detrans.ai 

← Back to studies

'Considerable Uncertainty': Systematic Review Finds No Reliable Evidence for Puberty Blocker Benefits

Puberty blockers for gender dysphoria in youth: A systematic review and meta-analysis

mental healthcohort studypuberty suppressionmedical ethicsgender dysphoria
Authors
Anna Miroshnychenko, Yetiani Roldan, Sara Ibrahim, Chan Kulatunga-Moruzi, Steven Montante, Rachel Couban, Gordon Guyatt, Romina Brignardello-Petersen
Year
2025
Journal
Archives of Disease in Childhood

Methodological Limitations

  • The review included only English language studies, which may introduce language bias and exclude relevant research published in other languages.
  • The authors modified the ROBINS-I risk of bias tool for assessing before-after and case series studies, which is a deviation from established methodology; while they defend this choice, the modification's validity is unverified.
  • The review included case series studies, which the authors themselves acknowledge 'should only be used for hypothesis generation' and cannot answer questions about intervention effects, yet these were used to assess progression to gender-affirming hormone therapy.
  • The authors rated down certainty of evidence for before-after studies due to 'prognostic imbalance associated with the observational study design not having a comparison group,' but this is a design limitation rather than a bias that can be meaningfully rated down—before-after studies inherently lack comparison groups by design.
  • The authors state they 'did not rate down for inconsistency' despite considerable statistical heterogeneity (I² values of 74%, 89%, 96%, 97%, 98%) because 'the overall effect estimate was not importantly affected,' which contradicts standard GRADE guidance where high heterogeneity typically warrants rating down.
  • For the depression outcome in comparative observational studies, the authors included a study with only 26 participants and rated down two levels for imprecision due to low sample size, yet this extremely small sample renders the evidence virtually uninterpretable.
  • The authors imputed a moderate correlation coefficient (r=0.5) for calculating mean change in before-after studies because original studies did not provide this, introducing potential bias in effect estimates.
  • The review was part of an 'umbrella search' conducted alongside 'another related systematic review,' raising potential concerns about outcome prioritization and whether all relevant studies were fully captured for this specific review.
  • The optimal information size of 200 participants was not met for most outcomes, with some analyses including as few as 6-13 participants, making meta-analyses statistically unreliable.
  • Missing data was a critical problem across included studies, with some studies having less than 50% outcome data available (e.g., 9.92%, 10.74%, 27.27%, 28.7%, 43.9%, 44.29%), yet the authors still included these studies in meta-analyses.
  • The authors assessed 'causal effect' using observational studies not designed for causal inference, and while they acknowledge this limitation, their GRADE approach of rating down for risk of bias may not adequately address the fundamental inability of these designs to establish causality.
  • The review prioritized certain outcomes due to 'feasibility considerations,' meaning important outcomes such as regret, anxiety, and pelvic pain were excluded, limiting the comprehensiveness of the evidence synthesis.
  • The management of conflicts of interest is referenced only to 'online supplemental appendix 9,' making transparency about potential conflicts impossible to assess from the main text.

Key Findings

  • The evidence for puberty blockers' effects on youth with gender dysphoria is mostly 'very low certainty' across all measured outcomes, meaning we cannot reliably conclude whether they help or harm.
  • Only 10 studies met inclusion criteria, with no randomized controlled trials found; most studies had serious methodological flaws like missing data and lack of proper comparison groups.
  • Potential mental health benefits (improved global function, reduced depression and gender dysphoria) were suggested but remain highly uncertain due to weak study designs. Another study (Olson-Kennedy et al., 2025) shows that depression got worse.
  • Bone mineral density at the hip, spine, and femoral neck appeared lower after puberty blocker use, though this finding also carries very low certainty.
  • The authors call for methodologically rigorous prospective studies and possibly randomized controlled trials to better understand both short-term and long-term effects of this intervention.

Abstract

Aim Gender dysphoria (GD) refers to the psychological distress associated with the incongruence between one's sex and one's gender identity. To manage GD, individuals may delay the development of primary and secondary sex characteristics with the use of puberty blockers. In this systematic review, we assess and summarise the certainty of the evidence about the effects of puberty blockers in individuals experiencing GD. Methods We searched Medline, Embase, PsychINFO, Social Sciences Abstracts, LGBTQ+ Source and Sociological Abstracts from inception to September 2023. We included observational studies comparing puberty blockers with no puberty blockers in individuals aged <26 years experiencing GD, as well as before-after and case series studies. Outcomes of interest included psychological and physical outcomes. Pairs of reviewers independently screened articles, abstracted data and assessed risk of bias. We performed a meta-analysis and assessed the certainty of a non-zero effect using the grading of recommendations assessment, development and evaluation (GRADE) approach. Results We included 10 studies. Comparative observational studies (n=3), comparing puberty blockers versus no puberty blockers, provided very low certainty of evidence on the outcomes of global function and depression. Before-after studies (n=7) provided very low certainty of evidence addressing gender dysphoria, global function, depression, and bone mineral density. Conclusions There remains considerable uncertainty regarding the effects of puberty blockers in individuals experiencing GD. Methodologically rigorous prospective studies are needed to understand the effects of this intervention. Trial registration number PROSPERO CRD42023452171.

Summary

This systematic review and meta-analysis examined the effects of puberty blockers in youth with gender dysphoria by analyzing 10 studies. The authors found that all available evidence—whether from comparative observational studies or before-after designs—was of very low certainty, meaning the true effects on psychological outcomes (gender dysphoria, depression, global function) and physical outcomes (bone mineral density) remain highly uncertain. The researchers conclude that methodologically rigorous prospective studies are urgently needed to properly understand the benefits and harms of this intervention.

Conclusion

The best available evidence reporting the effects of puberty blockers in individuals with GD was mostly very low certainty and therefore we cannot exclude the possibility of benefit or harm. There was evidence available for the outcomes of global function, depression, GD, bone mineral density and progression to gender affirming hormone therapy. High certainty evidence from prospective cohort studies and, if ethical, RCTs, is needed to understand the short and long term effects of puberty blockers in individuals experiencing GD.