Serum fructose levels are independently associated with hyperuricemia in PCOS
As shown in Table 2, the prevalence of hyperuricemia in the PCOS group was 42.12%, which was significantly higher than that in the control group (12.03%). Specifically, among all the groups, PCOS women with hyperuricemia had the highest serum fructose levels, and there was no difference in serum fructose levels between the hyperuricemia and non-hyperuricemia subgroups of control women (P > 0.05).
Then, we evaluated the clinical factors contributing to the risk of hyperuricemia in women with PCOS (Table 3). After adjusting for confounding factors affecting hyperuricemia via univariate logistic regression analysis, including age, BMI, HOMA-IR, free testosterone, HDL-C, and triglycerides, elevated serum fructose levels were strongly associated with a high risk of hyperuricemia in PCOS (P = 0.001; OR, 1.380; 95% CI, 1.207–1.577; Table 3).
Discussion
In this study, we reported for the first time that elevated serum uric acid in women with PCOS strongly and positively correlated to serum fructose, and serum fructose is an independent risk factor for hyperuricemia in women with PCOS. In addition, PCOS patients with metabolic dysfunction are usually found to have higher serum fructose and uric acid levels and there is a strong and positive association between elevated uric acid levels and fructose levels. These observations first suggested a link between elevated serum uric acid and fructose metabolic dysfunction in PCOS and fructose-associated elevation of uric acid may play a key role in PCOS-related metabolic disorders.
As reviewed by Taskinen et al., fructose influences several metabolic pathways which result in the generation of uric acid.22 In the liver, fructose is primarily phosphorylated to fructose 1-phosphate, significantly decreasing intracellular phosphate and adenosine triphosphate levels. This decrease stimulates adenosine monophosphate deaminase (AMPD), which catalyzes the degradation of AMP to inosine monophosphate, producing uric acid.23 Fructose also stimulates uric acid synthesis from amino acid precursors24 and competes with uric acid for renal excretion, reducing the rate of uric acid excretion and increasing blood uric acid levels.25 Although these studies have provided preliminary insights into the mechanism of fructose metabolism to produce uric acid, to date, no study has investigated the relationship between elevated fructose and uric acid in PCOS. Our studies have first confirmed the close and positive association between elevated serum uric acid and fructose levels in PCOS. Elevated serum uric acid levels may reflect an underlying disorder of fructose metabolism in patients with PCOS that further emphasize the potential and critical clinical role of measuring serum uric acid levels in routine practice.
In recent years, the treatment of PCOS not only aims at its hyperandrogenemia and infertility symptoms, but also focuses on its metabolic disorders. An interesting finding of this study is that PCOS patients with metabolic disorders showed higher serum fructose and uric acid levels, with a strong positive correlation. Previous studies provided evidence to support our results. High-fructose is associated with several PCOS-associated metabolic disorders, including dyslipidemia, insulin resistance, weight gain, and cardiovascular effects.26 Uric acid is a product of fructose metabolism and involved in reproductive and endocrine metabolic disorders.27 Mounting evidence has shown that uric acid promotes the development of insulin resistance, lipid metabolism disorders, and metabolic syndrome.28 Notably, fructose metabolism can induce hyperuricemia reduces NO levels in endothelial cells and induces insulin resistance.29 Moreover, uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome.30 Collectively, the potential role of fructose-associated elevation of serum uric acid in PCOS may be its effects on the metabolic disorders of PCOS. These preliminary results open new avenues toward improving our understanding of the biological role of fructose and uric acid in the metabolic disorder of PCOS.
The major strength of this study is that this is the first study to evaluate the relationship between serum uric acid and fructose levels in PCOS. Another strength of this study is the application of RCS, a flexible and powerful approach, to analyze the linear/non-linear relationship between fructose and uric acid in participants with different metabolic statuses. We further confirmed that elevated serum uric acid levels were positively correlated with serum fructose levels in PCOS with metabolic disorders, whereas no correlation was found in the controls. Additionally, our study still had several limitations. Although various biochemical measurements associated with PCOS have been considered, other possible covariates (such as diet, smoking, and ethnicity) were not evaluated and the mechanisms underlying the elevated fructose and uric acid levels in women with PCOS remain unclear which need to be clarified in follow-up research.