SCIENCE: NOTHING TO LOSE BUT YOUR CONDOMS

Drugs companies are close to perfecting a male Pill and, what's more, 93 per cent of women say they would trust their partner to take it. Norman Miller reports on the new sperm warfare

IT'S FAMILY PLANNING time in 2005 - time for a man to do what a man's gotta do. Take his Pill and let some more dust gather on that packet of condoms in the attic.

For 30 years, research into contraception has been overwhelmingly directed towards women, with male options remaining resolutely low-tech - would sir like his condom ribbed or flavoured? The main reason, of course, is that the medical and social burden of unplanned pregnancy falls overwhelmingly on women. But with 93 per cent of women in a recent survey at Scottish family planning clinics in favour of a "male Pill" - and happy to trust their partners to take it - researchers are beginning to shift the emphasis.

While rampant male hormones often cause trouble, in male Pill terms they may offer a solution. If that sounds odd, consider how the female Pill works - give the body a regular additional dose of the female hormone oestrogen, and it's kidded into turning off the woman's own supply, with the result that she doesn't ovulate. The same principle works for men, though this time it's the main male hormone, testosterone, that is used to trick the testes into downing tools on the sperm production line.

This approach to controlling the little guys down below is called "hormonally suppressed spermatogenesis", but it's just one of several methods that are being tried out to produce an effective male oral contraceptive. These basically split into two camps: suppressing sperm production, or disabling the sperm.

Testosterone is central to sperm production as part of a cycle which also involves compounds produced in the hypothalamus and pituitary, of which the most important in contraceptive terms is luteinizing hormone (LH). LH stimulates the production of testosterone in the testes, where it plays an essential role in spermatogenesis. Some, however, also enters the blood stream where it acts to maintain maleness - things like stubble, liking football, rampant libido, etc. To ensure things don't get out of hand (thumping your boss or whatever), the hypothalamus and pituitary monitor levels of testosterone in the blood, adjusting LH secretion to keep everything in balance. So when a man takes a extra shot of testosterone, this feedback system sounds an alert and cuts LH secretion, reducing testosterone levels in the testes and stopping sperm production. But don't worry, guys, the testosterone dose in the Pill is enough to keep you male.

The problem with the hormonal approach is that to sufficiently reduce the level of sperm production using testosterone alone requires doses large enough to cause worrying changes in the prostate gland, cardiac system and liver, as well as problems with mood swings, weight gain and a spot of acne.

Side-effect worries, particularly thrombosis, also dogged early oestrogen- only versions of the female Pill, until researchers added another hormone with contraceptive effects - progesterone - to the basic package, a move which allowed the oestrogen dose to be reduced. Since progesterone also works by inhibiting the secretion of LH (which in women stimulates ovulation), researchers reasoned that adding it to the testosterone in the male Pill would allow them to cut the dose of testosterone to reduce side-effects, while still packing a punch against sperm production. The thing was to get the dosages right, since too much progesterone (a female hormone) also causes side-effects in men, of which the most worrying is breast growth. The hormonal approach, therefore, requires a sort of contraceptive cocktail, with researchers mixing various combinations of testosterone and progesterone to find the one that works best.

The bartenders at the Contraceptive Cafe are also experimenting with other members of the progestagen family from which progesterone comes, with desogestrel looking like the best of the alternatives.

Human trials of the testosterone-progesterone male Pill have already taken place in the UK and USA, achieving zero sperm counts in 95 per cent of men, with negligible levels in the remaining 5 per cent. Further trials are now underway at Edinburgh's Royal Infirmary, as well as in South Africa and China.

While the hormonal approach is currently backed by pharmaceutical giants like the Dutch company Organon (one of the world's largest manufacturers of the female Pill) positive results are being achieved with various alternative methods, making some experts wonder whether we will end up with the sort of situation seen in other industries where better products (Betamax videos and Apple computers) came a cropper after commercial muscle was put behind technically inferior products (VHS videos and IBM-compatible PCs).

One novel approach pioneered at North Carolina State University by Joseph Hall involves "blinding" sperm using a synthetic sugar analogue. Hall's compound works by inhibiting the activity of an enzyme which exists only in sperm cells, giving them the ability to recognise and fertilise eggs. This enzyme (a form of N-acetyl-beta-D-hexosaminidase, if you want the full monty) gives sperm their chemical "eyes". Inhibit it, and the sperm become unable to recognise eggs. Early tests in animals showed this approach to be 92 to 98 per cent effective as a contraceptive. This system sidesteps all the problems associated with hormones and also acts much faster to cut sperm production, taking around two weeks instead of the one to two months the hormonal approach needs.

Rather than trying to tamper with sperm production in the testes, Hall's method tackles sperm's ability to function, something it acquires as it passes through a "finishing school" called the epididymis. This coiled tube between the testes and the sperm duct is where sperm pick up a variety of enzymes and proteins that help them perform the job they are sent out to do. "By targeting sperm after it has reached the epididymis," says Hall, "we do not affect the male's hormonal balance. We don't have to mess with androgens (male sex hormones) at all."

"Don't mess with androgens" is a rallying cry which has also been taken up by Ed Cook's team at North Carolina's Research Triangle Institute. Though their weapons are also non-hormonal, they also work by interfering with sperm production. Called antispermatogenic agents, the first of these compounds was identified as a "sperm buster" in the 1970s by scientists at the Sandoz Pharmaceutical Company but the research details lay unnoticed for a decade in the files of one of Cook's colleagues, Vladimir Petrow. In 1989, the RTI team began modifying the Sandoz compound to improve its effectiveness as a contraceptive while diminishing its sedative side-effect. The RTI team has now identified a key constituent which inhibits sperm production. "I think that our compound is interfering with the communication between the cells in the testes," says Patricia Fail, the team's head biologist. Animal tests have achieved a high level of contraception with no toxic side-effects, but even though the RTI compound has now been patented, Cook admits it will be several years before men could be popping it into their mouths.

Sperm's next nemesis has come out of environmental research by Gary Klinefelter of America's Environmental Protection Agency into the effects of pollutants on the body, and it takes the shape of a sperm protein dubbed SP22.

Many proteins are added to sperm in their journey through the epididymis, and Klinefelter found that when toxic compounds reduce the amount of SP22 in animals below a certain level they become infertile. The discovery of such fertility- linked molecules has attracted other researchers on to this route, including Rupert Amann, formerly a physiologist at Colorado State University, but like a growing number of academics, now involved with his own bio- technology company. "Sperm is coated by hundreds, if not thousands, of proteins," he says, "so it's not surprising that some are involved in fertility." Amann's own pet protein is a molecule discovered in chickens, but though convinced of its potential for creating a male Pill he, too, refuses to commit himself to a definite production timetable.

One reason for the doubt is corporate anxiety over backing new methods of contraception, particularly in the aftermath of the health problems - and huge lawsuits - that followed in the wake of products such as the Dalkon Shield IUD which led to massive payouts in the 1970s and '80s. "Private industry is gun-shy," says Amann. "They've simply decided they can't handle the litigation." This may explain why in the US funding for research into female contraception is roughly double that spent on finding a male contraceptive, even though female-oriented research involves little more than revamping old ideas.

Companies like Organon, however, are more up-beat, with promises of a hormonal Pill on the shelf in three to five years, a target echoed by the World Health Organisation. But many experts, see this as optimistic. "We reckon seven to 10 years," says Clodagh Corcoran of the British Family Planning Association, "since large-scale trials are nowhere near completion or evaluation."

Of course there are two other important issues to be considered. One is the question of trust. How many women will believe a man when he whispers to them: "It's all right, darling, I'm on the Pill"? Though there is growing evidence of a sea-change in attitudes of both sexes to the idea of a male Pill, it would be naive to say everything is rosy in the sexual garden. With this in mind, most researchers admit their product would initially be aimed at men in long-term relationships rather than lads off on a Club 18-30 holiday.

The other point, as Corcoran points out, is that "a male Pill wouldn't help prevent STDs". Condoms may not be ideal, but in the post-Aids era they serve a vital purpose. Again, this suggests the male Pill's initial target is long-term couples, but that is still a large - and eager - market.

A recent European survey found that around one in two married women were unhappy with their method of contraception and over half would ask their partner to go on a Pill if one were available. "I think it's time for men to be in control of their own destiny," says Patricia Fail, "to give the woman a chance to get a break from the responsibility." So, guys, are you man enough for the challenge? You have nothing to lose but your condoms. !