THE blunderbuss was not a subtle weapon. Beloved of buccaneers and highwaymen, it spattered lead shot in all directions from its flared muzzle – with deadly effect. It was great for clearing the decks as you boarded an enemy vessel, but you ran the risk of killing your comrades. And it was liable to blow up in your hand.
Men who have heard of attempts to develop a “male pill” could be forgiven for feeling as if they were on the wrong end of a blunderbuss. So far these efforts have focused on altering levels of testosterone, which controls sperm production. But testosterone is also the master hormone that affects nearly every masculine characteristic, from muscles to libido, from body hair to aggression. Like the blunderbuss, hormonal contraception for men carries the risk of some unappealing collateral damage.
Fortunately for the faint-hearted, there may be other options. Designs are on the drawing board for a whole arsenal of smarter weapons that precisely target sites of sperm production without threatening masculinity.
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Until recently we have known relatively little about sperm production – in contrast to egg development in females. But right now it is one of the hottest research topics around. And every new enzyme or signalling molecule that is discovered is a potential drug target. Compared with testosterone-based approaches, these new drugs will look like guided missiles.
A breakthrough in male contraception is long overdue. When it comes to birth control, men are stuck in the 19th century. Rubber condoms were first used in the 1840s and the vasectomy was developed in the 1890s. Since the second world war, 13 contraceptive pills and devices for women have been introduced, but not a single new potion or contraption has become available for men.
It’s not for lack of trying. In the 1960s, China and India began pushing for more research into male contraception to help check their burgeoning populations. The World Health Organization backed the cause, and by the 1970s feminists had joined the clamour for a male pill, arguing that women should not have to shoulder all the responsibility and health risks of birth control.
Taking a lead from the hormone-disrupting female pill, most efforts to create a male pill have targeted testosterone. This is secreted by Leydig cells in the testes, where it stimulates sperm production by nearby germ cells. But testosterone has many systemic effects too, as it is carried all over the body in the bloodstream. So any contraceptive that shut down testosterone production in the testes would have to be accompanied by a way of replenishing blood levels of the hormone.
The latest formulations rely on a combination of two hormones: a progestin, which blocks signals from the brain’s pituitary gland telling the testes to secrete testosterone, and a testosterone top-up for the bloodstream. As neither hormone is effective in pill form they have to be given via a patch, an implant or an injection. A male “pill” this is not.
Because testosterone’s effects are so wide-ranging, the dose has to be just right. Australian biologist Liza O’Donnell, who researches male contraception at Prince Henry’s Institute of Medical Research in Clayton, Victoria, sums up the dilemma: “You want to suppress testosterone production in the man’s testes as much as possible, but you don’t want to suppress the testosterone too much in his body because then he’s basically in a castration state and not very happy.”
She’s not kidding. Too little testosterone in his blood and a man starts to lose interest in sex. He experiences mood swings and his testicles shrink. Breasts are a real possibility. Pump him full of too much of the stuff, however, and in the short term he may get acne or become aggressive, and longer term he may get heart problems or prostate cancer.
Of course, no drug that did all those things would ever be licensed. Several groups around the world are developing various combinations of patches, jabs and implants that seem to minimise side effects. David Handelsman’s team at the ANZAC Research Institute in Sydney, Australia, hit the headlines in October with a small, one-year trial of four-monthly testosterone implants and three-monthly progestin injections. Handelsman defends the hormonal approach, saying that in his study, adverse effects were few and minor. “You can’t have a drug that works without side effects,” he says. “That’s an illusion.”
At first glance, the two pharmaceutical companies that make versions of the female pill, Schering and Organon, seem to agree. They recently began clinical trials of another progestin-testosterone combination involving a once-yearly implant and three-monthly injections. It is vital they get the formulation just right, as men could be taking it for years, even decades.
But no matter how finely tuned the formula, the spectre of chemical castration may prove too scary for many men. So Schering is hedging its bets, funding several groups to research non-hormonal strategies. While insisting that the hormonal approach is “absolutely feasible”, Farid Saad, a spokesman on male contraception research at Schering, concedes that non-hormonal methods “would probably be more elegant”. The company’s own survey, currently awaiting publication, shows that given the choice men would rather take a non-hormonal contraceptive. That survey also found that on average worldwide, 55 per cent of men would take a male pill of some form.
Hormonal approaches have another drawback: they block the earliest stage of sperm manufacture, so it takes a good three months of treatment to render a man infertile. Smarter drugs that halt proceedings farther along the conveyor belt of sperm production could take just a few weeks to work.
To appreciate the range of alternatives that researchers are exploring, it is worth taking a guided tour of a sperm factory. Each testis contains about 250 metres of seminiferous tubules lined with sperm-producing cells – the start of the production line. A healthy man churns out around 150 million sperm a day. They begin life as round germ cells in the outermost part the tubules’ wall (see Diagram). These divide continuously and some move slowly inwards towards the central space or lumen of the tubule, growing, dividing and becoming progressively more sperm-like as they go. Larger “Sertoli” cells – which extend from the outer wall of the tubule to the fluid-filled lumen – take the role of nursemaids to the young sperm. They provide nutrients and physically hold them in place, eventually releasing them into the lumen. The whole journey takes the infant sperm 64 days.
Sertoli cells have another crucial function: between them they form an impermeable sheath known as the blood-testis barrier, thanks to the so-called “tight junctions” that bind them together. Like the blood-brain barrier, the blood-testis barrier protects vulnerable cells – developing sperm – from infections, toxins and immune cells borne in the blood. Crucially, immature sperm have to pass through this barrier as they journey inwards towards the lumen. This is the first potential target for a contraceptive smart bomb.
Yan Cheng and his colleagues at the Population Council, a non-profit research group in New York, have suggested two ways to exploit the blood-testis barrier. A drug that held it open would allow developing sperm to pass through before they were ready. Alternatively, one that kept it permanently shut would not let any through at all. “If we can understand how this barrier is being regulated, it will yield potential targets for male contraceptive development,” says Cheng.
He has shown that immune-system chemicals called cytokines play a role in regulating the tight junctions, as does the signalling molecule nitric oxide. In October his group published a paper suggesting two drug candidates that would keep the barrier closed (Biology of Reproduction, DOI: 10.1095/biolreprod.103.021329).
Such drugs are still hypothetical, but one that could act at the next stage of sperm development already exists. Called miglustat, it is already licensed to treat a rare genetic disorder called Gaucher’s disease, in which a metabolic defect leads to the build-up of a fatty sugar called a glycolipid, leading to progressive damage of the liver, spleen and other organs. Now made by UK biotech firm Celltech, miglustat inhibits the synthesis of that class of glycolipid.
But miglustat seems to have another effect, at least in mice. It targets sperm after they have crossed the blood-testis barrier but before they are released into the lumen of the seminiferous tubules. Aarnoud van der Spoel and colleagues at the University of Oxford have shown that after only three weeks of drug treatment, mice start firing blanks (Proceedings of the National Academy of Sciences, vol 99, p 17173). Their sperm could not swim properly and they were abnormally shaped: some of them had their tails wrapped round their heads.
The Oxford team is applying for a patent on the use of miglustat as a contraceptive, and Celltech is considering developing it. The fact the drug has already passed safety tests for use in Gaucher’s disease is encouraging.
On with the guided tour of the sperm factory. In the seminiferous tubules, the now distinctly sperm-like cells are released into the lumen, a process known as spermiation. This is the stage that O’Donnell and her team in Australia are targeting – they are trying to block the signal that tells Sertoli cells to let go. “We believe that when the Sertoli cell can no longer release the sperm it basically has to pull it back down and eat it,” she says.
In October last year, Schering signed a deal with O’Donnell’s group to fund the screening of thousands of human proteins that may be involved in spermiation. They already have several potential targets in their sights, such as molecules called integrins that glue Sertoli cells and sperm together, and enzymes known as kinases in the signalling pathway that tells the cells when to let go.
But Cheng at the Population Council may have beaten them to it. Since the 1980s, researchers there have been investigating the potential of an anti-cancer drug called lonidamine as a male contraceptive. The drug disrupts the very same adhesion molecules that O’Donnell’s group is targeting, severing the apron strings that allow sperm to hang onto their Sertoli nursemaids.
Lonidamine is highly toxic, so Cheng and his colleagues have been looking at a similar compound called AF-2364. This renders rats infertile and its effect is reversible. Full toxicity testing will take at least another year, but early studies suggest the molecule causes no collateral damage.
Although Cheng thinks AF-2364 has potential as a stand-alone alternative to hormonal contraception, O’Donnell’s strategy would be to combine a spermiation inhibitor with hormones. An inhibitor alone may not be 100 per cent effective, she thinks, but it should allow a lower dose of hormones to be used. “A lot of the drug companies are getting to the end of their tether when it comes to hormonal formulations, because they are always going to have side effects,” she says. O’Donnell thinks a combination of hormones and a spermiation inhibitor may give the best of all worlds.
After sperm are released by Sertoli cells into the lumen of the seminiferous tubules, they pass into tightly coiled ducts that eventually converge to form the epididymis. Schering is financing basic research into potential drug targets in the epididymis, where the sperm are marinated in a solution that takes them through a final maturation process, giving them the ability to swim and fertilise an egg. For example, at least two groups, one in Hong Kong and one in MĂĽnster, Germany, are investigating whether disrupting the fluid balance of the epididymis is a potential line of attack.
After passing through the epididymis, sperm are corralled into the vas deferens, which acts as their final holding area before ejaculation. Cutting and sealing the vas – vasectomy – is the most effective and permanent contraception of all. The good news is that a reversible form of vasectomy called RISUG (reversible inhibition of sperm under guidance) is on the cards. Developed in India, where it is in the final stages of clinical testing, this involves injecting a fluid into the vas where it sets to form a loose polymer. This blocks the passage of sperm but not spermatic fluid. Flushing the polymer out with a chemical reverses the procedure.
The technique hit the headlines last year when Ronald Weiss, a vasectomy specialist at the University of Ottawa in Canada, vowed to bring the procedure to the west. But he has been held back so far because the animal toxicity testing carried out in India in the early 1980s does not meet the current stricter standards in the west. A large clinical trial of RISUG in India will be completed in two years, however, which may lead to its wider use.
By now the sperm in the vas deferens are ready for action, but there is one final stage at which a contraceptive pill could act, and this approach turns out to have a unique selling point – the drug could be taken by either men or women.
In 2001 a team led by David Clapham of Harvard Medical School discovered a calcium ion channel that is found exclusively in sperm cell membranes. When they made “knock-out” mice lacking the gene for this channel, the animals’ sperm were incapable of fertilising eggs (Nature, vol 413, p 603). The exact reason is unclear, but because the channel is found in mature sperm tails and nowhere else in the body, the chance of side effects would be minimal. “That was the most exciting part of all,” says Clapham.
Two years ago the academics hooked up with biotech firm Hydra Biosciences of Cambridge, Massachusetts, which began screening candidate molecules to block the calcium channel that could be developed into an oral drug. A large pharmaceutical company, which Clapham prefers not to name, has come on board. If they identify a suitable drug it could swing into action just before fertilisation. In other words, men wouldn’t have to take it every day – perhaps just 15 minutes before sex to give the chemical time to reach their semen.
Or women could take it, allowing a similar time before sex for the channel blocker to reach sufficient levels in their reproductive tract. It might even work if they popped the pill just after sex, says Clapham, because it takes sperm at least a couple of hours to reach the egg in the Fallopian tubes.
It sounds like the perfect contraceptive pill – one that you could take just before sex, or even just after, and it strikes a blow for sexual equality into the bargain. And not a hormone in sight. It is worth remembering, however, that a testosterone-based contraceptive is far more likely to reach the market first. Most of the non-hormonal approaches, including the unisex drug, are still in early development. But one thing is certain: the prospects for a smart, targeted male pill have never looked better. In five years’ time, bathroom cabinets all over the world could contain packs of pills marked “his” and “hers”.