How historically neglecting sex differences has impacted women’s health

Sex differences have historically been neglected in clinical research, design and practice. To mark International Women’s Day, we explored how this ‘one size fits all’ approach to medical research and treatment impacts women’s health.

The implications of a ‘one size fits all’ approach to medical research and treatment

Men and women are different in several ways in terms of their biological makeup, and it has been long known that the expression of genes on X and Y chromosomes have a profound effect on health and well-being. Difference in sex not only contributes to the physiological and anatomical variations but also influences the behavioural traits and disease risks. For instance, most autoimmune diseases occur more frequently in women while hypertension is observed more frequently in young men than in young women. Unsurprisingly, this is no exception for drug metabolism: most drugs are absorbed, metabolised, and eliminated differently between males and females.

Despite this knowledge, our current clinical management and medical treatment of most diseases is rarely gender-specific. Very few medical guidelines systematically address the difference in sex and gender, indeed this aspect is often overlooked in the design of clinical research in the first place. When interpreting the research findings without gender-specific analyses, the applicability to clinical practice becomes suboptimal. This makes it hard to achieve equitable treatment, because adjustments have not been made to the specific needs of each gender.

Failure to consider the differences in the physiology of males and females in the drug development process can lead to serious consequences. One prominent example is drugs commonly used to treat cardiovascular conditions, including digitalis, angiotensin-converting enzyme inhibitors, beta-blockers, and aspirin. Studies revealed that significantly more side effects occurred in women, particularly life-threatening arrhythmia (aka irregular heart rhythm).

Women and men metabolise drugs differently, however, cardiovascular drug recommendations are based on clinical trials in middle-aged men meaning that there is insufficient safety and efficacy data in women, who subsequently have more adverse reactions from current recommended doses. In fact, women tend to have different clinical presentations of chest pain compared to men and different diagnostic procedures need to be considered.

Immuno-oncology is yet another example of where sex has been ignored in the drug development process. The biological differences in the immune system of men and women unsurprisingly impact drugs aiming at the immune system. Despite these differences, it was only recently appreciated in a retrospective study that only one class of the two commonly used immune checkpoint inhibitors (in technical jargon, the two classes are called anti-CTLA-4 and anti PD-1/PD-L1 - the overall idea of these drugs is to reactivate the patient’s immune system to fight the cancer) in immuno-oncology is broadly beneficial for women. Outside of the case of the skin cancer melanoma, women that suffer from renal cell carcinoma or colorectal cancer do not benefit from receiving anti-CTLA-4 therapy, but do experience the potential side effects! Significantly, the first FDA approval an anti-CTLA-4 drug was in 2011 - meaning that it took 7 years until sex differences were actually analysed and appreciated.

Without taking into account the difference in sex and gender that underpins every aspect of our biological fundamentals, the inequality will continue to remain within our healthcare systems.

A look into future healthcare: how sex differences impacts precision medicine

Precision medicine aims to define endotypes, which are observable traits useful for identifying subpopulations of similar patients who are likely to have similar responses to drugs. The benefits of precision medicine are firstly, to ensure everybody who is prescribed a drug derives benefit (as opposed to the minority now) and secondly, to increase probability of success in clinical trials. Despite the promise of precision medicine in drug discovery and the idea of personalised medicine, sex differences are often simply ignored which thereby impacts the efficacy of the precision medicine approach.

As demonstrated above, failure to take into account sex differences in clinical research and design can have serious consequences on women’s health. But the story does not end here. Genome-wide association studies (GWAS), studies trying to link the genetic variation to a disease yielding in genetic hypothesis for drug discovery, tend to just exclude the sex chromosomes altogether in their analysis. The impact of this approach is that potentially interesting genetic variants linked to various diseases, but that are sex-specific, are never identified! To illustrate this, it was already shown that careful design in studies reveals sometimes surprising sex differences, such as the differential effect of nicotine during pregnancy on male or female off-spring - these differences would be missed without distinguishing between the sexes.

Moreover, large scale analysis of the expression of various genes across all tissues clearly shows that various genes are differentially expressed, beyond the reproductive organs. This implies that targeted therapeutic interventions might have quite different outcomes between the two sexes, depending on target tissue and mechanism. As mentioned previously, these differences in expression in the target tissues and organs that metabolise the drugs, such as the liver or kidneys, could impact the occurrence of adverse effects which affect disproportionately women. Another problematic point, related to side-effects, might be that despite trends that male-female ratios improved in the later stage trials (to actually prove the efficacy of a novel drug), the ratio in early stage trials (with the aim to investigate maximum tolerated doses and potential toxicity/adverse effects) is still heavily male-biased (64% male). This means potential side-effects in women may be missed in the early stages of clinical development due to underrepresentation.

What all of this implies is that precision medicine in the future needs to account for the biological differences in the sexes. Firstly, are the studies large enough to detect potential sex differences, and does the study represent the male-female ratio in the disease of interest? Secondly, are the tools that analyse the data actually capable of picking up sex differences?

These two points are of even greater importance in the age of AI-driven ‘big health data’ analysis. The AI algorithms and programs need to be able to pick up any sex differences and the input data needs to be appropriate for the actual patient population, without any over- and/or underrepresentation. Otherwise the results might be skewed and inappropriately represent the real world situation.

If these two aspects are not considered, precision medicine will fail to do maybe one of the most simple steps: account for sex differences. This implies different appropriate dosing regimens, better understanding of underlying biology of the targeted tissue and differential drug metabolism, and tailored diagnostics and potentially even sex-specific drugs where it is deemed appropriate.

Thirdly and maybe most importantly, the learnings from all this need to be translated faster into clinical practice. The worst case would be to give an ineffective drug at a too large dosage (which usually corresponds to increased risk of adverse effects) to a woman, which is still in practice today.

The ‘one size fits all’ approach to medical research and treatment has serious consequences on women's health. Historic underrepresentation in clinical study and design has meant we lack knowledge around the safety and efficacy of drugs when prescribed to women, who often experience more adverse reactions as a result, or fail to react to the drug altogether.

In the coming age of precision medicine, we must take action to ensure the benefits of new therapies are equally distributed by taking account of sex differences in our analysis and translating these findings faster into clinical practice. Raising awareness is a small step towards addressing the inequality that exists in our healthcare system. As we move into the new decade, we must translate this awareness into action to ensure that no one is left behind.

Pijika Watcharapichat, Senior Research Scientist and Gregor Lueg, Translational Medicine Scientist

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