Dòl Iain Dòmhnallach investigates the science of bringing new male contraceptives from bench to bedroom.
Written by: Dòl Iain Dòmhnallach
Art by: Winnie Lei
Acne. Low mood. Injection site aches and pains. These were the side effects that resulted in a clinical trial of a game-changing injectable male contraceptive which ended early last year. Cue collective online uproar and withering shakes of the head. As reported in the October 2016 edition of The Journal of Clinical Endocrinology and Medicine, the contraceptive – a combination of the hormones progesterone and testosterone – was about 98% effective, as good as most female oral contraceptives. But, it seems, men just couldn’t handle it.
The story was more complex than made out by the media, of course. The decision to end the trial early was taken by an expert external panel and the depression experienced by many participants is no laughing matter – one participant even committed suicide (although this was deemed to be unconnected to the drug). It’s not my aim to decide if discontinuing the trial was right or wrong – many a thundering thinkpiece has done that already. Instead I want to ask why this pill failed, and how science can help develop better male contraceptives.
Drugs fail in clinical trials because they don’t work. Of the drugs that do work, most have side effects that make them not worth working. Hormones are like the seasons or weather fronts of the body, affecting everything from growth, to emotions, to metabolism, to libido. Hence drugs that imbalance hormones can have unpredictable and wide-ranging side effects, just like a hurricane last week in the Caribbean can result in a storm in Scotland today. The combined female oral contraceptive pill, for example, packages together the hormones oestrogen and progesterone and can result in a litany of side effects, including heart and circulatory problems (to the extent that people have argued it would never pass safety trials today). Thus the injectable contraceptive used in the 2016 male pill study was explicitly designed to reduce side effects by using a lower testosterone dose. Side effects have felled every other male contraceptive, with one particular side effect providing the mortal blow. As Professor John Parrington, an Oxford University expert in reproductive biology, point outs, ‘there has been success with hormonal male contraceptives but as they can affect libido, a major problem is getting men to use them.’
What scientists in this field fantasize over, then, is a non-hormonal male contraceptive. Parrington says we need ‘a target that plays a key role in fertilization, but blocking its effect doesn’t affect libido, or have adverse effects on the rest of the body.’ Thankfully, 4% of the mammalian genome codes for proteins involved in sperm development, so there are targets aplenty. The theory is that if we could block these, we would reduce sperm counts and function, inducing infertility.
Normal sperm counts stand at 15 million/ml, and any male contraceptive needs to reduce this to 1 million/ml just to match the 1% pregnancy risk conferred by the female Pill. Fifty years ago a compound called WIN 18,446 was shown in 60 men to lower sperm counts below the 1 million/ml mark, with no hormonal side effects. However, it came with a critical side effect: men on the drug vomited and sweated profusely after drinking alcohol, so the trial was abandoned. In 2011, when the same drug was given to rabbits, it resulted in sterility by inhibiting production of retinoic acid, a key molecule in the manufacture of sperm. So a drug which blocks retinoic acid production but does not mess with alcohol metabolism could prove a potent contraceptive by stopping men making sperm.
But few studies monitor the long-term consequences of screwing up sperm development. Once off the drug, will men return to full fertility? Or will newly-made sperm show genetic changes and low viability? Moreover, given sperm production takes 10 weeks in humans, such a pill would have an obvious lag time. Perhaps it’s better to target the functioning of mature sperm. Sperm swimming up the reproductive tract are guided by environmental cues like pH, detected by sensors called ion channels – the particular forms of these sensors are found specifically and solely in sperm. These ion channels were discovered in dizzyingly fiddly experiments involving recording electrical currents inside sperm using tiny glass microelectrodes. CatSper, the first to be discovered, lets calcium into sperm, making them swim faster in response to pH changes. The dream would be to develop a drug which blocks CatSper to freeze swimming sperm in place, immobilizing them before they reach the egg. Unfortunately, nobody has got CatSper inside cell lines to screen for these drugs.
A promising alternative is to hijack the immune system with an anti-sperm vaccine. Antibodies are like the guided missiles of the immune system. They home in on specific targets on cells resulting in cell death. By giving mice antibodies targeted at CatSper, scientists were able to induce infertility. Similarly, some infertile men and women suffer from an autoimmune disorder where antibodies target the egg-recognizing izumo protein on sperm to destroy them. In female mice, vaccination against sperm using antibodies targeted at izumo resulted in complete sterility, which importantly could be reversed after ten months. Carrying this into the clinic would be revolutionary: we would have a reversible contraceptive vaccine targeted at sperm which could be taken by both men and women.
From retinoic acid to CatSper to izumo, there is no lack of drug targets for non-hormonal male contraception. And yet we have so far failed to bring them from the bench to the bedroom. Parrington says ‘there has been interest in developing a male non-hormonal contraceptive by the pharmaceutical industry at various times over the last few decades, but I think it’s fairly low priority right now.’ Many factors are purported to explain this low priority. Contraception in contemporary Western society is seen as a woman’s burden and overwhelmingly male pharma execs are said to be uninterested. Some feminists suggest this stems from Big Pharma’s fragile masculinity, where male sterility is seen as unmanly and weak. But economics is also at play. In the early days of the female Pill, the rubber industry – literally rubber barons – lobbied against it because they feared declining condom sales. Today, female contraceptives and male condoms give satisfactory contraception so there is inertia about developing the male contraceptive ‘add-on’ due to perceived low-demand among men. Funding for reproductive biology is more likely to go on lucrative artificial reproduction research like IVF.
Critics of male contraception research like to ask what woman would trust any man who said he’d taken the Pill. Yet one hint of hope for advocates: in the 2016 study, 87.9% of men said they’d take the Pill again, and – crucially – so did 87.5% of the female partners. Social and economic factors stand in the way of bringing a non-hormonal male contraceptive from the lab into your lovelife. But the targets are varied, the science is sound, and – judging by the online outcry after the 2016 trial was abandoned – the demand among men and women is there and waiting to be met.
–Dòl Iain Dòmhnallach