In the past decade, several population-based studies have reported the relationship between circulating Fetuin-A concentrations and PCOS. However, the conclusions of these studies are contradictory. In previous studies, circulating Fetuin-A levels were increased, decreased or unchanged in PCOS patients compared with normal women [22, 31–35]. In the current investigation, we found that circulating Fetuin-A concentrations were markedly elevated in women with PCOS compared to healthy women. Our results are consistent with those of Enli et al. [33–35], but contrary to those of Díaz et al. [22]. The cross-sectional nature of the study and population heterogeneity may be related to differences in outcomes.
Furthermore, previous studies had small sample sizes, and some had no healthy controls or did not include obese patients with PCOS. In this study, we avoid these shortcomings. In addition, we used newly diagnosed PCOS women to avoid the effects of medication, lifestyle interventions, and the duration of the disease that are associated with those patients who have been under treatment. The reason for the rise in circulating Fetuin-A is unknown. We speculate that the metabolic disorders and hyperandrogenism caused by IR (hyperinsulinemia) may promote the synthesis and release of Fetuin-A in vivo. In addition, increased Fetuin-A may be derived, at least in part, by the status of low-grade inflammation, since inflammatory cytokines, such as CRP, are increased in women with PCOS.
Two previous studies found that Fetuin-A inhibits the insulin receptor tyrosine kinase and Toll-like receptor 4 in liver and muscle cells to inhibit insulin signaling and stimulate inflammatory signaling pathways [13, 14]. However, population-based studies have shown that there is no correlation between Fetuin-A and IR in diabetic patients, and there is no correlation between Fetuin-A and the risk of diabetes [36–37]. In the current work, we find that serum Fetuin-A was positively correlated with BMI ,WHR, TG, TC ,LDL-C, HOMA-IR, LH, T and DHEA-S, suggesting that Fetuin-A is associated with hyperinsulinemia and hyperandrogenism. These data support the results of Pal et al. and Srivas et al. [13]. Because circulating Fetuin-A levels were associated with both T and IR, and hyperandrogenic and IR were important characteristics of PCOS, it is of clinical significance to consider Fetuin-A a biomarker for PCOS.
Surprisingly, serum Fetuin-A concentration increased significantly in obese/overweight PCOS women but did not change in overweight or normal women. The reason for this is unknown. We speculated that the main factors affecting circulating Fetuin-A might be hyperinsulinemia and hyperandrogenemia. In our study cohort, a small number of overweight women may have affected the results. In addition, under hyperinsulinemia and hyperandrogenism, elevated circulating Fetuin-A raises the question of whether lowering Fetuin-A concentrations are the key to improving IR and hyperandrogenism. Secondly, because serum Fetuin-A levels are related to hyperandrogenemia, it is important to observe whether circulating Fetuin-A concentration will change with the menstrual cycle due to the change of hormone levels. To address these questions, further study is necessary.
We analyzed the ROC curve to explore the best cut-off point for predicting PCOS with circulating Fetuin-A. Our results show that cyclic Fetuin-A is a good predictor for PCOS patients. We, therefore, believe that the relationship between Fetuin-A and PCOS may be due to the high prevalence of IR in these women.
Our research also has also some limitations. Firstly, the study population is young women, so our results may not apply to an elderly population. Secondly, our results are based on a single measurement of Fetuin-A. Without repeated measurements at different time points, the introduction of random measurement errors in determining biochemical variables is possible.. Finally, the nature of cross-sectional studies makes it impossible for our results to explain the causal relationship between increased Fetuin-A levels and the occurrence of IR and PCOS.