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30 November 2022

The Male Pill, a Dream That Is Never Realised

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In 1960, the US gave the green light to the contraceptive use of Enovid, the first drug licensed for this purpose; thus was born “the pill”, which beyond its primary purpose in family planning became the catalyst for a revolution in sexual and reproductive freedom for women. But as far as its original purpose in the couple’s sphere is concerned, more than 60 years later, women still bear the brunt of the burden of preventing unwanted pregnancies, while science and technology have built up a strong track record of relegating women or making themw invisible. This is despite the fact that, interestingly, researchers began seeking the male equivalent of the pill not long afterwards: research began in the 1950s, and clinical trials in the 1970s. The question of why the male pill does not yet exist today has no simple answer; it appears to be an amalgam of sexist bias, commercial disinterest, lack of funding and other less clear reasons.

As with any breakthrough, many different people contributed to the development of the pill. From the observation in the 1930s that progesterone and other steroid hormones inhibited ovulation, it would be two decades before the critical mass needed to bring the breakthrough to fruition came together: family planning pioneer Margaret Sanger was its ideologue and driving force, suffragist and philanthropist Katharine McCormick put up the money, biologist Gregory Pincus developed the drug, and gynaecologist John Rock undertook the first clinical trials. In 1957, Enovid was approved for the treatment of menstrual disorders, and three years later as a contraceptive.

Los primeros ensayos con compuestos para inhibir la formación de esperma coinciden con el lanzamiento de Enovid y otros anticonceptivos orales de primera generación. Crédito: Science History Institute.
First trials of compounds to inhibit sperm production coincide with approval of Enovid and other first-generation oral contraceptives. Credit: Science History Institute

But at the same time, in an Oregon prison, a team of scientists began testing on male inmates a compound called WIN-18,446, which had been found, accidently, to inhibit the production of sperm in mice. The results in humans were also spectacular: sperm counts plummeted, without the slightest side-effect, and this was completely reversible as soon as the medication was stopped. Just as the female pill was coming onto the market, it seemed that the male pill was not far behind.

The pitfall of the side effects

Only this was not the case. It was soon revealed that WIN 18,446 did have one serious adverse effect in one particular situation: when alcohol is drunk. The enzyme that this drug inhibits, aldehyde dehydrogenase, or ALDH, has one form involved in the maturation of sperm in the testes, but also another that metabolises ethanol—the alcohol in drinks—in the liver. When this latter form of ALDH doesn’t work, a toxic compound produced by the metabolism of ethanol, acetaldehyde, accumulates in the body and provokes violent illness. Nobody wanted a contraceptive that was incompatible with alcohol, so WIN 18,446 was abandoned as a potential male pill and relegated to drink aversion therapies.

This is curious, given that the female pill is by no means free of side effects. All the formulations that have appeared over the years are based on a combination of an oestrogen and a progestin (a synthetic analogue of progesterone). Enovid and other first-generation oral contraceptives were discontinued in 1988 due to the occurrence of thrombosis causing myocardial infarction or stroke. To avoid this risk, later formulations reduced the level of oestrogens and introduced new, more potent progestins at lower doses. 

Today, however, the pill continues to carry a multitude of adverse effects: menstrual bleeding and disorders, weight gain and appetite changes, depression, vaginal dryness and reduced libido, nausea, vomiting, headaches, fluid retention… Many women are particularly concerned about the link with cancer: the pill reduces the risk of ovarian, endometrial and colon cancer, but increases—albeit only slightly—those of breast, cervical and liver cancer. Although studies on the latter are not unanimous, the International Agency for Research on Cancer (IARC) of the World Health Organisation (WHO) classifies oral contraceptives in its group 1, agents “carcinogenic to humans”, in the group for which there is “sufficient evidence”, according to this body.

El compuesto WIN 18446 actúa impidiendo la formación del ácido retinoico necesario para la maduración del esperma a partir de la vitamina A. Crédito: Charles H Muller
WIN 18,446 treatment works by preventing the formation of retinoic acid needed for sperm maturation from vitamin A. Credit: Charles H Muller

Moreover, oral contraceptives are on the WHO list of essential medicines, the same organisation that classifies them as carcinogenic. The explanation for this paradox is no less curious: the risks of the pill are considered acceptable because they are lower than those of pregnancy and childbirth. Conversely, since these latter risks do not exist in men, “the tolerance for side effects drops to zero,” according to the journal Science. This search for a 100% safe male pill may be one of the factors that have slowed the progress of these drugs.

A new market and a lack of funding

The truth is that since the first clinical trials were undertaken by the US National Institutes of Health in the 1970s, we have yet to see a male pill reach the market. Those trials used injections of testosterone—essential for sperm formation, but which at high doses causes the opposite effect—alone or in combination with a progestin, which in men suppresses sperm production from the central control in the brain. The results showed similar effectiveness to the female pill with few adverse effects, which was confirmed in subsequent studies in the 1990s. 

And yet the large pharmaceutical companies that maintained research programmes in this area abandoned them at the beginning of this century. This means that major funding sources are closed to this field of research. “This is a completely new market, and contraceptives have to be 100% effective with zero side effects and cheap, so reticence is understandable,” Richard Anderson, co-director of the Centre for Reproductive Health at the University of Edinburgh, tells OpenMind.

The newness of the market is, for Anderson and other experts, a major stumbling block: when the female pill began to spread around the world in the 1960s, regulation was more permissive; it is said that today Enovid would never have made it through the filters. The problem is that there are still no regulatory standards for a male pill, so neither researchers nor companies know what targets they should meet. On the other hand, the market could be huge: according to Christina Chung-Lun Wang, a researcher in male contraception at the University of California, surveys show that from 55% to over 80% of men would be willing to use these methods. “There is a strongly growing feeling that men should contribute to contraceptive use,” says Anderson, who believes that the reluctance of pharmaceutical companies to take the risk of developing these products is clearly misguided.

Hormonal and physical methods

But behind the backs of the big companies, research and trials continue to progress. Hormonal methods aim for a daily tablet, as in the case of the female pill, but with testosterone it gets more complicated because it is quickly eliminated from the body. For this reason, injections or gels applied to the skin are also being tested. One of the latter, called NES/T, which contains testosterone and the progestin Nestorone, is in phase 2 clinical trials, a study in which Anderson and Chung-Lun Wang are participating. According to the researcher, the results so far are “promising with minimal side effects.” 

In 2022, the results of a phase 1 trial—aimed at testing the safety—of two hormone pills have also been announced, with favourable results. According to Anderson, at the present stage “hormonal contraception is highly effective and safe”. In his experience, and although there is currently mistrust among the population towards hormonal compounds because of their endocrine disrupting action, this resistance is in the minority, and only lasts “until they have an unwanted pregnancy.”

Una compañía alemana tiene en marcha un método anticonceptivo consistente en una válvula implantable con un interruptor para seleccionar la posición fértil/estéril. Crédito: BIMEK SLV
A German company has a contraceptive method in the pipeline consisting of a small implantable valve with a switch to select the fertile/sterile position. Credit: BIMEK SLV

Research is not limited to hormonal compounds. There are other drugs that target certain proteins involved in spermatogenesis that have worked in animal experiments, although they have yet to prove their efficacy and safety in humans. One example is a drug called YCT529, which works by inhibiting the action of retinoic acid needed for sperm maturation (WIN 18,446 functions by preventing the formation of this compound from vitamin A). In mouse trials, it has been shown to be 99% effective in preventing pregnancy without side effects. The researchers, from the University of Minnesota, hope to begin clinical trials soon.

Finally, other methods are physical, more along the lines of an easily reversible vasectomy. At least two different proposals use a hydrogel that is implanted by injection or by a small cut in the scrotum, which blocks the vas deferens through which semen circulates so that seminal fluid can pass, but not sperm. The proposal of a German company sounds even more audacious: a small implantable valve with a switch that allows the user to select the fertile/sterile position.

According to Pharmaceutical Technology, a total of 10 male contraceptives are currently in the pipeline, two of them in phase 2 clinical trials, one in phase 1, five in pre-clinical studies and the remaining two still under investigation. But Anderson is not optimistic about an imminent market launch: “Not for quite a few years yet,” he predicts. 

Javier Yanes


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