| Polycystic ovary syndrome(PCOS) is the most common reproductive endocrine disease among women around the world, and also the common cause of infertility. And its clinical manifestation is various, oligomenorrhea, chronic anovulation, insulin resistance(IR), androgen excess are the main features, and the chance of occur diabetes, angiocardiopathy, endometrial cancer will increase. PCOS was first reported by Stein and Leventhal, so it was called Stein-Leventhal syndrome. But up to date, its pathogenesis is still unclear. A number of latest studies suggest that IR may play an important and key role in the pathogenesis of PCOS.As we all know, good quality embryo and endometrial receptivity are two important and key factors for successful pregnancy for infertility patients. For PCOS infertility patients, who are due to ovulation disorders or along with mang kinds of male factors in sterility, ovulation induction or assisted reproductive technology, such as in vitro fertilization or intracytoplasmic sperm injection(IVF/ICSI), may help them become pregnant. On the dark side, after PCOS patients received the ART treatment, their pregnant rates and miscarriage rates are far from pleased and satisfactory when they were comparable with those in other subfertile populations. Endometrial receptivity refers to endometrial receptivity for embryo implantation and regulation. For patients with PCOS, sometime even they underwent the application of assisted reproductive technology and with high-quality embryos implanted, but results are still far from satisfactory, taking this into account the possibility of endometrial receptivity. Lastest studies included clinical and based research around the world have shown that the expression of homeobox gene A10, HOXA10), integrin β3(integrin β3, ITGB3) and endometrial and endometrial blood flow that on behalf of endometrial receptivity in endometrium during window of implantation in PCOS patients were significantly decreased and scarce.Establishment and maintenance of endometrial receptivity is affected by the fine regulation of a variety of proteins, nucleic acids and lipids in ovarian hormone mediated, including small RNA(microRNA, mi RNA). The present studies show miRNAs play a very important role in embryo implantation related factors influence process,Metformin as the most commonly used clinical insulin sensitizers, which at first was used in the treatment of type II diabetes, is a safe and effective biguanide hypoglycemic agents, with increased sensitivity of cells to insulin, improve tissue metabolism function. Many studies have shown that metformin enhances insulin sensitivity in patients with PCOS, ovulation and pregnancy rates increase and improve the metabolic function of the endometrium and receptive, but the mechanism is unclear. The miRNAs appear not only allow scholars to recognize the existence of the disease complex molecular mechanisms, but also provide the new ideas and methods for the metformin treatment about its effect on improving the endometrial receptivity and their pregnant in PCOS patients, especially those subferitility women. Objective:The prospectively study was conducted of metformin treatment for 120 PCOS patients in total who were first underwent IVF/ICSI treatment, and then we observe their pregnant outcomes between the two groups. For those PCOS patients who are not received embryo transplanted due to high level of OHSS(ovarian hyperstimulation syndrome), we collected their endometrium and used western blot and gene chip technology to study the endometrial tissue of endometrial receptivity(homeobox gene A10; integrin β3) and gene expression microarray miRNAs markers. Our main aim was to provide a theoretical basis for therapeutic intervention in patients with PCOS progesterone ago. Methods:1. The PCOS patients were randomly divided into metformin group(A) and control group(group B), and anthor, according if they received embryo transfer we divided agian in two groups: non-transplantation group(A1, B1). Patients in Group A during menstruation or withdrawal bleeding 2-5 day, will be given metformin treatment half an hour before a meal metformin, 500mg/time, 3 times/d to 6 days after the egg retrieval. Assisted reproductive pregnancy outcomes were compared in the A and B groups.2. Taken the endometrial tissue from PCOS patients in A1 and B1 Group. Western blot was perfprmed to test the protein level of the HOXA10, ITGB3, which are on behalf of endometrial receptivity. miRNA chip technology was conducted to test the different expression of miRNA in two groups, then use real-PCR to verify the result of mi RNA chip, at last, use bioinformatics system to perdict the target genes, Go and Pathway. Results:1. Metformin treatment can significantly decrease Homeostasis Model Assessment(HOMA)-IR in PCOS patients in the group A compared patients in Group B(2.76?1.52 vs. 3.79?1.56, P <0.05).2. Compared patients in Group B, metformin can increase the pregnant rate(58.9% vs. 37.5%, P<0.05), indrease the abortion rate(6.7% vs. 27.8%, P<0.05) and OHSS rate(8.3% vs. 21.7%, P<0.05) in Group A PCOS patients undergoing IVF/ICSI treatment.3. Metformin can increase the expression of endometrial receptivity molecular markers: HOXA10, ITGB3 protein levels(0.95?0.03 vs. 0.58?0.08,0.97?0.02 vs. 0.42?0.19, P<0.05) in PCOS patients in Group A compared with patients in Group B.4. The miRNA results showed that: there are a total of 40 miRNAs difference about endometrium in two PCOS patients groups, among 19 miRNAs were significantly upregulated and 21 miRNAs were significantly downregulated(according to 2-fold difference and P<0.05) and the verified results were consistent with miRNA chip results.5. Go and Pathway analysis showed that the differentially expressed miRNAs were involved in the main insulin signal energy metabolism, embryo implantation, and adhesion associated with the process of embryo implantation. Conclusions:1. Metformin can improve IVF/ICSI pregnancy rates in PCOS patients, reduce the abortion rate and OHSS incidence.2. Metformin may increase HOXA10, ITGB3 expression levels of endometrial receptivity in PCOS patients.3. Metformin may improve endometrial receptivity in PCOS patients through miRNA-194, mi RNA-491,miRNA-1910. |
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