IGF-II, IGFBP-4, -6, and -7, and HMGB1 show changes in follicular fluid in PCOS

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Introduction: Polycystic ovary syndrome (PCOS) is a multisystem endocrine and metabolic disease characterized by chronic low-grade inflammation, ovulatory dysfunction, hyperandrogenism, and insulin resistance. Chronic inflammation modifies the IGF system that regulates ovarian function and glucose metabolism. HMGB1 is an alarmin related with both inflammation and insulin sensitivity, and we previously described the increased follicular fluid concentration of HMGB1 in PCOS. This study aimed to investigate changes in IGF system protein concentrations in follicular fluid from PCOS with respect to control subjects. Methods: A total of 70 PCOS diagnosed according to the Rotterdam criteria and 70 control women were enrolled. Subjects were stratified based on BMI<25 (underweight/normal weight) or ≥25 (overweight/obese). PCOS and controls underwent induction of follicular development for IVF, and follicular fluid was collected during oocyte retrieval. IGF-I, IGF-II, IGFBP-1-7, and HMGB1 concentrations were measured in follicular fluids using specific ELISA kits. Results: IGF-II and IGFBP-4 were lower whereas IGFBP-6 and IGFBP-7 were increased in PCOS compared with controls. Instead, IGF-I and IGFBP-1, -2, and -3 were similar. IGFBP-5 was undetectable. HMGB1 was increased in PCOS. Stratification based on BMI showed that under/normal weight, PCOS women had lower IGF-II and IGFBP-4 and increased IGFBP-7 in follicular fluids compared with controls. IGFBP-2 was higher in under/normal weight controls with respect to their overweight/obese counterparts. When considering the molar ratios, IGF-II bioavailability was significantly lower in PCOS whereas IGF-I bioavailability was unchanged. IGFBP-3 correlated with IGFBP-4 in controls, and IGFBP-2 correlated with IGFBP-1 in PCOS. HMGB1 correlated with IGFBP-2 in PCOS and with IGF-I in controls. Conclusion: The reduction in IGF-II and IGFBP-4 in FF in PCOS is compatible with reduced follicular development. The changes in IGF-II, IGFBP-4, and IGFBP-7 in the under/normal weight PCOS women suggests that these changes are specific to PCOS. The correlation between HMGB1 and IGFBP2 is compatible with the increased inflammatory status in PCOS. The increase of IGFBP-6 and -7 is a novel finding that opens the way for further research.

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