Analysis of sex and gender-specific research reveals a common increase in publications and marked differences between disciplines

Gender medicine has evolved as an independent research field over the last decades. The establishment of its scientific validity through rigorous research has been a fruitful approach which is leading to its acceptance and the growth of scientific knowledge. Gender medicine originated from specialty-specific, initially mostly cardiologic, research questions and analysis has been frequently performed in the context of a particular discipline. Research on sex and gender differences includes a range of different approaches, from basic science and etiopathogenetic research, to the analysis of differences in signs and symptoms, diagnostics and management [1‐7].

Research publications in medicine increased over time and this might prompt the assumption that relevant and novel research topics are more frequently investigated today. However, this might not be true. Topics can be abandoned as time passes and interests within the scientific community shift [8]. Funding agencies are encouraging the incorporation of sex and gender aspects into biomedical research and leading scientific journals are requesting its inclusion into data analysis [9‐13]. This is promoting increasing attention to the subject; however, this methodological shift appears to be a lengthy process. In fact, the expected increase in gender-specific research publications over time has never been quantified.

In addition to publication trend differences, it is not known whether some disciplines are more inclined to one research approach rather than to others, and if differences in research design and cohort size exist. Specialty-specific interests have driven the development of the discipline and might be influencing its evolution.

At present, a quantitative and exploratory analysis of gender research is lacking. An overview about the discipline's development would, however, allow for a more systematic approach to present and future research definitions. Comparison among specialties might offer insight into distinct research practice and highlight fundamental gaps that might be subsequently explored. Furthermore, information about sex differences in a specific area of medicine could be relevant to others, as basic mechanisms and differences in clinical management may be similar. Knowing that one specialty offers abundant information about, for example, pathophysiologic research could encourage exploration of similar mechanisms in related disciplines using appropriately modified approaches.

The present study offers a systematic classification of research in gender medicine to provide an initial overview of the field, highlight relevant differences in research approaches between clinical disciplines and identify relevant information gaps.

Gender medicine is a novel and rapidly evolving discipline of research. The present study shows how in the last 30 years, publications including sex and gender differences have progressively increased and more strikingly since the 1990s. Different medical disciplines incorporate this type of analysis in different manners, choosing distinct research approaches, experimental designs and cohort sizes; however, one feature common to all disciplines, but cardiology, is the dramatic underrepresentation of investigation of sex and gender differences in clinical management.

This particular aspect needs to be emphasized and critically evaluated. Research on clinical management, that is, diagnostic approaches, referral practices, invasive and non-invasive therapy choices, is essential in understanding, shaping and improving our everyday clinical practice. Lack of knowledge about gender differences and inadequacies in health care provision have led to significant and potentially fatal imbalances in outcomes. This has been demonstrated in the field of cardiology, where the numbers of women dying of heart infarction at a young age [15‐17] significantly dropped after two decades of research and the dissemination of essential information about gender differences in clinical presentation, symptoms, diagnostic and therapeutic approaches [18, 19]. Examples from other disciplines are following [20, 21]; however, the information is still scarce and the benefits of this additional knowledge not yet widely accepted by the medical community.

Despite this critical lack of information we found a relevant increase in sex and gender-specific analysis over time, with publications markedly rising since the 1990s. This confirms early reports from the 1990s conducted on a limited set of medical journals [22, 23]. The phenomenon might be related to several factors. On the one side, the previously mentioned eye-opening reports about unexpectedly high numbers of female fatalities due to heart infarction [16] might have played a role, as well as the predominantly female fatalities related to torsade de pointes as a side effect of drug therapy [24, 25]. Both events have highlighted a previously ignored problem and created the momentum for the implementation of guidelines by the FDA [12] and NIH [11, 26]. Nonetheless, although the attention toward the topic is increasing, the publication numbers we are identifying are far from satisfactory.

This type of research might still be constrained by limited funds, as there are no specific funding agencies and still few calls for sex and gender-specific research. The difficulty in achieving publications in high impact journals might also play a role. While gender medicine is gaining attention in the scientific community, as demonstrated by the recent editorials in influential journals [10, 27‐30], several editors do not consider the topic worthy of publication and refer authors to the few gender medicine journals. Some causes for this imbalance might also be inherent in the project design. Information about sex and gender specific analysis might be included only in the body of the article and thus not captured by our research strategy; however, this should account only for a minority of the publications. Furthermore, it should be clarified that gender specific analysis is not limited to the enumeration of the number of female and male subjects in the study cohort, but extends beyond that in the form of distinct subgroup analyses [31]. This is not performed in many research publications and failure to do so may lead to incomplete or biased results leading to wrong conclusions and actions [32]. Misleading and, at times, incorrect use of the terminology "sex" and "gender" also plays a role. Authors not familiar with the subject oftentimes use the words interchangeably or use the term "gender" for any distinction between subjects, even if this is related to purely biological differences. This represents a further hurdle to the systematic analysis of publications. If one wanted to clearly identify which articles analysed solely biological differences and which ones cultural and psychosocial distinctions, many publications identifying "gender differences" would have to be reclassified as "sex differences". This warrants further analysis in the future.

Our analysis also revealed how the percentage of basic research performed in animal models varies greatly among disciplines. This is an interesting finding and may reflect intrinsic differences in the use of animal models in different specialties. The importance of using both female and male animals in basic research for etiologic investigations or drug testing is being increasingly recognized [29]. Sex differences in rodent and other animal models have been identified in wild type and congenic animals used in diverse disciplines. However, the variability of reaction in female animals due to their hormonal cycle and the potentially increased costs related to the need for larger numbers of animals to account for this variability during analysis still deters many investigators from doing so.

Last, a systematic collection of data is instrumental for research development and identification of needs and relevant questions. Diversity is the main focus of this area of research, but limited the possibility for comparison of strategies in the past. As we have seen, management research needs much attention if we strive to improve gender-sensitive health care, and although sex and gender-specific analyses are increasing, they are not increasing nearly as much as good research practice would lead us to expect. The present work represents a basic assessment of the status quo and will be used as basis for a public database, which will be made accessible to researchers in the field and open for input of their own research publications. We believe that this platform will encourage exchange among researchers interested in sex and gender-specific research and offer opportunities for fruitful cooperation to close some of the gaps identified in this analysis.

The present work represents the first systematic analysis of the incorporation of sex and gender in research design and evaluation in medicine. Marked heterogeneity characterizes different disciplines, possibly reflecting research approaches and gender roles in the specialties themselves. While a progressive increase in the literature can be noted, a striking underrepresentation of research about gender differences in management characterizes all disciplines but cardiology. Given that the area of clinical management has been identified as crucial in the perpetuation of differences in health care provision, this gap needs to be addressed and possibly closed in the future. This data is also needed for the update and improvement of clinical guidelines to include information about sex and gender differences. We believe that all areas where less then 10% of the performed research is about differences in management, that is, Gastroenterology, Nephrology, Rheumatology and Oncology, definitely need to improve this area. However, most other disciplines only slightly exceed these 10% and are thus amenable to improvement as well. Specific analysis of differences in symptoms, diagnostic accuracy and therapy provision need to be addressed. To date the area of Cardiology can be considered the most productive in addressing these concerns and also in partially translating some results into recommendations for practice.

Furthermore, the use of large cohorts for human studies does not automatically guarantee gender-specific analysis and should thus be regarded as a positive evolution, but not a solution. Gender aspects have to be actively identified and analysed in each study.