Ovarian microenvironment remodeling in premature ovarian insufficiency: From hormone replacement to regenerative strategies with mesenchymal stem cells and exosomes.

Premature ovarian insufficiency (POI) is a heterogeneous disorder characterized by loss of ovarian function before age 40, causing infertility, hypoestrogenism-related complications, and significantly impaired quality of life. Although hormone replacement therapy (HRT) remains the standard treatment for symptom relief and long-term health protection, it cannot restore ovarian reserve or natural fertility. This review summarizes the etiology and pathogenesis of POI, emphasizing mitochondrial dysfunction, oxidative stress, chronic inflammation, and progressive deterioration of the ovarian microenvironment. We critically evaluate the strengths and limitations of conventional HRT based on the latest 2024 international evidence-based guidelines, and comprehensively overview emerging regenerative therapies, focusing on mesenchymal stem cells (MSCs) and MSC-derived small extracellular vesicles (sEVs). MSCs exert therapeutic effects mainly through paracrine actions, including anti-apoptotic, anti-inflammatory, and pro-angiogenic activities. MSC-sEVs, particularly hypoxia-preconditioned ones, offer a safer cell-free alternative. They protect mitochondrial function via the SIRT3/PGC-1α pathway and other related mechanisms such as Nrf2/Keap1 and AMPK signaling. Current clinical evidence for both approaches remains preliminary, consisting mainly of small-scale trials with heterogeneous protocols and short follow-up. We propose an innovative ovarian microenvironment remodeling framework that integrates symptomatic HRT with etiology-targeted regenerative interventions using MSCs or engineered sEVs. In summary, while HRT forms the foundation of POI management, MSC-sEVs represent a highly promising cell-free platform that may shift the paradigm from hormone replacement to functional regeneration, restoring both endocrine function and fertility in POI patients.