Effect Of Fibroids Not Distortingthe Endometrial Cavity And Adenomyosis On The Outcome Of IVF Treatment

PartⅠEffect of fibroids not distortingthe endometrial cavity and adenomyosis on the outcome of IVF/ICSI treatmentBackground:Uterine fibroids are the most common benign tumor of the uterus.Fibroids are classically described as submucosal fibroids (SM), intramural fibroids (IM), or subserosal fibroids (SS).Estimated to be present in5-10%of infertile women, they may be solely responsible for Impaired fertility outcomes in2-3%of cases. The composition, size, location, and number of fibroids may affect a woman’s fertility and pregnancy complications. This may be due to distortion of the endometrial cavity, causing abnormal endometrial receptivity, hormonal milieu, and altered endometrial development For SM fibroids that distort the uterine cavity, there is consensus that a negative Impact exists on both clinical pregnancy rates and delivery rates after IVF/ICSI treatment. Conversely, SS fibroids do not appear to Impact IVF outcomes.The myomectomy of SS does not show any benefit either.However, the effect of IM fibroids on the outcome of IVF/ICSI treatment remains incompletely understood, with studies yielding conflicting results. To further determine the effect of fibroids (SS plus IM) on IVF/ICSI in the absence of uterine cavity distortion and identify potential subgroups of women with IM fibroids who experience deleterious outcomes when undergoing IVF/ICSI, a large sample size study is necessary. On the other hand,uterine adenomyosis is characterized by the presence of heterotypic endometrial glands and stroma in the myometrium and may be an epigenetic disease. Recently reports have focused on the relationship between adenomyosis and infertility but with controversial conclusions and no consensus. The most recent systematic review of five existing studies failed to draw any definite conclusions about the effect of adenomyosis on outcomes of assisted reproductive technology because of major differences in study design and populations.Here we intend to conduct a case-control study with a relatively large sample size to eliminate many confounding factors and to explore the extent of the effect of adenomyosis on IVF/ICSI.Objective:To investigate the effect of fibroids that do not distort the endometrial cavity and adenomyosis on IVF/intracytoplasmic sperm injection (ICSI) outcomes in order to guide clinical practice.Methods:We performed a retrospective, database-searched cohort study based on10,268patients undergoing controlled ovarian hyperstimulation and IVF/ICSI between2009and2011in our unit. Fibroids and adenomyosis were diagnosed by transvaginal ultrasound. A high-quality1:1matched cohort study with strict inclusion criteria was conducted, including age(±year),cycle and type of infertility, and also keep other factors matched as much as possible like cause of infertility, comorbidities and ovary stimulating protocols etc. We compared the basic characteristics and main IVF/ICSI outcomes between the two groups. In order to identify any subset of women with deleterious IVF/ICSI outcomes, patients were further classified into several subgroups. We also analyzed the predictive accuracy of fibroid size in identifying adverse effects on the delivery rate by calculating the appropriate receiver operating characteristic (ROC) curves.Results:We identified77patients with adenomyosis and249patients with fibroids less than6cm including51subserosal and198intramural fibroids who underwent IVF/ICSI. There were no significant differences between the two groups in terms of age, body mass index (BMI), duration of infertility, or ovarian reserve, ovary stimulation protocol, oocytes retrieved and embryo transferred. Higher day3FSH levels were found in women with fibroids compared with in control subjects (p=0.030). There was no significant difference in cycle cancellation rate, clinical pregnancy rate or delivery rate after adjusting for day3FSH levels between the two groups. Although SD in the subserosal group was larger than in the intramural group, there were no significant differences with regards to cycle cancellation rate, clinical pregnancy rate or delivery rate. After the ROC analysis, we identified2.85cm as the cutoff value for SD and2.95cm for TD. No significant differences were found in IVF/ICSI outcomes between the two groups. Patients with fibroids with SD>2.85cm or TD>2.95cm tended to have significantly higher age and BMI and lower DR compared with patients with lower diameter. Our results also showed that patients with larger BMI and age had more and larger fibroids. A significant negative effect on delivery rate was noted when intramural fibroids with the largest diameter greater than2.85cm were considered, compared with matched controls without fibroids (p=0.043, post-hoc power=0.91).We studied the effect of fibroid number on IVF/ICSI outcome. From our result, patients with single or multiple fibroids had similar IVF/ICSI outcomes19patients were found to have type3fibroids on TVS, compared with179patients with type4and5fibroids, patients with type3fibroids had relatively lower DR and CPR (15.8%vs33.5%,36.8%vs47.5%) and higher clinical MR (21.0%vs13.9%) but these differences did not reach a statistical significance. There were no significant differences between the adenomyosis group and the control group in terms of age, body mass index, duration of infertility, or ovarian reserve, ovary stimulation protocol, oocytes retrieved and embryo transferred. Higher day3estrogen levels (p=0.039) and a higher total of gonadotropin stimulation doses (p=0.020) were found in women with adenomyosis compared to control subjects. Patients with adenomyosis had a nonsignificant trend toward a lower clinical pregnancy rate (p=0.09) and a higher miscarriage rate (p=0.103). The delivery rate was significantly lower in the adenomyosis group in comparison to the matched controls (p=0.022)Conclusions: Our results suggest that although non-cavity-distorting fibroids (less than6cm) do not affect IVF/ICSI outcomes, intramural fibroids greater than2.85cm in size significantly Impair the delivery rate of patients undergoing IVF/ICSI. It is definitely unessary to do myomectomy before IVF/ICSI when SD is less than2.85cm.Our results also suggest that transvaginal ultrasound-diagnosed adenomyosis could have a negative Impact on the main IVF/ICSI outcomes. Improvement of the diagnosis and scoring of disease severity in patients with adenomyosis might add to the strength of these observations. Our study has Important strength in guiding the treatment of infertility patients combined with fibroids or adenomyosis before IVF/ICSI. Part ⅡH19/let-7axis regulates tumor cell migration and invasion AbstractBackground:The Imprinted, developmentally regulated H19long noncoding RNA (lncRNA) has been Implicated in the pathogenesis of diverse human cancers, but the underlying mechanisms have remained poorly understood., HMGA2, cMyc, and Imp3are proved let-7target and have been demonstrated to promote metastasis via regulating various downstream effector genes directly involved in cell migration and invasion.Objective:The aim of this study is to investigate the role of H19on promoting tumor cell migration and invasion by changing the expression of H19in tumor cells.Methods:We transfected ovarian cancer cell lines A2780and TaraR127and endometrial cancer cell line ARK2cells with siH19or H19plasmid.We tested the motility and invasiveness of tumor cells using transwell method. We also tested the expression of let-7down regulating oncogenes such as HMGA2, cMyc, and Imp3.We co-transfected let-7inhibitor,iLet-7,to see if this phenomena could be rescued.Resluts:The motility and invasiveness of tumor cells were Impaired by transfecting ovarian cancer cell lines A2780and TaraR127and endometrial cancer cell line ARK2cells with siH19,together with the down regulation of let-7targeted genes HMGA2, cMyc, and Imp3.Co-transfecting iLet-7could partially or completely rescue this phenomona. H19over-expression showed opposite results. Conclusion:We show that H19depletion impairs, whereas its overexpression enhances the motility and invasiveness of tumor cells. These phenomena occur, at least in part through affecting let-7-mediated regulation of metastasis-promoting genes, including HMGA2, cMyc, and Imp3.Our results reveal a novel mechanism underpinning H19-mediated regulation in metastasis and may explain why in some cases increased let-7expression unexpectedly correlates with poor prognosis. Targeting this newly identified pathway might offer therapeutic opportunities.