The ovaries of transgender men indicate effects of high dose testosterone on the primordial and early growing follicle pool

Abstract

Androgens are essential in normal ovarian function and follicle health, but hyperandrogenism, as seen in polycystic ovary syndrome, is associated with disordered follicle development. There are few data on the effect of long-term exposure to high levels of testosterone as found in transgender men receiving gender-affirming endocrine therapy. In this study, we investigate the effect of testosterone on the development, morphological health and DNA damage and repair capacity of human ovarian follicles in vivo and their survival in vitro. Whole ovaries were obtained from transgender men (mean age: 27.6 ± 1.7 years; range: 20–34 years, n = 8) at oophorectomy taking pre-operative testosterone therapy. This was compared to cortical biopsies from age-matched healthy women obtained at caesarean section (mean age: 31.8 ± 1.5 years; range: 25–35 years, n = 8). Cortical tissues were dissected into fragments and either immediately fixed for histological analysis or cultured for 6 days and subsequently fixed. Follicle classification and morphological health were evaluated from histological sections stained with hematoxylin and eosin and expression of γH2AX as a marker of DNA damage by immunohistochemistry (IHC). In uncultured tissue, testosterone exposure was associated with reduced follicle growth activation, poor follicle health and increased DNA damage. After 6 days of culture, there was enhanced follicle activation compared to the control with further deterioration in morphological health and increased DNA damage. These data indicate that high circulating concentrations of testosterone have effects on the primordial and small-growing follicles of the ovary. These results may have implications for transgender men receiving gender-affirming therapy prior to considering pregnancy or fertility preservation measures. Lay summary As part of gender transitioning, transgender men take testosterone therapy. While androgens like testosterone are essential to maintain ovarian health, the effects of long-term testosterone treatment on the ovary are unclear. This study examines whether testosterone impacts ovarian follicle growth activation, follicle health and whether it causes DNA damage. It also looks at how well these follicles grow in tissue culture. The results showed there was a higher proportion of non-growing ovarian follicles in the ovaries of trans men, they appeared less healthy and there were higher levels of DNA damage. After 6 days of tissue culture, there were more growing follicles in transgender ovaries compared to control, but follicle health further deteriorated and there are increased levels of DNA damage. These results identify new effects of testosterone on the ovary and highlight the importance of discussing fertility preservation options prior to starting testosterone.