NOT JUST A GIRL THING

Can one hormone be essential for male fertility, a cause of cancers and a way to reduce heart disease? It can if it's oestrogen. Hilary Bower reports on the latest conundrum for scientific minds

Blue jokes in sweaty locker rooms, predatory stares in the pub, the "phwoar" phenomenon, the Spice Girls, Loaded and new laddism - all are attributed to the rise of the "testosterone culture". But what if I told you that the true test of men's evolutionary masculinity - the ability to sire - depends not on this much applauded "male" hormone, but a "female" one. That while testosterone "shapes" a male and gives him the tools to play with, he won't fulfil his reproductive role without that supremely feminine hormone, oestrogen.

But doesn't oestrogen make men infertile? What about the oestrogenic chemicals in the water that are said to be decimating sperm counts and turning fish into hermaphrodites?

Well, that is a conundrum. And not the only one. Every few months, oestrogen grabs the headlines with what often appears to be quite contradictory news, alternately heart-warming or life-threatening. Just as we are agonising over whether the oestrogen in hormone replacement therapy and contraceptive pills causes breast cancer, we hear that oestrogen in food may protect against breast cancer. While one group of scientists reports that male rats exposed to oestrogenic chemicals become infertile, another group finds the male reproductive system shot through and dependent for good functioning upon a new type of oestrogen receptor cell. Women take oestrogen to prevent conception, yet they become infertile post-menopause when their oestrogen levels drop. Hailed as a problem-solver in everything from heart disease and osteoporosis to wrinkles and memory loss, oestrogen is also damned for its role in cancer, pregnancy failure, endometriosis and infertility.

So are oestrogens in the body, environment and food to be feared; female Trojan horses threatening to emasculate men and bring the human race as we know it to a halt? Or is it a much maligned and mis-sexed chemical at the very root of good health and long life?

To make any headway in this debate, it's important to know that "oestrogen" comes in an array of guises. First, there is "natural" or endogenous oestrogen - the stuff made by our bodies in sites such as the ovary and the adrenal cortex and, as scientists have recently found out, by the chemical conversion of testosterone - which is the most potent form. Then there are the exogenous or external oestrogens. These include so-called "environmental oestrogens" - chemicals which are used in a variety of manufacturing processes and which, in some situations, appear to mimic the actions of natural oestrogen; "synthetic" oestrogens, which is the label given to those chemicals used to make contraceptive pills (hormone replacement therapy is often dubbed "natural" because it is created from mares' urine); and phyto- (plant) oestrogens, found in foods such as soy and rye.

What they all have in common is that they appear to home into the oestrogen receptors which are being found in ever-increasing sorts of tissues throughout the body. But fitting into the receptor doesn't mean that they are all the same - far from it. A hole in a jigsaw for a piece with 10 knobs can be filled by a piece with three knobs that match the indents, even one with two or five or eight protrusions. And each empty gap or filled slot, it appears, reveals a different picture.

The growing awareness of oestrogen's prolific influence comes hot on the heels of three key developments which have knocked the sex-stereotyping of oestrogen for six, according to Professor Richard Sharpe of the Medical Research Council's Reproductive Biology Unit in Edinburgh. The first development came in 1993 with the surprise birth of living offspring from mice bred not to have oestrogen receptors. Such mutations were always thought to be lethal and unviable in life, says Dr Sharpe. Not only did the mutant mice live but, to the puzzlement of researchers, the male offspring were infertile. "We're still trying to work out why," says Professor Sharpe, whose own unit reported last year that rats exposed to some chemical oestrogens at similar levels to those found in the environment had smaller testes and reduced sperm counts. "It looks like the lack of oestrogen causes some inherent defect on the quality of sperm, but we don't know why." His unit is currently trying to repeat the mutations in non-genetically mutated animals using chemical interventions.

The second shock to the sex specificity of oestrogen was the discovery of two men born without the ability to process oestrogen - again thought to be impossible. One man had a naturally occurring DNA mutation which had deprived him of oestrogen receptors; the other lacked the genetic coding for an enzyme called aromatase and appeared to be oestrogen-resistant.

"Both situations produced similar effects," says Professor Sharpe. "Both men were 7ft tall and still growing, both had a bone age of 14 years - they were severely osteoporotic - and they were infertile." Suddenly, people realised that not only must oestrogen be involved in male fertility, but that aromatase must be converting male hormones into oestrogen, rather than there being a pattern of control tailored to men. "It all seems blindingly obvious in retrospect," says Professor Sharpe. "But at the time oestrogen in men was regarded as little more than an amusing side issue. Now we need to find more of these individuals to find out exactly what there is in this hypothesis."

The third key development came last autumn when scientists in Sweden, looking for something else, discovered a new type of receptor - oestrogen beta. The new receptor not only solved the long-held puzzle of how the ovaries, a huge source of oestrogen production in women, appeared to have no oestrogen receptors, but stunned scientists by turning up in abundance in male reproductive organs.

"Oestrogen receptors now appear to be in so many reproductive tissues in the male, you have to ask how we ever managed to explain reproduction in men without involving oestrogen," says Professor Sharpe, who is leading work to map exactly where the receptors are and what they might be doing. The unit's newest findings, published earlier this year, show that these receptors exist in the male reproductive system from early on in foetal life - information that raises interesting questions in the light of concern about the effects of oestrogenic chemicals in the environment on sperm count.

"It may be that oestrogen's role in the developing foetus is far more major than in the adult," Professor Sharpe speculates. One hypothesis is that falling sperm counts might be related to under- exposure to natural oestrogens in foetal life because they are being blocked from the receptors by other oestrogen-like substances, such as chemicals used in the manufacture of plastics, pesticides, paints and printing inks. These find their way into the body via the environment, or even by phyto-oestrogens. This may disrupt the normal programming for sperm production, although the reproductive system may appear to develop normally. But despite this hypothesis, and the acres of column inches recently devoted to it, the fear that chemicals in the environment, in water and in food which mimic oestrogens may be silently damaging male fertility is one many experts say simply cannot be justified on current scientific evidence. According to Dr Paul Harrison, head of environmental toxicology at the Institute for Environment and Health, there is "no evidence whatsoever to link the observed changes in human reproduction health to exposure to endocrine-disrupting chemicals [synthetic oestrogens]."

The fears are founded on a huge leap between laboratory findings and population data which, while worth attention, is far from complete, says Dr Harrison. Even the label "environmental oestrogens" is inaccurate because the industrial chemicals concerned are not oestrogens in any natural sense. In some laboratory situations they can appear to promote cellular responses similar to those prompted by natural oestrogens, but in other situations they can act in exactly the opposite way, as anti-oestrogens or even as mimics or blockers of male hormones. "There is no doubt that rates of testicular cancer are rising in westernised countries and can't be explained by known variables," says Dr Harrison. "There is also a rise in female breast cancer which appears real, though there is debate about the role of early screening in the rise. But when it comes to sperm count, there are trends but not always downwards ones. The strongest way you can put it is that there is a general view that sperm count is falling in some countries. As for increased rates of cryptorchidism (undescended testes) and hypospadia (genital abnormalities), the baseline data is so bad, it's difficult to know what's really happening.

"The only evidence we have of a link is that in lab tests these chemicals have certain oestrogenic properties. But even with DES (diethylstilboestrol, a drug prescribed in the Fifties to prevent miscarriage but discontinued due to foetal side-effects) where doses to male foetuses were high, there was no change in the fertility in male offspring - which is surprising given all the concern now around far less potent things."

Much of the concern about environmental oestrogens has been based on observations of changes in wildlife health, says Dr Harrison. These include changes in genital shape in female molluscs, hermaphroditism in fish, reduced fertility and abnormally developed genitals in male alligators and mammals in Florida, and abnormal nesting behaviour in gulls.

But in only one case, says Dr Harrison, has there been a proven relationship with a disrupting chemical: "All the other events are observational effects where either the exposure or the outcome is not well described." According to Professor John Sumpter, a water scientist at Brunel University, who is investigating how serious wildlife cases in Britain are, it is not known whether the changes seen in wildlife cases actually affect the ability of the population to reproduce.

Research published last year suggesting that the fertility of men living in London was under threat from oestrogenic-tainted water supplies was unreliable, says Professor Sumpter, because it took no account of "enumerable" other possible methods of exposure. His team has identified evidence of natural female oestrogens and contraceptive residue at low levels in some treatment plants in Britain which could cause wildlife a problem. "But getting into the drinking water and affecting humans is a completely different situation and completely unproven."

In the laboratory, there's little doubt that exposure to oestrogen-like chemicals can affect reproductive functions. Male rats exposed in the womb or through their mother's milk to some chemicals have reduced sperm counts, and researchers have also been able to induce undescended testes and hypospadia. In research at Professor Sharpe's laboratory, rats exposed to three oestrogenic chemicals, at concentrations which were only a third of the government permitted "safe" levels for humans, produced offspring whose sperm count and testicle size were reduced by 15 per cent. Other models suggest that exposure to certain chemicals affects thyroid functioning - a key factor in determining the number of sperm-making cells.

Other experiments show that exposing female rats to similar amounts of chemicals around the time of birth can cause them to be persistently on heat. This is thought to be the equivalent to polycystic ovary disease in women (a condition where multiple non-malignant cysts develop in and on the ovaries disrupting fertility), while lower levels of exposure appear to cause early abortion which could be confused with infertility. Effects on immune system function can also be induced in both sexes.

This and the wildlife damage are early warnings - ignored at our peril, according to environmental campaigners like Dr Michael Warhurst, an environmental chemist with Friends of the Earth. He says scientists and industry are hypocritical in accepting animal models and laboratory testing as reliable enough indicators of human toxicity when it comes to licensing new chemicals and drugs, but dismissing the same tests when they are raised to support the banning of an existing chemical. Plus, Dr Warhurst notes, recent research suggests that combinations of disruptive chemicals act together to have effects up to 1,000 times greater than those of the individual substances. "Industry tends to come out with statements like `we need proof of human harm', but the only way to get that is to expose enormous numbers of people which is totally unethical. Further research is necessary but many of the suspect chemicals should be phased out now, not in five or 10 years' time when another generation will have been exposed to them in their mothers' wombs."

Dr Harrison counters that it is impossible to know, on current evidence, which chemicals could be banned. "Over 40 per cent of chemicals tested have been shown to have oestrogenic qualities. What should they be replaced with? What about phyto-oestrogens? We're saying chemical oestrogens are bad, but we don't know whether phyto-oestrogens are good, bad, or either."

The phyto-oestrogens issue introduces yet another - potentially life- saving - contradiction. While synthetic oestrogens such as HRT continue to be linked to increased risks of breast cancer, population research comparing countries with high consumption of phyto-oestrogen-rich foods like soy, rye and linseed, with countries on more westernised diets show lower rates of heart disease and hormone-dependent tumours such as breast, testicular and prostate cancer. Japan, for example, has half the rate of breast cancer compared to the UK and about a 10th the rate of heart disease. In Finland, where rye bread is consumed in large amounts, testicular and breast cancer rates are far lower than other European countries.

In heart disease, it is thought that phyto-oestrogens affect clotting and cholesterol levels. A similar effect appears to be caused with HRT, which many doctors now promote as a way to counter the increased risk of heart disease after oestrogen production falls away in the menopause. Plant oestrogens have also been found to reduce menopausal symptoms such as hot flushes and vaginal dryness, yet they do not stimulate the lining of the uterus, a feature of natural oestrogen that increases the risk of endometrial cancers.

Just how plant oestrogens might achieve their apparently wide-ranging protective effects is still a mystery. Dr Ann Walker, senior lecturer in human nutrition at Reading University, who has just launched a study into the effect of soy-based infant milks, says plant oestrogens are some 1,000 times less potent than natural oestrogen but they still fit into oestrogen receptors. This means once they've taken the slot, they may simply have a mild oestrogenic action which doesn't trigger the whole effect of natural oestrogen, but does offer some of its benefits, such as relieving menopausal symptoms and maintaining bone health.

At other times, though, phyto-oestrogens appear to act as anti-oestrogens, sitting in the receptor slot and blocking access to more potent natural oestrogen, an action that could be one explanation for its protective effect against breast cancer. Another hypothesis is that high dietary oestrogen appears to lengthens the menstrual cycle which reduces lifetime exposure to natural oestrogens. Which action occurs seems to depend on the levels of natural oestrogen circulating in the body, says Dr Walker. "Phyto-oestrogens appear to be adaptogenic. They act as anti-oestrogens in people with high circulating oestrogen and as mild oestrogen promoters in people with low circulating oestrogen. This means they could be useful when levels of oestrogen are powerful, for example for women suffering premenstrual syndrome, and when levels are low, such as post menopause.

In studies in the US, new born rats fed on genistein (one of the three separate oestrogenic compounds found in soy) developed fewer and slower growing tumours when exposed to cancer-causing agents as adults. This has led to suggestions that exposure to soy oestrogens early in life could prove beneficial, warding off hormone- related cancers in middle age. Which brings the cycle back full circle - to the threat and promise of a hormone that while perhaps no longer strictly "female", retains a touch of feminine mystique.

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