فصل 10

PART IV

Going to the Doctor

CHAPTER 10

The Drugs Don’t Work

It took twelve years for Michelle to receive a diagnosis. ‘I was about fourteen when I first started having symptoms,’ she tells me. ‘I was too ashamed to go to a doctor for it.’ She kept her urgent, painful, frequent, sometimes bloody bowel movements a secret for two years, until one night, it hurt too much to hide anymore. ‘I couldn’t move from the foetal position on my bathroom floor. I was afraid I was dying.’ She was sixteen.

Michelle’s parents rushed her to the emergency room. A doctor there asked her (in front of her parents) if she could be pregnant. No, she couldn’t be, Michelle explained, because she hadn’t had sex, and in any case, the pain was in her intestines. ‘They wheeled me into an exam room and without any explanation, placed my feet into stirrups. The next thing I knew, a large, cold metal speculum was crammed in my vagina. It hurt so badly I sat up and screamed and the nurse had to push me back down and hold me there while the doctor confirmed that indeed, I was not pregnant.’ She was discharged with ‘nothing more than some overpriced aspirin and the advice to rest for a day’.

Over the next decade Michelle sought help from two more doctors and two (male) gastroenterologists, both of whom told her that her problems were in her head and that she needed to be less anxious and stressed. At the age of twenty-six Michelle was referred to a female GP who scheduled her for a colonoscopy: it revealed that the entire left side of her colon was diseased. She was diagnosed with both irritable bowel syndrome and ulcerative colitis. ‘Funnily enough’, Michelle says, ‘my colon is not in my head.’ As a result of the extended delay in receiving a diagnosis and treatment she has been left with an increased risk of colon cancer.

It’s hard to read an account like this and not feel angry with the doctors who let Michelle down so badly. But the truth is that these are not isolated rogue doctors, bad apples who should be struck off. They are the products of a medical system which, from root to tip, is systematically discriminating against women, leaving them chronically misunderstood, mistreated and misdiagnosed.

It begins with how doctors are trained. Historically it’s been assumed that there wasn’t anything fundamentally different between male and female bodies other than size and reproductive function, and so for years medical education has been focused on a male ‘norm’, with everything that falls outside that designated ‘atypical’ or even ‘abnormal’. References to the ‘typical 70 kg man’ abound, as if he covers both sexes (as one doctor pointed out to me, he doesn’t even represent men very well). When women are mentioned, they are presented as if they are a variation on standard humanity. Students learn about physiology, and female physiology. Anatomy, and female anatomy. ‘The male body’, concluded social psychologist Carol Tavris in her 1992 book The Mismeasure of Woman, ‘is anatomy itself.’ This male-default bias goes back at least to the ancient Greeks, who kicked off the trend of seeing the female body as a ‘mutilated male’ body (thanks, Aristotle). The female was the male ‘turned outside in’. Ovaries were female testicles (they were not given their own name until the seventeenth century) and the uterus was the female scrotum. The reason they were inside the body rather than dropped out (as in typical humans) is because of a female deficiency in ‘vital heat’. The male body was an ideal women failed to live up to.

Modern doctors of course no longer refer to women as mutilated males, but the representation of the male body as the human body persists. A 2008 analysis of a range of textbooks recommended by twenty of the ‘most prestigious universities in Europe, the United States and Canada’ revealed that across 16,329 images, male bodies were used three times as often as female bodies to illustrate ‘neutral body parts’. A 2008 study of textbooks recommended by Dutch medical schools found that sex-specific information was absent even in sections on topics where sex differences have long been established (such as depression and the effects of alcohol on the body), and results from clinical trials were presented as valid for men and women even when women were excluded from the study. The few sex differences that did get a mention were ‘hardly accessible via index or layout’, and in any case tended to be vague one-liners such as ‘women, who more often have atypical chest discomfort’. (As we’ll see, only one in eight women who have a heart attack report the classic male symptom of chest pain, so in fact this description is arguably not only vague, but inaccurate.) In 2017 I decided to see if much had changed, and set off to a large bookshop in central London with a particularly impressive medical section. Things had not changed. The covers of books entitled ‘Human Anatomy’ were still adorned with be-muscled men. Drawings of features common to both sexes continued to routinely include pointless penises. I found posters entitled ‘Ear, Nose & Throat’, ‘The Nervous System’, ‘The Muscular System’, and ‘The Vascular System and Viscera’, all of which featured a large-scale drawing of a man. The vascular-system poster did, however, include a small ‘female pelvis’ off to one side, and me and my female pelvis were grateful for small mercies.

The gender data gaps found in medical textbooks are also present in your typical medical-school curriculum. A 2005 Dutch study found that sex- and gender-related issues were ‘not systematically addressed in curriculum development’. A 2006 review of ‘Curr-MIT’, the US online database for med-school courses, found that only nine out of the ninety-five schools that entered data into the system offered a course that could be described as a ‘women’s health course’. Only two of these courses (obstetrics and gynaecology classes taught in the second or third academic years) were mandatory. Even conditions that are known to cause the greatest morbidity and mortality in women failed to incorporate sex-specific information. Ten years later, another review found that the integration of sex- and gender-based medicine in US med schools remained ‘minimal’ and ‘haphazard’, with gaps particularly identified in the approach to the treatment of disease and use of drugs. These gaps matter because contrary to what we’ve assumed for millennia, sex differences can be substantial. Researchers have found sex differences in every tissue and organ system in the human body, as well as in the ‘prevalence, course and severity’ of the majority of common human diseases. There are sex differences in the fundamental mechanical workings of the heart. There are sex differences in lung capacity, even when these values are normalised to height (perhaps related is the fact that among men and women who smoke the same number of cigarettes, women are 20-70% more likely to develop lung cancer).

Autoimmune diseases affect about 8% of the population, but women are three times more likely to develop one, making up about 80% of those affected. We don’t fully know why, but researchers think it might be down to women being the child-bearing sex: the theory is that females ‘evolved a particularly fast and strong immune response to protect developing fetuses and newborn babies’, meaning that sometimes it overreacts and attacks the body. The immune system is also thought to be behind sex-specific responses to vaccines: women develop higher antibody responses and have more frequent and severe adverse reactions to vaccines, and a 2014 paper proposed developing male and female versions of influenza vaccines. Sex differences appear even in our cells: in blood-serum biomarkers for autism; in proteins; in immune cells used to convey pain signals; in how cells die following a stroke. A recent study also found a significant sex difference in the ‘expression of a gene found to be important for drug metabolism’. Sex differences in the presentation and outcome of Parkinson’s disease, stroke and brain ischaemia (insufficient blood flow to the brain) have also been tracked all the way to our cells, and there is growing evidence of a sex difference in the ageing of the blood vessels, ‘with inevitable implications for health problems, examination and treatment’. In a 2013 Nature article, Dr Elizabeth Pollitzer points to research showing that male and female mice cells have been found to respond differently to stress; that male and female human cells ‘exhibit wildly different concentrations of many metabolites’; and to ‘mounting evidence’ that ‘cells differ according to sex irrespective of their history of exposure to sex hormones’. There are still vast medical gender data gaps to be filled in, but the past twenty years have demonstrably proven that women are not just smaller men: male and female bodies differ down to a cellular level. So why aren’t we teaching this?

The inclusion of sex-specific information in textbooks is dependent on the availability of sex-specific data, but because women have largely been excluded from medical research this data is severely lacking. Even the very basics of sex determination have a sex data gap: since the landmark 1990 paper that identified the Y chromosome as ‘the’ sex-determining region, the female sex has – the irony – been seen as the default. But in this case, the default didn’t mean we focused on the female. Rather, research instead focused on testes development as the supposedly ‘active’ process, while female sexual development was seen as a passive process – until 2010, when we finally started researching the active process of ovarian determination. Most early research into cardiovascular disease was conducted on men, and women continue to be under-represented, making up only 25% of participants across thirty-one landmark trials for congestive heart failure between 1987 and 2012. Women represent 55% of HIV-positive adults in the developing world, and in parts of Africa and the Caribbean women aged five to twenty-four are up to six times more likely to be HIV-positive than young men of the same age. We also know that women experience different clinical symptoms and complications due to HIV, and yet a 2016 review of the inclusion of women in US HIV research found that women made up only 19.2% of participants in antiretroviral studies, 38.1% in vaccination studies and 11.1% in studies to find a cure. Because of their routine exclusion from clinical trials we lack solid data on how to treat pregnant women for pretty much anything. We may not know how a disease will take hold or what the likely outcome may be, although the WHO warns that many diseases can have ‘particularly serious consequences for pregnant women, or can harm the foetus’. Some strains of influenza virus (including the 2009 H1N1 swine flu virus) have ‘particularly severe symptoms during pregnancy’. There is also evidence that SARS can be more severe during pregnancy. It is of course understandable that a pregnant woman may be reluctant to take part in medical research, but this doesn’t mean that we have to just throw our hands up in the air and accept that we know nothing: we should be routinely and systematically tracking, recording and collating pregnant-women’s health outcomes. But we aren’t – not even during pandemics: during the 2002-4 SARS outbreak in China, pregnant-women’s health outcomes were not systemically tracked and ‘consequently’, the WHO points out, ‘it was not possible to fully characterize the course and outcome of SARS during pregnancy’. Another gender data gap that could have been so easily avoided, and information that will be lacking for when the next pandemic hits.

Like the failure to include women in anatomy textbooks, the failure to include women in medical trials is a historical problem that has its roots in seeing the male body as the default human body, but this traditional bias was radically enhanced in the 1970s, to the great detriment of women’s health, following one of the biggest medical scandals of the twentieth century. In 1960 doctors began prescribing thalidomide to pregnant women who suffered from morning sickness. The drug, which had been available as a mild over-the-counter sedative in many countries since the late 1950s, was considered safe because its developers ‘could not find a dose high enough to kill a rat’. But while it didn’t kill rats, it did affect foetal development (something that in fact the manufacturers knew as early as 1959). Before the drug was taken off the market in 1962, over 10,000 children had been born around the world with thalidomide-related disabilities. In the wake of the scandal, the US Food and Drug Administration (FDA) issued guidelines in 1977 excluding women of childbearing potential from drug trials. This exclusion went unquestioned. The acceptance of the male norm went unquestioned.

The male norm continues to go unquestioned by many today, with some researchers continuing to insist, in the face of all the evidence, that biological sex doesn’t matter. One public-health researcher revealed that she had received the following feedback on two different grant applications: ‘I wish you’d stop with all this sex stuff and get back to science’, and ‘I’ve been in this field for 20 years and this [biological difference] doesn’t matter’. It isn’t just anonymous notes, either. A 2014 op-ed published in the journal Scientific American complained that including both sexes in experiments was a waste of resources; in 2015 an op-ed in the official scientific journal of the US National Academy of Sciences insisted that ‘focusing on preclinical sex differences will not address women’s and men’s health disparities’. Alongside insisting that sex differences don’t matter, some researchers advocate against the inclusion of women in research on the basis that while biological sex may matter, the lack of comparable data arising from the historical data gap makes including women inadvisable (talk about adding insult to injury). Female bodies (both the human and animal variety) are, it is argued, too complex, too variable, too costly to be tested on. Integrating sex and gender into research is seen as ‘burdensome’. It is seen as possible for there to be ‘too much gender’, and for its exclusion to be acceptable on the basis of ‘simplification’ – in which case it’s worth noting that recent studies on mice have actually shown greater variability in males on a number of markers. So who’s too complicated now?

Beyond the argument that women’s bodies, with their fluctuating, ‘atypical’ hormones, are simply inconvenient research vessels, researchers also defend their failure to include women in trials by claiming that women are harder to recruit. And it is certainly true that, due to women’s care-giving responsibilities they have less leisure time and may find it harder to make, for example, clinic appointments during the school run. However, this is an argument for adapting trial schedules to women, rather than simply excluding them, and in any case, it is possible to find women if you really want to. While reviews of FDA-mandated medical product trials found that women made up only 18% of participants in trials for endovascular occlusion devices (used if your foetal blood vessel hasn’t closed of its own accord) and 32% of participants in studies on coronary stents (which, incidentally, are another device where women have worse outcomes than men), women represented 90% and 92% of participants in facial wrinkle correction trials and dental device trials, respectively.

A more novel approach to addressing the problem of female under-representation in medical research is simply to claim that there is no problem, and women are represented just fine, thank you very much. In February 2018 a paper was published in the British Journal of Pharmacology entitled ‘Gender differences in clinical registration trials: is there a real problem?’ Following ‘cross sectional, structured research into publicly available registration dossiers of Food and Drug Administration (FDA)-approved drugs that are prescribed frequently’, the all-male-authored paper concluded that, no, the problem was not ‘real’.

Leaving aside any philosophical debate over what an unreal problem might be, the authors’ conclusions are baffling. For a start, data was available for only 28% of the drug trials, so we have no way of knowing how representative the sample is. In the data researchers were able to access, the number of female participants in over a quarter of trials did not match the proportion of women in the US affected by the disease the drug was supposed to treat. Furthermore, the study did not address trials for generic drugs, which represent 80% of prescriptions in the United States. The FDA describes a generic drug as ‘a medication created to be the same as an already marketed brand-name drug’ and they are sold after the patent for the original branded drug runs out. Drugs trials for generic drugs are much less rigorous than original trials, having only to demonstrate equal bioavailability, and they are conducted ‘almost exclusively’ in young adult males. This matters because even with the same active ingredient, different inactive ingredients and different fabrication technology can affect a drug’s potency. And sure enough, in 2002 the FDA’s Center for Drug Evaluation and Research showed ‘statistically significant differences between men and women in bioequivalence for most generic drugs compared with reference drugs’. Despite all this, the authors claimed that there was no evidence of any systematic under-representation of women in clinical trials because in phase two and three trials women were included at 48% and 49%, respectively. But the study authors themselves report that in phase one trials women represented only 22% of participants. And, contrary to what their conclusion might imply, the under-representation of women in phase one trials does matter. According to the FDA, the second most common adverse drug reaction in women is that the drug simply doesn’t work, even though it clearly works in men. So with that substantial sex difference in mind: how many drugs that would work for women are we ruling out at phase one trials just because they don’t work in men?

Digging deeper into the numbers, another issue the authors completely failed to address is whether or not the drugs were tested in women at different stages in their menstrual cycles. The likelihood is that they weren’t, because most drugs aren’t. When women are included in trials at all, they tend to be tested in the early follicular phase of their menstrual cycle, when hormone levels are at their lowest – i.e. when they are superficially most like men. The idea is to ‘minimise the possible impacts oestradiol and progesterone may have on the study outcomes’. But real life isn’t a study and in real life those pesky hormones will be having an impact on outcomes. So far, menstrual-cycle impacts have been found for antipsychotics, antihistamines and antibiotic treatments as well as heart medication. Some antidepressants have been found to affect women differently at different times of their cycle, meaning that dosage may be too high at some points and too low at others. Women are also more likely to experience drug-induced heart-rhythm abnormalities and the risk is highest during the first half of a woman’s cycle. This can, of course, be fatal.

Finally, the authors didn’t consider the number of drug treatments that might be beneficial to women but never even reach human testing because they were ruled out at the cell and animal trial stage. And this number could be substantial. Sex differences in animals have been consistently reported for nearly fifty years, and yet a 2007 paper found that 90% of pharmacological articles described male-only studies. In 2014 another paper found that 22% of animal studies did not specify sex, and of those that did, 80% included only males. Perhaps most galling from a gender-data-gap perspective was the finding that females aren’t even included in animal studies on female-prevalent diseases. Women are 70% more likely to suffer depression than men, for instance, but animal studies on brain disorders are five times as likely to be done on male animals. A 2014 paper found that of studies on female-prevalent diseases that specified sex (44%), only 12% studied female animals. Even when both sexes are included there is no guarantee the data will be sex-analysed: one paper reported that in studies where two sexes were included, two-thirds of the time the results were not analysed by sex. Does this matter? Well, in the 2007 analysis of animal studies, of the few studies that did involve rats or mice of both sexes, 54% revealed sex-dependent drug effects. These sex-dependent effects can be extreme. Dr Tami Martino researches the impact of circadian rhythms on heart disease, and during a 2016 lecture to the Physiology Society she recounted a recent shock discovery. Together with her team, she conducted a study which found that the time of day you have a heart attack affects your chances of survival. A heart attack that hits during the day triggers, among other things, a greater immune response. In particular, it triggers a greater neutrophil response (neutrophils are a type of white blood cell that are usually first on the scene in response to any injury), and this response correlates with a better chance of survival. This finding has been replicated many times over many years with many different animals, becoming, explained Martino, the ‘gold standard for survivorship in the literature’.

So Martino and her team were ‘quite surprised’ when in 2016 another group of researchers released a paper which also found that daytime heart attacks triggered a greater neutrophil response – but that this correlated with a worse chance of survival. After a substantial amount of head-scratching, they realised there was one basic difference between the historic studies and this one new study: the old studies had all used male mice, while this new paper had used female mice. Different sex: totally opposite result.

As for cell studies, a 2011 review of ten cardiovascular journals found that when sex was specified 69% of cell studies reported using only male cells. And ‘when sex was specified’ is an important caveat: a 2007 analysis of 645 cardiovascular clinical trials (all published in prominent journals) found that only 24% provided sex-specific results. A 2014 analysis of five leading surgical journals found that 76% of cell studies did not specify sex and of those that did, 71% included only male cells and only 7% reported sex-based results. And again, even for diseases that are more prevalent in women, researchers can be found ‘exclusively’ studying XY cells. As in animal and human studies, when sex has been analysed in cell studies, dramatic differences have been found. For years researchers were puzzled by the unpredictability of transplanted muscle-derived stem cells (sometimes they regenerated diseased muscle, sometimes they didn’t do anything) until they realised that the cells weren’t unpredictable at all – it’s just that female cells promote regeneration and male cells don’t. Perhaps of more urgent concern for women’s health is the 2016 discovery of a sex difference in how male and female cells respond to oestrogen. When researchers exposed male and female cells to this hormone and then infected them with a virus, only the female cells responded to the oestrogen and fought off the virus. It’s a tantalising finding that inevitably leads to the following question: how many treatments have women missed out on because they had no effect on the male cells on which they were exclusively tested?

In light of all this evidence, it’s hard to see how researchers can continue to argue in good faith that sex doesn’t matter. Rather, it seems clear that McGill University neuroscientist Jeffrey Mogil was right when he told the Organisation for the Study of Sex Differences that failing to include both sexes ‘right at the very beginning’ of your research ‘is not only scientifically idiotic and a waste of money, it is an ethical issue as well’. Nevertheless, women continue to be routinely under-represented in medical research, and you can’t even expect sex-specific trials to adequately represent women. When the ‘female Viagra’ that was released with much fanfare in 2015 was found to potentially interact negatively with alcohol (as most readers will know, the absorption of alcohol differs between men and women), its manufacturer, Sprout Pharmaceuticals, quite rightly decided to run a trial – for which they recruited twenty-three men and two women. They did not sex-disaggregate the data.

In this latter failure, they are not alone. Several reviews of papers published in major journals over the past ten years have all identified a routine failure to either present results by sex, or to explain why the influence of sex has been ignored. A 2001 US Government Accounting Office (GAO) audit of FDA records found that about a third of documents didn’t sex-disaggregate their outcomes and 40% didn’t even specify the sex of the participants. The auditors concluded that the FDA had ‘not effectively overseen the presentation and analysis of data related to sex differences in drug development’, a finding that was confirmed in a 2007 analysis of new drug applications submitted to the FDA which found a failure to establish standards for data analysis of applications. In 2015 the GAO criticised the US National Institutes of Health (NIH) for failing to routinely track whether researchers had actually evaluated any differences between the sexes. Things are often even worse in non-government-funded trials – which represent the majority of studies. A 2014 investigation into sex analysis in cardiovascular trials found that thirty-one of sixty-one NIH-sponsored trials analysed outcomes by sex compared with only 125 of 567 non-NIH-sponsored clinical trials. The lack of sex-disaggregated data affects our ability to give women sound medical advice. In 2011 the World Cancer Research Fund complained that only 50% of studies into the impact of diet on cancer that included both men and women disaggregated their data by sex, making it hard to establish dietary guidelines for cancer prevention that are valid for both sexes. Women, for example, should probably eat more protein than men as they age (because of muscle mass loss), but ‘the optimal dose per meal to support muscle protein synthesis in older women has not been determined’. The failure to sex-disaggregate when you’ve actually gone to the effort of including both sexes is baffling, not to mention, as Londa Schiebinger at Stanford University puts it, ‘money wasted [and] research that is lost to future meta-analysis’.84 And when female representation in trials is so low, the ability to conduct meta-analysis can mean the difference between life and death.

In 2014 a review of the FDA database of a cardiac resynchronisation therapy device (CRT-D – essentially a more complicated kind of pacemaker) trials found that women made up about 20% of participants.85 The number of women included in each individual study was so low that separating out the data for men and women didn’t reveal anything statistically significant. But when the review authors combined all the trial results and sex-disaggregated that data, they found something alarming.

A CRT-D is used to correct a delay in your heart’s electrical signals. They are implanted for established heart failure and the D stands for defibrillator. This defibrillator (a larger version of which most of us will have seen in one hospital drama or other) performs something like a hard reset on the heart, shocking it out of its irregular rhythm so that it can restart in its correct rhythm. A doctor I spoke to described CRT-Ds as ‘symptom control’. They aren’t a cure, but they prevent many early deaths, and if your heart takes 150 milliseconds or longer to complete a full electrical wave, you should have one implanted. If your heart completes a full circuit in under that time, you wouldn’t benefit from one.

Unless, the meta-analysis found, you happened to be female. While the 150 milliseconds threshold worked for men, it was twenty milliseconds too high for women. This may not sound like much, but the meta-analysis found that women with an electrical wave of between 130-49 milliseconds had a 76% reduction in heart failure or death and a 76% reduction in death alone from having the advanced pacemaker implanted. But these women would not be given the device under the guidelines. And so because the trials treated male bodies as the default, and women as a side-show, they had condemned hundreds of women to avoidable heart failure and death.

The CRT-D is far from the only piece of medical tech that doesn’t work for women – which is unsurprising given a 2014 analysis which found that only 14% of post-approval medical-device studies included sex as a key outcome measure and only 4% included a subgroup analysis for female participants. A 2010 paper found that ‘the female gender is associated with an increased risk of acute complications during primary pacemaker implantation, being independent from age or type of device implanted’. In 2013, a supposedly revolutionary artificial heart was developed that was too big for women. Its designers are working on a smaller version, which is great, but it’s striking that, like other artificial hearts, the female version comes years after the default male one.

Even something as basic as advice on how to exercise to keep disease at bay is based on male-biased research. If you run a general search for whether resistance training is good for reducing heart disease, you’ll come across a series of papers warning against resistance training if you have high blood pressure. This is in large part because of the concerns that it doesn’t have as beneficial an effect on lowering blood pressure as aerobic exercise, and also because it causes an increase in artery stiffness.

Which is all true. In men. Who, as ever, form the majority of research participants. The research that has been done on women suggests that this advice is not gender-neutral. A 2008 paper, for example, found that not only does resistance training lower blood pressure to a greater extent in women, women don’t suffer from the same increase in artery stiffness. And this matters, because as women get older, their blood pressure gets higher compared to men of the same age, and elevated blood pressure is more directly linked to cardiovascular mortality in women than in men. In fact, the risk of death from coronary artery disease for women is twice that for men for every 20 mm Hg increase in blood pressure above normal levels. It also matters because commonly used antihypertensive drugs have been shown to be less beneficial in lowering blood pressure in women than in men. So to sum up: for women, the blood-pressure drugs (developed using male subjects) don’t work as effectively, but resistance training just might do the trick. Except we haven’t known that because all the studies have been done on men. And this is before we account for the benefits to women in doing resistance training to counteract osteopenia and osteoporosis, both of which they are at high risk for post-menopause.

Other male-biased advice includes the recommendation for diabetics to do high-intensity interval training; it doesn’t really help female diabetics (we don’t really know why, but this is possibly because women burn fat more than carbs during exercise). We know very little about how women respond to concussions, ‘even though women suffer from concussions at higher rates than men and take longer to recover in comparable sports’. Isometric exercises fatigue women less (which is relevant for post-injury rehabilitation) because men and women have different ratios of types of muscle fibre, but we have ‘a limited understanding of the differences’ because there are ‘an inadequate number of published studies’. When even something as simple as ice-pack application is sex-sensitive, it’s clear that women should be included in sports-medicine research at the same rates as men. But they aren’t. And researchers continue to research men and act as if their findings apply to women. In 2017, a Loughborough University study was hailed around the UK news media as proving that a hot bath has anti-inflammatory and blood-sugar response benefits similar to exercise. Published in the journal Temperature with the sub heading ‘A possible treatment for metabolic diseases?’ the study included no women at all.

We know that men and women have different metabolic systems. We know that diabetes, one of the diseases particularly singled out as being relevant to this discovery, also affects men and women differently, and that it is a greater risk factor for cardiovascular disease in women than in men. But despite all this, the paper’s authors consistently failed to acknowledge any relevance of sex differences to their research. They cited animal studies that had similarly been conducted in all male populations, and perhaps most shockingly of all, in a section specifically looking at ‘limitations with the present investigation’ they completely failed to mention the fact that the study was all-male as a potential drawback, only referring to their ‘relatively small sample size’.

There have been some attempts to force researchers to properly represent females in medical research. Since 1993, when the US passed the National Institute of Health Revitalization Act, it has been illegal not to include women in federally funded clinical trials. Australia’s main funding body made similar rules for the research it funds, as has the EU, which in fact went even further, also requiring both sexes to be studied in pre-clinical animal studies. This requirement did not come into effect in the US until January 2016, which is also when the NIH introduced the requirement that the data in trials it funded be disaggregated and analysed by sex (unless there is a compelling reason not to). Other positive developments include the German Society of Epidemiology which has for more than a decade required researchers to justify including only one sex in any study where the results could potentially affect both sexes; and the introduction of the same by the Canadian Institutes of Health in 2012, as well as mandatory questions about the consideration of sex and gender in the study design. Some academic journals also now insist that papers submitted for publication should provide information about the gender of participants in clinical trials, for example. Trailing behind everyone is the UK, whose main funders ‘make no substantive reference to, or requirements regarding, the consideration of gender in research design and analysis’, and despite the at-risk population of women suffering more morbidity and mortality, UK research funding for coronary artery disease in men is far greater than for women. Indeed, such is the dearth of gender-based clinical research from within the UK, that Anita Holdcroft, emeritus professor at Imperial College London, has written that for cardiovascular treatment, ‘it is pertinent to use studies from North America and Europe where these issues have been investigated’. Still, while the situation in the UK is dire, significant problems remain elsewhere. For a start, the evidence we’ve just seen on the representation of women in trials suggests that these policies are not being rigorously enforced. And, indeed, this is what analyses of the NIH have found. Four years after the NIH announced their first policy calling for the inclusion of women in medical trials, a report was released by the GAO which criticised the NIH for having ‘no readily accessible source of data on the demographics of NIH study populations’, making it impossible to determine if the NIH was enforcing its own recommendations. By 2015 the GAO was still reporting that the NIH ‘does a poor job of enforcing rules requiring that clinical trials include both sexes’. There also remain plenty of loopholes for US drug manufacturers who don’t want the cost and complication of including unharmonious females with their messy hormones in their neat clinical trials, because the rules only apply to NIH-funded trials; independent drug manufacturers can do whatever they want. And the evidence suggests that many of them do: a 2016 paper found that ‘a quarter of the drug manufacturers in an industry survey did not deliberately recruit representative numbers of women as participants in drug trials.’ When it comes to generic drugs, the FDA only specifies ‘guidelines’ rather than rules and, as we’ve seen, these guidelines are being roundly ignored. And the NIH policy on including female subjects in clinical trials doesn’t apply to cell studies.

Then of course there’s the issue of legacy drugs. Two million women per year take Valium for conditions ranging from anxiety to epilepsy, and it was aggressively marketed towards women for decades. And yet, a 2003 paper points out, this ‘mother’s little helper’ was never tested in randomised clinical trials with female subjects. A 1992 survey by the US General Accounting Office (the Congressional watchdog) found that less than half of publicly available prescription drugs had been analysed for sex differences. A 2015 Dutch paper baldly states that ‘The specific effect on women of a huge number of existing medications is simply unknown.’ There is clearly a long way to go, and we must begin to address these gaps as a matter of urgency, because while they remain open, women (who ingest approximately 80% of pharmaceuticals in the US) are dying. Some drugs used to break up blood clots immediately after a heart attack can cause ‘significant bleeding problems in women.’ Other drugs that are commonly prescribed to treat high blood pressure have been found to lower men’s mortality from heart attack – but to increase cardiac-related deaths among women.’ Statins, which are regularly prescribed around the world as a preventative measure for heart disease have mainly been tested in men and recent research from Australia suggests that women taking statins at higher dosages may face an increased diabetes risk – which in turn is a higher risk factor for cardiovascular disease in women than in men. In 2000 the FDA forced drug manufacturers to remove phenylpropanolamine, a component of many over-the-counter medications, from all products because of a reported increased risk of bleeding into the brain or into tissue around the brain in women, but not in men. Drug-induced acute liver failure has also been reported more often in women, and certain HIV medications are six to eight times more likely to cause an adverse drug reaction (ADR) in women. In 2014, the FDA released a database of ADR reports between 2004-13 which showed that women are far more likely than men to experience an ADR: more than 2 million were recorded for women compared to less than 1.3 million for men. Although around the same numbers of men and women die from an ADR, death is ninth on the list of most common ADRs for women, compared to first on the list for men. The second-most common ADR for women (after nausea) is that the drug simply doesn’t work at all, and data on the number of deaths that occur as a result of the drug failing to work is not available. We do know, however, that women are more likely to be hospitalised following an ADR, and more likely to experience more than one. A 2001 US study found that 80% of drugs that had been recently removed from the market caused more ADRs in women, while a 2017 analysis points to the ‘large number’ of medications and medical devices removed from the market by the FDA that posed greater health risks to women. None of this should surprise us, because despite obvious sex differences, the vast majority of drugs, including anaesthetics and chemotherapeutics, continue with gender-neutral dosages, which puts women at risk of overdose. At a most basic level, women tend to have a higher body-fat percentage than men, which, along with the fact that blood flow to fat tissue is greater in women (for men it’s greater to skeletal muscle) can affect how they metabolise certain drugs. Acetaminophen (an ingredient in many pain relievers), for example, is eliminated by the female body at approximately 60% of the rate documented in men. Sex differences in drug metabolism is in part because women’s lower lean body mass results in a lower base metabolic rate, but it can also be affected by, among other things: sex differences in kidney enzymes; in bile acid composition (women have less); and intestinal enzyme activity. Male gut transit times are also around half the length of women’s, meaning women may need to wait for longer after eating before taking medications that must be absorbed on an empty stomach. Kidney filtering is also faster in men, meaning some renally excreted medications (for example digoxin – a heart medication) ‘may require a dosage adjustment’. For millennia, medicine has functioned on the assumption that male bodies can represent humanity as a whole. As a result, we have a huge historical data gap when it comes to female bodies, and this is a data gap that is continuing to grow as researchers carry on ignoring the pressing ethical need to include female cells, animals and humans, in their research. That this is still going on in the twenty-first century is a scandal. It should be the subject of newspaper headlines worldwide. Women are dying, and the medical world is complicit. It needs to wake up.