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A clarion call for high‐quality research on gender dysphoric youth

2023; Wiley; Volume: 112; Issue: 11 Linguagem: Inglês

10.1111/apa.16895

1651-2227

Paul W. Hruz,

Child and Adolescent Health

Accompanying the rapid increase and recognition of adolescents who experience a sex-discordant gender identity over the past decade is a sharp increase in the number of published papers addressing the suffering of this unique paediatric population. The timely review by Ludvigsson and colleagues in this issue of Acta Paediatrica1 assesses the current state of scientific understanding of hormone treatment for children under 18 years of age who experience gender dysphoria with a rigorous systematic review of the English language literature published as of November 2021. The nearly 10 000 published papers identified for consideration in this analysis reflect the enormous interest in this topic. Only 24 studies met the authors' PRISMA criteria as to relevance, risk of bias and quality of evidence. This paucity of relevant studies was also noted in the recent update of the WPATH clinical practice guidelines (SOC-8).2 Due to the absence of randomised controlled trials and limitations of the few longitudinal observational trials identified, this current review was unable to draw conclusions regarding long-term effects of hormonal interventions on psychological health. The review did identify adverse effects on metabolic and bone health. In particular, evidence was found to support concerns that GnRHa treatment delays bone maturation and bone mineral density gain. This effect was only partially recovered by cross-sex hormone administration when studied at age 22 years. Given the absence of high-quality data on the relative risks versus benefits of these treatments, the arrest of normally timed puberty was assessed as an experimental intervention for affected adolescents to be considered only in a research setting. With these limitations, the authors propose priorities to address current scientific deficiencies and a checklist to facilitate collaborative efforts, the GEnder Dysphoria HORmone treatment checklist (GENDHOR). The list consists of recommendations to consider when planning a study of gender dysphoria, whether observational or interventional. Among the many areas of active investigation in the still emergent field of gender medicine are the epidemiology of gender incongruence both in relation to incidence and prevalence, potential aetiologies, whether the many psychological co-morbidities found in children with gender dysphoria are contributing factors to the emergence of this condition or merely a result of social stress, and effective approaches to alleviate suffering in this vulnerable and often misunderstood patient population.3 Superimposed upon these scientific questions has been a growing cultural polarisation driven largely by ideological differences in understanding the nature of the human person with respect to sexual identity. As addressed by the authors of this review, there are several methodological limitations of published studies on the use of GnRH agonist and cross-sex hormone administration in adolescents with gender dysphoria. This includes study design that is incapable of establishing a causal relationship between study intervention and outcome. High subject dropout rates over time result in difficulties in obtaining adequate long-term follow-up and incomplete outcome measures for a large proportion of individuals. In addition to the inherent difficulties encountered by researchers in this field, serious potential for biases in methods for subject recruitment, data gathering, analysis and reporting are also highlighted. While not unique to studies on gender medicine, recognising and minimising such biases have a potential to significantly enhance the integrity scientific investigation of sex-discordant gender identity. Different scientific premises underlie different hypotheses regarding the most effective means to address suffering in this vulnerable patient population. The veracity of each premise will largely influence the likelihood of disproving the null hypothesis when investigating interventions both in relation to methods and intended outcomes. The premise that sex-discordant gender identity is the result of a bodily defect present within an individual with normal psychological function leads to hypotheses that health will be restored if the body is changed to align with gender identity. Conversely, the premise that sex-discordant gender identity is largely influenced by, or the result of psychological factors, leads to hypotheses that health will be restored by addressing the contributing psychological difficulties.4 While all scientific premises do not share the same level of merit, as premises, they themselves cannot be empirically tested. Rather, it is the results of the interventions based upon hypotheses arising from these premises that are the subject of scientific investigation and which was examined in this paper. In the event that two different approaches are found to be of equal or similar benefit, interventions with lower risk and cost are preferable to those with higher risk and cost. This is based upon the ethical principles of non-maleficence and justice.5 In this respect, the direct disruption of gonadal function with known or potential risk of loss or impairment of reproductive capacity and the lifelong medical dependency induced by such interventions raises a high bar to meet in comparison with potential psychologically based approaches.4 Delivery of medical interventions without a full understanding of risk versus benefit is common in clinical practice, particularly when addressing problems in children. However, the threshold for engaging in a novel therapeutic approach is proportionate to the accepted risk. With interventions of low or temporary risk, lower levels of evidence are generally tolerated. Given that gender-affirming medical interventions involve the disruption of normal endocrine and sexual function, with some components of this approach likely to be irreversible, it is appropriate to engage with considerable caution, informing patients of such risk. Ideally, if undertaken with serious knowledge deficits, such approaches should be done within the context of a controlled clinical trial. The primary conclusion of Ludvigsson and colleagues that the relative benefit versus risk of the affirmation approach has not been established is consistent with other recent analyses of the scientific literature using different methodologies. This includes a scoping review conducted by COHERE, the Council for Healthcare Choices in Finland6 and two reviews by the National Institute of Clinical Excellence in the United Kingdom that address separately the use of puberty blockers7 and cross-sex hormones.8 Several ethical considerations and logistical challenges must be acknowledged in conducting randomised controlled trials in gender dysphoric youth.9 Yet these obstacles are not insurmountable if attention is given to basic principles of rigorous clinical study design. Given the current low quality of evidence currently available, clinical equipoise continues to exist. Arguments to the contrary reflect underlying confirmation bias. While it is virtually impossible to envision a ‘placebo controlled trial’ where one group received gender-affirming medical interventions and the control group did not, both prudence and scientific principles can allow for both intervention and control groups to receive identical interventions in all respects except for the independent variable being tested. With clearly defined and, at least initially, short study duration under the oversight of established institutional review boards, the safety of study subjects can be reasonably preserved. Ludvigsson and colleagues propose an example of a study where subjects and controls are both provided affirmative medical interventions with the independent variable of psychotherapeutic intervention. When considered in light of existing data from a non-randomised study in which subjects receiving either pubertal blockade together with psychological support or psychological support alone were both found to have improved psychological function, such a proposal is reasonable and ethically justified.10 Scientific questions related to the prevalence of gender incongruence desistance and whether this is changing in relation to changing patient demographics are particularly sensitive to selection biases. As discussed by Ludvigsson and colleagues, where randomised controlled trials are not possible, there remains opportunity to conduct more rigorous longitudinal studies with sufficient sample size to allow assessment of outcomes for individual subjects. With a goal of providing medical care that will result in substantial and sustained improvements in human flourishing with minimization of collateral damage to bodily integrity, it is essential that scientific premises are appropriately scrutinised, innovative hypotheses for intervention continue to be considered, and diversity of viewpoints are allowed among grant review study sections, journal editorial boards, academic institutions and within professional organisations. The first step in elevating the field of gender medicine to that of other scientific disciplines is to be aware, with humility, of what remains unknown about the paediatric experience of gender incongruence. The scientific community should remain grateful for the contributions made by the pioneers who have initiated efforts to understand and address the human suffering experienced in affected youth. Yet the most important work of discovery remains in its infancy. Building upon a fragile foundation, tremendous opportunity remains for the design and conduct of high-quality scientific study. None.