Interventions for Gender Dysphoria and Related Health Problems in Transgender and Gender-Expansive Youth: A Systematic Review of Benefits and Risks to Inform Practice, Policy, and Research

Background

Individuals who identify as transgender, gender expansive, or both (gender expansive includes nonbinary and other identities outside male or female) can experience clinically significant distress and impairment associated with sex-related characteristics inconsistent with their gender identity (i.e., gender dysphoria). Professional organizations have identified standards of care for gender dysphoria—typically, interventions that seek to address psychosocial or physical sources of dysphoria. However, the research evidence on interventions that are part of those standards is rapidly evolving. The purpose of this study's systematic literature review was to summarize (1) the available research on the benefits and harms of interventions for gender dysphoria in transgender and gender-expansive (TGE) youth and (2) the amount and certainty of evidence available for outcomes, organized within broad intervention categories.

Systematic Review Methods

Following best practices for systematic reviews, we conducted a targeted search of studies cited in published clinical guidelines, reviews, and legal proceedings in the first phase of review (June 2023 through January 2024), which informed a broader search in PubMed (in April 2024). We included peer-reviewed studies reporting outcomes from interventions for gender dysphoria delivered to TGE youth, age 25 or younger, published between 1990 and 2023. We did not have a preregistered review protocol. Team members used a template to extract key details about study samples and recruitment, designs, and outcomes and assessed the methodological quality of each study using JBI's critical appraisal checklists. We then summarized the effect estimates and clinical significance for each outcome within a given intervention category, including an assessment of four certainty-of-evidence criteria from GRADE (Grading of Recommendations Assessment, Development and Evaluation; the most widely used framework for summarizing research evidence to inform clinical standards of care). Certainty of evidence is the level of confidence—from very low to high—that an intervention's estimated effect on an outcome (from reviewed research) represents the actual effects.

Findings

The review included 105 studies, representing seven intervention categories: TGE-affirming psychosocial, hormonal (puberty-suppressing hormones and hormone replacement therapy), surgical, and reproductive health interventions, plus two categories not recommended in current standards of care (i.e., gender identity and expression change efforts, treatment for co-occurring mental disorders to reduce gender dysphoria). Most evidence came from cross-sectional, pre-post, and cohort studies. In brief, the outcomes and certainty of evidence for intervention categories were as follows:

• Psychosocial interventions (e.g., social transition, professional psychological support; k = 22 studies) were associated with decreases in suicidality and depression (very low certainty).
• Puberty-suppressing hormones (e.g., gonadotropin-releasing hormone analogues; k = 49 studies) were associated with decreases in pubertal changes, and hormone replacement therapy (e.g., testosterone, estrogen; k = 56 studies) was associated with increases in pubertal changes associated with the youth's gender identity (both with low certainty). Both interventions were associated with reductions in youth-reported gender dysphoria in some studies; that outcome was measured infrequently, and evidence was rated very low certainty.
• Gender-affirming surgeries (k = 18 studies) were associated with reductions in gender dysphoria for mastectomy (low certainty) and other surgery types (very low certainty).
• Across these first four intervention categories, findings indicated low regret, low dissatisfaction levels, and low side effects and complications (all with very low certainty). For example, bone health metrics decreased relative to age-based reference values during puberty suppression; this outcome showed improvement after starting hormone replacement therapy (both very low certainty).
• Some studies found mental health improvements following hormones and surgeries, but others found no effects (very low certainty for all instances of the outcome, because of inconsistent study findings).
• Reproductive health interventions (k = 9 studies) were found to result in successful fertility preservation of viable oocytes, embryos, or semen (very low certainty).
• We did not identify relevant evidence for outcomes in youth for two intervention categories that are part of the standards of care: voice therapy and support for detransition.
• Treatment of co-occurring mental health or developmental disorders (k = 7 case reports) was not associated with improved mental health for interventions targeting eating disorders or depression and anxiety; for interventions targeting autism spectrum disorder, there was some evidence for improved autism symptoms but not gender dysphoria (all very low certainty).
• Gender identity and expression change efforts (sometimes referred to as conversion therapy or reparative therapy; k = 4 studies) were associated with increases in suicidality (low certainty) and increases or no change in mental health symptoms (very low certainty).

Implications

Despite the low certainty of the available evidence, practitioners and policymakers can use evidence-informed approaches that account for uncertainty in their decisions about health care for TGE youth, such as routinely updating the standards of care or developing relevant legislation. Researchers can use our findings to inform efforts to strengthen the evidence base by producing higher-certainty evidence with greater practice and policy relevance.