Fertility in transgender and gender diverse people: systematic review of the effects of gender-affirming hormones on reproductive organs and fertility

Abstract BACKGROUND Transgender and gender diverse (TGD) people seek gender-affirming care at any age to manage gender identities or expressions that differ from their birth gender. Gender-affirming hormone treatment (GAHT) and gender-affirming surgery may alter reproductive function and/or anatomy, limiting future reproductive options to varying degrees, if individuals desire to either give birth or become a biological parent. OBJECTIVE AND RATIONALE TGD people increasingly pursue help for their reproductive questions, including fertility, fertility preservation, active desire for children, and future options. Their specific needs certainly require more insight into the effects of GAHT on gonads, gametes, and fertility. This systematic review aims to provide an overview of the current knowledge on the impact of GAHT on gonads, gametes, fertility, fertility preservation techniques, and outcomes. SEARCH METHODS This review was registered in the PROSPERO registry under number CRD42024516133. A literature search (in PubMed, Embase, and Web of Science) was performed with a medical information specialist until 15 November 2024. OUTCOMES In all TGD people using GAHT, histological changes have been reported. Using testosterone GAHT, ovarian cortical and stromal changes were reported by various studies. In most studies, persistent activity in folliculogenesis can be concluded based on the descriptions of the follicle count, distribution, and oocyte retrieval yield. However, there may be a negative effect on the fertilization rate in the presence of testosterone. Reports of successful ovarian stimulation, fertilization, pregnancies, and live births have been published, describing cases with and without testosterone discontinuation. After using oestrogen GAHT, testes are reported to be more atrophic, including smaller seminiferous tubules with heavy hyalinization and fibrosis. Spermatogenic levels varied widely from complete spermatogenesis to meiotic arrest with spermatids, to spermatogonial arrest, Sertoli cells only, or even tubular shadows. Oestrogen and anti-androgen treatment causes higher proportions of sperm abnormalities (i.e. low total sperm count, low sperm concentration, poor sperm motility) or azoospermia. However, after cessation, this may be restored. WIDER IMPLICATIONS Although knowledge of the effect of GAHT is growing, blind spots remain to be uncovered. Therefore, additional research in this specific population is needed, preferably comparing outcomes before and after the start of GAHT. This may help to reveal the pure impact of GAHT on reproductive functioning. Research suggestions also include investigations into the reversibility of the GAHT effect, especially for those who start transition at a young age. Looking carefully at the presented data on GAHT effects on gonads and gametes, the correct advice is to assess and reassess reproductive wishes and preferences repeatedly, and also to explore individual fertility preservation needs during gender-affirming treatment, given the expanding knowledge and therapy opportunities. Finally, concerns regarding long-term health outcomes and quality of life of children born by the use of gametes preserved after exposure to GAHT require prospective follow-up studies.