboki: That’s pretty clever.
Sam: Right? This trial is a phase 2b, where the focus is dosing and efficacy in a large group of patients, and the results might already be out by the time you’re listening to this. There’s still a phase 3 to go before the drug can be submitted to the FDA for approval. But if everything goes smoothly, it could be available in a few years.
Deboki: The other male contraceptive drug we want to talk about isn’t as far along, but the science goes back to the early 20th century.
Gunda Georg: In the 1930s, pharmacologists put mice and rats on a vitamin A deficient diet. And what they found was that the males became infertile. And then they restored vitamin A in the diet and the fertility came back.
Deboki: The reversibility is promising there, because of course if you’re making a male contraceptive drug, you’d ideally want it to not be permanent. Now of course a vitamin-deficient diet is not a good contraceptive – for one thing we need vitamin A for all kinds of bodily functions and for another thing it’s kind of hard to avoid vitamin A – you don’t want to accidentally eat a carrot and end up getting someone pregnant.
Sam: Not sure that’s exactly how it would work haha…
Deboki: Correct. The vitamin A thing is a clue, though, just not a drug. To get to a drug you need to identify the pathway that vitamin A is part of and then design a molecule to inhibit that pathway.
Gunda Georg: And there are many ways you can start into the literature and you can see what have other people done before and maybe can build on what other people have done.
Deboki: What happened in this case was that a collaborator, Debra Wolgemuth, noticed that Bristol Myers Squibb had published a study in which they noted a particular compound was a testicular toxin – obviously not something you want as a side effect. But Debra saw this and thought…
Gunda Georg: What's their testicular toxin is maybe my male contraceptive. And so she did actually a very nice study to show that this compound actually was quite effective and also reversible.
Deboki: It turns out this testicular toxin acts on receptors that bind to retinoic acid, which is the form of vitamin a that our cells use to grow. So blocking the receptors essentially makes a cell unable to use vitamin A.
Sam: But there’s still a lot of work to go from the discovery of a potential drug to FDA approval.
Gunda Georg: You have to get the potency. You have to get selectivity of the compound for your target so that you're not getting unwanted side effects. And then also you have to have the right physical chemical properties. So what that means, we really have to make sure that we have oral bioavailability of our drugs, and then the drug has to have half-life so that you don't have to take the pill every two hours.
Sam: That basically involves making many different versions of the drug, each one slightly different, until you hopefully find a molecule that has all the properties you’re looking for.
Gunda Georg: You have to make many, many compounds. And the compound that we have developed, and that's now in clinical trials, we actually made over 300 compounds, which is actually not that much.
Sam: The molecule Gunda and Debra settled on is now referred to as YCT-529, and one of the interesting things is that the drug is not a hormone, which makes it a great example of how not all birth control has to be hormonal.
Deboki: And there’s another aspect of the drug that Gunda considered.
Gunda Georg: You have to also think about the price, right? I mean, you can't have something that's very, very expensive. So you have to be sure that you are in a price range. People actually can afford it.
Deboki: When Debra and Gunda first developed YCT-529, the number of steps they needed to actually make the drug meant they also needed a lot of reagents and resources, which translates to a more expensive drug. So part of developing the drug was cutting down the number of steps, and Gunda is still thinking about how to reduce it even further. The drug underwent its first clinical trial in 2023, and it’s currently still being trialed.
Sam: So we’ve got this potential option, YCT-529, in the kind of early-middle section of the pipeline, we’ve got NES/T in the middle/late section of the pipeline, and there are other approaches in various stages across the pipeline as well.
John Amory: I'm a history buff, so I always start out by saying before we had great female methods, before 1961 when the pill was introduced, male methods were actually the most common methods, specifically withdrawal and condoms. If you look in the modern era at couples, men actually account for about 30% of contraceptive use with 10% of couples relying on vasectomy, and about 20% of couples relying on condoms.
Sam: After hearing from all of these experts, I’m hopeful there will be more options for men soon. Having them won’t just mean that contraception is more equitable, it will mean there’s a much reduced risk of unintended pregnancy which, at the end of the day, is the goal.
All right, it is Tiny Show and Tell time.
Deboki: Cool. Sam, I can do my tiny show and tell?
Sam: Yeah, kick it off.
Deboki: Yeah, because a little bit family related, which I feel like is vaguely related to our topic for today. Only, we're talking about the superb starling, because scientists have found that the superb starling we'll babysit for each other, which is really cool, because the bigger implication is that these birds are friends.
Sam: Oh, I like that.
Deboki: Yeah. So in general, there are plenty of animals that are social, but the extent to which they form friendships, like with other members of their species that they're not actually related to has been less clear.
And superb starlings, they're songbirds that are found in the African savanna. They form flocks, and their flocks have different family groups in them. They also apparently will have immigrant groups that join the flock, which I thought was really cool too.
Sam: That is cool.
Deboki: And so researchers did a 20-year field study on the relationships between these birds. They also had to study their DNA to see who is actually related to each other, which I think is really cool. I feel like they must just have this little starling family tree going on.
And they found that starlings will help their family, obviously, but they'll also help their friends by feeding their friends' babies bugs. And this is a reciprocal thing. They'll feed each other bugs, and they're just taking care of each other's babies. So I just thought that was really sweet.
Sam: That is really sweet. I like that a lot. That's so nice. Wow. I'm not a big... I wouldn't say I'm an anti-bird person. Birds are very important.
Deboki: I feel like you're about to say something very anti-bird.
Sam: No, I think they're very cool. I don't like them very close to me. I think they're beaks, I'm just always like, are they going to get my eye? I don't know. They freak me out a little bit. But they're very cool and very important. I like watching them from afar. And I love this idea that they're helping each other out.
Deboki: Yeah. Yeah. That's weirdly how I feel about fish. I went diving in Hawaii once in college, and I got a fish in my face that was not even a big fish, but there's just something about having a fish in my face that I was like, "Uh-uh. No."
Sam: That's so funny. See, that wouldn't bother me at all.
Deboki: Yeah, it's so weird.
Sam: So different.
Deboki: Anyway, so it's not related, but when you were talking about your relationship to birds, I had this distinct memory of the time I saw fish, that was a small fish, it wasn't even a big fish. And I was just like, "No, this is too close.
Sam: Fish, don't get into Deboki’s face. All right, so I'm going to tell you about a new study. It's very brief, but essentially there's a group that has found that a cup of tea or a small piece of dark chocolate that contains these naturally occurring compounds called flavan-3-ols, does not roll off the tongue-
Deboki: No.
Sam:... seem to improve blood pressure and the health of our blood vessels. And the reason I'm bringing this up is because I feel like we hear all the time, "A glass of wine is good for you to drink. A cup of coffee is good," or this or that is good. And then two weeks later there's another study that's like, "Actually, no alcohol is actually good for you. And coffee is more bad than it is good." There's all this stuff.
But I thought that this was kind of an interesting study. So it was published in the European Journal of Preventive Cardiology, and what it did was it analyzed data from 145 randomized controlled studies. And what it found was that regular consumption of these flavan-3-ols can lead to reduction in blood pressure, and especially for people who are already dealing with high blood pressure.
So the reason I'm just bringing this in, because I don't think it's like, yeah, have a little piece of dark chocolate or a cup of tea, as long as they contain these compounds, it's not really groundbreaking or anything. But I also just thought it was an example of research in this kind of arena that I would actually believe more than a lot of what I see.
Deboki: Yeah, that makes a lot of sense. There's something about getting the specifics that makes a big difference.
Sam: Right. So I guess that part of what these compounds that I hate saying, the flavan-3-ols, can we call them something else? So I guess they were found to improve the function of the inner lining of blood vessels, so that endothelial layer, which is really, of course, important for heart health, for your cardiovascular health overall.
And I guess that that improvement was independent of blood pressure changes. So maybe it's even a broader impact on your circulatory system, beyond just, "Hey, if you have high blood pressure, it could help bring it down a little bit." So this isn't saying, "Hey, you should go eat a whole bar of dark chocolate, or chug a eight glasses of tea every day," or something like that. I think it's small amounts, and it seems like these compounds are particularly helpful. And it seems like there's a lot of research behind that at this point, which is very cool. So yeah, I'm kind of curious, hard to know how much of this compound is in any cup of tea or chocolate just as a consumer. And so I think it'll be more useful at some point if they're able to draw those connections, because now I'm like, that's cool, but what does that mean? Could I get any dark chocolate? Is this the... You know?
Deboki: Yeah. I mean, it actually kind of weirdly reminds me a little bit of what we were talking about today, with the Vitamin A, and how they saw a Vitamin A deficient diet. And obviously, on its own, that's not a thing we can necessarily do much with, but downstream, it's the kind of thing that helps you with developing a drug. Maybe there's something about this compound that somebody else down the road will have in mind, of like, "Oh, I could use that for this purpose," or "I found this pathway that does something, and this might be related to this compound."
Sam: Right. Absolutely. And I mean, this also makes me think of our last episode, which was about spices, and different compounds and spices, and could there be some sort of benefit if this is trialed and tested for safety, where it could be an option for maybe helping boost whatever medication someone's taking for high blood pressure? Or if someone's on the verge, could it be something that maybe has fewer side effects, but would still help maybe get them a little bit more into a normal range?
I don't know. There's a lot of potential here, I think. And I just thought that it was very thoughtful, the way that they analyzed the data. And it made me happy, because it wasn't just, hey, we did this one study with 20 people. It was like, no, there were, what did I say, 145 randomized studies that they were pulling from.
Deboki: But also, if you want me for your study on the benefits of eating chocolate...
Sam: Yeah, I will eat chocolate and drink tea all day, so sign me up.
Deboki: Yep. Well thank you, Sam, and thanks for tuning in to this week’s episode of Tiny Matters, a podcast produced by Multitude and brought to you by the American Chemical Society, a non-profit scientific organization based in Washington, DC. This week’s script was written by George Zaidan and edited by me, Michael David, and Sam Jones, who is also our executive producer. It was fact-checked by Michelle Boucher. Our audio editor was Jeremy Barr. Sound design was by Michael Simonelli and the Charts & Leisure team.
Sam: Thanks so much to John Amory, Gunda Georg, and John Reynolds-Wright for joining us. Go rate and review us wherever you listen, we really appreciate it. We’ll see you next time.
References:
- Drugs.com Birth control pills and medicine
- How effective is pulling out?.
- How effective are condoms?.
- Testosterone Is a Contraceptive and Should Not Be Used in Men Who Desire Fertility
- Testosterone and androstenedione concentrations in human testis and epididymis during the first two years of life
- Testosterone: What it is and how it affects your health
- A New Combination of Testosterone and Nestorone Transdermal Gels for Male Hormonal Contraception
- Male hormonal birth control? It may be closer than you think
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