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| Womens troubles |
20-Aug-2008 |
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Lack of gender-specific research leaves many question marks over diseases in women and their treatment.
By Bianca Nogrady
“WANTED: Single, White Male for Medical Research.” When USbioethicist Rebecca Dresser wrote these words in 1992, she was not recruiting for a clinical trial. But she might well have been. Her landmark article1 drew attention to the deplorable reality that women were being excluded from clinical research across the medical spectrum, from cardiovascular disease to HIV.
The article had a profound effect on Australian academic Wendy Rogers, now associate professor of medical ethics and health law at FlindersUniversity in Adelaide.
“I was horrified that women might not be included in research,” Professor Rogers says. She had long been interested in feminist bioethics, but her desire to investigate the gender divide in medical research was being stymied by a lack of information.
So Professor Rogers and colleague Dr Angela Ballantyne decided to dig up that information for themselves. They examined a big range of recent Australian studies to try to get a sense of how well women were being represented in medical research, and published their results earlier this year.2Although a decade-and-a-half have passed since Rebecca Dresser’s comments, it seems not a lot has changed.
At first glance, it’s hard to see a problem with what they found. In the 400 studies they looked at, representing a total of 546,824 participants, 73% of those studied were female.
But those figures concealed remarkable discrepancies. Generally speaking, the researchers found that the studies that involved large numbers of women tended to focus on “women’s issues”, such as reproductive capacity and pregnancy. In contrast, men were significantly more likely to be involved with non–sex-specific medical research.
Amazingly, 6% of the studies did not even list the sex of the participants and half of the investigators of those studies could not supply that information when asked. What’s more, 10% of the trials did not enrol any women, despite studying conditions that affect women.
“One of the main problems is that even though there might be men and women in the trial, they’re not looking at the differences,” Professor Rogers says. “We’re particularly worried with pharmaceutical research because there are known sex differences in the way the body handles drugs between women and men.”
More than that, the lack of information about the possible differences in how men and women respond to treatments, both pharmacological and otherwise, means that for many conditions, half of the population is effectively being treated ‘off-label’. Professor Rogers says this is a particular issue in pregnant and breastfeeding women, who are largely excluded from clinical research because of safety concerns. The unfortunate consequence of this understandable reluctance on the part of researchers is that pregnant and breastfeeding women are receiving treatments and medications that are unlikely to have been clinically tested on women in their condition.
ON those too-rare occasions that researchers look for differences between men and women, they often find them. Recent studies have identified differences in biochemistry, endocrinology and response to therapy that could all have major clinical implications.
For example, last year a review of sex differences in brain structure, function, and chemistry showed overall brain volume was greater in men than women — and that women had a higher percentage of grey matter, while men had a higher percentage of white matter.3
“Sex-specific differences in dopaminergic, serotonergic, and gamma-aminobutyric acid (GABA)ergic markers indicate that male and female brains are neurochemically distinct,” the review’s authors wrote.
Other data cited by Rogers and Ballantyne suggest the adverse effects of drugs such as antihistamines, antibiotics and antipsychotics are more common and even more severe in women than men.
The reason for these differences is not always clear. Hormonal influences and different metabolisms are the more obvious possible explanations, but in many cases, researchers are still very much in the dark over why a disease differs between the sexes or why a drug behaves differently in response to female physiology.
DIFFERENCES between men and women go beyond biology. Lifestyle and behavioural factors also play a major part in affecting their disease risk and response to treatment.
For example, mortality rates from cardiovascular disease are more than double in men compared with women, and there is a five-year age gap in comparable mortality rates from coronary heart disease.
Cardiologist Professor Andrew Tonkin, head of cardiovascular research at the department of epidemiology and preventive medicine at Monash University, notes that the 2004 Interheart Study established that the population-attributable risk for AMI — the measure of the extent to which one might eliminate the problem by having ideal risk factor levels — was about 90% for men and 94% for women.
“The reason Interheart is quite important is it showed that the variations in the rate of MI between men and women were minimised if one took into account what were the prevailing risk factor levels in women,”Professor Tonkin says. Women are less prone to indulge in the bad habits that get men into trouble, such as smoking, alcohol and eating unhealthily, which therefore dramatically reduces their cardiovascular risk compared with men.
But while women may be less inclined to the habits that increase the risk of cardiovascular disease, it is still a leading and underrecognised killer of Australian women, says cardiologist Dr Anushka Patel, director of the cardiovascular disease division of The George Institute in Sydney. According to 2004 data, the top three causes of death in Australian women are related to cardiovascular disease, while breast cancer mortality comes a distant fifth.
“The general misconception is that it’s a disease of men, but as women get older, particularly postmenopausally, it becomes the leading cause of death,”says Dr Patel, who adds that women also tend to do worse than men.
“Even though at younger ages cardiovascular disease is much more common in men than women, the case fatality is greater in women.
“If you have a heart attack you’re more likely to do worse if you’re a woman at any age.”
Women are also less likely to benefit from interventions such as angioplasty or CABG. Unfortunately, this is not reflected in the clinical research focus — women are still underrepresented in cardiovascular disease research, Professor Rogers says.
WITHOUT solid data on gender differences, public health interventions could fail half the population. Take the NHMRC’s colorectal cancer guidelines, for example.
“One of the recommendations was about physical exercise but in the research that informed that, less than one-third of participants were women,” Professor Rogers says. “There were no women in the research that informed the recommendation that physical activity reduces the risk of type 2 diabetes.”
Although there may be no difference between men and women in the effect of exercise on colorectal cancer risk or type 2 diabetes, Professor Rogers says we don’t necessarily know this because the research comparing men and women has not been done.
The lack of information about how and why men and women differ in presentation of MI is also complicating public health messages and management of the condition. For example, Professor Tonkin says there is continuing debate about whether statins have the same effect in women as they do in men. The problem is, despite so many trials being done on statins and heart disease, “trials are not [statistically] powered to address treatment in subgroups,” he says.
It is also becoming clear that women present differently with MI, yet public health messages about the early warning signs are tailored towards the signs most classically observed (and studied) in men. “Typical symptoms actually occur just as commonly in women as men but on top of that they are more likely to get atypical symptoms such as dizziness, abdominal pain,”Dr Patel says. “So women are more likely to get underrecognised, by women themselves and probably by health care providers.”
SO what is the solution? Professor Rogers says research should start with the premise of trying to find any differences and see if they are important. But she also believes there should be a systematic way of ensuring men and women are included equally in relevant trials and that the analysis includes a gender breakdown. One way to achieve this would be to make use of clinical trials registers.
“My view would be if you included the sex of participants in the information that’s required in those trials, it would be much easier to find out what’s going on,” she says.
This would also enable researchers planning clinical trials to identify neglected areas of research, for example, “looking at the field and saying ‘oops, this is interesting, all the research on exercise in type 2 diabetes is done in men, we’d better do some in women’”.
Journal editors are also in a powerful position to demand more from the papers they publish. “If they required researchers to provide analysis by sex then people would do it,” Professor Rogers says.
Legislation, such as that enacted in the US requiring equal numbers of men and women in research unless there was a specific concern about harm, could also help. In Australia, the governing principle in this area is the NHMRC’s national statement on ethical conduct of research involving humans, which requires that the processes of recruitment, selection and exclusion are “fair”. Unfortunately, fair doesn’t cut it with Professor Rogers. “It’s not enough detail.”
While the original, if unconscious, shift towards excluding women from clinical research stemmed from an ancient patriarchal protective urge, the times are changing. As the authors of an editorial accompanying Rogers’ and Ballantyne’s article put it, “It is time to recognise that women are complex biological creatures just as are men.”4
References
1. The
Hastings
Center
Report1992; 22:24-29.
2. Mayo Clinic Proceedings2008; 83:536-42.
3. Biological Psychiatry2007; 62:847-55.
4. Mayo Clinic Proceedings2008; 83:523-25.
A call to arms: women marginalised in clinical trials
“It is time to recognize that women are complex biological creatures just as are men,” Drs Sharonne Hayes and Rita Redberg wrote in the Mayo Clinic Proceedings when Professor Rogers and Dr Ballantyne published their data earlier this year.
The two authors, both of whom work in the area of cardiovascular disease, argue that all clinical studies should strive to include equal numbers of female and male participants or at least reflect the prevalence of the condition of interest by sex.
“Until we are able to make this leap, women will continue to be marginalized in clinical trials of diseases that affect them in numbers equal to men,” they wrote in an editorial. “We hope that this editorial and the work that has preceded it serve as a clarion call to researchers, authors, reviewers and journal editors to include sex-specific reporting in all clinical trials that include more than 50 participants.”
Doing so will help achieve the best possible care, they say. In fact, it is “the only way we will be able to begin to provide optimal care for all patients and is a critical step toward the ultimate goal of individualized medicine,” they say.
Mayo Clinic Proceedings 2008; 83:523-25.
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