Sex and gender disparities in research practices, diagnoses, and treatment are still rife—the impact of this is still tangible in medical and research settings today. Image credit: Timon Studler via Unsplash
Among medical researchers, it is now well-known that there are sex and gender differences in the causes, symptoms, treatment response, and long-term outcomes for many diseases. Yet, there is still a persistent lack of balance regarding the inclusion of males and females and the underreporting of sex and gender differences in both preclinical and clinical biomedical research.
Sex refers to the biological classification as male, female, or intersex based on sex chromosomes, whereas gender refers to the socially constructed roles, behaviours, and expressions of identity.
The majority of basic science research across various biomedical disciplines is conducted using male-derived cells or male animal models. There are important implications for patient health when results obtained from these outdated preclinical research approaches progress into tangible clinical practices.
There is still a persistent lack of balance regarding the inclusion of males and females and the underreporting of sex and gender differences in both preclinical and clinical biomedical research.
One key sex difference is that the likelihood of developing certain diseases differs between males and females.
For example, the prevalence of Alzheimer’s and Parkinson’s disease differs between the sexes, with Alzheimer’s being much more common in females (female:male prevalence being 2:1) and Parkinson’s being much more common in males (1:2). Genetics may explain, at least in part, this difference, as 2.6% of brain-expressed genes show sex-based differential expression and 95% show sex-based differences in modification prior their translation into proteins (known as splicing).
These differences may be confounded by environmental factors (e.g., diet, exercise) and thus preferentially predispose one sex to neurodegeneration. Certain genes are also exclusively expressed in one sex and can influence the susceptibility to diseases. One example is the male-specific Y chromosome containing the SRY gene, which encodes a transcription factor that ultimately leads to the production and release of testosterone. The expression of this SRY gene has been shown to be aberrantly elevated in human cell culture models of Parkinson’s. Blocking this elevated SRY expression has been shown to eliminate the male bias of Parkinsonian pathology in a rat model of Parkinson’s disorder.
Despite these evident genetic sex differences, only 33% of genome-wide association studies (GWAS) include the sex chromosomes, potentially meaning that important sex differences are missed.
The biological underpinnings of certain diseases also differ between males and females. In patients undergoing surgery due to severe stenosis (where heart valve openings narrow and harden due to mineral deposition), researchers determined that the type of minerals present in the valves differed in composition and in shape between the sexes.
The same study also found that, consistent with previous findings, for the same degree of severity of stenosis, females had fewer mineral deposits than males. Although further research is required to determine the specific cause of these cellular sex differences, in terms of clinical practice, these differences translate to stenosis usually being detected at later stages in women than in men.
This highlights how, in instances where evidence indicates that there are clear sex differences in a disease, both diagnosis and treatment should be sex-specific.
Distinctions between sexes exist not just in the susceptibility and origins of illnesses but also in the manifestation of their symptoms. During a heart attack, for instance, women are more likely than men to present without chest pain or with symptoms thought of as traditionally uncharacteristic of a heart attack (e.g. nausea, light-headedness, unusual tiredness, etc.).
Troponins (proteins released when the heart muscle has been damaged) detected in the blood are the gold standard biomarker for diagnosing heart attacks, but the criteria for troponin testing were created using data primarily collected from men. Men have 2.4 times the circulating levels of troponin as women, meaning that increased troponins in female heart attack patients may not exceed the diagnostic threshold. In fact, up to 20% of heart attacks in women are missed when using the male troponin threshold for identifying heart attacks.
This disregard of measurable sex differences in the presentation of severe cardiovascular pathology not only means women are less likely to be diagnosed, but are also less likely to receive recommended therapies, interventions, and rehabilitation opportunities.
Up to 20% of heart attacks in women are missed when using the male troponin threshold for identifying heart attacks.
The likelihood of disease diagnosis is also influenced by gender and social factors. For example, women are diagnosed with depression twice as often as men, even when men and women display the same symptoms at the same severity. Social expectations about gender-appropriate reactions to depression have a significant influence on men’s symptoms, coping strategies, and help-seeking behaviours.
Conversely, women are much less likely to receive a diagnosis for attention deficit hyperactivity disorder (ADHD). This is partly to due differences in the presentation of symptoms (women are more likely to present as inattentive, and men hyperactive/impulsive) but also the fact women with ADHD may develop better coping strategies than males to mask their symptoms.
It is paramount that healthcare professionals develop an awareness of the influences that sex and gender may have on disease presentation, such that appropriate measures can be taken to ensure there are accurate diagnoses.
Surprisingly, despite clear sex differences, there are no mandatory FDA requirements for prospectively designing clinical trials to investigate the impact of sex on drug receptivity, for adverse effects, or for conducting analyses of the study data by sex. Moreover, females are consistently underrepresented in different stages of drug development; only around 30% of participants in clinical trials are women.
The lack of inclusivity in clinical research has important consequences for treatment with drugs, particularly since the metabolism and side effects of drugs can differ between males and females. Statins, for instance, are commonly prescribed drugs taken to lower cholesterol, but sex and gender were, unfortunately, but not uncommonly, overlooked in initial clinical trials investigating their efficacy. The results investigating the efficacy of statins in men were simply extrapolated to women.
Surprisingly, despite clear sex differences, there are no mandatory FDA requirements for prospectively designing clinical trials to investigate the impact of sex on drug receptivity, for adverse effects, or for conducting analyses of the study data by sex.
There is a critical need for further research to explore the suitable dosage that should be advised for women. For one, it is essential to investigate whether the heightened muscle pain frequently reported by female (but rarely male) patients taking statins is genuinely attributed to the medication.
Evidently, data specific to sex holds the promise of enhancing disease prevention, diagnosis, and treatment, with the potential to mitigate health disparities. Although the inclusion of females has improved somewhat in recent years, research still has a male bias. Moreover, the emerging evidence of meaningful sex and gender differences in disease has led to the development of tools to make biomedical research more inclusive, such as sex-and gender-based analysis (SGBA).
Despite such tools, the relevance of sex and gender continue to rarely be evaluated throughout different stages of the health research process. As a result, many conclusions are made based on incomplete and sex-biased data.
As sex and gender diversity grows, it has never been more important to be inclusive and to consider sex and gender within preclinical and clinical research. Accounting for sex and gender in future biomedical research has the potential to make studies more rigorous, reproducible, and applicable to everyone.
