Challenges to the study of gender dysphoria.

Recently, it has been noted that a better understanding of the aetiology of gender dysphoria is needed to separate the science from the “politics”.1 A second report2 involved seven individuals engaged directly in transgender care or sociology and identified a range of issues with a compelling need for investigation and study. However, an understanding of the biology of gender dysphoria was not listed among them. We are five paediatrician-scientists, all White, cisgender and over 60. We acknowledge our professional and personal characteristics, as they could be considered by some readers of this commentary to be important for understanding our attempt to raise some of the challenges to scientific studies of gender dysphoria. Our goal in writing this commentary is twofold. First, we would like to bring attention to the possible benefits that might accrue from investigating the underlying biology of why some individuals readily acquire and maintain a gender identity throughout their lifetime, while other individuals experience gender dysphoria that might arise at almost any age and can change over time as well, although the latter is not a settled perspective. Second, we would like to describe some of the difficulties that we have faced in getting colleagues, clinicians, individuals with a history of gender dysphoria, scientists, editors and others to engage in a public discussion of how science might be applied in gender studies. This second intent has been heavily influenced both by our own status, the limited number of randomly chosen colleagues with whom we have consulted, and by the highly charged political environment, particularly in the United States, surrounding issues related to sex, gender and science. We have spent our careers trying to improve the scientific understanding of normal childhood traits and ones that might benefit from medical or surgical interventions. Our work with preterm infants led us to recognise that gender dysphoria might have some of its origins in events occurring early on in development, perhaps even prior to birth. We have used novel machine-learning algorithms integrating diverse features, such as multiomics, sociodemographic, psychosocial and environmental factors to predict spontaneous preterm birth and preeclampsia.3, 4 These latter two distinct adverse outcomes of pregnancy will hopefully be reduced both by the early prediction of preterm birth and preeclampsia months before they are likely to occur and by earlier interventions to prevent or mitigate the occurrences. Whereas many of the individual omics measures have been shown to be predictive biomarkers, their computational integration with the more traditional risk factors has enhanced their predictive power and been helpful in identifying potentially causative biologic pathways as preventive or therapeutic targets. Using advanced machine-learning methodologies, even electronic health records can be used to identify novel associations between maternal conditions and neonatal outcomes that have clinical plausibility.5 Importantly, we are not suggesting, however, that the use of such advanced machine-learning approaches should be used for the prediction of gender dysphoria, but instead for informing better, and perhaps earlier, decision-making when such analyses are considered in the context of the current clinical approaches employed to help individuals suffering from gender dysphoria. However, there seems to be a limited literature on the biological contributors to gender dysphoria. Two small, inadequately powered twin studies6, 7 support a possible genetic component. Transitional sexes, sex switching, same-sex interactions and other aspects of non-binary sexual behaviour are common in non-human animals supporting a direct role for evolutionarily determined factors in human gender dysphoria.8 However, other familial, environmental and stochastic factors also likely contribute to this phenomenon, as they do for any complex trait. We hypothesised that identifying biologic measures if integrated with other sociodemographic, psychosocial and environmental factors, might help with the decision-making at the time when physical transitioning is being considered. Understanding this biology might play a future role as one tool in helping families make decisions about the best path forward when children express concerns that their gender assignment given at birth is in conflict with their gender identity. Although our hypothesis could be correct, we also realise that the potential contribution of knowing about any biological correlates of these conditions would likely be small and might have little practical impact on decision-making compared to the possible risk of causing harm to the individuals and communities experiencing gender dysphoria, their parents or healthcare providers in light of the current social and political climate. Early in discussions on whether the type of science we work on—genomics, proteomics, metabolomics or development—might be of some use or benefit to individuals involved directly with descision-making about physical transitioning of children experiencing gender dysphoria, we approached colleagues and experts (some of them affected personally) working clinically with such children. We found that most of these experts were enthusiastic about how new scientific approaches might add to the ability of families and clinicians to help children along this path to quicker and safer resolution. However, at the same time, many also expressed concerns that such science could lead to further discrimination (e.g. if used predictively). Some were concerned that it would affect their ability to provide care or would bring disruptive attention to them or their patients and families. While we do not have any intention to conduct a formal survey of professional views on the topic or overstate the concerns raised in our discussions with others to date, we found this reluctance, unlike any previous experience we had had in applying new technologies to scientific discussions about typical, atypical or other developmentally important traits. When a highly charged political environment limits individuals with the most expertise from joining those interested in exploring these questions, the very issues raised may never be adequately addressed. Thus, we thought that a productive way to proceed would be to express our opinions on the matter in a commentary and look forward to a wider range of opinions and constructive responses. Our discussions were based on several important points. The transition to affirm one's self-realised gender identity by changing one's physical sexual characteristics may bring a sense of freedom from living an inauthentic life and perpetuating a personal falsehood. The benefits of affirmation may outweigh the physical risks of complex and sometimes multiple surgeries, and the possible medical risks from long-term hormonal therapies, such as altered profiles for cardiovascular disease or cancer. However, those affected may also face social or societal risks because of conscious or unconscious biases, with impacts on interpersonal relationships and career development during and after the transition. Moreover, society may impose risks through laws or policies that would adversely affect persons with diverse gender identities. As noted, we encountered an understandable reluctance among our colleagues providing healthcare to trans-children to proceed with biologic inquiries because of concern about doing harm to the children, their parents and even themselves. Of course, the biologic information itself (genetics, epigenetics, transcriptomics, etc.) would not be harmful, but how it might be applied or used by others with agendas divergent from good health care could be. Despite our best intentions, such biologic information could be perceived as stigmatising by trans-persons themselves or might be considered risky because it could be misunderstood, misinterpreted or misused by others who have biases against LBGTQIA+ persons generally—or trans-persons, particularly. Moreover, we found that concern or fear was common among the healthcare providers with whom we spoke. Their perceptions of an unfavourable ratio of risks to benefits for undertaking such an inquiry tended to discourage us from recommending any exploration of biologic correlates to a condition which is also such a fraught sociopolitical construct. Any efforts to identify biologic factors contributing to gender identity would face practical, technical, computational and ethical challenges. Such biologic factors, if they were found to exist, would only be contributory in nature, and not diagnostic. These contributing effects would have to be considered among many powerful psychosocial impacts as a part of a rigorous evaluative programme, as is currently recommended, assessing whether and when it might be in a child's best interest to transition sexually. In conclusion, there may be a way forward for science to help with some of the most difficult and challenging decisions facing young or older trans-persons experiencing gender dysphoria, as well as helping their parents and their healthcare providers. Nevertheless, despite our good intent, we recognise that the way is also fraught with potential social and political pitfalls and unintended consequences. For the time being, it will take the continuing efforts of transdisciplinary teams of competent, thoughtful and caring individuals, including trans-persons, their parents and healthcare providers to consider when such an inquiry would best be undertaken. Indeed, we are not discouraged by the difficulty of the task of improving healthcare for persons experiencing gender dysphoria. Circumspection is essential for researchers in pursuit of a deeper understanding of the biologic underpinnings of the diverse phenotypes of human sexuality. A checklist to improve gender dysphoria research has also been suggested to assist investigators in producing "high quality longitudinal studies that not only assess medical outcomes, but also those outcomes that matter most for affected individuals".9 Such careful investigative efforts might also relieve possible objections to gender dysphoria research by the people who have these phenotypes themselves. In parallel with this recommendation, it is paramount that we ensure access to healthcare for trans-persons of all ages, but especially children, and that we rely on the relevant professional organisations to provide guidance to state-of-the-art care. These organisations and the scientific community need to continue investigating therapies and generating longitudinal data based on outcomes to enable improvement in the care of individuals who need such help. Finally, advocates from all constituencies should continue to oppose healthcare provided by government fiat of non-experts, violating the sanctity of the physician-patient relationship and to educate the communities involved in what best practices are for trans-children and how to support those most in need, the children themselves. No conflicts of interest to declare.