Informing Decision Making for Fertility Preservation in Genetic Conditions Associated with Primary Ovarian Insufficiency

About This Grant

Premature ovarian insufficiency (POI) – defined as the loss of ovarian function before age 40 – is a leading cause of infertility and affects approximately 1% of women in the general population. The risk is significantly higher in girls and women with certain genetic conditions, including Turner syndrome (TS) and classic galactosemia (CG), where the majority will experience POI before adulthood and many even prior to puberty. Individuals with these conditions rank POI as one of the most devastating aspects of their diagnosis. Hormone- assisted oocyte retrieval is an established fertility preservation option, but it is only an option if follicles remain following spontaneous menarche. For prepubertal girls, ovarian tissue cryopreservation (OTC) is the only available method, but involves surgical removal of an ovary from a child who potentially might otherwise have achieved spontaneous menarche or natural conception. Clinicians currently lack validated biomarkers to predict which girls with TS or CG are at highest risk of POI prior to menarche, which is critical to choosing the best option for fertility preservation. The proposed study addresses this gap by testing the predictive value of prepubertal Anti-Müllerian Hormone (AMH) and Follicle Stimulating Hormone (FSH) for future ovarian function. AMH is widely used to estimate ovarian reserve in adult women, and FSH measured during the minipuberty of infancy may also have predictive value, but their utility in high-risk, prepubertal populations remains unclear. Aim 1 will test the predictive value of prepubertal AMH and FSH for spontaneous menarche and sustained menstrual cycling in girls with TS and CG from large national cohorts with hormonal data and clinical outcomes. Aim 2 will characterize longitudinal AMH and FSH trajectories and use latent class mixed modeling to identify distinct prepubertal hormone patterns in these populations. This study will be the first to evaluate the longitudinal utility of AMH and FSH as predictive biomarkers of future ovarian function in prepubertal girls with TS and CG—two rare, high-risk populations with limited fertility preservation options. By validating early biomarkers of follicular depletion, this project will directly inform clinical counseling for families navigating complex fertility decisions and support earlier, more personalized intervention planning. The results will establish foundational data for future development of multivariable predictive models incorporating clinical, hormonal, and genetic data to optimize reproductive health outcomes. Ultimately, this work will advance precision fertility care in pediatric populations and may serve as a model for risk stratification and fertility preservation decision-making in other conditions associated with early-onset POI.