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Use of gender-affirming hormones (GAH) in transgender and nonbinary youth helped improve psychosocial functioning in a four-site prospective, observational study.

In the study of 315 participants in the U.S., taking GAH was linked with a 0.48-point annual increase (on a 5-point scale) in scores for appearance congruence -- defined as alignment between gender identity and physical appearance -- during the 2 years after treatment initiation, reported Diane Chen, PhD, of Robert H. Lurie Children's Hospital of Chicago, and colleagues.

GAH, like testosterone or estradiol, was also associated with a 0.8-point annual increase (on a 100-point scale) in positive affect and 2.32-point annual increase (also on a 100-point scale) in life satisfaction scores, the team reported in the .

At the same time, transgender and nonbinary youth on GAH treatment saw a 1.27-point drop in depression scores each year, as well as a 1.46-point drop in anxiety scores each year.

"[O]n average, depression started in the mild range and decreased to the subclinical level by 24 months," Chen and co-authors said.

In addition, they noted, many of the participants suffered from depression at baseline -- with 27 participants scoring in the severe range. But after 2 years of GAH treatment, 18 (67%) of those with severe depression had their scores drop to the minimal or moderate range.

Similarly, 38.5% of youth with clinical anxiety at baseline recovered after 2 years of GAH treatment.

The timing of treatment initiation also appeared to play a role, the researchers noted. Youth who started GAH in early puberty had higher baseline scores for appearance congruence, positive affect, and life satisfaction and lower baseline scores for depression and anxiety compared with those who started GAH in late puberty. Still, participants who initiated GAH later on in puberty had a greater improvement in appearance congruence.

The authors of an said the "much-awaited" findings provide evidence backing the mental health benefits of GAH, although the study leaves some concerns unanswered.

"Although overall psychological functioning in the study participants improved, there was substantial variation among participants," wrote Annelou de Vries, MD, PhD, and Sabine Hannema, MD, PhD, both of Amsterdam University Medical Centers in the Netherlands. "[A] considerable number still had depression, anxiety, or both at 24 months, and two died by suicide."

In addition to the two suicides, there were another 11 reports of suicidal ideation during study visits, along with two events of severe anxiety triggered by a study visit.

The editorialists added that other factors that may have played a role in these outcomes, like the exact extent of mental healthcare provided during GAH treatment, were missing from the analysis, thus limiting the study. And while only nine participants (2.9%) stopped GAH during the study, it's unclear whether this was because they de-transitioned or ceased GAH because they weren't satisfied with the treatment.

The researchers noted that the vast majority of the study cohort initiated GAH in late puberty (92.4%), with 15 the most common age of initiation (range of 12-20). Few participants reported past use of a gonadotropin-releasing hormone agonist (7.9%). A third of the cohort identified as transfeminine (i.e., persons designated male at birth who identify along the feminine spectrum), 60% as transmasculine, and 6% as nonbinary. Most were white (58.7%), followed by Latinx (24.8%), Black (3.5%), and Asian (3.2%).

Outcomes were measured with the Transgender Congruence Scale, the Beck Depression Inventory-II, the Revised Children's Manifest Anxiety Scale (Second Edition), and the Positive Affect and Life Satisfaction measures from the NIH's Toolbox Emotion Battery.

Chen and co-authors said they will continue to follow this cohort and hope to find "additional predictors of change" to see who might need more than GAH alone to address their mental health challenges.

"We intend to initiate further work with this cohort to focus on understanding reasons for discontinuing GAH among the small subgroup of youth who stopped medical treatment," the team wrote.

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