The unexamined woman

New medical treatments must be proven effective, but the majority of research studies are carried out on men. This discrepancy negatively affects the quality of care women receive.

 Illustration by  May Simargool

Illustration by May Simargool

Women are disadvantaged in medical research, and this could negatively impact the health of more than half the world’s population. This is because there is a significant sex bias in research subjects, with females being dramatically underrepresented. The imbalance occurs at every stage of medical research. It means countless drugs, vaccines, medical devices, disease risk factors and symptoms are designed and evaluated primarily with male subjects, and this has serious consequences for women.

Equal but different

While men and women should be equal in society, we are fundamentally different in our biology. One apparent biological difference is sex hormones. They regulate our sexual characteristics and reproduction, but also impact our body composition, growth, development, and metabolism.

The sexes also have different sets of genes. Men have a Y chromosome, which carries its own unique genes, while women get two copies of the X chromosome. Genetic imprinting turns off one of these copies so that only the gene from one parent is expressed, and this varies between the sexes. According to Dr Lauren Drogos from the University of Calgary in Canada, even when men and women have the same genetic risk factors for disease, the level of risk linked to a particular gene can vary by sex. 

There are also societal differences that lead to different diets and lifestyles between the sexes. Dr Tracy Schumacher, a Dietetics Researcher from the University of Newcastle says, “Men typically consume more meat and poultry and less fruit, while women are more likely to report avoiding high-fat foods, and consume more fibre. Women are also more likely to report they are dieting, and less likely than men to be overweight or obese”. However, she does caution that self-reported data can be problematic, as under-reporting is prevalent in both sexes. These differences are significant because diet and weight are risk factors for many diseases.

The female body also changes over time in a way that the male body does not. Monthly, it changes with the menstrual cycle, and dramatic changes happen during pregnancy and with the onset of menopause. On average females are also smaller, have a higher body fat percentage, and less muscle mass and water.

All these differences combine to create sex-specific responses when it comes to medicine and health. The doses, half-lives and side effects of drugs can vary by sex due to differences in metabolism and excretion and other factors. There are also differences in the ways that males and females experience many diseases. The incidence, prevalence, symptoms, biomarkers, age of onset, and severity of multiple conditions vary by sex. These conditions include neurological disorders, inflammation, cancers, and heart disease, the single biggest killer of women. 

 
  The majority of medical research is done with male cells, male lab animals, and male clinical trial participants, which has negative consequences for women.   Getty Images for International AIDS Vaccine Initiative (IAVI)/Flickr  (CC BY-NC-ND 2.0)

The majority of medical research is done with male cells, male lab animals, and male clinical trial participants, which has negative consequences for women. Getty Images for International AIDS Vaccine Initiative (IAVI)/Flickr (CC BY-NC-ND 2.0)

 

Women have been underrepresented in medical research

Despite obvious and well-documented differences, women have been underrepresented in all types of medical studies, ranging from basic research in cell culture, to animal and human studies that are crucial for regulatory approval. Historically, clinical trials were almost completely dominated by male participants. While the situation has improved, we’re still far from parity. In 2011, a study found that human cohorts had an average female enrolment of 37% (excluding studies of sex-specific diseases). When you consider drug trials specifically, it was even worse, with only 24% female participants. Even when both sexes were included, only 13% of studies analysed data by sex, and most don’t even mention why sex as a variable was ignored.

Women are frequently excluded due to “a combination of the best intentions of safety and culture,” says Dr Drogos. “Historically, women were excluded because they could be pregnant or become pregnant during the course of the study, and it was deemed too dangerous to expose them and their fetus to untested procedures and drugs”.

Angela Hehir, the manager of Women and Heart Disease at the National Heart Foundation of Australia, points out that excluding women of reproductive age leads to the exclusion of “a significant proportion of the female population.” As women are more likely to have the role for primary carer, they may also find it more difficult to participate in time-consuming trials.

Even when not pregnant, it is thought that females are more difficult to study than males. “Research has often labeled studying females as ‘complicated’ due to our hormones,” says Dr Drogos. The variation of the menstrual cycle can cause more variable results, so you need to study more women to get the same quality of results, which costs more. According to Dr Drogos, researchers may simply sacrifice the female data to avoid having to account for these perceived complexities.

Even in pre-clinical animal studies, where the influence of pregnancies and menopause and time-poor female carers is avoided, the same bias against females exists. This is problematic, as the results of animal studies direct future research in humans. A review of scientific literature in 2008 found male bias in eight out of 10 biological disciplines. In neuroscience, the worst offender, only 15% of the animals studied were female, followed by pharmacology (17%) and physiology (21%). The exceptions were a female bias in reproductive science and immunology.

Fears that the estrous cycle will influence the outcomes studied is the most common reason cited for favouring male research animals. However, a recent meta-analysis investigated behavioural, morphological, physiological and molecular traits from 293 neuroscience studies and found that variability was no higher in female mice than males. Even so, sex-specific responses evidently exist. Dr Lin Ong, a neuroscientist from the University of Newcastle says, “although it is more informative to study both sexes, you need to monitor the ovulation cycle and this means more work.” Nevertheless, Dr Ong has found benefit in this extra work, as his research has identified sex-specific differences in the neurological responses to stress and diet. Dr Ong believes it is precisely because males and females are different that the issue of sex bias should be taken seriously in medical research.

However, the high-pressure and short-term nature of research projects may mean some researchers sacrifice additional information for simplicity. Susan Rapley, a PhD candidate from the University of Canterbury in New Zealand, agrees that wherever possible, both sexes should be used in experiments. However, she points out that in the finite timeframes that exist for projects, such as her PhD research, this is not always feasible.

“Teasing out the influence of the hormone cycle is an entire research question on its own,” says Ms Rapley. Indeed, researchers such as Dr Drogos have based their careers on it. She now specifically studies the influence of hormones on memory, attention and verbal abilities.

 
  Preliminary medical research is done with cells which are more likely to be sourced from male patients.   Zeissmicro/Flickr  (CC BY-NC-ND 2.0)

Preliminary medical research is done with cells which are more likely to be sourced from male patients. Zeissmicro/Flickr (CC BY-NC-ND 2.0)

 

The sex disparity in research even extends to the cell lines scientists often manipulate in culture to study mechanisms, pathways and associations. Although cell lines are separate from the context of the body and all its hormones, they still have different sex chromosomes and gene expression can vary between sexes.

Searching the site of the leading provider of biological resources reveals that 55% of available human cell lines were sourced from males. When sex-specific tissue sources are excluded, this rises to 63%. As an example, of the 24 most commonly used colorectal cancer cell lines, 11 were from males but only six were from females and the remaining seven were of unknown sexual origin.

This bias in cell supply is reflected in their usage. In a leading cell physiology journal, only 25% of studies bothered to report the sex of the cell lines used. Amongst those studies, cell lines were sourced from males four times more often than from females.

The consequences

While the differences between the sexes may legitimately increase variability, it is difficult to argue that it is good practice to prioritise the quality of the results over the health outcomes. The historical and ongoing neglect of females in medical research means that medicine as applied to women is often less evidence-based than it is for men. 

Drugs and other treatments can be released before it is known what is safe, or even effective, in females. Sex-specific differences in responses and interactions are often only discovered post-release. In one case, the sleeping tablet zolpidem (Ambien™) was patented in 1992, yet it wasn’t until 2013, following multiple reported incidences of “sleep driving” and other side effects in women, that the FDA directed that the dose be halved for women.

Even when the drugs are known to have sex-specific differences in absorption, metabolism and excretion, sex-specific dosage recommendations are often not given. For example, between 1995 and 2000, the FDA reviewed 11 new drug applications where there was a known difference of more than 40% in pharmacokinetics between men and women, yet dosing suggestions were the same. This may partly explain why females report more adverse reactions to drugs than males.

 
  While many medications exhibit different pharmacokinetics in men and women, different dosing recommendations are not common.   Frédérique Voisin-Demery/Flickr  (CC BY 2.0)

While many medications exhibit different pharmacokinetics in men and women, different dosing recommendations are not common. Frédérique Voisin-Demery/Flickr (CC BY 2.0)

 

Cardiovascular disease, the leading cause of death in both sexes, is a condition where the sex differences are particularly clear, as men and women present with different symptoms. “Women are less likely to present with central chest pain. They are more likely to experience pain in the back, jaw, arm and neck, with fatigue, nausea and sweating,” says Angela Hehir. These were regarded as atypical symptoms, as diagnostic criteria were established based on research in males. Current ignorance of these differences in symptoms results in delayed diagnosis and poorer outcomes for women. According to Hehir, women are more likely to die in hospital after a heart attack than men.

New research into heart disease has found links between vascular conditions such as hypertension during pregnancy, and the subsequent risk for heart disease in later life, Hehir explains. This suggests we need to focus studies on women, rather than avoid studying women. Encouragingly, “gender-specific diagnostic tests and treatments are increasingly being studied”.

However, male bias in research is not just a hangover from history. Modern medical technologies, such as the artificial heart used in patients waiting for transplant surgery, have been designed for males, and are simply too big to be suitable for women. One particular model fits 86% of men, but only 20% of women. Women may be dying while we wait for a female-sized device to be designed. 

The solutions

There are a number of potential solutions for achieving sex parity in medical research. Suggestions include the promotion of greater awareness of the need for balance, and the introduction of parity funding incentives by funding bodies and drug regulators. More journals could insist on disclosure of the sex composition of the humans, animals and cells under study.

Improving the gender balance of researchers, particularly those in the senior ranks, might help to develop an environment where sex parity is valued. Women could also be empowered to act on an individual level, by asking their medical professionals how their prescribed drugs have been tested.

 
  Female patients can ask their medical professional how prescribed medications were tested prior to approval.   ILO/Thierry Falise/Flickr  (CC BY-NC-ND 2.0)

Female patients can ask their medical professional how prescribed medications were tested prior to approval. ILO/Thierry Falise/Flickr (CC BY-NC-ND 2.0)

 

Dr Drogos believes the caution surrounding pregnant women has been taken too far. Instead of categorical exclusion she suggests carefully including women in such research. Better efforts could be made to collect and analyse retrospective data from pregnant women who took medication out of necessity whilst pregnant. Pregnant women could also be included in later phase trials, after safety testing has been completed. After all, women at all stages of life get sick and take medications.

A number of countries have introduced legislation and other initiatives over the last 50 years to attempt to remedy the imbalance. The US congress, for example, has passed bills to increase the representation of women and other minorities in clinical trials, and the US National Institutes of Health set up its Office of Research on Women's Health. Research centres focused on sex-specific health have opened worldwide and in 2010 the journal Biology of Sex Differences was launched.

Many organisations have also launched female-focused health campaigns. For example, the National Heart Foundation of Australia’s Go Red for Women and #womenshearts campaigns aim to raise awareness of heart attack warning signs in women. They will also soon award the inaugural Women in Heart Disease Research grant for research into heart disease in women. 

Some believe the bias has been corrected. A 2008 opinion piece in Science declared that the bias had turned against men and further initiatives for recruiting women were unnecessary. However this appears to be the result of a few large single-sex studies, such as the Women’s Health Study and trials on female-specific cancers, rather than genuine parity.

While many studies now include sufficient numbers of women, the results are most often not analysed according to gender, says Angela Hehir. Therefore, it remains impossible to determine the differential effects of interventions on men and women.

Although the differences between the sexes may complicate some studies, which is ironically the exact reason that we need sex-specific data. To continue the underrepresentation of women in medical research does a disservice to half the world’s population and perpetuates the relative disadvantage of women in society.

Edited by Ena Music