Circadian Rhytthm Disorder Accelerates The Development Of Polycystic Ovary Syndrome And Its Related Mechanism

Polycystic ovary syndrome(PCOS)is the most common endocrine and metabolic disease in women of childbearing age.The incidence of PCOS has increased year by year in the past 20 years,reaching 10-19.9%.The clinical manifestations:ovarian polycystic changes,ovulation disorders,hyperandrogenemia and metabolic abnormalities,which not only affect women’s fertility,but also lead to many short-term and longterm complications,seriously affecting women’s physical and mental health.In recent years,many scholars have been devoted to the study of the pathogenesis of polycystic ovary syndrome.It was believed that polycystic ovary syndrome is polygenic inheritance,which is the result of the interaction between genetic susceptibility genes and environmental factors.In the past 20 years,contrary to the traditional Chinese life and work style of "sunrise and sunset",with the development of rapid industrialization and economic globalization,non-traditional work and rest time arrangements such as shifts,cross-jet lag work and staying up late leads to young people’s biological rhythm disorder.This feature of modern society,seriously affecting endocrine,metabolism and immunity.Biological clock(circadian rhythm)plays an important role in the pathogenesis of endocrine,metabolic,immune diseases and tumors as a strong environmental risk factor.Polycystic ovary syndrome is an endocrine and metabolism disease.This study hypothesizes that modern women’s shift work,cross-jet lag work and staying up late may be one of the reasons for the increasing incidence of polycystic ovary syndrome over the years.We established a new model of polycystic ovary syndrome:continuous light and androgen reduction model.The results showed that continuous light affected the reproductive endocrine and metabolism of mice.Compared with the traditional PCOS model,the androgen reduction model could achieve the effect of the traditional PCOS model in the same time.These results suggest that continuous light accelerates the occurrence of PCOS.The circadian rhythm disorder is an important environmental factor for the occurrence and development of PCOS,and may be one of the important reasons for the increasing incidence of PCOS in recent years.Objective:in this study,continuous illumination(Control-Light-Light)which used to simulate circadian rhythm disorder,traditional androgen modeling(DHEA6mg/100g-Light-Dark),and a new type of PCOS model:continuous illumination and androgen reduction(DHEA4mg/100g-LightLight)were established and compared to explore the effects of circadian rhythm disorders on the occurrence and development of PCOS,and its related mechanisms were studied in depth.Methods:1.The successful establishment of continuous illumination(Control-LL),traditional DHEA modeling(DHEA6mg/100g-LD),continuous illumination and androgen reduction(DHEA4mg/100g-LL)model;2.The oscillation modes of biological clock genes under different treatments were detected by real-time quantitative PCR.3.The effects of different treatments on the reproductive function of female mice and the related mechanism were studied by the determination of hormone,insulin index through ELISA,ovarian HE,immunohistochemistry,real-time quantitative PCR,immunofluorescence,primary culture of granulosa cells in vitro and other techniques.Results:1.Continuous light interfered with the estrous cycle of female mice by changing the amplitude and rhythm of clock genes:the estrous period of female mice was prolonged and the maintenance period of corpus luteum was shortened;the level of luteinizing hormone secreted by pituitary gland of female mice was increased;the endocrine of granulosa cells of female mice was affected:the level of androgen was increased;The insulin resistance of model mice was increased;The number of ovarian antral follicles was increased,and the genes related to follicular development and oocyte maturation were down-regulated.2.Compared with the traditional PCOS model(DHEA6mg/100g-LD),although the new PCOS model(continuous light and androgen reduction DHEA4mg/100g-LL)reduces the amount of androgen,it interfered with the estrous cycle of female mice,affected the endocrine of granulosa cells of female mice,and affects the metabolism and follicular development and maturation of female mice.The results suggest that the circadian rhythm disorder caused by continuous light accelerates the occurrence and development of PCOS.3.Continuous light may change the circadian clock gene by affecting the function of mitochondria in granulosa cells:affecting the distribution of mitochondria;reducing membrane potential;disturbing the dynamic balance of mitochondrial division and fusion leading to abnormal function of granulosa cells:destroying the endocrine of granulosa cells and affecting the proliferation of granulosa cells,thus accelerating the occurrence and development of PCOS.Conclusion:circadian rhythm disorder caused by continuous light is an important environmental factor in the occurrence and development of PCOS.Together with hyperandrogenemia,it accelerates the occurrence and development of polycystic ovary syndrome by affecting female reproductive endocrine and metabolism.Circadian rhythm disorder may be one of the important reasons for the increased incidence of PCOS in recent years.