When sex matters

when sex matters

“Women have to know that many of the medications they are taking were identified and the dosages defined based on studies on male animals or men. And it’s well known that women metabolize some drugs differently, their size is different and even the underlying causes of the diseases might be different. Does that mean the medication is bad? No, it means that we need to define the population for which the medication provides the most benefit with the least risk at a reasonable cost”, says Virginia Miller, professor of physiology and surgery at the Mayo Clinic in Rochester, MN, USA and president of the Organization for the Study of Sex Differences (OSSD), an international society for basic and clinical scientists.

The first time I have ever heard about sex-gender bias in biomedical research and gender medicine, some months ago while reading the Science magazine, my first thought was how come I had never wondered how it was possible that drug prescription have the same dosages for me, not even 1,60 meters tall, and let’ say for my Dutch 1,90 meters tall male friend if it’s so obvious we are different. And, as I do every time I find out something new and interesting to me, I started guessing that maybe I wasn’t the only one ignoring the issue and its causes. So I started researching the topic.

“The stereotype getting sex and gender bias in biomedical research off the ground is that we are all Caucasian, 1,75 meters tall males”, Flavia Franconi, founder of the Gender Pharmacology Group of the Italian Society of Pharmacology and coordinator of the first European Gender Pharmacology’s Ph.D. says.

Recently behavioural neuroscientist Irving Zucker, a professor emeritus at the University of California, Berkeley and postdoctoral researcher Annaliese Beery, as the Science Magazine quoted, conducted a survey of journal articles reporting results of almost 2,000 animal studies that used mammals, published in 2009. “We found a male bias in 8 out of 10 biological disciplines, most pronounced in neuroscience (5.5 males to 1 female), pharmacology (5 males to 1 female) and physiology (3.7 males to 1 female). Although we identified a female bias in studies on reproduction and in the few immunology reports that indicated the animals’ sex, 75% of studies in three highly cited immunology journals did not specify whether the animals used were male or female”, they themselves write in the article “Males still dominate animal studies” published in Nature last June.

Using female animals in basic research is more expensive than using males. Female rodents, the default animal model for many diseases, have a 4-day ovarian cycle, so researchers who use them must take daily vaginal swabs in experiments where hormones might play a role and need to use many more animals. “The reality is that women do have menstrual cycles and fluctuations in hormones”, Virginia Miller points out. “This variability may increase ranges in some data parameters but it represents a type of “steady state” for women within reproductive age and anyways it cannot be a valid scientific rationale to eliminate women or female animals from scientific experiments”.

It wasn’t indeed a good reason at least for Deborah Clegg, obesity researcher of the University of Texas Southwestern Medical Centre. She has recently published a micro array study in the International Journal of Obesity that shows major sex-based differences in the gene-expression profiles of fat tissue from mice on a high-fat diet. The study was funded by the Society for Women’s Health Research, an American non-profit organization working in partnership with the OSSD.  “We know that when women go through menopause they change where their body fat is distributed and they also change the type of fat cells they have”, Clegg explains. “We wanted to ask whether this was also true in mice and have found out that the main difference in obesity depends on where women and men deposit fat and that this is directly related to sex hormones”. How it is related is still the unknown she is now trying to investigate. “I believe that in the future we’ll have personalized medicine so if you are a woman you’ll get different kind of drugs and different doses than if you are a man”, she says. “But we are just now appreciating how different males and females are”.

Gender medicine as a field started at the end of the last century thanks to Bernardine Healy, the first woman heading the National Institute of Health (NIH) who, in 1991, published in the New England Journal of Medicine a study called “The Yentl syndrome” which reported that women were not given the same treatment for heart disease as men.

Things have changed since then. In 1993, the same National Institutes of Health Revitalization Act mandated that women and minorities be included in clinical research and since then more women than men have been enrolled in NIH-sponsored phase III trials –those intended for complete assessment of safety and effectiveness in the prevention of diseases-. Unfortunately most of these have been single-sex studies such as breast and uterine cancer or research into menopausal women.  A survey of clinical studies published in 2004 in nine influential medical journals found that only 37% of participants were women (24% when restricted to drug trials), and only 13% of studies analysed data by sex.

What has undoubtedly changed is the awareness of the biological differences between genders, mainly attributable to organizations such as the OSSD, the International Society for Gender Medicine, the numerous Centres for Gender Medicine across European and American universities, the single efforts of interested researchers throughout the world but, most of all, as three of the four sources quoted in this article confirm, “to the fact that before all the researchers were men and now things are changing”.

We now know that the underlying differences between the two genders are determined by our chromosomes, by effects of the sex hormones on expression of genes and by epigenetics (influence of the environment on genes). “One of the challenges of the future for biologists and sociologists is to come together and work in an interdisciplinary way to understand how environmental factors interact with the biological ones”, Miller points out.

Sex differences in the incidence, prevalence, symptoms and severity of diseases have already been shown in many cases. Diagnosis for anxiety and depression are twice as common in women as men but, according to data obtained from the Thomson Reuters Web of Science 2009, quoted in Zucker and Beery’s article, only 45% of animal studies into these disorder use females. Women have more strokes than male but only 38% of the studies use female. Some thyroid diseases are 7 to 10 times more common in women than men but only 52% of the studies use females, always according to the same source. At the moment no guide-line on basic research taking into account sex differences exists nor in the States nor in Europe.

Differences are particularly acute in cardiovascular diseases, the leading cause of death for both women and men. “Women have smaller vessels, a smaller heart, develop heart thickening in a much faster and sever way while also display particular types of diseases”, Maria Grazia Modena, past-president of the Italian Society of Cardiology (first woman heading it), Chief of Cardiology, University of Modena and Director of the Women’s Well-being Centre, which she founded in 1996 and has already examined 4,000 women. She mentions the Takotsubo disease, also called the “broken heart syndrome” for being caused by a deep sorrow such as the loss of a child. “It prevails in elderly women with a short-lived, very strong pain, often in the back, sometimes with flu-like symptoms and it is reversible”, Modena explains. Differences in how symptoms present have also been underlined with women also presenting nausea and vomit while men only pain in the chest.

The majority of the studies she leads are funded by her university. At the moment there are no European funds for specific sex-based studies.

“We need them”, Modena claims. “I think we should start from researching with both sexes and genders in those areas where there is evidence of relevant differences”.

“It is not only a matter of using female animals”, Franconi points out. “We also have to find the right animal model for each disease. For thrombosis, type 2 diabetes and ischemic heart disease, for instance, we are using around 30 rat models of which only one gets sick, but women do die much more than men because of them”. Besides, “We always need to include whether the women we are studying are taking birth control pills or whether they’re cycling normal or going through menopause”, Deborah Clegg says. “Heart, pancreas, liver, brain, bones, muscles, every single tissue in the body is influenced by sex hormones”.

“The whole idea is to do basic research to understand where sex-based differences exist and then translate that information into medications and other treatments”, Virginia Miller says.

A 2005 study of 300 new drug applications between 1995 and 2000 found that even those drugs that showed substantial differences in how they were absorbed, metabolized and excreted by men and women had no sex-specific dosage recommendations on their labels. This may be part of the reason why women are 1.5 times more likely to develop an adverse reaction to prescription drugs than men. “Around the 70% of all the drugs we know are metabolized by CYP3A, an enzyme that women metabolize and so remove faster than men do, having less chance to undergo therapeutic effectiveness”, Franconi explains. “Besides, there are physiological variations, such as less water and more fat in women’s body, which cause different drug distribution”. The answer to my first question, how it is possible that drugs keep having the same dosages for all of us in spite of all this evidence, comes from her. “Once there haven’t been enough trials either at basic or clinical level, our evidences are considered to be level C ones (meaning that the balance between benefits and risks are considered too close for making general recommendations)”, she explains. “And we still have to deal with ironic smiles from many men researchers and the pharmaceutical industry”.

But if what I wrote in the first post of this blog is true most of the researchers who have gotten here have already cut their teeth enough not to be easy to scare. Flavia Franconi, Maria Grazia Modena and other researchers together with the Italian National Agency for Regional Health Services are meeting later this month to write new guide-lines on Cardiovascular Clinical Research while they will all meet from November the 30tn until December the 3rd in Tel Aviv, where the 5th International Congress on Gender Medicine will take place. We will definitely hear more about them.

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