None of this should surprise us, because despite obvious sex differences, the vast majority of drugs, including anaesthetics and chemotherapeutics,132 continue with gender-neutral dosages,133 which puts women at risk of overdose.134 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.135 Acetaminophen (an ingredient in many pain relievers), for example, is eliminated by the female body at approximately 60% of the rate documented in men.136 Sex differences in drug metabolism is in part because women’s lower lean body mass results in a lower base metabolic rate,137 but it can also be affected by, among other things: sex differences in kidney enzymes;138 in bile acid composition (women have less);139 and intestinal enzyme activity.140 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.141 Kidney filtering is also faster in men, meaning some renally excreted medications (for example digoxin – a heart medication) ‘may require a dosage adjustment’.142
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.
CHAPTER 11
Yentl Syndrome
In the 1983 film Yentl, Barbra Streisand plays a young Jewish woman in Poland who pretends to be a man in order to receive an education. The film’s premise has made its way into medical lore as ‘Yentl syndrome’, which describes the phenomenon whereby women are misdiagnosed and poorly treated unless their symptoms or diseases conform to that of men. Sometimes, Yentl syndrome can prove fatal.
If I were to ask you to picture someone in the throes of a heart attack, you most likely would think of a man in his late middle age, possibly overweight, clutching at his heart in agony. That’s certainly what a Google image search offers up. You’re unlikely to think of a woman: heart disease is a male thing. But this stereotype is misleading. A recent analysis of data from 22 million people from North America, Europe, Asia and Australasia found that women from lower socio-economic backgrounds are 25% more likely to suffer a heart attack than men in the same income bracket.1
Since 1989, cardiovascular disease has been the leading cause of death in US women and, following a heart attack, women are more likely to die than men.2 This disparity in deaths has been the case since 1984, and young women appear to be particularly at risk: in 2016 the British Medical Journal reported that young women were almost twice as likely as men to die in hospital.3 This may be in part because doctors aren’t spotting at-risk women: in 2016, the American Heart Association also raised concerns about a number of risk-prediction models ‘commonly used’ in patients with acute coronary syndrome, because they were developed in patient populations that were at least two-thirds male.4 The performance of these risk-prediction models in women ‘is not well established’.
Common preventative methods may also not work as well in women. Acetylsalicylic acid (aspirin) has been found to be effective in preventing a first heart attack in men, but a 2005 paper found that it had a ‘nonsignificant’ effect in women aged between forty-five and sixty-five.5 Prior to this study, the authors noted, there had been ‘few similar data in women’. A more recent study from 2011 found that not only was aspirin ineffective for women, it was potentially harmful ‘in the majority of patients’.6 Similarly, a 2015 study found that taking a low dose of aspirin every other day ‘is ineffective or harmful in the majority of women in primary prevention’ of cancer or heart disease.7
Perhaps the greatest contributor to the numbers of women dying following a heart attack, however, is that their heart attacks are simply being missed by their doctors. Research from the UK has found that women are 50% more likely to be misdiagnosed following a heart attack (rising to almost 60% for some types of heart attack8). This is partly because women often don’t have the ‘Hollywood heart attack’ as it’s known in medical circles (chest and left-arm pains).9 Women (particularly young women) may in fact present without any chest pain at all, but rather with stomach pain, breathlessness, nausea and fatigue.10 These symptoms are often referred to as ‘atypical’, a designation to which the British Medical Journal took exception in a 2016 article, saying that the term ‘may lead to the under-appreciation of risk associated with this presentation’.11 And under appreciation of the risk may in turn explain why a 2005 US study found that ‘only one in five physicians across multiple specialties was aware that more women than men die from cardiovascular disease each year, and most of these physicians did not rate themselves as effective in treating sex-tailored cardiovascular disease’.12
Atypical or not, for certain types of heart attacks, women (and again especially young women) who present without chest pain are at particular risk of death13 – which makes it extremely concerning that current NHS England guidelines specify ‘acute cardiac sounding chest pain’ as part of the criteria for a patient being referred for primary percutaneous coronary interventions (PPCI) at one of the country’s specialist twenty-four-hour heart-attack centres.14 PPCI is an emergency treatment that restores blood flow during a heart attack, and which according to one doctor I spoke to has ‘massively improved survival and outcome’. But this treatment is only carried out at the twenty-four-hour heart-attack centres and, perhaps as a result, 75% of those who receive this treatment are men.15
The tests doctors use to determine what’s wrong with a patient are also likely contributing to women’s higher death rates following a heart attack. Standard tests like the electrocardiogram or the physical stress test have been found to be less conclusive in women.16 A 2016 BMJ paper refers to recent work from Edinburgh which showed that the ‘normal’ diagnostic threshold for troponin (a protein released into the blood during heart damage) may be too high for women.17 And it’s not just about ‘standard’ levels for biomarkers being incorrect in women, we also need to establish new female-specific biomarkers.18 A biomarker is a biological characteristic (like troponin) whose presence can act as a diagnostic criteria for a specific disease, and a 2014 literature review of sex difference studies suggests that this may be a fruitful area to research.19 Unfortunately, it concludes that the work done so far is too limited to be able to say whether or not female-specific biomarkers will be found.
Because women’s heart attacks may not only present differently, but may in fact be mechanically different, the technology we’ve developed to search for problems may not be suitable for female hearts.20 For example, a heart attack is traditionally diagnosed with an angiogram, which will show where there are obstructed arteries.21 But women often don’t have obstructed arteries, meaning that the scan won’t show up any abnormalities,22 and women who turn up at hospital with angina (chest pain) may simply be discharged with a diagnosis of ‘non-specific chest pain’ and told they have no significant disease.23 Except they do: women with ‘normal’ angiograms have gone on to suffer a heart attack or stroke shortly after being discharged from hospital.24