The effect of adding L-Carnitine to the GnRH-antagonist protocol on assisted reproductive technology outcome in women with polycystic ovarian syndrome: a randomized clinical trial.

OBJECTIVE: This study aimed to investigate the effect of adding L-Carnitine to the gonadotropins on ART outcome in frozen-thawed embryo transfer cycles among PCOS women. METHODS: In this randomized clinical trial, 83 patients with PCOS were randomized to either L-Carnitine supplemented (n = 42) or control (n = 41) groups. The L-Carnitine group was given 3000 mg of oral L-Carnitine daily until the final day of ovulation. The numbers of metaphase II (MII) oocytes, 2-pronuclears (2PNs), oocyte maturity rate, fertilization rate, fertilization proportion as well as implantation, chemical and clinical pregnancy rates were compared between the two groups. RESULTS: Even though the duration of stimulation and endometrial thickness were comparable between groups (p > .05), serum estradiol level on the day of oocyte triggering, was significantly higher in the L-Carnitine group compared to the control group (p < .05). In contrast, the number of retrieved and MII oocytes as well as the number of 2PNs and obtained embryos were similar between groups (p > .05). Moreover, oocyte maturity rate (0.85 ± 0.38 vs. 1.02 ± 0.90), fertilization proportion (0.62 ± 0.44 vs. 0.80 ± 0.86), fertilization rate (0.70 ± 0.22 vs. 0.76 ± 0.19) along with implantation rate (18.1 vs. 13.7%), chemical (26.8 vs. 30.7%) and clinical (24.3 vs. 25.6%) pregnancy rates, were all comparable between L-Carnitine and control groups respectively (p > .05). CONCLUSIONS: Our result showed that oral L-Carnitine administration during induction of ovulation among PCOS women could not improve laboratory and pregnancy outcome.

The alarmin S100A9 hampers osteoclast differentiation from human circulating precursors by reducing the expression of RANK.

The alarmin S100A8/A9 is implicated in sterile inflammation-induced bone resorption and has been shown to increase the bone-resorptive capacity of mature osteoclasts. Here, we investigated the effects of S100A9 on osteoclast differentiation from human CD14+ circulating precursors. Hereto, human CD14+ monocytes were isolated and differentiated toward osteoclasts with M-CSF and receptor activator of NF-κB (RANK) ligand (RANKL) in the presence or absence of S100A9. Tartrate-resistant acid phosphatase staining showed that exposure to S100A9 during monocyte-to-osteoclast differentiation strongly decreased the numbers of multinucleated osteoclasts. This was underlined by a decreased resorption of a hydroxyapatite-like coating. The thus differentiated cells showed a high mRNA and protein production of proinflammatory factors after 16 h of exposure. In contrast, at d 4, the cells showed a decreased production of the osteoclast-promoting protein TNF-α. Interestingly, S100A9 exposure during the first 16 h of culture only was sufficient to reduce osteoclastogenesis. Using fluorescently labeled RANKL, we showed that, within this time frame, S100A9 inhibited the M-CSF-mediated induction of RANK. Chromatin immunoprecipitation showed that this was associated with changes in various histone marks at the epigenetic level. This S100A9-induced reduction in RANK was in part recovered by blocking TNF-α but not IL-1. Together, our data show that S100A9 impedes monocyte-to-osteoclast differentiation, probably via a reduction in RANK expression.-Di Ceglie, I., Blom, A. B., Davar, R., Logie, C., Martens, J. H. A., Habibi, E., Böttcher, L.-M., Roth, J., Vogl, T., Goodyear, C. S., van der Kraan, P. M., van Lent, P. L., van den Bosch, M. H. The alarmin S100A9 hampers osteoclast differentiation from human circulating precursors by reducing the expression of RANK.

ß-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance.

Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic pathways. Transcriptional inactivity in response to a second LPS exposure in tolerized macrophages is accompanied by failure to deposit active histone marks at promoters of tolerized genes. In contrast, ß-glucan partially reverses the LPS-induced tolerance in vitro. Importantly, ex vivo ß-glucan treatment of monocytes from volunteers with experimental endotoxemia re-instates their capacity for cytokine production. Tolerance is reversed at the level of distal element histone modification and transcriptional reactivation of otherwise unresponsive genes. VIDEO ABSTRACT.

A comparison of pregnancy rate before and after the administration of HCG in intrauterine insemination.

PURPOSE: Intrauterine insemination (IUI) is one of the first treatments of infertility. In natural cycles, women conceive when an intercourse takes place during a 6-day period ending on the day of ovulation. The current practice in IUI cycles is to perform IUI 24-36 h after the HCG administration, when the ovulation already took place. In this study, HCG was administered after IUI, which more closely resembles the fertilization process in natural cycles. The aim of the present study is to compare the fertility rates in an IUI protocol in women who took an HCG injection before and after the IUI. METHODS: This study was conducted on 100 infertile couples who referred to the infertility research center of Shahid Sadoughi University of Medical Sciences. They were divided into two groups: HCG injection before IUI and HCG injection after IUI. The main outcome measure was the result of a ß HCG test that was done two weeks after the IUI; if it was positive, transvaginal sonography would be performed in the seventh week for clinical confirmation of pregnancy. RESULTS: The analysis included 50 cycles with HCG administered before and 50 cycles with HCG administered after the IUI. The pregnancy rates were 10 and 12 % (P = 0.85), respectively. Independent factor affected the cycle outcome was the time of infertility. CONCLUSION: HCG administration after IUI brought about no improvement in the pregnancy rate. Therefore, HCG can be administered either before or after IUI.

Dilatation and curettage effect on the endometrial thickness.

BACKGROUND: Endometrial receptivity is required for successful implantation and pregnancy. Despite the remaining controversy, many studies have shown that ultrasonographic endometrial thickness can be considered as an indicator of endometrial receptivity. OBJECTIVE: The study objective was to investigate the effect of dilatation and curettage on the endometrial thickness. MATERIALS AND METHODS: Enrolled in the study were 444 patients visited in Obstetrics & Gynecology clinic of Shahid Sadoughi hospital between Jan. 2011 to Sep. 2012. Only patients whose menstrual cycle was regular were included in study. Patients with myoma, adenomyosis, endometrial polyps or other uterine anomaly, those who smoked, whose BMI was greater than 30 and who were taking medications that could affect endometrial thickness were excluded. Endometrial thickness was measured one day before evolution (n = 444) and 5-7 days after it (n = 444) using transvaginal ultrasonography. The endometrial thicknesses were correlated to the patients' history of dilatation and curettage. Data analysis was done through SPSS software version 16 and using descriptive statistics, independent T-test and Anova. RESULTS: Endometrial thickness in patients who had 0, 1, 2, 3 and 4 D&C were 10.00 ± 0.58, 9.83 ± 0.47, 8.90 ± 0.92, 7.42 ± 0.18 and 7.40 ± 0.07, respectively one day before ovulation (spearman's correlation coefficient = -0.33) and 10.62 ± 0.68, 9.64 ± 0.49, 8.48 ± 0.96, 6.32 ± 0.15 and 6.90 ± 0.04, respectively, 5-7 days after ovulation (spearman's correlation coefficient = -0.66) estradiol and progesterone levels, measured in the day of 2nd ultrasonography had not statistic relation with endometrial thickness (P = 0.27 and 0.31). The relation of endometrial thickness and age was not significant (P = 0.54 and 0.06). CONCLUSIONS: Dilatation and curettage has a significant effect on the endometrial thinning.

A comparative study of luteal estradiol pre-treatment in GnRH antagonist protocols and in micro dose flare protocols for poor-responding patients.

PURPOSE: This study aims to verify if luteal estradiol pre-treatment improves IVF/ICSI outcomes in a GnRH antagonist protocol as compared with a micro dose GnRH agonist protocol in poor-responding patients. METHODS: A total of 116 IVF/ICSI cycles were included in this prospective randomized single blind clinical trial. The selected women were randomly assigned to receive an estradiol pre-treatment in a GnRH antagonist protocol (daily oral Estradiol Valerate 4 mg preceding the IVF cycle from the 21st day until the first day of the next cycle) or in oral contraceptive pill micro dose GnRH agonist protocol. RESULTS: The patients in the luteal estradiol protocol required more days of stimulation (10.9 ± 1.6 vs. 10.2 ± 1.8) and a greater gonadotropin requirement (3,247.8 ± 634.6 vs. 2,994.8 ± 611 IU), yet similar numbers of oocytes were retrieved and fertilized. There was no significant difference between the two groups in terms of the implantation rates (9.8 vs. 7.9 %) and the clinical pregnancy rates per transfer (16.3 vs. 15.6 %). CONCLUSION: This study demonstrates that the use of estradiol during a preceding luteal phase in a GnRH antagonist protocol can provide similar IVF outcomes when compared to a micro dose GnRH agonist protocol.

Metformin-letrozole in comparison with Metformin-clomiphene citrate in clomiphene-resistance PCOS patients undergoing IUI.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with approximately 75% of women who suffer from infertility due to anovulation. Additionally, around 20- 25% of anovulatory women with PCOS do not respond at all to clomiphene citrate and are considered to be "clomiphene- resistant". Aromatase inhibitors have been suggested as an alternative treatment to clomiphene as the discrepancy between ovulation and pregnancy rates with clomiphene citrate has been attributed to its anti-estrogenic action and estrogen receptor depletion. OBJECTIVE: The aim of this study is to compare results of Metformin-letrozole with Metformin-clomiphene citrate in clomiphene resistance PCOS patients undergoing IUI. MATERIALS AND METHODS: In this single blind randomized trial, ovarian cycles were studied in 100 clomiphene- resistant patients with PCOS. The inclusion criteria were patients who received 150mg clomiphene citrate daily for 3 cycles and failed to become pregnant. The patients were matched for their age, body mass index (BMI), and infertility period. They were randomly allocated to a metformin-letrozole group (n=50) and a metformin-clomiphene citrate group (n=50). Chemical and clinical pregnancies were assessed after IUI. Abortion rates were determined in both groups. RESULTS: Regarding pregnancy rate, there was no significant difference between the two groups. One miscarriage (2%) occurred in the metformin-clomiphene citrate group, whereas none was seen in the metformin-letrozole group. CONCLUSION: There is no significant difference in pregnancy rate between clomiphene citrate and letrozole groups although it has been 2% in the former and 5% in the latter.

GnRH antagonist/letrozole versus microdose GnRH agonist flare protocol in poor responders undergoing in vitro fertilization.

OBJECTIVE: To evaluate and compare the efficacy of microdose gonadotropin-releasing hormone (GnRH) agonist flare (MF) and GnRH antagonist/letrozole protocols in poor responders undergoing in vitro fertilization. MATERIALS AND METHODS: A total of 94 poorly responding patients were randomized in an ovarian stimulation protocol with a MF, or a letrozole and high dose follicle-stimulating hormone/human menopausal gonadotropin and flexible GnRH antagonist protocol. RESULTS: There was no significant difference in mean age, body mass index, basal serum follicle stimulating hormone and estradiol levels, duration of infertility, distribution of etiology of infertility, and the number of previously failed in vitro fertilization cycles. The days of stimulation, mean gonadotropin dose, the number of mature follicles, and oocytes retrieved and metaphase II oocytes retrieved, serum estradiol level on the day of human chorionic gonadotropin administration, and the percentage of top and good quality embryos were significantly higher in the MF group. The endometrial thickness, fertilization rate, and the number of embryos transferred were similar in both groups. The implantation and clinical pregnancy rates were higher in the MF group and the total cancellation rate was higher in the GnRH antagonist/letrozole group, but these findings were not statistically significant. CONCLUSION: The addition of letrozole to the GnRH antagonist for poor responders does not improve the outcome of assisted reproductive technology cycles. The MF protocol remains the most appropriate protocol in poor responders.

Comparing GnRH agonist long protocol and GnRH antagonist protocol in outcome the first cycle of ART.

PURPOSE: This prospective study evaluated the efficacy of gonadotropin-releasing hormone (GnRH) antagonist protocol in comparison with the GnRH agonist protocol in the first cycle of assisted reproductive technique (ART). METHODS: We randomized 235 patients undergoing ART for the first time. The first group was stimulated with a standard long protocol and the second group stimulated with GnRH antagonis. RESULTS: There was no statistically significant difference in the age, infertility cause, basal FSH, BMI, the number of oocytes retrieved, number of M2 oocytes, embryo obtained and endometrial thickness between the two groups. But Serum estradiol, consumption of gonadotropins and ovarian hyperstimulation syndrome were significantly lower in the antagonist protocol. Cancellation rate of embryo transfer due to poor-quality embryo in the antagonist protocol was higher, but it was not significant. There was no significant difference in the clinical pregnancy and ongoing pregnancy between the two groups. CONCLUSION: GnRH-antagonist is an effective, safe, and well-tolerated alternative to agonist in the first cycle of ART.

The effect of early removal of indwelling urinary catheter on postoperative urinary complications in anterior colporrhaphy surgery.

OBJECTIVE: To assess whether immediate removal of an indwelling catheter after anterior colporrhaphy influences the rate of re-catheterisation and symptomatic urinary tract infections. METHODS: A prospective randomised study conducted on 90 women divided into two groups who underwent anterior repair. The indwelling catheter was removed immediately (early catheter removal), and at least 24 h after the operation in case and control groups, respectively. The association between clinical variables and the duration of catheterisation and continuous data were analysed by chi(2) test and two-tailed t-test, respectively. Excel and SPSS 15.0 software were used, and a P-value of 0.05 or less was considered to indicate statistically significant differences. RESULT: Symptomatic urinary tract infection was significantly lower in early catheter-removal group; also patients in this group reported significantly less pain and voiding disturbances. Only a few of women required re-catheterisation after failing to void and all were able to resume normal voiding, also had shorter ambulation time and hospital stay. CONCLUSION: Early removal of an indwelling catheter immediately after anterior colporrhaphy was not associated with adverse events and increased rate of re-catheterisation. In this group, symptomatic urinary tract infection was significantly lower. Moreover, early removal of indwelling catheters immediately after operation seemed to decrease the ambulation time and hospital stay.