In silico Docking Analysis for Blocking JUNO-IZUMO1 Interaction Identifies Two Small Molecules that Block in vitro Fertilization.

Combined hormone drugs are the basis for orally administered contraception. However, they are associated with severe side effects that are even more impactful for women in developing countries, where resources are limited. The risk of side effects may be reduced by non-hormonal small molecules which specifically target proteins involved in fertilization. In this study, we present a virtual docking experiment directed to discover molecules that target the crucial fertilization interactions of JUNO (oocyte) and IZUMO1 (sperm). We docked 913,000 molecules to two crystal structures of JUNO and ranked them on the basis of energy-related criteria. Of the 32 tested candidates, two molecules (i.e., Z786028994 and Z1290281203) demonstrated fertilization inhibitory effect in both an in vitro fertilization (IVF) assay in mice and an in vitro penetration of human sperm into hamster oocytes. Despite this clear effect on fertilization, these two molecules did not show JUNO-IZUMO1 interaction blocking activity as assessed by AVidity-based EXtracellular Interaction Screening (AVEXIS). Therefore, further research is required to determine the mechanism of action of these two fertilization inhibitors.

Do vitrified frozen-thawed embryos generated from successful fresh cycles have higher potential for favorable outcome?

BACKGROUND: Many variables, including woman's age, embryo quality and endometrial receptivity, influence the success rate of either fresh embryo transfer (ET) or frozen-thawed ET (FT-ET) cycles. This study aims to examine whether the results of a fresh in-vitro fertilization (IVF) cycle correlate with its frozen-thawed embryos transfer outcomes. METHODS: A retrospective cohort study conducted in a tertiary medical center single IVF unit between 2014-2017. The study population was comprised of women who underwent fresh ET with the remaining embryos frozen using vitrification and at least one consecutive FT-ET cycle. Comparison of FT-ET cycle's details and outcomes were assessed in relation to the outcome of preceding fresh ET cycle. RESULTS: A total of 599 women underwent fresh ET and at least one consecutive FT-ET cycle. Significantly higher rates of successful FT-ET cycle outcomes were observed in the group of patients with a successful fresh cycle compared to the group with an unsuccessful fresh cycle (48.9% vs. 20.8%, P<0.001). Logistic regression demonstrated an adjusted OR of 5.02 for successful FT-ET after a successful fresh cycle. CONCLUSIONS: Frozen-thawed embryos generated from successful fresh IVF cycles have higher potential to implant when compared to frozen-thawed embryos obtained in an unsuccessful fresh cycle.

High ovarian response to ovarian stimulation: effect on morphokinetic milestones and cycle outcomes.

PURPOSE: To assess the effect of high ovarian response on oocyte quality and ovarian stimulation cycle outcomes. METHODS: A retrospective cohort study conducted at three IVF units. The high ovarian response (HOR) and polycystic ovary syndrome (PCOS) with HOR (PCOS HOR) groups included 151 and 13 women who underwent controlled ovarian stimulation (COS) resulting in more than 15 retrieved oocytes, for a total of 1863 and 116 cultured embryos, respectively. The normal ovarian response (NOR) group comprised 741 women with 6-15 retrieved oocytes, resulting in 4907 cultured embryos. Data collected included fresh cycle data and pregnancy rates, in addition to annotation of morphokinetic events from time of pronuclei fading to time of initiation of blastocyst formation of embryos cultured in a time lapse incubator, including occurrence of direct unequal cleavage at first cleavage (DUC-1) (less than 5 h from two to three blastomeres). Comparison was made between morphokinetic parameters between the 3 groups. Cycle outcomes were compared in the high vs. normal ovarian response groups. RESULTS: Oocyte maturation rate was significantly lower in the HOR vs. NOR groups (56.5% vs. 90.0%, p < 0.001), while the fertilization rates were similar (60.2% vs. 58.1%, p = 0.397). The prevalence of DUC-1 embryos was higher in the PCOS HOR and the HOR groups as compared to the NOR group (22.7% vs. 16.2% and 12.0%, respectively, p < 0.001). After exclusion of DUC-1 embryos, remaining embryos from the NOR and HOR groups reached the morphokinetic milestones at similar rates, with comparable implantation and clinical pregnancy rates, while the PCOS HOR showed shorter time to 5 blastomeres compared to the NOR and HOR groups. CONCLUSIONS: High ovarian response might be associated with decreased oocyte quality, manifested as a higher proportion of immature oocytes and higher rate of direct uneven cleavage embryos, while embryos exhibiting normal first cleavage have similar temporal milestones and implantation potential.

Gonadotropin releasing hormone analogue treatment of central precocious puberty is not associated with altered prevalence of polycystic ovary syndrome: a single center cohort study.

BACKGROUND: There is conflicting evidence regarding an association between gonadotropin releasing hormone analogue (GnRHa) therapy and polycystic ovary syndrome (PCOS). This study aimed to compare the prevalence of endocrine disorders, primarily PCOS, between women who had been treated with GnRHa for central precocious puberty (CPP) and those who were not treated. METHODS: This was a retrospective cohort study, including women diagnosed with central precocious puberty between 1989 and 2011 in a university affiliated tertiary medical center. Data collected included demographic data, medical background, clinical presentation at diagnosis and duration of treatment (zero for non-treated). Gynecologic and endocrine long-term outcomes were compared by treatment group. RESULTS: Fifty-one women were included in the study, 27/51 had been treated with gonadotropin releasing hormone analogue (GnRHa). Overall prevalence of PCOS was 19.6%. No statistically significant difference in prevalence of PCOS was demonstrated between the treated and non-treated groups. Similarly, overall prevalence of either clinical or laboratory hyper-androgenism, was 29.4% and 33.3%, for the treatment and non-treatment groups respectively (p = non-significant). CONCLUSIONS: GnRHa treatment for precocious puberty is not associated with increased risk of polycystic ovary syndrome.

Chemotherapy-based gonadotoxicity risk evaluation as a predictor of reproductive outcomes in post-pubertal patients following ovarian tissue cryopreservation.

BACKGROUND: The sterilizing effect of cancer treatment depends mostly on the chemotherapy regimen and extent of radiotherapy. Prediction of long-term reproductive outcomes among cancer survivors according to chemo-radiotherapy regimen may improve pre-treatment fertility preservation counseling and future reproductive outcomes. METHODS: The aim of this study was to evaluate long term reproductive outcomes in cancer survivors according to gonadotoxicity risk estimation of the chemo-radiotherapy regimens utilized. This retrospective cohort study was comprised of post-pubertal female patients referred for fertility preservation during 1997 and 2017 was performed. Eligible adult patients were addressed and asked to complete a clinical survey regarding their ovarian function, menstruation, reproductive experience and ovarian tissue auto-transplantation procedures. Results were stratified according to the gonadotoxic potential of chemotherapy and radiotherapy they received-low, moderate and high-risk, defined by the regimen used, the cumulative dose of chemotherapy administered and radiation therapy extent. RESULTS: A total of 120 patients were eligible for the survey. Of those, 92 patients agreed to answer the questionnaire. Data regarding chemotherapy regimen were available for 77 of the 92 patients who answered the questionnaire. Menopause symptoms were much more prevalent in patients undergoing high vs moderate and low-risk chemotherapy protocol. (51.4% vs. 27.3% and 16.7%, respectively; p < 0.05). Spontaneous pregnancy rates were also significantly lower in the high-risk compared with the low-risk gonadotoxicity regimen group (32.0% vs. 58.3% and 87.5%, respectively; p < 0.05). CONCLUSION: Patients scheduled for aggressive cancer treatment have significantly higher rates of menopause symptoms and more than double the risk of struggling to conceive spontaneously. Improving prediction of future reproductive outcomes according to treatment protocol and counseling in early stages of cancer diagnosis and treatment may contribute to a tailored fertility related consultation among cancer survivors.

Does quantity equal quality?-A morphokinetic assessment of embryos obtained from young women with decreased ovarian response to controlled ovarian stimulation.

PURPOSE: To assess oocyte quality in young patients with decreased ovarian response to controlled ovarian stimulation using time-lapse analysis. METHODS: A retrospective cohort study conducted at five medical centers between 2013 and 2017. The "decreased ovarian response" (DOR) group consisted of 241 women who underwent controlled ovarian stimulation with ≤ 5 retrieved oocytes and 519 cultured embryos. The "normal response" (NOR) group consisted of 667 women with ≥ 6 retrieved oocytes resulting in 3633 embryos. Data included annotation of morphokinetic events of embryos cultured in a time-lapse incubator from time of pronuclei appearance to time of starting blastocyst formation (tSB). Comparison was made between morphokinetic parameters of DOR and NOR patients with additional subgroup analysis according to the implantation status. RESULTS: Implantation and clinical pregnancy rates were significantly higher in the NOR group compared with the DOR group (44.5% vs. 31.6% and 51.5% vs. 37.7%, respectively; p < 0.05). Embryos from the DOR group reached the morphokinetic milestones later than embryos obtained from NOR patients. In the DOR group, implanted embryos reached starting blastocyst formation (tSB) faster than embryos which failed to be implanted, however, manifested a protracted course compared with implanted embryos from the NOR group. In a multivariate analysis-decreased ovarian response, nulliparity, number of transferred embryos, and t4, and were predictive for implantation. CONCLUSIONS: The quantitative decrease in ovarian response is associated with reduced oocyte quality, reflected by a slower developmental rate and lower implantation and pregnancy rates.

Does sperm origin-Ejaculated or testicular-Affect embryo morphokinetic parameters?

BACKGROUND: It is unclear whether sperm origin, either ejaculated or testicular, in couples diagnosed with male factor infertility, affects the timing of the embryo's developmental events evaluated by time-lapse monitoring and implantation rates. OBJECTIVE: To examine the effect of sperm origin on embryo morphokinetics in couples diagnosed with male factor infertility. MATERIALS AND METHODS: This study included a retrospective analysis of morphokinetic parameters performed by time-lapse monitoring between 2013 and 2017. The developmental processes and morphokinetic parameters of 419 embryos obtained from couples with male factor infertility attributed to oligo-astheno-teratozoospermia, 158 embryos derived from surgically extracted testicular spermatozoa from couples diagnosed with non-obstructive azoospermia, and 190 embryos from couples with normal ejaculated spermatozoa and female mechanical factor-related infertility, were evaluated. A comparison of morphokinetic parameters, implantation, and clinical pregnancy rates was performed between the groups with additional analysis in accordance with implantation status. RESULTS: Embryos from the normal ejaculated spermatozoa and oligo-astheno-teratozoospermia patients reached the later morphokinetic milestones-synchronous division (S3) and time to morula (tM)-faster than embryos obtained from testicular spermatozoa. Implantation rate was similar in the normal ejaculated spermatozoa and oligo-astheno-teratozoospermia groups (41.9% vs. 45.8%, NS), with higher implantation rate in the oligo-astheno-teratozoospermia group compared to the testicular spermatozoa group (45.8% vs. 33.6%, p = 0.02). Comparison of Known Implantation Data (KID) positive (KIDp) and KID negative (KIDn) embryos in each group revealed more rapid development in KIDp embryos in the normal ejaculated spermatozoa and the oligo-astheno-teratozoospermia groups, while in the testicular spermatozoa group implanted embryos reached the late morphokinetic milestones (time to 8 cell stage-t8, ECC3, S3, and tM) significantly faster than embryos that failed to implant. In a multivariate logistic regression analysis of the male factor infertility population, (oligo-astheno-teratospermia) (OR = 2.54, p = 0.003) and t8 (OR = 0.95, p = 0.027) were predictive of successful implantation. Male factor infertility embryos that reached the t8 milestone within 48-56 h had favorable implantation rates (p < 0.001). DISCUSSION: The study results may highlight another pathophysiology by means of which sperm origin affects embryo developmental kinetics. Selecting embryos demonstrating a faster developmental rate at t8 and specifically the 48- to 56 h interval following time of pronuclei fading (tPNf) may improve implantation rates in cases of male factor infertility. CONCLUSION: This study showed that ejaculated spermatozoa is associated with faster late cell divisions, more rapid compaction, and higher implantation rates compared to testicular spermatozoa. Additionally, t8 is an important predictor for implantation in the male factor infertility population.

In vitro maturation rates in young premenarche patients.

OBJECTIVE: To evaluate in vitro maturation (IVM) efficacy and oocyte retrieval rates after ovarian tissue cryopreservation in young premenarche girls facing chemo- and radiotherapy. DESIGN: A retrospective cohort study. SETTING: University-affiliated tertiary medical center. PATIENT(S): A total of 84 chemotherapy-naïve patients ages 0-18 years referred for fertility preservation between 2004 and 2017: 33 premenarche and 51 postmenarche patients. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): IVM in the pre- and postmenarche groups and in the subgroups of very young (up to age 5 years) and older (5-10 years) premenarche girls. RESULTS: The number of oocytes retrieved did not significantly differ between the postmenarche and premenarche groups (10.8 ± 8.5 and 8.1 ± 6.8, respectively). However, the overall IVM rate was significantly higher in the postmenarche group (28.2% vs. 15.5%, respectively; odds ratio = 0.47). A separate analysis for patients up to 5 years of age demonstrated significantly lower oocyte yield compared with the older (5-10 years) premenarche girls (4.7 ± 5.2 vs.10.3 ± 7.0 oocytes, respectively) and much lower IVM rates (4.9% and 18.2%, respectively). Correlation of age with number of retrieved and matured oocytes showed a positive significant correlation (r = 0.45 and r = 0.64, respectively). CONCLUSIONS: IVM performed after ovarian tissue cryopreservation in premenarche girls and specifically in very young girls (4 years and younger) yields substantially decreased maturation rates compared with postmenarche patients, raising a question as to the utility of current IVM technique in this age group. Further studies are required to assess modification of the IVM technique for young girls.

Which semen analysis correlates with favorable Intracytoplasmic morphologically selected sperm injection (IMSI) outcomes?

OBJECTIVE: To assess whether a correlation exists between different sperm pathologies and Intracytoplasmic morphologically selected sperm injection (IMSI) outcomes. STUDY DESIGN: A retrospective cohort study which included couples with recurrent implantation failures (2 or more unsuccessful IVF-ICSI cycles) undergoing their first IVF-IMSI cycle in Hebrew-University Hadassah Medical Center between January 2008 and May 2017. RESULTS: A total of 170 couples with at least two IVF failures attempting their first IVF-IMSI cycle were included, of them 56 (32.9%) achieved a clinical pregnancy. No correlation was found between clinical pregnancy and a specific abnormal semen parameter. However, a positive correlation with clinical pregnancy was demonstrated when all three semen parameters were abnormal (OR-3.33, p = 0.015). CONCLUSIONS: Our findings suggest that IMSI procedure may be more efficient in severe compound sperm pathologies than in patients with one abnormal sperm parameter. Future prospective trials are required to reinforce these findings and allow formation of clear indications for IMSI.

Trial of labor after cesarean delivery in twin gestations: systematic review and meta-analysis.

BACKGROUND: Trial of labor after cesarean is offered as a routine option for singleton gestations with previous cesarean delivery. However, adequate data are not available to determine whether the approach is equally valid in women with twin gestation. OBJECTIVE: This systematic review and meta-analysis aimed to assess maternal morbidities associated with trial of labor after cesarean delivery in twin gestations. STUDY DESIGN: Electronic databases were searched for cohort studies and randomized controlled trials evaluating the association between trial of labor after cesarean delivery in twin gestations and pregnancy outcomes. Maternal mortality and severe morbidities, such as uterine rupture and hysterectomy, were compared between women who had trial of labor and women who had a planned repeat cesarean delivery. Pooled odds ratios were calculated using a random-effects model. Additional analyses were performed to compare trial of labor after cesarean outcomes in singleton and twin gestations. RESULTS: Eleven cohort studies including a total of 8209 twin gestations with previous cesarean delivery were included in the present study. Of these gestations, 2484 were intended for planned vaginal birth and 5725 were intended for planned repeat cesarean delivery. The rate of uterine rupture in twin gestations was higher in the trial of labor after cesarean group than the elective cesarean group (odds ratio, 10.09, 95% confidence interval, 4.30-23.69, I2 = 68%). However, no statistically significant difference was found in the rate of uterine rupture between twin and single gestations attempting trial of labor after cesarean delivery (odds ratio, 1.34, 95% confidence interval, 0.54-3.31, I2 = 0%). Women who attempted a trial of labor after cesarean delivery with twins did not have an increased risk of uterine scar dehiscence, hemorrhage, blood transfusion, or neonatal morbidity and mortality compared with elective repeat cesarean delivery. Patients with twins had similar rates of successful vaginal delivery as patients with singletons (odds ratio, 0.85, 95% confidence interval, 0.61-1.18, I2 = 36%). CONCLUSION: This meta-analysis demonstrates that, although trial of labor with twins after previous cesarean delivery is associated with higher rates of uterine rupture compared with elective cesarean delivery, pregnancy outcomes and success rates are similar to a trial of labor after previous cesarean delivery in singleton gestations. Planned vaginal birth for women with twin gestation and previous cesarean delivery may be a safe alternative to a planned repeat cesarean.

Risk factors for cesarean delivery and adverse neonatal outcome in twin pregnancies attempting vaginal delivery.

INTRODUCTION: Twin vaginal delivery presents a unique clinical challenge for obstetricians. The Twin Birth Study demonstrated the safety of planned vaginal delivery regarding neonatal outcomes. However, that study lacked a description of the risk factors associated with and the outcome of unplanned cesarean section. The aim of this study is to identify potential risk factors for cesarean section and delivery related neonatal morbidity and mortality in women with twin pregnancy attempting vaginal delivery. MATERIAL AND METHODS: A retrospective cohort study including 1070 women with twin pregnancy that underwent a trial of labor between 2003 and 2015. The study population was divided according to the mode of delivery: vaginal delivery, combined vaginal-cesarean and intrapartum cesarean delivery of both twins. Several risk factors and neonatal outcomes were examined by both univariate analysis and multinomial logistic regression analysis. RESULTS: The rate of vaginal delivery of both twins was 88.3%, whereas the rates of combined vaginal cesarean and unplanned cesarean delivery were 4.6% and 7.1%, respectively. Nulliparity and nonvertex presentation of twin B were found to be independently associated with cesarean delivery for both twins. Additionally, nonvertex presentation of twin B was independently associated with combined vaginal-cesarean delivery. The proportion of neonates with Apgar score <7 at 5 min was increased for both twins in the combined vaginal-cesarean group compared with those delivered by the vaginal route alone. CONCLUSION: Nulliparity and nonvertex presentation of twin B were found to be associated with intrapartum cesarean delivery in twin pregnancies.

Single-Incision Laparoscopic Surgery for Ovarian Tissue Cryopreservation.

STUDY OBJECTIVE: To present single-incision laparoscopic surgery (SILS) as an alternative to standard multiport laparoscopic surgery (MPLS) for ovarian tissue cryopreservation. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Tertiary medical center. PATIENTS: Two hundred thirty-one patients referred for oncologic fertility preservation. INTERVENTION: Non-inferiority comparison of SILS with MPLS for ovarian cryopreservation for future transplantation. MEASUREMENTS AND MAIN RESULTS: We compared duration of the procedure, intra- and postoperative complications, hospital stay, and time (days) from surgery to chemotherapy. We additionally compared number of ampules (each ampule contains 10 slivers of ovarian cortex tissue) preserved and number of oocytes retrieved during the preparation process. Adjustments for age, previous chemotherapy, and partial versus complete oophorectomy ratio were performed. MPLS was performed in 163 patients (71.2%) and SILS in 66 patients (28.8%). Ten patients (15.2%) in the SILS group and 32 (19.8%) in the MPLS group were prepubertal. Malignant conditions distribution was similar. Procedure duration and overall complication rates were similar. Number of ampules extracted from the preserved tissue was somewhat higher in the SILS group as compared with the MPLS group (14.7 vs 10.6, respectively; p < .01). CONCLUSION: Our findings suggest that SILS is an interesting alternative to MPLS. Future prospective trials may prove some benefit in ovarian tissue volume or time until chemotherapy initiation.

Does cryopreservation of sperm affect fertilization in nonobstructive azoospermia or cryptozoospermia?

OBJECTIVE: To compare intracytoplasmic sperm injection (ICSI) outcomes with the use of fresh or frozen-thawed ejaculated or testicular sperm in patients with cryptozoospermia or nonobstructive azoospermia. DESIGN: Retrospective cohort study. SETTING: Tertiary medical center IVF unit. PATIENT(S): A total of 274 patients evaluated from 1999 to 2011. INTERVENTION(S): A total of 103 patients underwent testicular sperm extraction (TESE) because of nonobstructive azoospermia, and 171 patients were diagnosed with cryptozoospermia. MAIN OUTCOME MEASURE(S): ICSI outcomes during the first cycle in each technique performed according to the sperm origin (testicular vs. ejaculated) and processing (frozen vs. fresh). RESULT(S): Forty-eight cycles with the use of frozen testicular sperm, 22 cycles with fresh testicular sperm, 66 cycles with frozen ejaculated sperm, and 138 cycles with fresh ejaculated sperm were examined. Significantly more motile sperm were found in the fresh ejaculate group compared with the frozen-thawed ejaculate group (96% vs. 88%, respectively). Furthermore, fresh ejaculated sperm were found to have better fertilization rates than frozen ejaculated sperm (64% vs. 56%, respectively). No significant difference was found between fresh and frozen-thawed testicular sperm, either in motile sperm available for ICSI or in fertilization rate (64% vs. 62% and 52% vs. 49%, respectively). CONCLUSION(S): In cases of cryptozoospermia, frozen-thawed ejaculated sperm is inferior to fresh ejaculated sperm in fertilization rates. However, in nonobstructive azoospermia, no major differences were found between fresh and frozen-thawed testicular sperm. Therefore, uncoupled TESE/oocyte pick-up (OPU) should be considered in NOA cases to prevent possible unnecessary ovarian stimulation and OPU when no sperm cells are detected.