Polycystic ovary syndrome is an endocrine disease that affects female reproduction. It often exhibits hyperandrogenemia, insulin resistance, and low inflammation. It also increases the risk of type 2 diabetes, metabolic syndrome, hypertension and blood lipids. So far, the molecular mechanism of PCOS is still unclear . More and more studies have focused on oxidative stress caused by mitochondrial dysfunction, which has a negative impact on the development of follicles, indicating that mitochondrial dysfunction plays an important role in the development of PCOS [22, 23]. In recent years, abnormal mtDNA copy numbers and mitochondrial gene mutations in PCOS patients came to the focus of research. In an Iraqi study, a variety of mutations were observed in the mitochondrial transfer RNA in the PCOS group and the mtDNA copy number of this group was lower, whether have diabetes or not . Similar studied were also conducted and discovered the variants of the mitochondrial genome and lower mtDNA copy number of PCOS subjects . In a Han Race family study, the members have inherited insulin resistance and the third generation exhibited PCOS. Analysis of the mtDNA copy number and sequencing data showed that the patients had a mutation in the transfer RNA gene and a lower copy number .
Consistently, in this study, we observed the same trend. MtDNA copy number of the PCOS group was significantly lower than that of the control group in peripheral blood. The multiple logistic regression results showed that mtDNA copy number was negatively correlated with PCOS, and BMI and pulse were positively correlated with PCOS. Based on these results, we tried to construct the ROC curve to find if these factors have the diagnostic potential for PCOS. The ROC curve showed that these factors can suggest the PCOS occurrence to some degree. On the other hand, PCOS is associated with cardiovascular diseases [27, 28]. Analysis of clinical characteristics showed that the systolic BP and pulse were greater in PCOS patients compared with the healthy subjects. As the PCOS patients and control subjects are age-matched, the effect of age can be ignored. Since the BMI was not matched between these two groups and it is a crucial factor for cardiovascular diseases, in this study, we cannot prove with strong evidence that PCOS is correlated with cardiovascular diseases.
At present, the molecular mechanism of the pathogenesis of PCOS is still unknown and oxidative stress has been considered as one of the inducing factors. Mitochondria are the main place where ROS are produced and the hub of metabolic activities , so the role of mitochondria in the pathogenesis of PCOS cannot be ruled out. Unlike nuclear DNA, mtDNA does not have protective histones and is continuously exposed to the endogenous ROS generated nearby, thus it is more susceptible to environmental carcinogens. The mechanism for lower peripheral mtDNA copy number in PCOS patients is unknown and we are not sure it is the reason or the result of PCOS. Different from the other studies that only detecting peripheral samples, mtDNA copy numbers in PCOS ovarian tissue were also detected in this study. Most strikingly, there was no correlation between peripheral mtDNA copy number and tissue mtDNA copy number. Changes in peripheral blood makers do not reflect changes in tissues. This gave us a hint that peripheral mtDNA copy number changes in PCOS may be related to the immune system as the peripheral mtDNA comes from leukocytes. Some studies also found some risk factors which were related to mtDNA copy number in other diseases, including age , smoking, and PM 2.5 exposure levels . It was also reported a low level of progesterone causes overstimulation of the immune system, thus producing more estrogen which leads to the accumulation of autoantibodies in PCOS . This opens a new chapter for mtDNA research in PCOS.
This study had some limitations. First, the sample size for the control group is not as large as the PCOS group, as it was hard to recruit healthy women who were willing to join our study. Second, there was no insulin data for all the participants. Third, normal ovarian tissues were not obtained in this study. We could not compare tissue mtDNA copy numbers between the PCOS and the control group. In the future study, larger population samples as well as, “normal ovarian tissues”, are necessary.
In conclusion, we reported decreased peripheral mtDNA copy number in PCOS patients is independent of biochemical markers. Future studies in these circumstances may uncover the mechanism of PCOS, thereby helping to identify early biomarkers and develop strategies to reduce the risk of the onset of PCOS in women.