Bioengineering Ovarian Endocrine Function: From Follicle Modeling to Cell-Based Hormone Therapy

Premature ovarian insufficiency (POI) is a complex endocrine disorder characterized by the loss of ovarian function before age 40, leading to infertility, hypoestrogenism, and systemic complications. Conventional hormone replacement therapies (HRTs) offer only partial relief, failing to replicate the dynamic feedback of endogenous hormone regulation. Advances in tissue engineering, stem cell technology, and microphysiological systems have catalyzed the development of bioengineered platforms that mimic native ovarian endocrine function. This review outlines progress from three-dimensional (3D) follicle-mimetic constructs and scaffold-free organoids to dynamic ovary-on-a-chip systems, emphasizing advances in steroidogenesis reconstitution, innovations in granulosa-theca co-cultures, and the design of cell-based hormone replacement therapies (cHRTs) capable of re-engaging the hypothalamic-pituitary-ovarian (HPO) axis. We also address critical translational challenges including immunoisolation, vascularization, and regulatory pathway. By bridging bioengineering and reproductive medicine, cHRTs represent a paradigm shift, offering the potential to restore endocrine health, fertility, and systemic homeostasis in a personalized and physiologically relevant manner.