Decoding premature ovarian insufficiency: A full spectrum review from epidemiology to management with emphasis on cyclophosphamide-evoked ovarian injury.

Premature ovarian insufficiency (POI) is a complex condition characterized by the termination of ovarian function before the age of 40, affecting approximately 1 % of women within this age group. This review offers a comprehensive overview of POI aspects, including its definition, epidemiology, clinical presentations, etiological factors, diagnostic approaches, complications, and management strategies. A particular emphasis is placed on cyclophosphamide (CPA), an alkylating agent widely used in cancer and autoimmune disease treatment, which is known to cause serious ovarian toxicity leading to POI. The review explores the molecular mechanisms underlying CPA-induced ovarian injury, highlighting the roles of oxidative stress, inflammatory responses, and apoptosis. Key signaling pathways, including TLR4/MYD88/NF-κB, NLRP3 inflammasome, Nrf2/HO-1, α-klotho, and several implicated pathways, are discussed with respect to their contributions to ovarian damage and potential as therapeutic targets. This study seeks to consolidate all data about POI aspects, focusing on the molecular pathways underlying CPA-induced POI and recent pharmacological and natural drugs that showed a protective impact against CPA provoked ovarian injury. Additionally, the impact of CPA on male infertility is discussed. In conclusion, studying these molecular pathways might open the way for early alleviation of POI.