BEYOND THE CONDOM

Men want an alternative birth control. So why can’t researchers create one?

IMAGINE THE SCENE: Arms tensed, bow lexed, a hunter on the African savanna draws in a slow breath as his prey moves into view. Perhaps it’s an impala, maybe even an elephant or giraffe — beasts one might think too large for a single archer to fell. But the arrow’s tip has a secret weapon: the deadly poison ouabain. An extract of plants native to much of sub-Saharan Africa, the compound stops hearts, sometimes within just a few minutes.

SURPRISE: This heart-stopping poison could one day be our best option for a male contraceptive.

On a molecular level, ouabain is a disrupter. Throughout the body, membrane proteins control the movement of salts in and out of a cell, an exchange crucial to the cell’s survival and function. Ouabain molecules bind to the enzymes employed by the proteins in this process and prevent the exchange.

Ouabain traditionally affects cells in the heart, leading to cardiac arrest. Earlier this year, however, researchers announced that they had modiied the ouabain molecule to target enzymes used by a type of protein found only in sperm. When the enzymes get gummed up and derail the cellular exchange process, sperm lose their ability to swim — and sperm can’t fertilize an egg if they can’t reach it. A preliminary study in rats indicated that the drug is both safe and effective.

“I think that’s a very attractive way of thinking about a male contraceptive agent,” says Gunda Georg, head of the department of medicinal chemistry at the University of Minnesota. Georg is co-author of the study on ouabain’s contraceptive potential, published in January in The Journal of Medicinal Chemistry. “Nothing is changed, everything is developed normally, but once it’s ejaculated, the [sperm] can no longer move.”

Georg is working on a variety of projects in contraceptive research, but she’s especially excited about ouabain’s potential for inally delivering a new birth control option to men.

“I’m very optimistic about this particular approach and this particular project,” she says. “I have a feeling that this might be the winner.”

It will be years before an ouabain-based male contraceptive makes its way to drugstore shelves, if it ever makes it at all. Scientists have been attempting to develop a male contraceptive for more than four decades, with little to show for their efforts. It’s been a dificult road, full of dead ends and detours. But a small group of researchers is still on the hunt for that elusive winner.

NO KIDDING

Men, we owe G.D. Searle & Co. — big time.

The irst drugmaker to win FDA approval for a hormonal birth control pill, Searle made it possible more than a half-century ago for women to take control of their reproductive systems.

Today, nearly 10 million women in the U.S. are on the pill, and around 80 percent have used it at some point in their lives. The ability to prevent pregnancy has given women greater sexual freedom and made it easier for many to pursue education and careers before choosing to start a family.

Men have been pretty content to let that happen. After all, they have condoms to use, and if someone wants to go all out, a vasectomy is an option.

Neither method is ideal, however. In lab tests, condoms have a failure rate of just 2 percent. But in the real world, where condoms are sometimes used improperly, that rate jumps to more than 10 percent. And while vasectomies are nearly 100 percent effective, they’re also, for the most part, irreversible. Not many men, younger ones especially, are willing to commit to that.

Compare these limited options for men with the range available for women, for whom birth control has been a reality for generations: Pills, patches, shots, intrauterine devices (IUDs) and more are available to those who want to prevent a pregnancy.

Some of the most well known, like the birth control pill, work by upsetting the balance of hormones that regulate menstruation and ultimately prevent the release of a mature egg from the ovary. Given the success of hormone-based methods for women, researchers have turned to the hormone testosterone time and again as a potential male contraceptive.

A TESTY TOPIC

Naturally produced testosterone plays a critical role in making sperm. Introducing a combination of synthetic hormones, including testosterone, into the bloodstream convinces the brain it’s made enough testosterone and should stop production in the testes. If men keep taking that testosterone cocktail every day, their natural production levels of the hormone fall below what’s needed to signal the testes to create new sperm. Within a few months, most men don’t have enough sperm to fertilize an egg.

Even better, a testosterone-based male contraceptive should be fully reversible. If men stop taking it, their sperm counts will return to normal within a few months. They can choose to have children if, and when, they want.

The concept will be put to the test this summer in a trial involving 420 couples: The men will apply a gel containing testosterone and a synthetic sex hormone, progestin, to their shoulders. An earlier preliminary study indicated that the treatment was effective for most of the men, and the larger experiment could pave a path to FDA approval for the gel as a male contraceptive. The trial is hardly breaking new ground. Testosterone has previously been tested as a contraceptive in both pill and injection form, potentially giving men multiple options.

And yet, testosterone has never been approved as a male contraceptive. The reasons aren’t entirely obvious. “The concept is clear; testosterone should work. The problem is it doesn’t work in all men, and we don’t know why,” says John Amory, a reproductive researcher at the University of Washington. “If you take 10 men and you start them on a hormonal contraceptive, you say, ‘Well, it’ll work well for eight or nine of you.’ ” That makes the failure rate about equal to that of condoms.

Another issue could be the potential for unpleasant side effects. Testosterone is the same hormone that loods a man’s body during puberty, and men participating in hormonal contraceptive studies that include it have complained of mood swings, weight gain and acne, among other things. It’s unclear, however, whether testosterone is entirely to blame: Many of the hormonal cocktails tested also included progestin. Regardless, more than one promising testosterone-based trial has been undone by reported side effects.

Consider what happened with a large multinational male contraceptive study in 2016. Sponsored by the World Health Organization (WHO), early results indicated that the injectable hormonal formula the researchers chose was working well, says study coauthor Doug Colvard, a researcher at reproductive health non-proit organization CONRAD, based in Arlington, Virginia.

Of the 320 participants, 96 percent saw their sperm counts fall low enough to render them sterile. During the trial, only four of the men’s partners got pregnant, making the failure rate less than 2 percent.

Then, without warning, the study was shut down.

Although WHO had reviewed the study just two months prior and allowed it to continue, an external committee took another look at the same preliminary data and found safety concerns, bringing the trial to an abrupt end.

In addition to the expected rise in acne cases, researchers saw more changes in mood and behavior than anticipated. These side effects appeared to be concentrated among participants from particular locations within the multinational study. For example, at one site, Colvard says, “almost all the men were experiencing what the investigator was calling an ‘emotional disorder’ — they seemed more agitated than they were prior to receiving the injections.”

The study’s premature end was a letdown for the researchers, especially because such large-scale studies are dificult to fund and set up.

“The field collectively was disappointed, and there were people who felt that it shouldn’t have been stopped, that the data available didn’t warrant it,” says Colvard.

Other major male contraceptive trials based on testosterone have suffered a similar fate. In one trial more than a decade ago that involved over 300 participants and was organized by two major pharmaceutical companies, the men experienced mood swings, acne breakouts and weight gain. One participant attempted suicide. The work was dropped.

In addition to meeting high safety standards, potential contraceptives also need to be tested for long-term effectiveness. But trials of a male contraceptive that run for more than a year are rare.

“I think people don’t appreciate that when you’re not dealing with, say, a cancer-causing or a life-threatening situation, the studies have to be very large and very long to have enough evidence to be able to demonstrate to the FDA and the people that are going to take it that this is a safe and effective method,” says Diana Blithe, chief of the contraceptive development program at the National Institutes of Health’s National Institute of Child Health and Human Development.

Of course, female contraceptives that have been approved carry side effects, too: Weight gain and mood swings are common, as well as the risk of potentially deadly blood clots. But doctors justify prescribing women these contraceptives because pregnancy comes with many side effects of its own, some serious and even fatal. A blood clot, for example, is much more likely to happen during pregnancy than it is from taking a hormonal birth control.

“If you’re a sexually active woman and you don’t want to get pregnant, it’s much safer to take a birth control pill than to get pregnant,” Amory says. “You cannot make the same argument there for a man.”

PUTTING UP A ROADBLOCK

Tampering with hormone levels isn’t the only way researchers are trying to prevent a pregnancy.

For example, a non-hormonal compound known as WIN 18446 was irst tested in the 1960s. It suppresses the ability of the testes to make retinoic acid, which is necessary for sperm production. But it also caused men in a study to become violently ill if they drank alcohol. Several other research ideas were scientiically shaky, such as the Indonesian herb gossypol, which some say can lower sperm counts non-hormonally. But the herb turned out to render some men infertile.

Other researchers want to put up a blockade in the vas deferens — a tube between the testicles and urethra — to stop sperm’s passage.

After sperm are created in the testes, they travel through the long, looping vas deferens and eventually into the urethra, where they exit the penis. The idea is to introduce a gel to either block or destroy them. Men could still ejaculate and hormone levels would remain balanced, but the sperm would never reach the woman’s egg.

The concept dates back to the 1970s, when Indian researchers began experimenting with a technique called reversible inhibition of sperm under guidance (RISUG). In RISUG, a polymer gel is injected into the portion of the vas deferens passing through the scrotum. The gel then hardens to form a sperm-blocking barrier.

The RISUG technique made it through several human trials in India over the past four decades. Few side effects have been reported. But despite the success and favorable media coverage, the technique was never picked up by a drug company. RISUG has not made it to market anywhere in the world.

Part of the reason may be that the observations of the trial participants lasted less than a year. While there are reports of individual RISUG use for up to 10 years, there have been no long-term studies, and Indian regulatory agencies haven’t yet reached a conclusion as to the safety of both the technique and the gel’s ingredients.

In the U.S., the non-proit Parsemus Foundation began developing a similar gel, called Vasalgel, in 2010. Although the two gel formulas are different, the method of insertion is the same. To inject the gel, a short loop of the vas deferens is pulled through a small hole in the scrotum — similar to the technique for a no-scalpel vasectomy. A 2017 study found that the gel successfully blocked sperm in rhesus monkeys, but Vasalgel has yet to be tested in humans.

Biotechnology company Contraline, founded in 2015 by Kevin Eisenfrats and his University of Virginia adviser John Herr, offers another entry into the vas deferens-blocking category: Echo-VR.

The biggest difference between Contraline’s Echo-VR and other blockers is the formulation, according to CEO Eisenfrats, though the company hasn’t yet shared any data on it. Contraline wants to offer an ultrasound-guided injection, which doesn’t involve a scrotum incision — an additional selling point for men who may be squeamish about incisions or holes “down there,” Eisenfrats says.

According to Eisenfrats, the company only recently locked down its gel formulation and began animal trials.

Contraline claims it can remove its vas-blocking plugs, but the company doesn’t have published results to share. Researchers have successfully tested the reversibility of RISUG in monkeys, and Vasalgel had similar success in rabbits. To make it to market, these methods would need to pass human trials for safety and eficacy, as well as reversibility without causing damage.

When asked about vas-blocking techniques, Amory, the University of Washington researcher, expressed some concern. Even though the human studies of RISUG, the only vas-blocker that has made it that far, haven’t revealed any major side effects, he’s not convinced that stopping up the vas deferens with an artiicial dam is totally reversible.

“The vas is a living tissue,” Amory says. “It’s possible that putting chemicals in there to form some sort of plug might damage the vas. It’s very muscular, and damage to the muscles could cause ejaculatory problems.”

PROFITS AND POTENTIAL

Jessie Goodpasture, a drug development consultant and advisory board member of the non-proit Male Contraception Initiative (MCI), thinks a successful male contraceptive will be one that takes proitability into account from the very start.

Goodpasture participates in reviewing applications for the yearly grant MCI offers, and part of her personal evaluation criteria includes considering a potential product’s commercial viability. This includes looking at whether the proposed studies are logical extensions of the research already done, and if she thinks the applicant can take the project to a point of completion.

“You need to know whether or not you have a market and what your market is demanding,” she says. “Can you actually develop something that will be marketable, not just to three people, but to 300 million?”

This year alone, MCI received over two dozen project queries for a single $500,000 grant, she says. Of those, just seven of the groups were invited to apply.

While researchers struggle to bring a viable male contraceptive to market, it looks like many men are ready and waiting. Several studies have revealed that a consistent majority of men (and their partners) the world over are willing to try male contraception. A 2005 study of 9,000 men in nine different countries found that, on average, over half of the men would be willing to try male birth control, though the percentage varied by country. Another study that polled men in England, South Africa and China found similar results.

And so, the research continues. Georg and her group are reining their potential ouabain-based approach that will stop sperm rather than hearts. Amory’s team is ine-tuning WIN 18446, the 1960s compound that made men vomit after drinking alcohol — though he hasn’t solved that drawback yet. A team at Michigan State University announced in 2017 that it had made male mice infertile by editing out a single gene, a technique that could one day be applied to humans, though it’s unclear if it would be reversible.

As for Colvard, whose testosterone trial was derailed by side effects in 2016, he remains hopeful. He needs more funding to continue his work, but he thinks a few subtle tweaks to the formula could make the side effects more tolerable.

Colvard brushes aside any concerns that there may be no market for male contraceptives. Though his ill-fated study rode to media prominence on claims that men couldn’t handle the side effects, he says that follow-up surveys indicated the opposite.

“Even though quite a number of men were experiencing some of the side effects, they weren’t dropping out of the study,” he says. Questionnaires indicated that over three-quarters of the participants were willing to continue using the contraceptive after the trial was completed, Colvard says. “They didn’t want to stop.

Written by Nathaniel Scharping in "Discovery Magazine", USA, May 2018, vol.39, n. 4, excerpts pp. 30-35. Digitized, adapted and illustrated to be posted by Leopoldo Costa.