Very Low Certainty Evidence: Major Review Questions Mental Health Benefits of Cross-Sex Hormones in Under-26s

Gender affirming hormone therapy for individuals with gender dysphoria aged <26 years: a systematic review and meta-analysis

Systematic & evidence reviews Cross-sex hormones Mental health & suicide

Authors: Anna Miroshnychenko, Sara Ibrahim, Yetiani Roldan, 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/39855725/

Summary

This review collected studies up to September 2023 on testosterone or oestrogen for teens and young adults with gender distress, and rated the evidence. Of 24 studies, none was a randomised trial, where people are assigned to treatment by chance. Most ignored other mental health care, family support or missing results. Almost every finding on mental health and gender distress was rated very low quality. One study linked hormones to somewhat less depression, but this too was weak evidence. In one study, about 4% of females on testosterone had a heart or blood vessel event over several years. With no comparison group, this cannot show the hormones caused them. The authors conclude benefit or harm cannot be ruled out. The findings match other reviews, but the review was commissioned and paid for by SEGM, a group critical of youth transition, and newer studies are not included.

Key findings

The review found 24 studies of cross-sex hormones in people with an average age under 26: 9 compared treated and untreated people, 13 measured people before and after, and 2 only described treated patients.
There were no randomised trials, where people are assigned to treatment by chance.
Evidence on gender distress, daily functioning and depression was mostly rated very low quality.
One study found people on hormones were somewhat less likely to be depressed (about a quarter lower odds), but this was rated low-quality evidence.
In one records study, 151 of 3,875 females (3.9%) had a heart or blood vessel event between 7 months and 9 years after starting testosterone; another study found 3 of 1,893 (0.2%) after about 2 years.
In one study, 2 of 315 people (0.6%) died by suicide within 2 years, but this evidence was rated very weak.
Many studies did not account for psychiatric treatment, other mental health conditions, income or family support, and several had results for fewer than half of the people.
The authors conclude benefit or harm cannot be ruled out and call for careful studies that follow people forward in time.

Abstract

Objective In this systematic review and meta-analysis, we assessed and summarised the certainty of the evidence about the effects of gender affirming hormone therapy (GAHT) in individuals with gender dysphoria (GD). Methods We searched Medline, Embase, PsychINFO, Social Sciences Abstracts, LGBTQ+ Source and Sociological Abstracts from inception to September 2023. We included studies comparing GAHT with no GAHT in individuals aged <26 years with GD. Outcomes of interest included psychological and physical effects. Pairs of reviewers independently screened articles, abstracted data and assessed the risk of bias in the included studies. We performed meta-analyses and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. Results We included 24 studies. Comparative observational studies (n=9) provided mostly very low certainty evidence regarding GD, global function and depression. One comparative observational study reported that the odds of depression may be lower (OR 0.73 (95% CI 0.61 to 0.88), n (number of studies)=1, low certainty) in individuals who received GAHT compared with those who did not. Before-after studies (n=13) provided very low certainty evidence about GD, global function, depression and bone mineral density. Case series studies (n=2) provided high certainty evidence that the proportion of individuals with cardiovascular events 7-109 months after receiving GAHT was 0.04 (95% CI 0.03 to 0.05, n=1, high certainty). Conclusion There is considerable uncertainty about the effects of GAHT and we cannot exclude the possibility of benefit or harm. Methodologically rigorous prospective studies are needed to produce higher certainty evidence. Trial registration number PROSPERO CRD42023452171.

Conclusion

The best available evidence reporting on the effects of GAHT in individuals with GD ranged from moderate to high certainty for cardiovascular events and low to very low certainty for the outcomes of GD, global function, depression, sexual dysfunction, BMD and death by suicide. We did not find evidence of sexual dysfunction in NMs. The evidence in this SR and meta-analysis does not exclude the possibility of benefit or harm upon receipt of GAHT. Prospective studies giving higher certainty evidence are needed to understand the short and long term effects of GAHT.

Methodological limitations

Funder has a stated position: The review was commissioned by the Society for Evidence-Based Gender Medicine (SEGM) under an agreement with McMaster. SEGM board member William Malone and contributor Evgenia Abbruzzese helped shape the review question.
Authors paid by the funder for other work: Two authors (RB-P, AM) were paid by SEGM for separate work rating gender-medicine papers for its website. They say this was independent of the review.
Search is out of date: The search ended in September 2023, so later long-term studies are not included.
English-language studies only: The authors admit this. Studies in other languages may have been missed.
Mixes teens and adults: Studies counted if the average age was under 26, so average ages ranged from 15 to 25. This makes the results less useful for decisions about teenagers.
Heart figures only show how often, not why: The 3.9% rate comes from one study with no comparison group. It shows how often events happened, not whether hormones caused them, even though the review rated it high-quality evidence of frequency.
Other factors not accounted for: The comparison studies were at serious or critical risk of bias because they did not account for psychiatric treatment, other mental health conditions, income or family support.
Comparison group was not really untreated: In one study, 28% of the 'no hormones' group were taking puberty blockers or a testosterone-blocking drug (spironolactone). This blurs the comparison.
Lots of missing results: Several studies had results for only 20% to 47% of people. This is a serious source of bias the review cannot fix.
Adjusted quality-rating tool: The authors changed a standard bias-rating tool so it could be used on simpler studies. They say other tools would give similar conclusions, but the changed version has not been tested.
Conflicting results handled by judgement: Results varied hugely between studies. The authors did not always lower their rating for this, and explained the differences only after the fact.
A guessed number and no 'does it matter' test: The authors assumed a figure needed to calculate before-and-after change. They also set no threshold for what size of change matters to patients, so real-world importance is not judged.
Some harms not looked at: To keep the work manageable, regret, anxiety, pelvic pain and cancers were not assessed. So several important possible harms are not covered.

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Summary

Key findings

Abstract

Conclusion