New Systematic Reviews of Puberty Blockers and Cross-Sex Hormones Published by NICE

Weighing potential benefits against profound long-term uncertainties

In 2020, the UK National Institute for Health and Care Excellence (NICE) undertook two systematic evidence reviews of the use of GnRH agonists (also known as "puberty blockers") and cross-sex hormones as treatments for gender dysphoric patients <18 years old. These reviews were commissioned by NHS England, as part of a review of gender dysphoria healthcare led by Dr Hilary Cass OBE. The reviews were published in March 2021.

The review of GnRH agonists (puberty blockers) makes for sobering reading. Its major finding is that GnRH agonists lead to little or no change in gender dysphoria, mental health, body image and psychosocial functioning. In the few studies that did report change, the results could be attributable to bias or chance, or were deemed unreliable. The landmark Dutch study by De Vries et al. (2011) was considered “at high risk of bias,” and of “poor quality overall.” The reviewers suggested that findings of no change may in practice be clinically significant, in view of the possibility that study subjects’ distress might otherwise have increased. The reviewers cautioned that all the studies evaluated had results of “very low” certainty, and were subject to bias and confounding.

The review of cross-sex hormones identified similar shortcomings in the quality of the evidence. The reviewers noted that “a fundamental limitation of all the uncontrolled studies in this review is that any changes in scores from baseline to follow-up could be attributed to a regression-to-the-mean,” rather than the beneficial effects of hormone treatment. No study reported concomitant treatments in detail, meaning that it is unclear if positive changes were due to hormones or the other treatments participants may have received. The reviewers suggested that hormones may improve symptoms of gender dysphoria, mental health, and psychosocial functioning, but cautioned that potential benefits are of very low certainty and “must be weighed against the largely unknown long-term safety profile of these treatments.”

These two latest systematic reviews echo serious concerns with the quality of evidence outlined by Professor Carl Heneghan, the Director of Oxford's Centre for Evidence-Based Medicine (CEBM) and the Editor-in-Chief of BMJ EBM. Similar concerns with the absence of quality studies in this vital area of medicine were also noted by systematic review efforts undertaken by Sweden and Finland in the last 18 months. A recent Cochrane review examining hormonal treatment outcomes for male-to-female transitioners > 16 years found "insufficient evidence to determine the efficacy or safety of hormonal treatment approaches for transgender women in transition." It is remarkable that decades after the first transitioned male-to-female patient, quality evidence for the benefit of transition is still lacking.

Two systematic reviews commissioned by the US-based Endocrine Society in 2018 concur with the finding of the weak evidence base, stating that the finding of benefits of hormonal interventions in terms of "psychological functioning and overall quality of life" comes from "low-quality evidence (i.e., which translates into low confidence in the balance of risk and benefits)." Despite this sober assessment, the Endocrine Society instructed clinicians to proceed with treating gender-dysphoric youth with hormonal interventions in its guidelines, which have now been broadly adopted by a number of medical societies. 

In SEGM's view, the "low confidence in the balance of risks and benefits" of hormonal interventions calls for extreme caution when working with gender-dysphoric youth, who are in the midst of a developmentally-appropriate phase of identity exploration and consolidation. While there may be short-term psychological benefits associated with the administration of hormonal interventions to youth, they must be weighed against the long-term risks to bone health, fertility, and other as yet-unknown risks of life-long hormonal supplementation.

Further, the irreversible nature of the effects of cross-sex hormones, and the potential for puberty blockers to alter the natural course of identity formation should give pause to all ethical clinicians. Studies consistently show that the vast majority of patients with childhood-onset gender distress who are not treated with "gender-affirmative" social transition or medical interventions grow up to be LGB adults. However, there is emerging evidence that socially-transitioned and puberty-suppressed children have much higher rates of persistence of transgender identification, necessitating future invasive and risky treatments. The trajectory of the novel, and currently the most common presentation of gender dysphoria, which emerges for the first time in adolescence following a gender-normative childhood is unknown, but the increasing voices of desisters and detransitioners suggest the rate of regret within this novel cohort will not be as rare as previously estimated. 

It is SEGM's position that the significant uncertainties regarding the long-term risk/benefit profile of "gender-affirmative" hormonal interventions call for noninvasive approaches as the first line of treatment for youth. If pursued, invasive and potentially irreversible interventions for youth should only be administered in clinical trial settings with rigorous study designs capable of determining whether these interventions are beneficial. In addition to undergoing rigorous psychological and psychiatric evaluations, patients and their families should participate in a valid informed consent process. The latter must accurately disclose the limited prognostic ability of the gender dysphoria/gender incongruence diagnosis for young people, and the many uncertainties regarding the long-term mental and physical health outcomes of these poorly studied and largely experimental interventions.