MiRNAs secreted by human blastocysts could be potential gene expression regulators during implantation.

BACKGROUND: Micro RNAs (miRNAs) are small non-coding RNAs known as essential regulators of cell-cell communication. Recent studies have revealed that miRNAs are secreted by a blastocyst in culture media. We hypothesized that endometrial epithelial cells take up embryo-derived miRNAs as well as other soluble factors and regulate their receptivity-related gene expression. METHODS AND RESULTS: Blastocyst culture media (BCM) were collected from the individually cultured embryos, while human endometrial epithelial cells (HEECs) were collected from healthy fertile volunteers. To evaluate the effect of BCM on the endometrial receptivity gene expression, HEECs were co-cultured with implanted BCM, non-implanted BCM, and a control culture medium. After determining altered gene expression in the HEECs, the miRNAs-related genes through bioinformatics databases were identified and evaluated in the BCM. Co-culture of primary HEECs with BCM significantly stimulated the expression levels of VEGFA, HBEGF, HOXA10, and LIF in the implanted group compared with non-implanted and control groups. The fold changes of miR-195 significantly diminished in the implanted BCM group compared with the non-implanted BCM group. Reduced fold changes of miR-29b, 145 and increased miR-223 were also observed in the implanted BCM group compared with the non-implanted ones. CONCLUSION: miRNAs could function as potential gene expression regulators during implantation. These molecules are secreted by human blastocyst, taken up by endometrial epithelial cells, and cause a change in the endometrial function. We found that BCMs can be effective in implantation process by stimulating related receptivity gene expression.

Comparative evaluation of NOTCH signaling molecules in the endometrium of women with various gynecological diseases during the window of implantation.

OBJECTIVES: NOTCH signaling pathway is well known for its role in cell fate, cell survival, cell differentiation, and apoptosis. Some of the NOTCH signaling genes are critical for endometrial function and implantation in animals and appear to play a similar role in humans. The purpose of the current study was to investigate the potential roles of some main components of the NOTCH family in human endometrium during implantation period in common gynecological diseases. MATERIALS AND METHODS: Endometrial NOTCH receptors NOTCH1, 3, 4 and ligand JAG1, 2 and survivin mRNA expression were investigated using the Q-PCR technique and the amount of the JAG1, 2 proteins was also determined by Western blot. Samples were obtained from 12 patients with endometriosis, 12 patients with repeated implantation failure (RIF), 12 patients with Polycystic Ovary Syndrome (PCOS) and 10 healthy fertile women as a control group. Data were analyzed using SPSS version 18. Group comparisons were performed by one-way ANOVA or Kruskal-Wallis. RESULTS: All patient groups failed to show the expected mid-luteal increase in NOTCH1, JAG 1, 2, and survivin expression as documented in the control group. Moreover, a significant rise in NOTCH3 expression levels was found only in PCOS women. There was a direct correlation between gene expression and protein level for JAG 1, 2. CONCLUSION: Aberrant NOTCH signaling molecules expression suggests that altered development of the endometrium at the molecular level may be associated with the impaired decidualization and implantation failure in gynecological disorders such as endometriosis, PCOS, and RIF.

The impact of laparoscopic cystectomy on ovarian reserve in patients with unilateral and bilateral endometrioma.

OBJECTIVE: To evaluate the effects of laparoscopic cystectomy on serum anti-Müllerian hormone (AMH) level as a marker of ovarian reserve in patients with endometrioma. METHODS: A prospective observational study enrolled patients aged younger than 40 years who were referred to a tertiary center in Tehran, Iran, between January 1, 2013 and December 31, 2014 to undergo laparoscopic cystectomy for ovarian endometriomas at least 30 mm in diameter, or regardless of size for patients with infertility, dysmenorrhea, dyspareunia, or dyschezia. Baseline and 6-month post-operative AMH levels were compared. RESULTS: Data from 70 patients were included in the analyses. Among patients with unilateral endometriomas, lower pre-operative AMH levels were observed in patients with endometriomas at least 50 mm in diameter (P=0.027), whereas cyst size was not associated with differences in pre-operative AMH level in patients with bilateral endometriomas (P=0.227). Across the entire study population, post-operative AMH levels were lower than the baseline (P=0.008). Greater post-operative decreases in AMH were associated with bilateral cysts compared with unilateral cysts (P=0.046), cysts being at least 50 mm in diameter among patients with unilateral cysts (P=0.028), and both cysts being at least 50 mm in diameter among patients with bilateral cysts (P=0.025). CONCLUSION: Laparoscopic cystectomy was associated with post-operative decreases in serum AMH, particularly with bilateral involvement and endometriomas at least 50 mm in diameter.

Comparison of intramuscular progesterone with oral nifedipine for treating threatened preterm labor: A randomized controlled trial.

Background: Threatened preterm labor (TPL) is the leading cause of hospitalization during pregnancy. Tocolytic agents are the primary therapeutic options for TPL. The aim of this study is to compare intramuscular progesterone with oral nifedipine as a tocolytic agent. Methods: This randomized controlled trial was carried out in a teaching hospital (Shahid Akbarabadi) in Tehran, Iran, from December 2011 to November 2012. Three hundred and fifteen singleton pregnant women aged >18 yrs at 26-34 weeks' gestation with the diagnosis of threatened preterm labor (TPL) were randomly received either intramuscular progesterone or oral nifedipine for tocolysis. Maternal and neonatal outcomes were then compared between the two interventions. P value less than 0.05 was considered statistically significant. IRCT registration number of this study is IRCT201112198469N1 Results: The success rate of progesterone and nifedipine in treating TPL were 83% and 82.7%, respectively. There was no significant difference between the two interventions with regard to gestational age at delivery, type of delivery, the time interval until the delivery, birth weight, NICU admission rate and hospital stays. Progesterone administration was associated with lower duration of NICU stay as compared with nifedipine (0.33±0.77 days vs.1.5±3.2 days, p<0.05). None of the two drugs caused any major side effects. Conclusion: Single dose intramuscular progesterone is as effective as oral nifedipine in treating TPL. It also significantly reduces the NICU stay.

Advantages of Recombinant Follicle-Stimulating Hormone over Human Menopausal Gonadotropin in Intrauterine Insemination: A Randomized Clinical Trial in Polycystic Ovary Syndrome-Associated Infertility.

BACKGROUND: Various gonadotropin preparations have been used for ovarian stimulation in intrauterine insemination (IUI). The purpose of the current study was to compare human menopausal gonadotropin (hMG) and recombinant follicle-stimulating hormone (rFSH) combined with clomiphene citrate (CC) in IUI cycles for polycystic ovary syndrome-associated infertility. METHODS: In this prospective trial, couples prepared for IUI cycles were randomly allocated either to receive CC and rFSH (group A, n = 132) or CC and hMG (group B, n = 144) for ovarian stimulation. Outcomes including rates of clinical pregnancy, miscarriage, ovarian hyperstimulation syndrome, multiple pregnancy, cancellation and live birth were compared. RESULTS: The duration of gonadotropin therapy was shorter and total doses of gonadotropins was lower in the rFSH group. The number of stimulated follicles reaching >17 mm diameter was comparable between groups, but the mean follicular diameter was significantly higher in the rFSH group. The endometrium was also significantly thicker at the time of human chorionic gonadotropin administration in the rFSH group. However, pregnancy outcomes, including the rates of clinical pregnancy, ongoing pregnancy, live birth, miscarriage, ovarian hyperstimulation syndrome and cancellation, were similar between groups. CONCLUSION: IUI cycles in which rFSH is administered may result in shorter duration of treatment, a lower total gonadotropin dose and better follicular and endometrial characteristics on the day of human chorionic gonadotropin injection. © 2015 S. Karger AG, Basel.

In vitro fertilization outcome following embryo transfer with or without preinstillation of human chorionic gonadotropin into the uterine cavity: a randomized controlled trial.

BACKGROUND: Intrauterine injection of human chorionic gonadotropin (hCG) at embryo transfer (ET) has been shown to improve the outcome of assisted reproductive techniques. The aim of this study was to confirm previous findings. METHODS: In this randomized controlled trial, 483 infertile women who were candidates for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) for the first time were randomly assigned to receive an intrauterine injection of 500 IU hCG or placebo (tissue culture media) before ET. The main outcome measures were implantation and clinical pregnancy rates. RESULTS: Both the hCG-treated group (n = 240) and control group (n = 243) were similar at baseline in terms of demographic and obstetrical characteristics. There were significant differences between the two groups regarding the implantation rate (23.6 vs. 12.2%, p < 0.001), pregnancy rate (54.6 vs. 35.8%, p < 0.001), clinical pregnancy rate (50 vs. 32.1%, p < 0.001), ongoing pregnancy rate (15.3 vs. 9.2%, p < 0.001) and live delivery rate (14.3 vs. 8.4%, p < 0.001). The rate of fertilization and abortion rates were not statistically different. CONCLUSION: Intrauterine injection of hCG before ET improves implantation and pregnancy rates and may be considered an adjuvant in IVF/ICSI.

Recurrent IVF failure and hereditary thrombophilia.

BACKGROUND: The largest percentage of failed invitro fertilization (IVF (cycles, are due to lack of implantation. As hereditary thrombophilia can cause in placentation failure, it may have a role in recurrent IVF failure. OBJECTIVE: Aim of this case-control study was to determine whether hereditary thrombophilia is more prevalent in women with recurrent IVF failures. MATERIALS AND METHODS: Case group comprised 96 infertile women, with a history of recurrent IVF failure. Control group was comprised of 95 healthy women with proven fertility who had conceived spontaneously. All participants were assessed for the presence of inherited thrombophilias including: factor V Leiden, methilen tetrahydrofolate reductase (MTHFR) mutation, prothrombin mutation, homocystein level, protein S and C deficiency, antithrombin III (AT-III) deficiency and plasminogen activator inhibitor-1 (PAI-1) mutation. Presence of thrombophilia was compared between groups. RESULTS: Having at least one thrombophilia known as a risk factor for recurrent IVF failure (95% CI=1.74-5.70, OR=3.15, p=0.00). Mutation of factor V Leiden (95% CI=1.26-10.27, OR=3.06, P=0.01) and homozygote form of MTHFR mutation (95% CI=1.55-97.86, OR=12.33, p=0.05) were also risk factors for recurrent IVF failure. However, we could not find significant difference in other inherited thrombophilia's. CONCLUSION: Inherited thrombophilia is more prevalent in women with recurrent IVF failure compared with healthy women. Having at least one thrombophilia, mutation of factor V Leiden and homozygote form of MTHFR mutation were risk factors for recurrent IVF failure.

Advantages of recombinant follicle-stimulating hormone over human menopausal gonadotropin for ovarian stimulation in intrauterine insemination: a randomized clinical trial in unexplained infertility.

OBJECTIVE: To compare two different gonadotropin preparations, human menopausal gonadotropin (hMG) and recombinant follicle-stimulating hormone (rFSH), combined with clomiphene citrate (CC) in women with unexplained infertility undergoing intrauterine insemination (IUI). STUDY DESIGN: In this prospective clinical trial, couples prepared for IUI cycles were randomly allocated to two groups either to receive CC and hMG (group A, n=127) or CC and rFSH (group B, n=132) for ovarian stimulation. Outcomes including rates of clinical pregnancy, miscarriage, OHSS, multiple pregnancy, cancellation, and live birth were compared between groups. RESULTS: Duration of gonadotropin therapy was significantly shorter in group B (5.1±0.84 vs. 4.7±0.8 days, CI=95%, P<0.001). The total dose of administered gonadotropin was also significantly lower in group B (386.9±68.2 vs. 348.2±56.3IU, CI=95%, P<0.001). Dominant follicle number (>17mm), mean follicular diameter, and endometrial thickness on the day of hCG injection were similar. Clinical pregnancy, multiple pregnancies, abortion, live birth, ovarian hyperstimulation syndrome (OHSS), and cancellation rates were not statistically different between the groups. CONCLUSION: IUI cycles in which rFSH had been administered may require shorter duration and a lower total gonadotropin dose.

The role of infertility etiology in success rate of intrauterine insemination cycles: an evaluation of predictive factors for pregnancy rate.

BACKGROUND: The objective of this study was to identify the prognostic factors that influence the outcome of ovarian stimulation with intrauterine insemination (IUI) cycles in couples with different infertility etiology. MATERIALS AND METHODS: This retrospective study was performed in data of 1348 IUI cycles with ovarian stimulation by clomiphene citrate (CC) and/or gonadotropins in 632 women with five different infertility etiology subgroups at Akbarabbadi Hospital, Tehran, Iran. RESULTS: The pregnancy rate (PR)/ cycle was highest (19.9%) among couples with unexplained infertility and lowest (10.6%) in couples with multiple factors infertility. In cases of unexplained infertility, the best PRs were seen after CC plus gonadotropins stimulation (26.3%) and with inseminated motile sperm count>30×10(6) (21.9%), but the tendency didn't reach statistical significant. In the ovarian factor group, the best PRs were observed in women aged between 30 and 34 years (20.8%), with 2-3 preovulatory follicles (37.8%) and infertility duration between 1and 3 years (20.8%), while only infertility duration (p=0.03) and number of preovulatory follicles (p=0.01) were statistically significant. Multiple logistic regression analysis determined that number of preovulatory follicles (p=0.02), duration of infertility (p=0.015), age (p=0.019), infertility etiology (p=0.05) and stimulation regimen (p=0.01) were significant independent factors in order to predict overall clinical PR. CONCLUSION: The etiology of infertility is important to achieve remarkable IUI success. It is worth mentioning that within different etiologies of infertility, the demographic and cycles characteristics of couples did not show the same effect. Favorable variables for treatment success are as follows: age <40, duration of infertility ≤5 years and a cause of infertility except of multiple factors.