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Gentle Persuasion

Plenty of sex before conception could well be the key to encouraging a woman's body to accept pregnancy.Douglas Fox discovers the unsung virtues of semen.

ONE OF THE great mysteries of the human condition is what makes us, unlike most other animals, spend such an inordinate amount of time having sex... and so little time actually getting pregnant. Nor is this a new phenomenon that came along with contraception. Couples still have plenty of sex when conception is out of the question either because of the time of the woman's cycle, or because she is already pregnant or breastfeeding.

But now the mystery of these fruitless bonkings might he solved. According to reproductive biologists at the University of Adelaide in South Australia, far from being an exercise in futility, plenty of sex even up to a full year before conception-helps guard against a litany of ailments. And Puritans prepare to he shocked-fellatio may work just as well as missionary-style intercourse.

The disorders, which range from infertility to high blood pressure during pregnancy, all appear to be linked to the reluctance of the mother's immune system to accept the fetus and placenta, both of which come armed with an arsenal of foreign proteins courtesy of the father's genes. Sex, early and often, and with the intended father; may help overcome that reluctance, say the Adelaide team.

Clearly, if the mother's immune system remains unconvinced the consequences will he dire. She may immediately and repeatedly reject new embryos-in which case, she's infertile. If her immune system takes a little longer to shun the foreign tissue, she may suffer frequent miscarriages. And if the rejection is milder still it might only affect the placenta-although even that can be a disaster. The placenta is the fetus's lifeline, supplying oxygen and nutrients from the mother's blood. If the placenta fails to grow, or becomes clogged with angry immune cells, the supply line is cut, and an underweight baby is the result or even a stillbirth.

Immune rejection can even threaten the mother's life. According to one still controversial theory, it's the mother's rejection of the placenta that causes pre-eclampsia, a condition where the mother's blood pressure soars, in some cases triggering convulsions, coma and death. In this frightening scenario, fragments of dead placental cells are swept into the mother's circulation, where they damage vessels, sending her blood pressure skywards. "It's just different expressions of one underlying theme," says Gustaaf Dekker, a member of the Adelaide group. "We see patients that have two miscarriages, then they finally manage to get through their miscarriage period, and they have preeclampsia, or the placenta detaches and they have a stillbirth at 24 weeks."

A big hand for the little guys
Sperm could explain the differences between chimps and humans

THE secret to what makes us human may lie not in our brains, but in sperm. Tiny changes in these little cells may have made all the difference to our evolution. DNA is packed into sperm heads by proteins called protamines, which help to squash the chromosomes into a tiny space. These proteins were never considered very important in human development because people thought their influence stopped shortly after fertilisation. But Caro-Beth Stewart at the University of Albany, State evolved with lightening speed just as humans split from the common ancestor of animals like gorillas and chimps, indicating that the proteins have a much bigger role in human development than previously thought.
Researchers are constantly on the hunt for ways of explaining why humans are so different, and so much brighter, than our close relatives (New Scientist, 23 February, p 15). Chimpanzees and humans parted ways only 5 million years ago, leaving us with 98.5 per cent of the same DNA. Working genetic make-up can explain all the differences between species is proving tough.
Stewart's team looked for genes that have changed dramatically since the evolutionary split. They found that one group of genes has evolved remarkably quickly: protamine 1, protamine 2, protamine 3 and histone H1t These are all genes that code for proteins involved with binding sperm DNA. Protamine 1, for example, now codes for a protein sharing only 84 per cent of the same amino acids with chimps. Changing 16 per cent of the amino acids in 5 million years is "screamingly fast evolution", says Stewart. In most other primates, protamines have not changed at all over this period. That's not too surprising, says Stewart. Sperm performs a vital task and tinkering with its DNA is more likely to cause harm than good. She thinks the new proteins in human sperm were probably specifically selected for because they gave some kind of advantage. These crucial changes may have altered how protamines bind DNA. Because these proteins are present at the very moment of fertilisation when an embryo's genetic material is first being programmed, Stewart guesses that even small changes in their function might have huge consequences for the fate of the embryo. Different protamines could set off a different pattern of gene activation during development, she says, even in genes that are identical between species. Stewart points out that other recent studies suggest that protamine genes are also switched on in fetal brains and adult human brainstems. So the proteins might continue to affect us even after the embryo stage. To understand how these changes have shaped humans, Stewart will study exactly how protamine proteins bind and shape DNA.[New Scientist 2 March 2002. ]

It's easy to understand why the mother's immune system might be tempted to annihilate that developing fetus. As if having foreign genes weren't bad enough, the fetus behaves brutishly during its stay in the womb. Its placenta invades the wall of the uterus like a cancer, infiltrating a nearby artery to guarantee steady supplies of oxygen and nutrients. It also casts millions of foreign cells adrift in the mother's bloodstream, cells that re-attach and grow in places like her lungs. The mother's immune system should positively squash those cells like cockroaches, but amazingly in normal pregnancies it lets them be.

"Acceptance of the conceptus is a much more dynamic affair than anyone's ever given credit for," says Rodney Kelly, a reproductive immunologist at the University of Edinburgh, who strongly suspects that the Adelaide group is on to something. "There's fetal cells in the maternal circulation, there's plenty of antigen, [so] there's obviously an enormous amount of immune modulation preventing rejection."

That process of immune modulation begins with the first drop of semen. You wouldn't suspect it during those dreamy post-coital moments, but for the next 15 hours or so a woman's cervix is swarming with immune cells. They swoop in like government agents investigating an alien crash site-which is essentially what they are doing. They busy themselves collecting the man's foreign proteins-even entire sperm cells-and lug them back to the lymph nodes where other immune cells learn to recognise them. Normally those foreign proteins would end up on the immune system's Most Wanted list: antibodies would be made against them, and primed to annihilate the sperm next time they dared to darken their doorstep. But the miracle of sex is that semen contains not only millions of sperm loaded with foreign proteins, but also some recently discovered components that tilt a woman's immune response away from hostility and toward acceptance.

"If there's repeated exposure to that signal," says Dekker, "then eventually when the woman conceives, her [immune] cells will say, 'we know that guy, he's been around a long time, we'll allow the pregnancy to continue."' Of course acceptance of the sperm by the mother's immune system isn't all that's needed for a straightforward pregnancy. But when things do go wrong, sperm have the power to provoke a vicious immune response. Following intercourse, women very occasionally go into anaphylactic shock, an immune response so severe that breathing can be nigh on impossible, and blood pressure plummets dangerously low. For these luckless women, just a drop of semen on a thigh can raise boils. The problem appears to stem from lacklustre attempts by the woman's immune system to become tolerant to sperm, combined with the man's semen doing a really bad job of convincing it. In some cases switching partners is all it takes to solve the problem. And there's other tantalising evidence of semen's power over the mother's immune response. An analysis of pre-eclampsia patterns in 1.7 million births from the Medical Birth Registry of Norway found that certain "dangerous males" are nearly twice as likely to father a pre-eclamptic pregnancy. These dangerous males carry their high risk from one female partner to the next.

But these are the rare examples where a man's semen isn't functioning properly. It was Pierre-Yves Robillard, a neonatologist now at the Sud Reunion Hospital on Reunion in the Indian Ocean, who showed that under normal circumstances semen exposure actually helps prevent pre-eclampsia-evidence that flies in the face of mainstream explanations for the disorder such as the popular "pantyhose" theory.
According to this theory, pre-eclampsia develops not because the mother's immune system sees the placenta as foreign, but because the blood vessels that supply the placenta don't expand enough. The placenta runs short of oxygen, and once again dying cells push up the woman's blood pressure. By a second pregnancy the blood vessels are already widened like worn pantyhose, which is why, say the textbooks, pre-eclampsia usually only happens in a first pregnancy. According to Robillard's studies, however, later pregnancies can be just as risky under certain circumstances.

In the late 1980's, Robillard was on the French island of Guadeloupe in the Caribbean, a territory dotted with sugar and banana plantations, where families are often made up of a single woman who has several children by different men. There he made the curious discovery that most of his patients with pre-eclampsia were actually on their second or third pregnancy. But it was specifically the women who had changed partners since their last pregnancy who were developing the condition. Robillard speculated that the mother's immune system requires time (and contact with semen) to learn to accept the father's foreign genes and not attack the placenta and cause pre-eclampsia. Changing fathers between pregnancies "puts your counter back at zero immunologically speaking", he says.

Men be having badly
It's not just women who suffer from hormonal ups and downs

BAD-TEMPERED? Nervous? Easily reduced to tears? If you are a man, you could be suffering from irritable male syndrome.
This newly recognised condition plays havoc with male animals, temporarily turning confident, chest-beating Tarzans into withdrawn, grumpy wimps. And there's some evidence that irritable male syndrome, which is triggered by a sudden drop in testosterone, affects men as well as animals, says Gerald Lincoln of the Medical Research Council's Human Reproductive Sciences Unit in Edinburgh. The symptoms may resemble those of the so-called male menopause, but Lincoln believes the condition can affect men of any age when stress causes testosterone levels to plummet.
If he's right, it's not just women who have their hormonal ups and downs. Lincoln first pinpointed the syndrome in Soay sheep. In the autumn, the rams' testosterone levels soar and they rut. In the winter, testosterone levels plummet and they lose interest in sex. High testosterone is supposed to mean more aggression. But the rams were more likely to injure themselves when testosterone was low. So Lincoln monitored the activity of eight rams, such as how often they struck out with their horns. As testosterone levels fell, the rams changed from competent males who addressed each other in a ritualistic fashion, to nervous, withdrawn animals that struck out irrationally, he says.
Red deer, reindeer, mouflon and Indian elephants also show clear signs of irritable male syndrome when testosterone levels fall off at the end of their breeding seasons, says Lincoln. "The mahouts sometimes starve the elephants after the must, or tie them up to keep them under control." But what does this mean for people? Here the evidence is shaky, Lincoln admits. But it's clear that testosterone has a major impact on human behaviour. The brain is loaded with receptors for testosterone and its conversion products. What's more, Richard Anderson, also at Edinburgh, has found that when men who cannot produce testosterone come off hormone replacement therapy they become irritable and depressed. Their mood improves when they resume treatment. Lincoln thinks that stresses such as bereavement, divorce or life-threatening illnesses could send testosterone levels plummeting. There are few human studies on stress and testosterone, he says, but numerous studies on animals, including primates, show that testosterone levels fall when stress sends corticosteroid levels skywards. " It's right on the money," says reproductive endocrinologist David Abbott of the Wisconsin Regional Primate Research Center in Madison. "Testosterone effects have been missed. When a bloke gets grumpy and irritable, [researchers] try and explain it only in terms of cortisol levels and depression. They ignore the fact that testosterone levels are probably falling too." But David Handelsman, an expert on male hormones at the University of Sydney, is more cautious. He says the changes in testosterone levels in normal adult men are far smaller than the dramatic swings seen in Soay rams, with one notable exception:
levels fall by at least 90 per cent in men who undergo castration for advanced prostate cancer. "The wives notice it first," says Keen-Hun Tai of the Peter MacCallum Cancer Institute in Melbourne. "The men become more withdrawn, but more emotional. They laugh and cry more easily." Clearly, the jury's still out when it comes to people. But if irritable male syndrome does affect men, diagnosing it won't be easy. It's far from clear what normal testosterone levels are (see New Scientist, 22 July 2000, p 36), while extra doses of the hormone may increase the risk of heart disease. But the syndrome could still be worth investigating. "Instead of putting stressed men on Prozac, a little testosterone may do the job," says Abbott. Rachel Nowak, Melbourne More at: Reproduction, Fertility and Development (vol 13, p 56)[New Scientist 2 March 2002. ]

He confirmed his hunch in his next study of 1011 pregnant women on Guadeloupe. Women who had sex with the father for 12 months or more before getting pregnant had a 5 per cent chance of developing preeclampsia compared to a massive 40 per cent chance for those who'd only been having sex with the father for four months or less. What's more, another study found that using condoms, which naturally prevent women from coming into contact with semen, increases the risk of pre-eclampsia.
Robillard's studies make an excellent case for the medicinal virtues of semen exposure. But it was Dekker, then at the Free University of Amsterdam, who took the studies one eyebrow-raising step further when he looked to see if the same goal could be achieved with oral sex-or more specifically, fellatio.

It's well known that our immune systems tolerate things better when they enter the body via the mouth. This is why we're not usually allergic to our food even though it's always genetically foreign, and why girls with nickel braces on their teeth are less likely to develop nickel allergies after their ears are pierced than girls without these braces.
Sure enough, when Dekker compared 41 pregnant women with pre-eclampsia and 44 without, he found that 82 per cent of those without pre-eclampsia practised fellatio, compared with only 44 per cent of those with the disorder. And in keeping with the "condom effect", the protective effect of oral sex was strongest if the woman actually swallowed the semen rather than coughing it onto the pillow. True, it's only one study, but for some couples who can't seem to carry a pregnancy to term, a little fellatio can hardly do any harm, suggests Dekker. "I tell them, 'semen exposure's good, and you could think of oral sex."'

Some people are a little less gung-ho. "The idea is cool," says James Roberts, director of the Magee-Women's Research Institute at the University of Pittsburgh, "but generating data that's not confounded is very difficult because sexual practices aren't independent of one another." The couples indulging in oral sex might, for example, have more sex overall. Sure they could, acknowledges Dekker, "but even then it still supports the same message that semen exposure is protective."

Roberts also points out a potential weakness in Robillard's father-switching data from Guadeloupe: it's possible that pregnancies with new partners tend to happen longer after the last pregnancy than those with the same father, which might mean that increased pre-eclampsia is triggered not by lack of exposure to semen, but by the stress of re-expanding uterine blood vessels that have shrunk back down since the last pregnancy. Still, this is just a minor quibble. "There are other ways to read the data," says Roberts, but there's nothing that holds together quite as well as the idea of immune rejection contributing to pre-eclampsia, and semen exposure preventing it. If you are wondering whether the exhortation for fellatio is a case of male fantasies hijacking science, as one New Scientist editor thought, consider that the Adelaide group is spearheaded by a woman-reproductive biologist Sarah Robertson.

Robertson and obstetrician Kelton Tremellen have already helped show that one component of semen (see below) plays a key role in persuading the mother's immune system to accept foreign sperm and a foreign fetus-a discovery that could lead to medical treatments that are more refined than your basic fellatio. "We might be able to devise artificial therapies to augment natural intercourse or maybe even replace natural intercourse in people who have problems getting this immune thing going on their own," says Robertson.

Their key component is called transforming growth factor beta. TGF-beta summons immune cells to the woman's cervix after sex to gather the man's foreign proteins. And according to Robertson and Tremellen's mouse studies, TGF-beta also acts as a switch, transforming what would usually be a hostile reaction to sperm from the immune cells into a friendly one. When the two researchers injected sperm protein into mouse uteruses, then injected the same protein under the skin of the mice a few days later, it triggered a severe allergic reaction-unless the first injection also included TGF-beta.

What makes their discovery particularly exciting as a potential therapy is that TGF-beta has this effect the first time sperm enter the vagina, although, says Robertson, repeated exposure to the sperm and TGF-beta is probably necessary for complete tolerance.
Dekker and Tremellen are currently comparing TGF-beta levels in the semen of men who have fathered normal pregnancies with the dangerous males where conception has ended in miscarriages or pre-eclampsia. Their hunch is that dangerous males simply don't sport enough TGF-beta in their semen. If they are right, the next step will be to treat women who suffer repeated miscarriages or IVF failures with TGF-beta.

Of course, the TGF-beta will have to be given along with the father's foreign proteins, which means during intercourse, perhaps in a vaginal gel. Intercourse during an IVF cycle is already known to up the chances of pregnancy (New Scientist, 9 December 2000, p 6). Tremellen suspects that's partly due to the TGF-beta in the semen. The gel, he says, would provide an additional boost.
Nor are the potential pay-offs to understanding how a woman's immune system tolerates a fetus for nine months confined to reproductive medicine. Autoimmune diseases such as lupus and multiple sclerosis, where the body's immune system attacks its own organs, are another target. "There's nothing to say we couldn't deliver myelin in a vaginal immunisation that might benefit women with MS," says Tremellen.
The Adelaide group's work is also satisfying for other reasons more to do with, eh, lifestyle. After all, it provides validation for what many people already hoped-that all those long, lingering Saturday mornings in the sack are anything but a wasted effort.

A LITTLE OF WHAT YOU FANCY There's more than one way that sex makes people happy. Women who had been exposed to semen were found to be less depressed than those who weren't. Gordon Gallup and his team at the State University of New York studied women whose partners used condoms and compared them with a group that didn't. They found that women who regularly used condoms during sex were more depressed and more likely to commit suicide. It seems that semen contains mood-altering hormones that are absorbed through the vagina. However, Gallup emphasises that there are plenty of good reasons to continue using condoms.[New Scientist 29 June 2002]

CANBERRA, Australia (Reuters) -- Australian scientists believe they have rediscovered an effective use for lemon juice -- as a contraceptive and also a killer of the AIDS virus. Reproductive physiologist Roger Short, from the University of Melbourne's obstetrics department, said a few drops of lemon juice can be a cheap, easy-to-use solution to protect women from both HIV and pregnancy. The juice should be squeezed onto a piece of sponge or cotton wool and placed into the vagina before sex, he said. "We can show in the lab that lemon juice is very effective in immobilizing human sperm and also very effective in killing HIV," Short told Australian Broadcasting Corp. television in a science programme to be shown later on Thursday. He said lime juice, which has similar acid levels, can also be used, with both fruits often freely available in poor countries where contraception is hard to come by. Short said laboratory tests found not only does lemon juice kill sperm, it also kills the AIDS virus itself.

Further Reading

"The role of semen in induction of maternal immune tolerance to pregnancy" by Sarah Robertson and David Sharkey, Seminars in Immunology. vol 13, p 243 (2001) "Correlation between oral sex and a low incidence of pre-eclampsia: a role for soluble HLA in seminal fluid?" by Carin Koelman and others, Journal at Reproductive Immunology, vol 46. p 155 (2000)


Douglas Fox is a science writer living in northern California





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