The Clinical Research Of Polycystic Ovary Syndrome And The Establishment Of Pathological Model Of Cynomolgus Monkey

PART1 Follicular hyperandrogenism and insulin resistance exist despite normal circulating testosterone levels in a subgroup of PCOS patientPolycystic ovary syndrome(PCOS)is a common reproductive disease with highly heterogeneous.The role of excess androgen in PCOS etiology remains disputed,since around 20-50% of PCOS women do not display hyperandrogenemia.Microenvironment of the ovary critically influences follicular development.In the present study we assessed the role of androgen in PCOS by investigating whether follicular fluid(FF)hyper androgen existed in PCOS patients with normal serum androgen levels and was influenced by FF insulin resistance(IR).FF samples of 105 women with PCOS and 105 control were collected.Levels of steroid hormones,glucose and insulin in FF were examined and compared with the data from serum biochemistry tests.We found that 64.9%(63/97)of PCOS patients with normal serum androgen level displayed abnormally high FF androgen level.The FF androgen level was positively correlated with FF IR within a certain range and FF-estrogen-totestosterone ratio(FF-E2/T)was significantly reduced in these patients.These results indicated that there existed a subgroup of PCOS patients who displayed FF hyper androgen and IR despite their normal circulating testosterone(T)levels.Our study highlighted the importance of ovary local hyperandrogenism(HA)and related IR in etiology of PCOS.Part 2 Establishment of a model of polycystic ovary syndrome in adolescent cynomolgus monkeysPolycystic ovary syndrome(PCOS)is a common complex reproductive disorder prevalent among reproductive-aged women worldwide,associated with the complex and unclearly etiologic and pathogenesis.Animal model plays an irreplaceable role in the pathogenesis and clinical study of PCOS.Nonhuman primates have the most similar reproductive and physiological characteristics to those of humans than other experimental animals.Rhesus macaque(Macaca mulatta)as one of the non-human primates was commonly used in PCOS model establishment.The rhesus monkey model of PCOS can be constructed by means of prenatal and postnatal androgen exposure,but it needed a long cycle(several years)for producing the PCOS-like traits.However,with no ovulation in half a year,the reproductive cycle of rhesus macaques is very different from that of human beings.In contrast,cynomolgus monkey(Macaca fascicularis)has more similar reproductive cycles with human beings.The genome sequencing of cynomolgus monkey has been completed,with a smaller size and lower feeding costs,made it a proper choice to establish the PCOS-like traits model.In this study,by using a short time treatment of dihydrotestosterone(DHT)in the adolescent cynomolgus monkey,we tried to obtain a nonhuman primates model of PCOS which is representative of the disease phenotype and suitable for carrying out further research.Thirteen female cynomolgus monkeys(age between 4-5 years)were separated into the control group,DHT group and DHT+HFD group,separately received subcutaneous injections of vehicle(soybean oil),DHT or DHT coupled with high fat diet treatment for about twelve-menstrual cycles.And a series of serology and molecular biology and morphologic detection were carried out at the end of the process.Our results showed that the cynomolgus monkeys in DHT and DHT+HFD groups occurred obviously phenotype of PCOS compared with the control group,including reduced number of menstruation and delayed menstrual cycles,polycystic ovary,the visceral adipose tissue accumulation without increased body weight,and insulin resistant.And DHT+HFD group showed more obviously phenotypes compared with the DHT group.These results indicated that(1)By using DHT or combined HFD exposure modeling method during the adolescence,can effectively establish a PCOS-like traits cynomolgus monkey model within a year;(2)High androgen exposure after birth was an important inducement of PCOS;(3)High-fat diet could increase the risk or severity of PCOS caused by high androgen exposure.Our research provided a new way of thinking and strategy to establish non-human primate animal models of PCOS,and showed strong theoretical significance and application potential in pathogenesis study and clinical intervention of PCOS.