Extracellular Vesicles and Their Contribution to the Pathophysiology and Management of Polycystic Ovary Syndrome.

Polycystic Ovary Syndrome (PCOS) is a complex metabolic-reproductive condition, which is linked with a hormonal imbalance, ovarian dysfunction, insulin resistance, and chronic lowgrade inflammation. Although much research has been conducted over the years, there are no potential diagnostic methods, and existing therapies are symptomatic. Extracellular Vesicles (EVs), such as exosomes and microvesicles, are known to play a critical role in intercellular communication, are significant for reproductive signaling, metabolic regulation, and immune modulation, and are altered in PCOS. No thorough review has been conducted to date that brings together evidence regarding EVs in PCOS. These issues have been addressed separately in the past or in a narrow context with regard to vesicles of the follicular fluid. This review aims to report the association among EV biogenesis, molecular cargo, and the pathophysiological mechanisms underlying endocrine, metabolic, and inflammatory changes in PCOS. The paper is organized as follows: first, it describes the clinical complexity and unmet needs of PCOS, and then briefly describes EV biology. The paper then provides evidence supporting the hypothesis that dysfunctional EV signaling dysregulates granulosa and theca cells, leading to follicular arrest, the development of a dysmetabolic condition, endothelial cell destruction, and systemic inflammation. Biomarkers of EVs are discussed, including circulating markers, phenotypic markers, and the potential for monitoring disease response to treatment. Lastly, the article compares potential therapeutic breakthroughs, such as EVs derived from mesenchymal stem cells, engineered vesicles for targeted delivery, and emerging clinical evidence, and ends with preclinical and emerging clinical evidence. This review aims to facilitate the translation of mechanistic insights into clinical practice, thereby expediting the use of EVs as diagnostic biomarkers and therapeutic tools for diagnosing and treating PCOS.