Gender-Affirming Hormone Therapy for Transgender Youth: Telomere Homeostasis, Psychological Wellbeing, and Barriers to Research

Abstract

Transgender youth face uniquely high rates of psychological distress. Such stress – particularly when prompted by childhood adversity – has been well-documented as concomitant with accelerated telomere shortening and depressed telomerase activity, which increase genomic instability and susceptibility to numerous health concerns. The relationship between stress and telomere length has not yet been studied in trans youth, nor has there been any research on whether telomere homeostasis in trans youth is impacted by gender-affirming hormone therapy (GAHT), which is a notably understudied field of medicine. Thus, we set out to (1) use PCR-based analyses of telomerase activity and hTERT expression to determine the effects of sex hormones on telomere homeostasis in vitro; (2) establish an infrastructure for a larger clinical study of trans youth undergoing GAHT that assesses longitudinal changes in physiological and behavioral parameters, including telomere homeostasis and psychological wellbeing; and (3) examine the procedural and systemic barriers to our clinical study using a continuing quality improvement (CQI) approach. Validated by repeat measures and the use of appropriate controls, our in vitro analysis revealed that telomerase is post-translationally upregulated by β-estradiol and testosterone, thus establishing a baseline biological relationship between telomere homeostasis and steroid hormones in normal human somatic cells. This will complicate any results derived from our future in vivo analyses of telomere homeostasis in trans youth receiving β-estradiol or testosterone treatment. Establishing a foundation for our larger clinical study, we successfully formed an interdisciplinary research team, recruited a cohort of patients undergoing GAHT, validated the functionality of the surveys used for their psychological assessment, and initiated the formation of a biological repository for use in in vivo analyses of their telomere homeostasis. Finally, our CQI investigation revealed 7 major areas of concern in our patient recruitment strategies. This allowed for the implementation of reforms that will not only improve our own methodologies but also provide insight into best practices for future clinical research on GAHT for trans youth. Amidst a notably volatile sociopolitical climate around GAHT, this thesis serves as a roadmap for establishing reliable research infrastructure for investigating the longitudinal impacts of gender-affirming medical care on the wellbeing of trans youth, both at the macroscopic and molecular levels.