Dear Editor,
The medical transition of children and adolescents with gender dysphoria remains hotly debated, and there are significant policy discrepancies internationally. Mills and colleagues review the interventions that make up the "gender-affirming" care pathway, an approach currently promoted by many medical organizations in North America. We wholeheartedly agree with the authors that pharmacists have a responsibility to "understand the evidence" and "place the patient's well-being above any personal cultural beliefs". However, we believe that the use of evidence to support the authors' claim that gonadotropin-releasing hormone (GnRH) analogues are fully reversible and have been shown to improve mental health requires critical evaluation.
GnRH analogues have been used for decades to successfully delay the early onset of puberty in children with precocious puberty.9 Although they are generally considered safe for this indication, concerns have recently been raised about impacts on polycystic ovary disease, metabolic syndrome and future bone density. Even less is known about the use of GnRH analogues to arrest normally programmed puberty in young people with gender dysphoria; there are no long-term longitudinal studies of GnRH analogues for this indication.
Puberty-related hormones have a wide range of effects on brain structure, function and connectivity. Concerns have been raised that hormonal suppression of puberty may permanently alter neurodevelopment. The possible impact of puberty blockade on a young per- son's cognition has important implications for the decision to initiate exogenous hormones of the opposite sex and the ability to give informed consent.14 Furthermore, it has been suggested that puberty suppression may alter the course of gender identity development, essentially "locking in" a gender identity that might have reconciled with biological sex during natural puberty. Over 95% of young people treated with GnRH analogues subsequently receive hormones of the opposite sex. In contrast, 61% to 98% of young people cared for by psychological support alone reconcile their gender identity with their biological sex during puberty. This lack of evidence to support the durability of transgender identification is conceptually consistent with significant psychosocial determinants of transsexual identity, while belief in immutable biological influences can best be described as a "common assumption."
There is also concern that GnRH analogues may have irreversible effects on sexual function and bone development.In some young people
In some young people, pubertal blockade at Tanner stage 2 followed by exogenous hormones of the opposite sex has resulted in a complete absence of sexual function in adulthood. Profound effects on future sexual function can even occur when puberty is interrupted and then allowed to continue, since the precise timing of hormone exposure during the peripubertal period is a determining factor in adult sexual function. Finally, several studies have shown that the expected pattern of bone mass accumulation during adolescence does not occur when puberty is interrupted. The long-term clinical consequences of the absence of normal bone mass accumulation are unknown.
Uncertainties about the long-term risks of medical transition are often overshadowed by the most powerful argument provided by advocates of the affirmative model: the lack of affirmation of a young person's transgender identity can lead to suicide. Suicidal ideation and self-destructive behaviors were found to be higher than in age-matched peers, but comparable to those of non-gendered dysphoric youth referred for management of other mental health diagnoses. However, the pertinent question is whether positive management reduces the risk of suicide.
Mills and colleagues' claim that GnRH analogues have been shown to decrease suicidal ideation over a lifetime stems from an unrepresentative, low-quality survey of transgender adults, which has been extensively criticized by others. Moreover, their claim that these drugs are effective for other mental health problems is at odds with recent systematic reviews that have concluded that there is little change between the start and end of treatment in depression, anxiety, body image, gender dysphoria or psychosocial functioning. A seminal Dutch case series of children with early-onset gender dysphoria is cited to support the claim that GnRH analogues improve psychological functioning. The magnitude of post-treatment improvement in mental health outcomes in this study was small and of questionable clinical significance. Furthermore, the applicability of the results to the most common population presenting today, i.e. adolescent girls with pre-existing mental health problems or neurodevelopmental disorders and no history of gender dysphoria, is questionable. A recent attempt to replicate the results of the Dutch study in the UK revealed no psychological benefit with GnRH analogues, but the treatment was associated with adverse effects on bone development.
Several European countries, which pioneered the medical transition of young people, are now taking a more cautious approach to the use of GnRH analogues and transsexual hormones, after their own evidence reviews failed to show any mental health benefits and highlighted a profound lack of knowledge about harms. The UK's Cass review highlighted the lack of data in its interim report, stating "it is important not to assume that outcomes and side effects in children treated for precocious puberty will necessarily be the same in children or young people with gender dysphoria". Updated NHS guidelines on the treatment of gender dysphoria have removed statements about the reversibility of GnRH analogues, and now state that "little is known about the long-term side effects of hormones or puberty blockers in children with gender dysphoria." The Swedish health authority no longer offers GnRH analogues to minors, except in exceptional cases, stating that "the risks of puberty-suppressing treatment with GnRH analogues and gender-affirming hormone treatment currently outweigh the possible benefits." Finland has severely restricted their use and now recommends psychotherapy as the first-line treatment for gender dysphoric young people. Finally, the French National Academy of Medicine recently issued a press release stating that "great medical caution must be exercised in the case of children and adolescents, given the vulnerability, particularly psychological, of this population and the many undesirable effects, and even serious complications, that some of the therapies available may entail." While puberty blockers and transsexual hor- mones will always be available, the Academy stresses, "the utmost reserve is required in their use, given side effects such as impact on growth, bone fragility, risk of sterility, emotional and intellectual con- sequences and, for girls, symptoms reminiscent of the menopause."
In summary, we believe that the authors' analysis fails to present a balanced assessment of the evidence and betrays a bias in favor of uncritical promotion of medical transition. The widespread methodological and logical weaknesses of the research, coupled with the lack of certainty that the benefits outweigh the harms, should raise questions about the assertion positioned as the "standard of care" in the US and Canada. Patients and their families are counting on pharmacists to resist ideological influences and communicate transparently. To that end, we ask Mills and colleagues to revisit their important study and provide a more nuanced discussion of the evidence base for gender-affirming care.