For decades, scientists have been trying to develop a male contraceptive similar to the birth control pill that can be taken orally and is reversible, with minimal side effects. An oral male contraceptive could also be a more effective alternative to using a condom or undergoing surgery for a vasectomy, while helping to reduce the number of unintended pregnancies, which account for nearly half of all pregnancies worldwide.
Wei Yan is a professor and director of the Center for Reproductive Biology and the School of Molecular Biosciences at Washington State University who has spent two decades in the quest to develop a male contraceptive pill. His current investigation involves a compound derived from an herb used in traditional Chinese medicine that is showing encouraging lab results. In a commentary he recently wrote for an academic journal, he argues that the development of a new male contraceptive needs to be reframed as a “women’s health priority” that would allow reproductive responsibility to be more equitably shared.
Yan joins us to share his perspective, the status of his own research efforts and the funding landscape to advance this work.
Note: The following transcript was transcribed digitally and validated for accuracy, readability and formatting by an OPB volunteer.
Dave Miller: From the Gert Boyle Studio at OPB, this is Think Out Loud. I’m Dave Miller. Scientists have been trying to develop a male contraceptive along the lines of the birth control pill for more than half a century, something that can be taken orally and is reversible with minimal side effects. Wei Yan has been working on this for two decades. He is a professor and the director of the Center for Reproductive Biology and the School of Molecular Biosciences at Washington State University. His current investigation is showing encouraging lab results. In a recent commentary in an academic journal, Yan argued that the development of a new male contraceptive should be considered a priority for women’s health that would allow reproductive responsibility to be more equitably shared.
Wei Yan joins us now. It’s great to have you on Think Out Loud.
Wei Yan: Well, thank you for having me here.
Miller: I want to get to the societal and the funding challenges in just a bit, but I want to start with the basic science here. What makes this a scientific challenge?
Yan: Well, as you know, the reproductive process in women and men is very different. We all know that the female contraceptive pill has been available for half a century so far, but there’s no such pill for men because, largely, the complexity of the sperm production process. So it’s very challenging. Unlike women, you have the monthly cycle, men, you don’t have this monthly cycle. So there are a whole lot of physiological differences that I think contributes to the difficulty of developing a male version of the pill.
Miller: No cycle. So, once men pass puberty, how much sperm are they producing on average, any given day?
Yan: Yeah, so that’s an interesting number. Every minute, a man of reproductive age produces about 1,000. So you can imagine by the end of this show, any man in the reproductive age would have produced about 15,000 or 20,000 sperm already. So it’s such a robust, effective system.
Miller: Robust and effective, but then that makes it a challenge if you want to stop it. Back in the 1950s, I’ve read that researchers had what they thought might be an effective male contraceptive and they tested it on inmates in the Oregon State Penitentiary – the kind of experiment that, I think, would never get approval today. What happened?
Yan: Yes, I’m very familiar with that story. That compound was initially designed to be used for treating diseases caused by parasites. So basically, that’s a compound that was expected to be able to kill parasites. It turned out that people find that if you use that compound the men become infertile. So, later on, people tested on inmates, as you said. I mean, it would never have been possible these days. But the point is that it’s effective in suppressing spermatogenesis. Spermatogenesis is the terminology we use describing the process through which sperm are produced. And what happens is that this is an inhibitor of an enzyme required for making retinal acid. So retinal acid is essential for sperm production.
But the problem is that this enzyme actually also interferes with the alcohol metabolism. So people taking this compound, they can achieve contraception, but with one condition: they cannot consume any alcohol. The interaction with alcohol, that can be lethal. So that’s why the compound was discovered to be effective for contraception, but because of the side effect, the whole project was put on hold. People right now are looking for other forms, the similar enzyme, so basically taking advantage of this mechanism to develop a male version of the contraceptive pill.
Miller: What has research been like since then? I mean, that was back in the 1950s, 70-something years later. What, over the years, have researchers tried to do?
Yan: Many of my colleagues have been working on developing non-hormonal male contraceptive pills for the past 50 years, as you mentioned. As a matter of fact, I think that the progress has been extremely slow. You can imagine 50 years … There’s one interesting saying in our field that’s called “five years away for the past 50 years,” meaning that every time, when people discover something and, “Oh, we’re only five years away from developing a male version of the pill.” But people have been saying this for the past 50 years – basically highlighting the difficulty of developing such a pill.
As I mentioned earlier, one biggest reason is that the biology, our understanding of spermatogenesis, is quite limited. For example, there’s some … and the idea is that most of the people believed about 20, maybe 10 or 20 years ago, that we have to eliminate all the sperm and the sperm precursor cells, because it takes only one sperm to fertilize an egg. So this idea is actually maybe a hurdle of developing a good drug. The reason is that, as I mentioned, spermatogenesis has evolved to become one of the most resilient processes in the body. To eliminate all the sperm without hurting yourself, without hurting other somatic cells is extremely hard. So that may partially explain why it took so long and we still don’t have a male contraceptive pill on the shelf.
Miller: My understanding is that you and your team have taken a different approach. Instead of saying, “let’s prevent any individual sperm from being created,” you’ve chosen a different tack. So what are you working on?
Yan: Yeah, that’s correct. So, when I was a graduate student, I listened to talks given by my senior colleagues, talking about how to eliminate all the sperm. At that moment, actually, I was pretty doubtful. And based on my own research over the years, I drew the conclusion in a paper we published back in 2009, where we claimed that it’s very hard to eliminate all the sperm cells and their precursor cells, but it’s easier, much easier to disable them. Meaning that, if we design compounds that target the last couple of steps of sperm assembly, it’s not going to cause the elimination of all sperm cells, but instead, we’re going to disable them. Meaning that you have the sperm produced, but they are non-functional or dysfunctional. So as a consequence, they cannot fertilize the egg and thereby we can achieve our goal.
So that’s the idea we developed. We followed the idea for the past two decades and eventually that led to the discovery of triptonide, which is the compound isolated from a Chinese medicinal herb. So we’re working on it. This compound seems to be promising.
Miller: What have you found in animal models?
Yan: We test the triptonide on mice and monkeys, and both are effective. So basically, you gave the monkeys and the mice triptonide, a daily dose, oral dose, at very low doses for three weeks or four weeks. So basically, all the sperm produced by mice and monkeys are deformed. Specifically their head and back, 180 degrees. And then they don’t have motility. So these mice, treated mice, are completely infertile.
And when we stop giving them this compound, it takes about three to four weeks for them to regain their fertility. Then when you check their semen, all the sperm become normal. Basically from the deformed situation becomes normal sperm, and then they regain their fertility. So these are on the animal studies.
Miller: How would a human trial for that work? Because I guess I’m imagining if the test were simply to look under the microscope at sperm and to see, hey, that the head and tail are in funny places, they’re not going to be good swimmers, that wouldn’t be enough for me. I’d want to know that people were on this pill, and thousands of people then had sex over the course of a long enough period of time and nobody got pregnant. How do you actually do that kind of a study?
Yan: As I said, the spermatogenesis is a continuous process, so many people imagine that you take a pill and immediately your sperm will become dysfunctional. It’s not going to happen. That’s the biology. It takes many days to produce a functional sperm. So if your drug targets one specific step during spermatogenesis, it will take some time to reach full effects, what we call the full penetrance.
In other words, even if you take the pill on a daily basis, it will take a couple of weeks before it reaches the full potential. So before you get the full penetrance, you cannot have sex for a while, but once you reach that status, you can keep it going until you stop taking the drug. That’s the design.
We haven’t started human clinical trials and we’re doing the last couple of steps to get FDA approval to gain the so-called “IND” – Investigative New Drug – status, so that we can start a clinical trial.
Miller: I guess I’m just wondering if the clinical trial would need to have some number of people who were having unprotected sex in order for it to eventually get approval, or if it would be enough for people to look at microscopes and say, “Yeah, these sperm, they’re never going to make it to the egg?”
Yan: Yeah, that’s right. Of course, for any clinical trial you need to have the control group and that’s going to be the placebo group. And for the treating group, they’re going to take this compound and at a certain dose. That’s the future work we’re trying to clear up the last hurdle, which is the approval by the FDA, so that’s what we’re working on right now.
Miller: I want to turn to the societal point that you had been arguing in your recent opinion piece, your commentary in a scientific journal, which is that we need to rethink entirely male contraception and see this as an important piece for women’s health. What’s your overall point?
Yan: Yes, as I mentioned to you, the development of male contraceptive has been going on for the past 50 years, so it has been going really slow. As I mentioned earlier, one important reason is that we don’t have a really thorough understanding of sperm production process. Another major reason is that we’re lacking funding. As you know, a couple of big pharmas, they work on it for a period of time and then they all dropped the ball, because developing male contraceptives, it’s really high risk and maybe not that profitable compared to developing a drug that can cure cancer.
Right now, the funding sources are really, really limited. You can only get funding from NIH and a couple of private foundations there. On the other hand, I witnessed the explosion of funding opportunities for women’s health. So if you really review all these funding opportunities for women’s health, there’s no mentioning of male contraceptive development at all.
To me, it’s really puzzling. The reason is that my notion is very simple. If you don’t have the male version of the pill, and people continue to have sex, guess what happens? Women will get pregnant. As a matter of fact, globally, including the U.S. and other countries around the world, every year about half of the pregnancies are unintended. Suggesting to me, the current available contraceptives are mainly geared towards the women’s use and it’s not sufficient to prevent unintended pregnancy. So to me, I think that unintended pregnancy causes a lot of social-psychological problems and also costs a lot of money, in terms of healthcare.
My point is that, if you don’t develop a male contraceptive, the women will bear this pregnancy outcome, so unintended pregnancy rates will remain high. My commentary really tries to emphasize that developing male contraceptives is critical for women’s health. I’m hoping that the people among your listeners and your audience could have the policymakers, the donors and the philanthropists realize that developing male contraceptives is part of the women’s health issue. So hopefully, we can get more funding so that we can expedite the process of developing a male contraceptive pill.
Miller: There’s the enormous pot of federal money, which since the Cold War has been the world’s largest funder of basic science, willing to back basic research before there are obvious commercial applications. We’ve also, in the last nine months or so, seen an unprecedented rollback in federal interest in funding science.
And then there’s the pharmaceutical side, which I’m curious about here. I mean, pharmaceutical companies, they seem pretty savvy about knowing which drugs are going to find big markets. Viagra, notably, was a gigantic seller starting in the 1990s. In the last five years or so, the new class of weight loss drugs like Ozempic have found huge audiences as well, huge markets. If these companies are not putting a lot of money behind a male contraceptive, I assume it’s because they think that a lot of men won’t want to buy them. Do you think they’re right?
Yan: I don’t think they think that way. As a matter of fact, my colleagues at the MCI, the Male Contraceptive Initiative, also the Bill Gates Foundation, they did a survey a couple of years ago, they published online. And basically they asked thousands of men, “If the male contraceptive pill becomes available, are you willing to take it?” And the overwhelming majority actually said, “Yes.” So I don’t think that’s a problem. The biggest reason for dropping the ball by big pharma is that I think that the risk is very high.
I mean, think about it. If you have a cancer drug, the patients who are close to death, they’re going to take it even if they find a whole lot of side effects. Some can be very severe. But think about who are taking those male contraceptive pills. They are young, reproductive, active men. You cannot have any side effects.
So the stakes are super high. That really makes a lot of big pharma hesitant to develop it. The chance to fail is just greater than any other drugs that can cure or prolong the lifespan of people or cure some acute conditions that can kill people. So I think that they have the … I published another paper where I reported the market size of male contraceptive pills. Actually, it’s quite profitable. I think the higher risk makes big pharma hesitant to join efforts of developing a male contraceptive pill.
Miller: Wei Yan, thanks very much.
Yan: Yeah, thank you for having me here.
Miller: Wei Yan is a professor and the director of the Center for Reproductive Biology and the School of Molecular Biosciences at Washington State University.
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