Welcome to our serialized overview of an important and often neglected subject in healthcare: the persistent lack of research and treatments for women. This multi-part series, “The Care Gap – Rethinking Women’s Health in Medicine,” reviews the history and institutional practices in medical research, diagnostics, and interventions that have resulted in patient care that often falls short (sometimes dangerously so) when it comes to meeting the needs of women.

Women make up 49.7% of the world’s population; however, they have been historically underrepresented in healthcare research and treatments. Despite many amazing advancements in medicine, there remains a persistent gap in developing diagnostics and therapies that meet the unique needs of female physiology. The elimination of these gaps would not only reduce patient suffering and lost productivity, but there is also an enormous untapped opportunity for economic benefits through innovative product development.

Each installment of this 7-part series will focus on a specific aspect of the gender gap in healthcare, from research through clinical practice, and the impact on women’s health. We’ll also examine how intersecting factors like race, socioeconomic status, and weight bias further disadvantage women seeking treatment. Finally, we’ll discuss the types of changes needed to bridge these gaps and advance the quality of healthcare for all women. In a world advancing towards personalized medicine and precision healthcare, we cannot continue to leave women behind.

Whether you’re a healthcare professional, policymaker, researcher, or a woman frustrated with the system, this series is designed to inform, possibly validate your experience, and hopefully raise awareness and stimulate a conversation around what we can do to improve the delivery of healthcare for all women.

Chapter 1. The Research Gap: A Critical Flaw in Medical Understanding

For decades, women’s healthcare has been shaped by a medical research system that has largely excluded them from participating. From research labs to doctor’s offices, the limited inclusion of women in studies has led to diagnostics, procedures and treatments that often do not adequately address the unique needs of female physiology.

The core of this issue is rooted in a striking disparity between genders in medical research. Historically, studies have focused primarily on male subjects, both human and animal, even to the extent of using male cells in vitro¹, because it was thought that female hormonal cycles would introduce too much variability in behavioural measures (newsflash: that’s largely been disproven).

Women were generally banned or excluded from participating in clinical research studies in the US until the 1990s due to fears of them potentially being pregnant – a fear that was exacerbated by the thalidomide tragedy (which, in 1997, resulted in the FDA barring reproductive-aged women from participating in Phase 1 and 2 clinical trials). Ironically, the exclusion of females due to concerns about hormone cycles interfering with research findings didn’t translate to the clinic, where most drugs currently on the market were considered to have the same efficacy (and dose) in both sexes, despite never having been tested on women.

A consequence of this history is sobering gaps in the understanding and delivery of women’s healthcare. For example, many ‘normal’ clinical ranges are derived primarily from male data and may not be appropriate for females. Recent studies highlight this discrepancy:

1. Women with type II diabetes exhibit distinctly different cardiovascular risk factors, yet clinical trials for diabetes treatments have historically underrepresented female populations.²
2. In June 2024, Alberta Precision Laboratories reported that urinary cortisol reference intervals should be lowered for females, suggesting a 2-4% underdiagnosis of Cushing’s syndrome in female patients.
3. A Chinese study revealed significant differences in blood coagulation factor reference intervals between pregnant and non-pregnant women, stressing the importance of considering pregnancy status in clinical assessments.³

Further compounding this issue is the lack of test and reference interval standardization between different laboratories.⁴ Each lab typically establishes its own reference ranges, which can be influenced by both testing methodology and the population chosen to produce the samples. For instance, in 2017, Dynacare Labs in Ontario updated their reference ranges for complete blood counts (CBCs) because their previous ranges were derived retrospectively from an Ontario population that may have contained anemic patients. The new reference ranges were also enhanced to properly address ethnicity, age and gender.

This pattern of exclusion is also present in preclinical animal studies. Until recently, most researchers routinely used only male animals, assuming that findings would apply equally to females. We now know this assumption is often incorrect, as sex differences can significantly impact everything from drug metabolism to disease progression⁵ (and we will go into these differences in detail in subsequent posts).

Progress towards including females in research has been slow, with advances largely due to institutional mandates around granting and funding. The Canadian Institute for Health Research (CIHR) only required that grant applicants address the consideration of sex in 2010. The US National Institutes of Health (NIH) did not mandate the inclusion of sex as a biological variable in pre-clinical research until 2015. The European Union only mandated sex-specific inclusions in 2014, and this did not come into law until 2016.

Despite these mandates, a survey of over 3,000 papers found that even though the use of females increased significantly from 2009 to 2019, only 16.5% of neuroscience and psychiatry studies in 2019 were designed to identify sex differences.⁶  Of the studies that used both sexes, a significant percentage had design flaws. Importantly, the number of studies using only females remained static at just 3% over that 10-year period. It isn’t much better in acute care trials: a systematic review of 88 trials between 2018-2020 found that participants were still predominantly white males.⁷ While more research is including women and females, we are nowhere near parity, and there is a dearth of female-specific research on conditions that primarily impact women. We can and must do better.

This history of excluding females from both pre-clinical and clinical research has had far-reaching effects that still impact women’s healthcare today. In the next article in this series, we’ll examine how these gaps translate into real-world impacts on women’s health outcomes, from delayed diagnoses to inappropriate and inadequate treatments.

References

1. Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, et al. Sex and gender: modifiers of health, disease, and medicine. Lancet. 2020;396(10250):565-582. doi:10.1016/S0140-6736(20)31561-0

2. LeBlanc ES, Brooks N, Davies M, Chatterjee R. Sex-Specific Cardiovascular Risk Factors and Treatment in Females With T2DM and CVD: Developments and Knowledge Gaps. J Clin Endocrinol Metab. 2024;109(12):e2167-e2177. doi:10.1210/clinem/dgae655

3. Fu M, Liu J, Xing J, et al. Reference intervals for coagulation parameters in non-pregnant and pregnant women. Sci Rep. 2022;12(1):1519. doi:10.1038/s41598-022-05429-y

4. Friedberg RC, Souers R, Wagar EA, Stankovic AK, Valenstein PN. The Origin of Reference Intervals: A College of American Pathologists Q-Probes Study of “Normal Ranges” Used in 163 Clinical Laboratories. Arch Pathol Lab Med. 2007;131(3):348-357. doi:10.5858/2007-131-348-TOORI

5. Rich-Edwards JW, Kaiser UB, Chen GL, Manson JE, Goldstein JM. Sex and Gender Differences Research Design for Basic, Clinical, and Population Studies: Essentials for Investigators. Endocr Rev. 2018;39(4):424-439. doi:10.1210/er.2017-00246

6. Rechlin RK, Splinter TFL, Hodges TE, Albert AY, Galea LAM. An analysis of neuroscience and psychiatry papers published from 2009 and 2019 outlines opportunities for increasing discovery of sex differences. Nat Commun. 2022;13(1):2137. doi:10.1038/s41467-022-29903-3

7. Granton D, Rodrigues M, Raparelli V, et al. Sex and gender-based analysis and diversity metric reporting in acute care trials published in high-impact journals: a systematic review. BMJ Open. 2024;14(5):e081118. doi:10.1136/bmjopen-2023-081118