Association between uric acid to high-density lipoprotein cholesterol ratio and infertility risk: evidence from a cross-sectional study

Infertility is a prevalent and multifaceted health issue that affects millions of women worldwide. It is defined as the inability to conceive after 12 months of regular, unprotected sexual intercourse.¹ In the USA, approximately 7% to 15.5% of women of reproductive age experience infertility.^2,3 This condition is influenced by various factors, including advancing age, hormonal imbalances, metabolic disorders, and environmental exposures.^4–6 Beyond its profound physical and emotional toll, infertility poses significant societal and economic challenges. Identifying and understanding the underlying risk factors are essential for developing effective prevention and treatment strategies.

The uric acid to high-density lipoprotein cholesterol ratio (UHR) has recently emerged as a novel biomarker for evaluating metabolic function and inflammatory status. Elevated uric acid levels are associated with oxidative stress, inflammation, and endothelial dysfunction,^7,8 while reduced levels of high-density lipoprotein cholesterol may impair lipid transport and vascular health. Recent studies have identified UHR as a predictive indicator for conditions such as type 2 diabetes, metabolic syndrome, coronary artery disease, and hypertension.^9–12 This study aims to explore the relationship between UHR and the risk of infertility, providing insights into its clinical significance for women’s reproductive health.

This study included a total of 4717 participants from the National Health and Nutrition Examination Survey (NHANES) database between 2013 and 2020. Fig. 1 illustrates the participant selection process. The definition of infertility in this study is consistent with that used in previous studies published utilizing the NHANES dataset.⁵Table 1 provides a detailed summary of the baseline characteristics of the participants, divided into the infertility group (n = 659) and the non-infertility group (n = 4058). The mean age of participants in the infertility group was significantly higher (42.29 years) compared with the non-infertility group (39.49 years, P < 0.0001). In terms of racial composition, White participants were the majority in both groups; however, the proportion was higher in the infertility group (68.21% vs 62.03%). Additionally, significant differences were observed between the groups regarding marital status, body mass index (BMI), poverty income ratio, and the prevalence of hypertension and diabetes. Overall, the infertility group was characterized by older age, a higher prevalence of overweight individuals, and an increased rate of hypertension and diabetes.

Fig. 1.

The selection process of NHANES 2013–2020.

Table 2 presents the weighted logistic regression analysis exploring the relationship between UHR and infertility. Participants were stratified into quartiles based on UHR levels, with Quartile 1 serving as the reference group. In the unadjusted model (Model 1), participants in Quartile 4 (OR: 1.48, 95% CI: 1.04–2.12, P = 0.02) exhibited significantly higher odds of infertility compared to those in Quartile 1. After adjusting for age and race in Model 2, this association remained significant for Quartile 4 (OR: 1.52, 95% CI: 1.08–2.15, P = 0.02), but not for Quartile 3 (OR: 1.39, 95% CI: 1.05–2.02, P = 0.04). Further adjustments in Model 3, which accounted for socioeconomic and lifestyle factors such as marital status, educational attainment, poverty income ratio, recreational activity, smoking status, and alcohol consumption, yielded consistent results. In the fully adjusted Model 4, which additionally controlled for hypertension, diabetes, cardiovascular disease, and age at menarche, the odds ratios for infertility were 1.50 (95% CI: 1.06–2.12, P = 0.02) for Quartile 3 and 1.48 (95% CI: 1.04–2.10, P = 0.03) for Quartile 4, compared to Quartile 1. A clear dose-response relationship was observed across quartiles, with P for trend <0.0001 in all models. The dose-response relationship between UHR and infertility was further examined using restricted cubic spline regression (Fig. 2), with comprehensive adjustment for confounding factors (Model 4). A positive, linear association was observed, indicating that infertility risk increases significantly with rising UHR levels (P for overall <0.0001).

Fig. 2.

Dose-response relationship analysis between UHR and infertility. Restricted cubic spline regression was adjusted for age, race, marital status, education level, poverty income ratio, recreational activity, smoking status, drinking status, hypertension, diabetes, CVD, and age of menarche (Model 4). The red solid line represents ORs, red shaded region represents 95% CI.

The results of the subgroup analysis indicate that the association between UHR and the risk of infertility remained consistent across different age, race, BMI, and age at menarche subgroups (all P for interaction >0.05) (Table 3).

In conclusion, this study establishes a significant positive association between the UHR and infertility risk. Utilizing a large, nationally representative cohort from the NHANES database, we identified a clear dose-response relationship, where higher UHR levels were consistently linked to an increased risk of infertility. These findings highlight the potential of UHR as a valuable biomarker for identifying women at elevated risk of infertility, offering opportunities for early detection and targeted interventions. However, as a cross-sectional study, our findings cannot establish causality, limiting the ability to determine the temporal relationship between UHR and infertility. Future research should focus on elucidating the underlying mechanisms connecting metabolic dysregulation to reproductive health and assessing the clinical utility of UHR in the management and prevention of infertility.