Reversibility of testosterone-induced acyclicity after testosterone cessation in a transgender mouse model

Abstract

Objective: To establish if the cessation of testosterone (T) therapy reverses T-induced acyclicity in a transgender mouse model that allows for well-defined T cessation timing.

Design: Experimental laboratory study using a mouse model.

Setting: University-based basic science research laboratory.

Animals: A total of 10 C57BL/6NHsd female mice were used in this study.

Intervention(s): Postpubertal C57BL/6NHsd female mice were subcutaneously implanted with T enanthate (n = 5 mice) or placebo (n = 5 mice) pellets. Pellets were surgically removed after 6 weeks to ensure T cessation, after which the mice were followed for four estrous cycles after the resumption of cyclicity.

Main outcome measure(s): Primary outcomes included daily vaginal cytology and weekly T levels before, during, and after T enanthate or placebo pellet implantation and removal. Secondary outcomes included ovarian follicle distribution and corpora lutea numbers, body metrics, and terminal diestrus hormone levels.

Result(s): T-treated mice (100%) resumed cycling within one week of T pellet removal after six weeks of T therapy. T levels were significantly elevated during T therapy and decreased to control levels after surgical pellet removal. No detectable differences were observed in the follicle count, corpora lutea formation, diestrus hormone levels, or body metrics after four estrous cycles, with the exception of persistent increased clitoral area between T-treated mice and controls. One T-treated mouse was sacrificed early due to vaginal prolapse and not included in subsequent analyses.

Conclusion(s): Our results demonstrated a close temporal relationship between estrous cycle return and T levels dropping to control levels following T pellet removal. The return of regular cyclic ovulatory function is also supported by the formation of corpora lutea and the lack of detectable differences in key reproductive parameters as compared to controls four cycles after T cessation. These results may be relevant to understanding the reversibility of T-induced amenorrhea and possible anovulation in transgender men interested in pausing T to pursue pregnancy or oocyte donation. Results may be limited by the duration of T treatment, lack of functional testing, and physiological differences between mice and humans.

Keywords: Testosterone; mouse model; ovary; reversibility; transgender.