Psychological and physical effects of short-term discontinuation of feminizing gender-affirming hormone therapy among older transgender women: a within-subject clinical trial.

study questionWhat are the psychological and physical effects of short-term discontinuation and subsequent reinitiation of feminizing gender-affirming hormone therapy (fGAHT) in older transgender women receiving long-term therapy? SUMMARY ANSWER: Short-term fGAHT discontinuation increased estradiol deprivation-related symptoms while reinitiation showed opposite effects, and psychological well-being was not affected. WHAT IS KNOWN ALREADY: With growing numbers of older transgender individuals, questions arise regarding the necessity of long-term continuation of fGAHT, particularly since cisgender women have low estradiol concentrations after menopause. However, data on the effects of fGAHT discontinuation in older transgender women are lacking. STUDY DESIGN, SIZE, DURATION: This within-subject clinical trial included 19 participants and was conducted in 2024 and 2025. PARTICIPANTS/MATERIALS, SETTING,

methodsTransgender women aged ≥55 years (median age 66 years), on fGAHT for ≥5 years (median 23 years), were recruited from the Center of Expertise on Gender Dysphoria, Amsterdam, the Netherlands. Estradiol deprivation-related symptoms, sleep quality, quality of life, mental health, and body image were assessed via questionnaires at baseline, 12 weeks after fGAHT discontinuation, and 12 weeks after reinitiation. Outcomes were analyzed using multilevel models. Differences were considered substantial based on 95% CIs and ≥10% change between measurements. Perceived psychological and physical changes and willingness to permanently discontinue fGAHT were also assessed via open-ended questions. MAIN RESULTS AND THE ROLE OF CHANCE: Experiences varied, but after discontinuation, unfavorable mean changes were found for somato-vegetative symptoms (β 0.4, 95% CI -0.7 to 1.5, %Δ 11.5), sleep disturbance (OR 1.6, 95% CI 0.2 to 10.3, %Δ 10.7), and happiness to a lesser extent (β -0.5, 95% CI -0.9 to -0.1, %Δ -6.4). Reinitiation showed favorable changes for somato-vegetative and total estradiol deprivation-related symptoms (β -0.8, 95% CI -1.9 to 0.3, %Δ -22.1; β -3.0, 95% CI -4.8 to -1.2, %Δ -36.3), total sleep quality (β -0.7, 95% CI -1.5 to 0.2, %Δ -10.3), sleep onset latency (β -2.8, 95% CI -8.1 to 2.5, %Δ -14.9), and sleep disturbance (OR 0.1, 95% CI 0.0 to 1.0, %Δ -46.6). No mean differences were found for depressive symptoms, anxiety, quality of life, or body satisfaction. Perceived psychological and physical changes were diverse and generally aligned with known menopause-related changes. One participant wished to permanently stop fGAHT. LIMITATIONS, REASONS FOR CAUTION: The study was not blinded or placebo-controlled, which may have introduced expectancy bias. The small clinical sample may limit generalizability to the broader population of transgender women. WIDER IMPLICATIONS OF THE

findingsTransgender women, like cisgender women, experience symptoms in response to estradiol deprivation, which may support the continuation of fGAHT in older age. This study did not identify psychological or body image barriers to discontinuation for those who wish to stop. STUDY FUNDING/COMPETING INTEREST(S): Funded by an Amsterdam UMC PhD scholarship to J.O.v.H. and by departmental funds from the Department of Endocrinology and Metabolism, Amsterdam UMC, location VUmc. K.M.A.D. declares receipt of consulting fees from Recordati, paid to their institution. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER: This study was registered in the EU Clinical Trials Register (EUCTR2023-505143-39-00).