Restoration of ovarian endocrine function with encapsulated immune-isolated human ovarian xenograft in ovariectomized mice

Anticancer treatments may cause depletion of the nonrenewable ovarian reserve of follicles, the source of key hormones, leading to premature ovarian insufficiency (POI) and substantial endocrine, musculoskeletal, and neurological complications. Hormone replacement therapy, the only approved treatment for POI, poorly mimics ovarian physiology. Here, we examined whether human ovarian tissue implanted in an immune-isolating hydrogel-based capsule restored ovarian endocrine function in ovariectomized immunodeficient mice. Daily vaginal cytology, hormone measurements, and histological analysis demonstrated that the encapsulated xenografts integrated into the murine hypothalamic-pituitary-gonad axis and responded to circulating gonadotropins. Without exogenous stimulation, regular estrous cyclicity resumed 12 weeks postimplantation, and mice experienced three to eight estrous cycles in 20 weeks. Large antral follicles, ~3 millimeters in diameter, were present in the grafts, consistent with regular cyclicity and increasing levels of estradiol that reached 50 picograms per milliliter, demonstrating integration with the host physiology and restoration of ovarian endocrine function, similar to the nonencapsulated controls.