Gender medicine: the half evidence

How a science lost its other half

The story begins with a protective idea that flipped into its opposite. In 1977 the American drug regulator recommended excluding women of childbearing age from early clinical trials. The background was understandable: the experience with thalidomide and diethylstilbestrol, the concern for unborn life. The effect was not. For more than two decades, half the population was kept away from precisely that phase of drug development in which doses are determined.

It took the NIH Revitalization Act of 1993 to oblige American research funding to include women and minorities in clinical trials. Only in 2016 did the NIH require biological sex to be considered as a variable in preclinical research as well[9]. Until then the laboratory standard was male: male mice, male rats, male cell lines, because female animals were considered «too variable».

What this costs was made visible by the US General Accounting Office in a 2001 investigation that is still cited today. Of ten prescription medicines withdrawn from the US market since the beginning of 1997, eight posed a greater health risk to women than to men[1].

The pharmacological mechanism behind this is by now well described. An analysis published in 2020 examined 86 approved active substances for which sex-specific pharmacokinetic data were available. For 76 of them, women reached higher plasma concentrations and longer elimination times at the same dose. In 96 per cent of the cases with female-shifted pharmacokinetics, adverse effects occurred more frequently in women. The difference could not be explained by body weight[2]. Consistent with this, analyses of hospital admissions show that women develop adverse drug reactions roughly 1.5 to 1.7 times more often[3].

The best-known individual case is zolpidem. Women show a mean clearance around 35 per cent lower, independent of body weight, and therefore retain higher levels in the morning. Eight hours after 10 mg of an immediate-release preparation, concentrations of at least 50 ng/ml were still present in 15 per cent of women but only 3 per cent of men. In 2013 the FDA consequently halved the recommended dose for women[4].

Above this biological level lies a second one, which should not be confused with it. Biological sex determines enzyme equipment, body composition, hormone status and organ size. Social gender determines who visits a practice and when, how complaints are described, how they are heard and which explanation is examined first. The two act together, and both are changeable. Only by different means.

And a third preliminary remark, because honesty requires it: gender medicine is now producing exaggerations of its own. The popular claim that women have «completely different symptoms» in a heart attack is, in that form, wrong and potentially dangerous. Where the evidence is clear, it is stated clearly here. Where it is not, that is stated too.

Heart attack: not different symptoms, but different ones more often

The largest investigation on this comes from the American myocardial infarction registry and covers 1,143,513 patients from the years 1994 to 2006. Result: 42.0 per cent of women and 30.7 per cent of men presented without chest pain. In-hospital mortality was higher in women, and the decisive factor was the interaction with age: the mortality difference between women and men without chest pain was greatest in the youngest patients and disappeared with increasing age[5].

This is precisely where the necessary qualification lies. In women too, chest pain is the most common single symptom. The majority have it. The difference is relative, not categorical: women have it less often than men, and they more frequently have additional or accompanying complaints such as shortness of breath, nausea and vomiting, pain in the back, neck or jaw, cold sweat and unusual exhaustion.

Anyone who turns this into the message that women do not get chest pain does harm: a woman with classic retrosternal pressure might then assume that this could not possibly be an infarction in her case. The correct message is that the absence of chest pain does not rule out an infarction.

Added to this are differences in pathophysiology. Myocardial infarction without obstructive coronary stenosis, as well as spontaneous coronary artery dissection, occur considerably more often in women, particularly in younger ones. Both escape the classic notion oriented towards plaque rupture, and both are overlooked when the coronary angiogram looks unremarkable and the complaints are subsequently classified as functional. The American Heart Association summarised these constellations in a dedicated scientific statement in 2016[8].

Stroke and atrial fibrillation

Women suffer strokes at a higher mean age, more often with a more severe course and a poorer functional outcome. Alongside the classic warning signs, non-specific presentations occur, including confusion, altered consciousness, generalised weakness or headache, which make classification harder and lengthen the time to treatment.

In atrial fibrillation, female sex is an established risk modifier and appears as such in the common risk scores. Women with atrial fibrillation have a higher stroke risk and were, over the years, less often anticoagulated in accordance with the guidelines in registry data. For the pharmacy this means, concretely: with a woman who has atrial fibrillation and no oral anticoagulation, it is worth asking.

Diabetes: the strongest documented effect

Nowhere is the data situation as clear as here, and nowhere is it communicated as little.

Two large meta-analyses have quantified the sex-specific risks. Women with diabetes have a 44 per cent higher relative risk of incident coronary heart disease compared with men with diabetes; 64 cohorts with 858,507 individuals and 28,203 coronary events were analysed[6]. For stroke the corresponding difference is 27 per cent, based on 64 cohorts with 775,385 individuals[7].

The interpretation matters. In absolute terms, men still have the higher cardiovascular event rates. But diabetes costs women a larger part of their protection: it abolishes the relative advantage that women have over men before the menopause. A 55-year-old woman with type 2 diabetes is not, in cardiovascular terms, the low-risk patient she is often perceived to be.

Heart failure, lungs and oncology

Three further fields deserve a mention because they are common in everyday practice.

In heart failure with preserved ejection fraction, women clearly predominate, while the form with reduced ejection fraction affects men more often. That is more than a statistic, because the treatment options differ, and the preserved form was for decades dismissed as a «diastolic disturbance without good treatment». In practical terms this means: exertional dyspnoea and oedema in an older woman with hypertension and normal pump function are not an all-clear but a diagnosis to be looked for.

In pulmonology, chronic obstructive pulmonary disease is still regarded as a men’s disease, although women apparently react more sensitively to comparable smoking exposure and become symptomatic earlier. Lung cancer in people who have never smoked also affects women disproportionately. Both lead to cough and breathlessness in women being classified as pulmonary later.

And in oncology there are sex-specific differences in the tolerability and toxicity of chemotherapies that can only be partly explained by body surface area as the basis for dosing. Here too the data basis is thinner than the matter-of-factness of the application would suggest.

Autoimmunity, pain and the question of attribution

Autoimmune diseases predominantly affect women; for the great majority of entities, the proportion of women is around four out of five of those affected. In several of these diseases the diagnostic delay is considerable, because the early symptoms are non-specific: fatigue, joint pain, difficulty concentrating, shifting complaints without findings.

For endometriosis, European surveys regularly report a delay of several years between the first symptoms and the diagnosis. The mechanism behind this is remarkably simple: severe menstrual pain is culturally regarded as normal, in medicine too.

That names the underlying pattern, which goes beyond the individual diagnosis. When complaints are described by women without a clear finding, a psychological explanation is more often examined first and a somatic one later. In men the order tends to be reversed. This pattern has been described repeatedly in pain research and explains part of the delays better than any biology.

What this means for drug therapy

The pharmacological differences are concrete and relevant in everyday practice.

On average women have a higher proportion of body fat and a smaller volume of distribution for hydrophilic substances, which means lipophilic active substances are stored for longer and hydrophilic ones are more highly concentrated. The glomerular filtration rate is on average lower, which affects renally eliminated substances. Among the cytochromes there are substance-specific differences, with a tendency towards higher CYP3A4 activity in women and the reverse relationship for other isoenzymes.

Clinically significant is cardiac repolarisation: women have a longer QTc interval and are markedly over-represented in reports of drug-induced torsades de pointes. With QT-prolonging substances — and there are plenty of them in every pharmacy — that is a real safety aspect, particularly in combination with electrolyte disturbances.

And then the simplest observation of all: the standard dose of a proprietary medicine is usually a dose, not a dose range. A woman weighing 55 kilograms and a man weighing 95 kilograms receive the same tablet. For the majority of active substances that is defensible. For those with a narrow therapeutic index it is an assumption one should be aware of.

The case of acetylsalicylic acid

No example shows better why pooled evidence can mislead.

In the Women’s Health Study, 39,876 initially healthy women aged 45 and over received 100 mg of acetylsalicylic acid every other day or placebo over ten years. The result contradicted what had been expected from the studies in men: the stroke rate fell by around 17 per cent, while myocardial infarction risk and cardiovascular mortality remained unaffected[10]. In the corresponding study in male physicians it had been exactly the other way round, with a reduction in the infarction rate and no effect on stroke.

A sex-specific meta-analysis across six studies with 95,456 individuals subsequently confirmed this pattern[11].

There is no need to derive a recommendation from this, since primary prevention with acetylsalicylic acid has in any case since been considerably restricted. What one should derive from it is a methodological lesson: had both populations been analysed together, the opposing effect would have disappeared and both sexes would have been presented with a false average truth.

Anticoagulation and platelet inhibition

In anticoagulation, two effects come together that reinforce one another.

First, female sex is an established risk modifier in atrial fibrillation, reflected in the common scores. Second, registry analyses repeatedly show that women are less often anticoagulated in line with the guidelines and more often receive a reduced dose of the direct oral anticoagulants without the formal criteria for this being met. The obvious explanation is a combination of lower body weight, higher age and the intuitive but undocumented assumption that women are at greater risk of bleeding and therefore generally need less.

For the pharmacy this yields a very concrete check question: does the dispensed dose match age, weight and renal function, or was it reduced as a precaution? An unjustified underdose is not the safe option; it increases stroke risk without meaningfully lowering bleeding risk.

Psychotropic drugs

Depression is diagnosed roughly twice as often in women as in men, and women accordingly receive psychotropic drugs more frequently. It is precisely in this substance group that the pharmacokinetic sex differences are particularly well documented: for numerous antidepressants and antipsychotics, women reach higher plasma levels at the same dose and show longer elimination times[2].

Three consequences are practically relevant above all. First, the QT problem, which is more pronounced in women anyway and adds up with QT-prolonging psychotropics. Second, the stronger prolactin elevation under certain antipsychotics with the corresponding consequences for cycle, libido and bone density. Third, adverse effects such as sedation, weight gain and metabolic changes, which lead more often to treatment discontinuation in women and are not infrequently interpreted as poor adherence rather than as overexposure.

The question of whether an intolerable dose might simply be too high is asked too rarely.

The counter-check

A text that describes only one direction is ideology, not medicine. Hence the counter-check, because sex-specific blind spots exist in both directions.

Osteoporosis is regarded as a women’s disease and is therefore systematically underdiagnosed and undertreated in men, even though mortality after a hip fracture is higher in men. Depression is recognised less often in men because it more frequently manifests as irritability, withdrawal, risk-taking or substance use rather than as expressed sadness; at the same time the suicide rate is markedly higher in men. Eating disorders are regarded as female, which costs male sufferers access to the diagnosis. And men make less use of preventive services overall, which explains part of their shorter life expectancy.

Gender-sensitive medicine therefore does not mean thinking about women. It means carrying sex along as a variable, in both directions.

What follows from this in the pharmacy

Four things can be implemented immediately.

First, the assessment of symptoms in middle-aged and older women. Persistent unusual exhaustion, breathlessness on exertion, nausea with cold sweating, jaw or back pain without a musculoskeletal explanation: this combination does not belong in self-medication but in a diagnostic work-up. The sentence that helps is not «that’s surely your back» but «we had better have that looked into».

Second, risk assessment in diabetes. A woman with type 2 diabetes is not a low-risk cardiovascular patient, and the question of a statin, blood pressure and anticoagulation in atrial fibrillation is at least as justified in her case as in a man of the same age.

Third, drug safety. With newly occurring adverse effects in women, it is worth considering overexposure, particularly with low body weight, impaired renal function and substances with a narrow therapeutic index. And reports to Swissmedic are particularly valuable here, because the data basis is thin in exactly that area.

Fourth, the conversation itself. Anyone who hears a woman’s complaint for the third time and offers the same trivialisation the third time is prolonging precisely the delay this text is about.

What remains

Medical evidence is becoming more gender-equitable, but slowly. The proportion of women in clinical trials has risen; separate analysis by sex far less so. Many more recent studies include both sexes and then analyse the data pooled, which makes the difference invisible again.

Until that changes, an interim solution applies that claims less and achieves more than any campaign: keeping in mind the question of whether a study from which a recommendation derives actually included women in relevant numbers.

Usually the answer is: partly. That is no reason to distrust therapies. It is a reason to look more closely.