'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

Systematic & evidence reviews Puberty blockers Mental health & suicide

Authors: Anna Miroshnychenko, Yetiani Roldan, Sara Ibrahim, Chan Kulatunga-Moruzi, Steven Montante, Rachel Couban, Gordon Guyatt, Romina Brignardello-Petersen
Journal: Archives of Disease in Childhood
Year: 2025
Source: pubmed.ncbi.nlm.nih.gov/39855724/

Summary

This review collected every study it could find, up to September 2023, on puberty blockers for young people with gender distress, and rated how trustworthy the evidence was. Only 10 studies qualified, and none was a randomised trial, where people are assigned to treatment by chance. The studies were small and often missing results for many people. Every result on mental health, gender distress and bone density was rated very low quality. Bone density seemed lower after treatment, and nearly all young people went on to cross-sex hormones. The authors conclude we cannot tell whether blockers help or harm, and call for better studies. Its findings match other independent reviews, including those for England's Cass Review. But it was funded by SEGM, a group critical of youth transition, it only searched English-language studies, and it misses newer studies.

Key findings

The review found 10 studies: 3 compared young people who did and did not take blockers, and 7 only measured the same people before and after.
There were no randomised trials, where people are assigned to treatment by chance.
All evidence on gender distress, daily functioning and depression was rated very low quality, so neither benefit nor harm can be ruled out.
In the comparison studies, daily functioning scores looked somewhat better with blockers after 12 months, but the result was so uncertain it could mean anything from slightly worse to much better.
Bone density at the hip and spine fell behind others the same age after blockers, though this evidence was also rated very weak.
In two studies, 92% of young people given blockers went on to cross-sex hormones within 1 to 3 years.
Several studies had results for fewer than half of the young people, and none properly accounted for therapy, other mental health conditions or family support.
The authors call for careful studies that follow young people forward in time and, if ethical, randomised trials.

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.

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.

Methodological limitations

Funder has a stated position: The review was commissioned and paid for by the Society for Evidence-Based Gender Medicine (SEGM) under an agreement with McMaster University. SEGM members helped shape the review question.
Later correction: In 2025 the journal corrected the funding statement to clarify the roles of the university and the funder (Arch Dis Child 2025;110(12):1027).
Search is out of date: The search ended in September 2023. Later studies, including newer long-term data, are not included.
English-language studies only: The authors admit this limit. It may miss useful research from clinics in other countries.
Very few people studied: Some combined results come from as few as 6 to 26 people, far below the 200 the review itself says it needs. So the estimates are very rough.
Lots of missing results: Some studies had results for only about 10% to 44% of people. This is a serious source of bias that the review can point out but not fix.
Mostly no comparison group: Seven of the 10 studies only measured people before and after treatment. So any change cannot be separated from growing up, therapy, or people naturally improving from a low point.
Adjusted quality-rating tool: The authors changed a standard bias-rating tool so it could be used on simpler studies. They say this did not change the conclusions, but the changed version has not been tested.
Conflicting results handled by judgement: The studies' results varied hugely. The authors often chose not to lower their rating for this, reasoning that the overall picture was not much affected.
A guessed number: Studies did not report a figure needed to calculate before-and-after change, so the authors assumed one. They did not report checking whether a different guess changed the results.
Some results not looked at: To keep the work manageable, regret, anxiety and other results were not assessed. So the review does not cover every possible benefit or harm.
Wide age range: Including people up to age 26 mixes studies of teens and young adults, even though blockers are mainly given to teens.
No 'does it matter' test: The review only asked whether effects differed from zero, not whether they were big enough to make a real difference to patients.

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Abstract

Conclusion