Current Status of Animal Models for Premature Ovarian Insufficiency: Similarities to Clinical Manifestations and Therapeutic Applications

Abstract Background: Premature ovarian insufficiency (POI) is a reproductive disorder characterized by the early loss of ovarian function before the age of 40, resulting in infertility and increasing the long-term risk of health issues such as osteoporosis, cardiovascular disease, and neuropsychological disorders. Although many studies have been conducted to understand POI pathophysiology and to develop regenerative therapies, the effectiveness of these therapies in restoring ovarian function remains limited. This review provides a comprehensive evaluation of the establishment of animal models of POI and assesses their similarity to clinical manifestations and therapeutic outcomes observed in human patients. Methods: Published preclinical and clinical studies investigating POI animal models and regenerative therapies were comprehensively reviewed. Animal models were compared with human POI in terms of pathological features, endocrine changes, and therapeutic responsiveness. Evidence from studies of mesenchymal stem cell (MSC)-based therapies, stem cell-derived extracellular vehicles (EVs), platelet-rich plasma (PRP), and scaff old-assisted combination therapies was integrated. Results: POI models induced by chemotherapeutic agents, autoimmune mechanisms, or oxidative stress reproduce POI features, including follicular depletion, disrupted estrous cycles, and altered hormone profiles. However, they do not fully capture the systemic progression of the condition that is observed in human patients. We summarize emerging regenerative treatment strategies, including mesenchymal stem cell-based therapies, stem cell-derived exosome-like extracellular vesicles (EVs), platelet-rich plasma, and scaffold-assisted combination therapies, combining findings from both preclinical experiments and clinical studies. Comparing shared outcome markers, such as estradiol levels and follicle counts, while emphasizing age- and duration-of-amenorrhea differences in treatment response, is critical for assessing therapeutic efficacy, with younger patients and those with shorter disease duration showing more favorable responses. Conclusions: Current rodent models provide valuable insights but have limited ability to predict clinical efficacy. Further POI research should prioritize the development of more physiologically relevant models, such as non-human primates, which more closely resemble humans in both reproductive endocrinology and aging, omics approaches, and artificial intelligence (AI), which may significantly enhance the translational accuracy of POI research.