Current estimates suggest a population of 1.7?2.0 million transgender adults in the United States, many of whom are on cross-sex hormone therapy with estradiol or testosterone (T). National and international medical organizations recommend fertility preservation counseling prior to initiation of cross-sex hormone therapy, based on an assumption of fertility loss. However, the impact and reversibility of long-term cross-sex hormone therapy on reproductive health is largely unknown, particularly in transgender men (female-to-male or FTM). Observational studies in transgender men have yielded conflicting reports around whether long-term T therapy leads to ovarian histopathology similar to polycystic ovary syndrome. Furthermore, there have been almost no studies on the reversibility of T-induced changes after cessation of T for reproductive purposes. Rigorous controlled studies on the effects and reversibility of cross-sex T therapy on postpubertal reproductive function and fertility cannot be ethically performed in humans. None of the published animal models that address the effect of androgens on reproductive function in females are directly applicable to the clinical paradigm of cross-sex T therapy in transgender men. To address this knowledge gap, we have developed a mouse model to mimic T treatment for FTM gender transition. We administered male-range T to postpubertal female mice, who subsequently stop cycling and have defects in ovarian architecture. This model provides a powerful tool to clarify the effects and reversibility of T therapy on reproductive phenotype and function, in a manner not possible in humans. The overall objective of this proposal is to use our FTM mouse model to investigate the reversibility of T-induced changes on reproduction. My central hypothesis is that adverse reproductive changes induced by T therapy will be only partially reversible with T cessation. To test this hypothesis, I will investigate the reversibility of T-induced changes on cyclicity, hormone levels, and fertility in postpubertal female mice (Aim 1), and investigate the reversibility of T-induced changes in ovarian architecture / function and underlying mechanisms (Aim 2). The rationale for conducting this research is that these findings will provide insights into the reversibility of T-induced reproductive changes and lay the foundation for further translational studies to inform clinical practice and counseling around the need (if any) for fertility preservation in transgender men. Additionally, completion of the proposed studies will provide me with critical scientific training in pursuit of my future career as an independent physician-scientist in the reproductive sciences.
The effects and reversibility of exogenously administered cross-sex testosterone (T) on reproductive function in transgender men have not been well characterized. Given guidelines assuming T-induced fertility loss and emerging evidence to the contrary, it is currently not known whether transgender men can expect to pause cross-sex T therapy, resume reproductive function, and produce qualitatively normal eggs or get pregnant. Successful completion of the proposed research will (1) clarify the reversibility of cross-sex T therapy on future reproductive function and uncover mechanisms underlying T-induced ovarian changes in our clinically-relevant female-to-male transgender mouse model, and (2) lay the groundwork for further translational studies to inform clinical practice and counseling around the timing and necessity of fertility preservation in transgender men.
