In Issue 3, we spoke about how genes can affect an individual’s risk of getting a disease, and how they may respond to a given treatment. In some ways, this problem is quite basic, relying on genes found on just two chromosomes: X and Y.
The Institute of Medicine in the US has said that every cell in our bodies has a sex. By this they mean to say that each of our cells is equipped with either a pair of XX chromosomes, or a set of XY chromosomes. Often times we relate this difference purely to the reproductive systems. However, it goes far beyond this, and in ways that are not so obvious. The sex chromosomes are responsible mainly for differences in hormone production; females predominantly make oestrogen and progesterone while males predominantly make testosterone and associated hormones. Although it may seem reductionist to view biology in this way, this small difference in X and Y has very significant effects on the body. Indeed, those hormones influence many genes, and impact the expression of those genes. Furthermore, sex chromosomes comprise approximately 5% of the human genome.
However, researchers have largely failed to take this into consideration when studying diseases, treatments, or chemicals that might affect the sexes differently. The exclusion of women in all areas of health research has led us down the road of health inequity.
Male animals have become the default for several reasons; mainly funding (male mice are cheaper) and they are easier to work with due to the 4-day ovarian cycle of female rodents
It begins in the preclinical setting, where there is a widespread bias toward male animals, and female animals are sparsely used in the study of diseases and the testing of drugs. Researchers from Brigham and Women’s Hospital in Boston said in a 2014 report that: “The science that informs medicine—including the prevention, diagnosis, and treatment of disease—routinely fails to consider the crucial impact of sex and gender. This happens in the earliest stages of research, when females are excluded from animal and human studies or the sex of the animals isn’t stated in the published results.”
Although this may not seem like a big deal, when female mice are excluded from pre-clinical studies, they fail to test for how the drugs may interact with the various reactions that are happening differently in females. The sex of the animal can lead to different results, and this bias can compromise the effectiveness and safety of drugs in women, should the drug make it to the market. Male animals have become the default for several reasons; mainly funding (male mice are cheaper) and they are easier to work with due to the 4-day ovarian cycle of female rodents. Indeed, this causes greater expenses when caring for female mice, and funding agencies often do not cover the larger cost of using female animals. The lack of sex-based animal testing perpetuates the gap down the road, and the use of female animals in research could aid the acceleration of personalized medicine for women.
This problem then bleeds into clinical trials, often the next phase of pharmaceutical research. Women are under-represented in clinical trials. This was first brought up as an issue in 1989, after a major study on the effects of aspirin on cardiovascular disease was revealed to have included 22,071 men and zero women. Indeed, up until the late 1980s, clinical trials of new drugs by the Food and Drug Administration (FDA) in the US were predominantly conducted on men, despite the fact that women consume approximately 80% of pharmaceuticals in the US.
Since then, women have been included in trials more often, however, researchers seldom analyse and report the results of the trials by sex. As a result, they fail to determine whether there are gender differences in adverse drug reactions. The results from these studies are often simply extrapolated to women, without any consideration of how it may affect them. Women are therefore, still to this day, prescribed doses that are calculated based on men’s average weight, the way men metabolise the drug and the rate at which it is excreted from men’s bodies. For example, paracetamol, a very commonly used pain reliever, is eliminated from the female body at approximately 60% of the rate than it is in men. Other widely used drugs such as Aspirin and Valium have never been tested in a randomized controlled trial setting with data stratified by sex. This oversight of drug dosing based on sex puts women at higher risk of adverse effects of medication, or even overdosing.
There are several reasons why historically women have been excluded from clinical trials. However, the main reasons often revolved around pregnancy. After the thalidomide scare in the 1970s, researchers became very reluctant to test medication on women of childbearing potential for fear of the effects it may have on foetuses. This is problematic in many ways. First, women of childbearing potential make up part of the demographic who would be using these drugs, and failing to include them in studies leads to failure of understanding the effects it would have on these women. Similarly, there has been widespread reluctance to test treatment of pregnant women because of the risks associated to developing foetuses. Although this does indeed pose an important risk, pregnant women who get sick or who are affected by chronic diseases that require medication are unable to fully understand their risks or weigh the potential benefits due to lack of sufficient evidence on treatment effects in pregnant women.
Moving past clinical trials and into practice, the bias continues. The translation of research includes using the discoveries made in research studies to create new diagnostic and treatment protocols. When women are excluded from the evidence, they will inadvertently become excluded from these protocols as well, and sex differences will not be integrated into clinical practice. This has been most noticeably remarked upon in the study and clinical presentation of cardiovascular disease (CVD). It is the leading cause of death in women, and presents very differently in women and men at every level: in terms of prevalence, risk factors, physiology, presenting symptoms, and ultimately, outcomes. Despite this, only 35% of clinical trial subjects in CVD research are women, and only 31% of studies report the outcomes by sex.
Only 35% of clinical trial subjects in CVD research are women, and only 31% of studies report the outcomes by sex
Although the number of trials including women has increased, these results are often not translated into practice. For example, the concentration of biomarkers that suggest acute coronary syndromes differ in women and men, however the tests continue to use cut-off levels associated with male blood levels. Similarly, the gold standard of diagnosing non-obstructive coronary artery disease is through catheterization, despite the fact that women are more likely to experience ischemia from this procedure. This diagnostic test therefore is not suitable for diagnosing disease in women, however it is still the mainstream.
Although this seems like a bleak state of affairs for women, things are changing. In the past, women’s health revolved around reproductive health: birthing, contraception, abortion, breast and uterine cancer, premenstrual syndrome, and other illnesses affecting only women. However, the definition of women’s health has now expanded to encompass general female health – diseases unique to women, with higher prevalence in women, or diseases that present differently in women than in men. Starting with animal models, action is coming from the academic journals, which are moving toward adopting a common set of guidelines for studies using animals and requiring details of the study methodology to include the sex of the animals used in their experiments. The FDA has also taken formal steps to support the inclusion of premenopausal women into clinical trials. Furthermore, clinical care practices should incorporate a sex-based focus in care and research.
This change however has not come without difficulties. Reforming certain aspects of the way in which medical research is done requires changes in judgements of social worth and political will. Research on sex differences and sex-specific protocols must become the norm and not the exception, in order to promote the health of women.