Gender-Affirming Medical Care: Longitudinal Effects on DNA Methylation and Psychological Well-Being in Transgender and Gender Diverse Youth

Abstract

Transgender and gender diverse (TGD) individuals exhibit higher levels of anxiety, depression, and stress than their cisgender peers; this is particularly true of TGD youth. Psychological survey and questionnaire responses have shown that these adverse mental health outcomes are significantly ameliorated by the receipt of gender-affirming medical care, which includes puberty suppression, gender-affirming hormones (GAH), and surgery. However, few studies have investigated the biological effects of gender-affirming care on TGD individuals, and even fewer have explored this question specifically regarding TGD youth. The present study begins to address this gap by analyzing parallel changes in mental health and DNA methylation from blood samples of TGD youth as they receive GAH. Our findings reproduce the results of previous studies that observed improvements in anxiety and stress after a period of time on GAH. Furthermore, this study highlights the limitations of epigenetic aging as a biological indicator of mental health and well-being during the first several months of GAH in TGD youth but suggests a potential role for average M-value (a measure of overall DNA methylation) in predicting self-reported anxiety and stress. Lastly, the present study identifies six differentially methylated CpG sites after 12 months of GAH in transmasculine youth and reproduces the loss of methylation observed at four sites in a differentially methylated region previously reported in transmasculine adults. Not only does this study provide additional psychologically based support for the benefits of GAH, but it also offers new insights into the impact of GAH on the methylome of TGD youth in terms of epigenetic aging and differential methylation.