Gender Data Gap: (Why) Are Women Invisible in Medical Research?

In roughly half of the world’s population, disease trajectories are somewhat inadequately researched: “sex bias in clinical research” or “male default” … bad enough that there are so many euphemisms for this medical phenomenon, this medical failure. We want to bring women into the spotlight — because it would not take much to close this knowledge gap.

What follows is not about “women’s complaints,” but about disease trajectories in women and the (inadequate) research into them.

(Historical) Context of These Sex-Specific Knowledge Gaps

For many decades, women were not included in clinical trials to the same extent as men.

In the United States, a recommendation by the U.S. Food and Drug Administration led to women of childbearing age being largely excluded from early drug studies — due to concerns about pregnancy risks and hormonal “confounding factors” (FDA, 1977). Although this practice was formally limited to the U.S., it significantly shaped international approaches, because many studies were designed as multinational trials based on U.S. standards. One reason women (who could potentially become pregnant) were not allowed to participate in drug studies was the Contergan/thalidomide scandal of the late 1950s and early 1960s. Internationally, pregnant women taking a sleeping pill considered safe — though not as part of approval trials — led to severe malformations in their children. This product had even been advertised as a safe remedy for pregnancy nausea. Without clear evidence regarding effects on the unborn (“Dark Remedy,” 2001).

Only in 1993 did the FDA change its guideline. The earlier recommendation was withdrawn and instead it was emphasized that clinical trials should take sex differences into account and include women in all phases (FDA, 1993).

In parallel, the National Institutes of Health passed a federal law requiring that women and minorities be adequately represented in NIH-funded research and that data must be analyzed separately by participants’ sex (NIH, 1993).

In Germany, there was no explicit ban on admitting women to studies. Nevertheless, study designs, ethical considerations, and pharmaceutical development programs were long guided by lines of argumentation as they applied in the United States. Evidence on numerous medicines that were later approved in Europe initially relied on U.S. studies.

With the EU Directive on Clinical Trials and later regulatory adjustments, the demand gradually prevailed to consider both sexes equally and to evaluate collected data in a differentiated way (2001/20/EC; EU Regulation No. 536/2014).

These historical developments explain why the so-called gender data gap affects not only individual states, but to this day influences international guidelines, textbooks, and treatment recommendations.

When Such Gaps Can Have Particularly Severe Consequences

These omissions become fatal, unfortunately, in clearly defined emergency presentations. They also become especially obvious in diseases with non-specific, diffuse, or hard-to-classify symptoms — logically, one must say. In particular, when diagnostics strongly depend on “typical” courses of disease that were historically based on male reference values, differences in women are still not infrequently overlooked.

These conditions include:

·             Heart attacks — different symptoms, later diagnosis: In women, heart attacks often do not present with the classic chest pain, but with nausea, back or jaw pain, exhaustion, shortness of breath, or dyspnea. For a long time, these differences led to misdiagnoses and delayed treatment (Maas & Appelman, 2010).

·             Strokes — different symptoms, delayed diagnosis: In stroke as well, symptoms in women more often deviate from the “classic” textbook pattern. Instead of one-sided paralysis or speech disturbances, female patients more frequently report dizziness, confusion, nausea, headaches, or general weakness. These seemingly non-specific complaints mean that the urgency of a stroke is more often underestimated in women and treatment is initiated later (Reeves et al., 2008).

·             Dementia types — different risk profiles, higher affectedness, but later diagnoses: Women are more often affected by dementia than men. For a long time, this was explained mainly by higher life expectancy. Meanwhile, it is being discussed that hormonal factors (estrogen decline in menopause), vascular health, metabolic processes, and educational biography play an independent role. These sex-specific aspects were scarcely considered in dementia research for a long time. In addition, women more often take on the role of caregiving relatives, which can mean that early symptoms in them are recognized later. The gender data gap shows up here both in research and in care practice (Beam et al., 2018).

·       Autoimmune diseases — less understood in women, even though they are more often affected: Lupus, Hashimoto’s thyroiditis, multiple sclerosis, or rheumatoid arthritis predominantly affect women. The hormonal and immunological causes of these sex differences are still not fully understood to this day (Ngo et al., 2014).

·       Pain syndromes — psychologized for too long: Chronic pain syndromes such as migraine or fibromyalgia often affect women. For a long time, these conditions were classified as psychosomatic before neurobiological mechanisms were investigated more strongly (Mogil, 2012).

·       Neuropsychiatric disorders — different symptoms: Depression often presents differently in women than in men. As a result, diagnoses in girls and women are often delayed for a long time (Young et al., 2020).

·       Pediatrics and adolescent medicine — using boys as the reference standard: This continues to affect how many conditions and developmental delays are handled, such as ADHD, hyperactivity, or autism (Young et al., 2020).

·       Cycle-related conditions — ignored or trivialized: Despite high prevalence, many years often pass before endometriosis is diagnosed. Pain is trivialized, causes long misunderstood (Zondervan et al., 2018). A similar situation applies to premenstrual syndrome (PMS): mood swings, pain, exhaustion, or concentration problems are often classified as “normal” cycle complaints or psychological strain, the hormonal cause remains unrecognized (Rapkin & Lewis, 2013).

·       Effects and side effects — dosages for the “average man”: Because differences in, for example, height, weight, enzyme activity, and hormonal status influence how drugs are absorbed, distributed, and metabolized in the body, substances not infrequently affect women differently than men — and women are more often affected by side effects (Zucker & Prendergast, 2020).

The Standardization of Laboratory Values Is Also Based on Male Populations

Many reference ranges for blood values were defined in male populations. This affects, among others, inflammatory markers, iron status, or cardiac markers (Holdcroft, 2007). Deviations in women are therefore still quickly classified as “non-specific,” simply “atypical,” or “psychosomatic.”

Male Default: When the “Medical Norm” Does Not Reflect Women

Whatever one calls the problem: as long as symptoms, lab values, and dosages are aligned with male reference data, women remain medically disadvantaged. Sex-sensitive medicine is therefore not a social trend, but a prerequisite for more precise diagnostics and more effective therapies. In the upcoming articles, we want to address diseases that require a more differentiated view in this context. First: dementia (in men and women).

FAQ – Frequently Asked Questions About The “Gender Data Gap”

1. Does the gender data gap play a role in clinical guidelines?

Yes, many guidelines are based on older study populations in which women were underrepresented.

2. Does it influence the delivery of pain therapies?

Yes, pain in women is more often classified as emotional or stress-related, while in men it is more likely seen as physically caused. In practice, this leads to women, despite comparable reports, receiving strong analgesics less often or receiving specialized therapies later.

3. Does it also influence the allocation of research funding?

Diseases that predominantly affect women (traditionally) received less research funding than those with predominantly male affectedness. Today, many funding programs and professional journals require sex-specific analyses; nevertheless, the historically developed backlog continues to have an impact to this day.

4. Does it also play a role in the use of medical devices?

Yes, for example with pacemakers, stents, or dosage settings in infusion pumps that were originally tested on male body measurements.

5. Are older women still strongly affected by gender data gap effects?

Yes, because women often live longer than men, while many geriatric guidelines still rely on data collected predominantly from men.

Further information on this regrettable “data gap” and many other topics can be found in the articles on our blog, the volumes of our “Codex Humanus,” and the “Medizinskandale” series. Please feel free to visit our online shop.

Sources:

·       U.S. Food and Drug Administration (1977): “General Considerations for the Clinical Evaluation of Drugs”.

·       Stephens, T. D., & Brynner, R. (2001): “Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine,” Perseus Publishing.

·       U.S. Food and Drug Administration (1993): “Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs.”

·       National Institutes of Health (1993): “NIH Revitalization Act of 1993. Public Law 103-43.”

·       Europäisches Parlament und Rat der Europäischen Gemeinschaften (2001): “Richtlinie 2001/20/EG des Europäischen Parlaments und des Rates vom 4. April 2001 zur Angleichung der Rechts- und Verwaltungsvorschriften der Mitgliedstaaten über die Anwendung der guten klinischen Praxis bei der Durchführung klinischer Prüfungen mit Humanarzneimitteln.”

·       Europäisches Parlament und Rat der Europäischen Union (2014): “Verordnung (EU) Nr. 536/2014 des Europäischen Parlaments und des Rates vom 16. April 2014 über klinische Prüfungen mit Humanarzneimitteln und zur Aufhebung der Richtlinie 2001/20/EG.”

·       Maas, A. H. E. M., & Appelman, Y. E. A. (2010): “Gender differences in coronary heart disease,” Netherlands Heart Journal.

·       Reeves, M. J. et al. (2008): “Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes,” The Lancet Neurology.

·       Beam, C. R. et al. (2018): “Differences Between Women and Men in Incidence Rates of Dementia and Alzheimer’s Disease,” Journal of Alzheimer’s Disease.

·       Ngo, S. T. et al. (2014): “Gender differences in autoimmune disease,” Frontiers in Neuroendocrinology.

·       Mogil, J. S. (2012): “Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon,” Nature Reviews Neuroscience.

·       Young, S. et al. (2020): “Females with ADHD: An expert consensus statement,” BMC Psychiatry.

·       Zondervan, K. T. et al. (2018): “Endometriosis,” Nature Reviews Disease Primers.

·       Rapkin, A. J., & Lewis, E. I. (2013): “Treatment of premenstrual dysphoric disorder,” Women’s Health (London).

·       Holdcroft, A. (2007): “Gender bias in research: how does it affect evidence-based medicine?,” Journal of the Royal Society of Medicine.

·    Zucker, I., & Prendergast, B. J. (2020): “Sex differences in pharmacokinetics predict adverse drug reactions in women,” Biology of Sex Differences.