MON-169 - Myo-Inositol Modulates Endoplasmic Reticulum Stress Signaling in Granulosa Cells in Polycystic Ovary Syndrome

Objective: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by ovulatory dysfunction and metabolic abnormalities. Recent studies suggest that dysregulated endoplasmic reticulum (ER) stress signaling in ovarian granulosa cells contributes to impaired follicular development in PCOS. Myo-inositol (MI) is widely used to improve reproductive and metabolic features of PCOS; however, its molecular actions on ER stress pathways remain poorly defined. This study investigated whether MI improves ovarian endocrine function via attenuation of ER stress in granulosa cells, and whether MI is also associated with metabolic improvements in PCOS models.

Methods: Human granulosa lutein cells (GLCs) were pretreated with MI and exposed to the ER stress inducers tunicamycin or thapsigargin. The expression of unfolded protein response–related genes was quantified by real-time PCR, and cell viability was assessed using the CCK-8 assay. For ex vivo analysis, isolated mouse ovarian follicles were cultured under ER stress conditions with or without MI to evaluate follicular growth. In vivo, a PCOS mouse model induced by dehydroepiandrosterone (DHEA) combined with a high-fat diet (HFD) received MI via drinking water. Estrous cyclicity, insulin tolerance tests (ITT), and serum lipid profiles were evaluated. Ovarian morphology and immunohistochemical expression of ER stress markers were analyzed.

Results: MI significantly suppressed ER stress–associated gene expression, including CHOP, ATF4, and spliced XBP1, and improved cell viability in GLCs under ER stress conditions. MI also restored Akt phosphorylation (p-Akt) suppressed by ER stress, suggesting crosstalk between ER stress signaling and the PI3K/Akt pathway. In cultured mouse follicles, MI attenuated ER stress–induced growth arrest. In DHEA-induced PCOS mice, MI administration normalized estrous cyclicity, reduced follicular atresia, and decreased ER stress marker expression in granulosa cells. In addition, MI significantly improved insulin sensitivity as assessed by ITT and ameliorated dyslipidemia, with reductions in serum LDL cholesterol and triglyceride levels in DHEA+HFD-induced PCOS mice.

Conclusion: MI alleviates excessive ER stress signaling in ovarian granulosa cells and improves reproductive phenotypes in PCOS via attenuation of ER stress, potentially involving restoration of PI3K/Akt signaling through ER stress–PI3K/Akt cross-talk. In line with previous reports, MI also improves metabolic parameters, and these metabolic effects may contribute to the amelioration of PCOS as a disorder in which metabolic and reproductive dysfunctions are closely interrelated. Together, these findings support MI as a non-hormonal endocrine modulator that improves the integrated metabolic–reproductive pathophysiology of PCOS.

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