Is circulating heme oxygenase-1 (HO-1) associated with the risk of polycystic ovary syndrome (PCOS)? Lower circulating HO-1 is associated with a higher risk of PCOS in non-obese women, in a dose-related manner. PCOS is one of the most common endocrine disorders in women of reproductive age, with increasing worldwide incidence. HO-1 plays a crucial role in many physiological systems, with potent anti-inflammatory, antioxidant and antimetabolic properties. This hospital-based casecontrol study included 80 women with PCOS and 80 healthy control women seen at the Reproductive Center of Tongji Hospital (Wuhan, China) from November 2011 to May 2012. Cases and controls were frequency-matched on age and BMI and were enrolled into the study once written informed consent had been obtained. Serum hormones, glucose, insulin and lipid concentrations were measured using an automated platform. Correlation coefficients and multiple linear regression models were calculated in the combined group (both cases and controls) using serum HO-1 concentration as the independent variable and age and BMI as covariate variables to explore the association between HO-1 and the pathophysiology of PCOS. To examine the independent association of serum HO-1 levels with the likelihood of PCOS, multivariate logistic analysis was used. The strength of the association was tested further by receiver-operating characteristic (ROC) curve models, with or without the addition of HO-1. Compared with controls, women with PCOS were found to have significantly increased insulin resistance (IR), oxidative stress (OS) and inflammation levels, creating a vicious circle of effects in the pathophysiology of PCOS. However, serum HO-1 was negatively associated with this vicious circle. Women with the highest tertile of HO-1 (5.29 ng/ml) had an odds ratio (OR) of PCOS of 0.02 (95 CI 0.00340.07) compared with women with the lowest quartile (3.14 ng/ml) (P 0.01). This trend remained after adjustment for potential confounders in the multivariable model (all P 0.01). ROC analysis based on an existing prognostic model yielded significantly discriminative values for PCOS, with or without the addition of HO-1 (areas under the curves were 0.86 (95 CI 0.810.92) versus 0.95 (95 CI 0.920.98); P for difference 0.0005). It is difficult to establish a time-integrated measure of circulating HO-1 during the progression of PCOS and these findings should be confirmed in large-scale studies involving different ethnic groups. Moreover, the study lacks measurements of glycated hemoglobin (HbA(1c)) to provide an index of blood glucose concentrations over time. Circulating HO-1 that provides protection against IR, OS and chronic inflammation is markedly reduced in non-obese women with PCOS. Low serum HO-1 is suggested as an independent risk factor for PCOS; thus, circulating HO-1 levels may be a novel biomarker for PCOS in young, non-obese women. This work was supported by grants from the National Natural Science Foundation of China (81202210) and the National Science and Technology Support Program of China (2012BAI02B02). None of the authors has any conflict of interest to declare.