Exosomal microRNAs as biomarkers of multimorbidity risk in lean and obese women with polycystic ovary syndrome

Polycystic ovarian syndrome (PCOS) is a multifactorial endocrine disorder that is characterised by reproductive, metabolic and cardiometabolic abnormalities. Besides typical hormonal abnormalities, inter-organ communication has a crucial role in the development of PCOS-associated multimorbidity. PCOS causes early changes in the insulin signalling pathway, inflammatory pathways, androgen synthesis genes, and ovarian theca cell activity even before the appearance of regular symptoms such as irregular periods, polycystic ovaries, weight gain, and hyperandrogenism. Exosomes are tiny extracellular vesicles discharged into the circulation. It transports molecular cargoes such as microRNAs (miRNAs), proteins that influence gene expression and reflect the underlying pathophysiological condition of target tissues. Exosomes facilitate early disease detection by carrying stable, selectively packaged gene-regulatory molecules that reflect early cellular and molecular alterations before phenotypic manifestations occur. Although exosomal miRNAs (ExomiR) are stable, non-invasive, and easily detectable in body fluids, they serve as a potent biomarkers. These circulating ExomiR have contributed to multiple organ dysfunctions, including the ovary, adipose tissue, liver, cardiovascular system, and brain, thereby raising the risk of comorbid conditions like endometrial disorder, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. In obese PCOS, circulating ExomiR influences pathways related to steroidogenesis, insulin signalling, inflammation, oxidative stress, and lipolysis. However, its role in lean PCOS is not well studied. This review summarises the potential roles of ExomiR as novel biomarkers that bridge reproductive and non-reproductive facets of PCOS, indicating new paths for precision medicine and tailored treatment interventions in both lean and obese PCOS phenotypes.