The Italian Society of Paediatric Endocrinology confirms the effectiveness of puberty blockers in improving the mental health of trans adolescents

A scientific literature review has just been published by Tornese and colleagues in the journal Frontiers in Endocrinology, following a request from the Italian Society of Paediatric Endocrinology and Diabetology (SIEDP). The conclusions of this review, which support the prescription of puberty blockers for trans adolescents, reinforce the official recommendations of the World Professional Association for Transgender Health (WPATH) (cited here on Trans Youth Trajectories), those of the professional societies of Germany, Austria and Switzerland (AWMF) (cited here on Trans Youth Trajectories), those of the French Society of Paediatric Endocrinology and Diabetology (SFEDP) (cited here on Trans Youth Trajectories), and those of the European Society for Paediatric Endocrinology (ESPE) (cited here by Trans Youth Trajectories), among others.

This Italian literature review is situated in a context in which medical care for trans and gender-diverse youth has evolved radically over the past decade. Until recently, gonadotropin-releasing hormone agonists (GnRHa) – also known as puberty blockers – were prescribed on the basis of clinical observations of their effectiveness. However, in the absence of randomised clinical trials or meta-analyses, they have been the subject of debate regarding their long-term impact on the physical and psychological health of adolescents. The work of Chew and colleagues (2018) had already highlighted clear effectiveness in pubertal suppression, while pointing to a lack of robust data on psychological and cognitive consequences. A later review by Ludvigsson and colleagues (2023) confirmed this lack of strong longitudinal studies. Finally, the recent literature review by Taylor and colleagues (2024), commissioned by British paediatrician Hilary Cass, concluded that the lack of studies of sufficient quality prevented drawing any conclusions regarding the effectiveness of puberty blockers on the mental health of trans adolescents.

A robust methodological approach

In response to these gaps, Tornese and colleagues undertook a comprehensive review of all data published between February 2011 and February 2024, seeking to determine – using the well-established GRADE methodology, notably employed by the WHO – not only the demonstrated benefits but also the potential risks of this intervention.

The body of evidence included in this systematic review comprises fifty-one studies of varying levels of evidence, primarily observational, prospective or retrospective, with treatment cohorts ranging from a few dozen to several hundred adolescents. No randomised controlled trial was identified, highlighting the ethical and methodological challenges involved in conducting such interventions. The inclusion criteria – age under 18 years, advanced pubertal stages, and a diagnosis of gender dysphoria or gender incongruence – reflect the recommendations of professional societies in paediatric endocrinology. The authors implemented a rigorous strategy combining keyword searches in PubMed, EMBASE and the Cochrane Library, along with manual screening of references, in order to maximise the completeness of the literature review.

The effectiveness of puberty blockers in improving mental health

From a physiological standpoint, the synthesis of studies of moderate to high quality convergently shows that GnRHa effectively halt the progression of secondary sex characteristics. Pubertal suppression, measured by low levels of gonadotropins and sex steroids, translates clinically into the cessation of breast development in people assigned female at birth (AFAB) and the stabilization of testicular volume in people assigned male at birth (AMAB). In AFAB individuals, this early intervention considerably reduces the need for later chest surgery (mastectomy), by limiting the development of breast tissue during puberty. In AMAB individuals, the reduction in penile and testicular volume induced by treatment can make penile inversion vaginoplasty (in adults who later undergo estrogen therapy) technically more difficult, sometimes necessitating the use of alternative vaginal reconstruction techniques.

These findings had already been anticipated by earlier reviews, but Tornese and colleagues additionally provide an updated and more nuanced assessment of variations in height and growth velocity, notably pointing to a more marked deceleration of linear growth among youth who initiate treatment later in puberty.

Questions regarding bone health represent a key focus of the review, echoing earlier warnings issued in studies of central precocious puberty and bone mineral density (BMD). Four studies of moderate to high quality report a decrease in lumbar and femoral bone density Z-scores during pubertal suppression, followed by partial recovery under subsequent hormone therapy. These findings support existing recommendations for regular radiological and biochemical monitoring of bone remodelling markers.

On a psychological level, the article highlights a growing body of literature that attributes a crucial role to puberty blockers in reducing mental distress. Several prospective studies show significant decreases in depressive and anxiety symptoms, as well as improvements in overall functioning, with effects strengthened when pubertal suppression is followed by gender-affirming hormone therapy. These findings corroborate the conclusions drawn by de Vries and colleagues (2011, 2014) and are particularly relevant for adolescents assigned male at birth, who often present with higher levels of anxiety prior to treatment.

The most striking finding is undoubtedly the impact on suicidality: Tornese and colleagues report that the incidence of suicidal thoughts and behaviours decreases by more than 70 % among youth receiving GnRHa or gender-affirming hormone treatments. This trend aligns with the observations of van der Miesen and colleagues (2020) regarding the effects of GnRHa alone, and is all the more striking in that it underscores the life-saving dimension of these interventions. This dramatic reduction in suicide risk highlights the major ethical imperative to guarantee access to early, supervised pubertal suppression.

By contrast, the review highlights the lack of “moderate to high” quality studies regarding future fertility, adult sexual function, and cancer risk. This gap prevents the formulation of robust conclusions on these issues, and the authors call for the establishment of long-term cohorts and national registries to resolve these uncertainties. The absence of longitudinal data perpetuates a recurring debate, particularly within ethics committees, about the long-term risk–benefit balance of GnRHa when they are followed by gender-affirming hormone treatments.

Ultimately, Tornese and colleagues advocate for a precision-medicine approach, integrating personalised monitoring of bone density, fertility counselling at treatment initiation, and continuous psychological support. They also emphasise the co-production of long-term research, with strong involvement of trans youth and their families, in order to address unresolved research questions. Among the many articles devoted to gender affirmation in paediatric endocrinology, this systematic review stands out for its methodological rigour and its ambition to bridge the gap between moderate evidence and clinical practice.

Fundamental divergences with the Cass Review

A critical comparison is warranted with the systematic review by Taylor et al. (2024), commissioned as part of the Cass Review in the United Kingdom. This review adopted an approach to assessing study quality that has raised many concerns. Taylor and colleagues used a modified version of the Newcastle–Ottawa Scale (NOS), in violation of the pre-established research protocol, and this adaptation was not scientifically validated, a point recently criticized by Noone and colleagues (see the summary of their critical study on Trans Youth Trajectories). As a result, several key studies – such as those by Achille et al. (2020) and Tordoff et al. (2022), despite being published in peer-reviewed journals and frequently cited – were classified as “low quality” and excluded from Taylor et al.’s results synthesis. This decision had considerable effects on their conclusions, preventing them from formally recognizing improvements in mental health or quality of life among transgender adolescents treated with puberty blockers. By contrast, the Italian review conducted by Tornese et al. uses the ROBINS-I tool, recommended by the GRADE working group for assessing the quality of non-randomized studies, and considers these same two studies to be of sufficiently high quality to be included in the narrative synthesis. By incorporating these studies into their analysis, the Italian authors reach much more affirmative conclusions regarding treatment benefits, particularly in terms of reductions in depression, anxiety, suicidal ideation, and self-harming behaviors. This methodological divergence therefore has a direct impact on health policy recommendations. Whereas Taylor et al. conclude that the evidence is insufficient to justify the use of GnRHa, Tornese et al. instead consider the current body of studies sufficient to support their effectiveness for the mental health of transgender adolescents.

This opposition illustrates how technical choices in study evaluation strongly shape scientific conclusions and, in turn, clinical and regulatory directions. Following the Cass Review, the United Kingdom restricted the prescription of puberty blockers for transgender adolescents to clinical trials, while continuing to allow their routine prescription for cisgender children in cases of precocious puberty. The HHS report commissioned by the Trump administration in the United States also relies heavily on the Cass Review to justify encouraging the discontinuation of puberty blocker prescriptions specifically for transgender youth. In a context where medical decisions are highly politicized, this Italian review makes a valuable contribution by reaffirming that the most recent data, when rigorously analyzed, support a cautious but justified use of puberty blockers for transgender youth.

More broadly, this divergence highlights a recurring epistemological tension in pediatric medicine: many clinical decisions rely on levels of evidence below that of randomized controlled trials, which are often unrealistic or unethical in certain populations. The very history of GnRHa use in the treatment of central precocious puberty in cisgender children illustrates this reality: approved as early as 1981, these treatments were based on short-term open-label studies and small sample sizes, with a body of literature dominated by non-comparative case series. Demanding randomized controlled trials today in the transgender population, while they are considered unfeasible in children with precocious puberty, would amount to imposing an asymmetric requirement.

A recent review further shows that within Cochrane Reports, more than 90 % of medical interventions are based on evidence of less than “high” quality. In this context, denying transgender adolescents access to a treatment whose benefits are now well documented, on the grounds of a lack of randomized trial data, would raise a serious ethical concern. Tornese and colleagues therefore defend a nuanced and pragmatic position: advancing research, certainly, but not suspending access to care while that research is being developed.

To access the Italian study (in English), click here