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Purpose: To compare pregnancy rates in GnRH-antagonist cycles triggered with hCG after luteal phase support with intranasal GnRH agonist as sole luteal phase support versus standard vaginal progesterone preparation. Methods: Prospective randomized controlled study of patients who underwent antagonist-based IVF cycles triggered with hCG at university-affiliated tertiary medical center between 2020 and 2022. Patients meeting the inclusion criteria were randomly assigned to either intranasal GnRH-agonist or vaginal progesterone for luteal phase support. Pregnancy rates were the main outcome compared between the two study groups. Results: A total of 150 patients underwent 164 cycles, 127 cycles of which were included in the study cohort. Of them, 64 (50.4%) and 63 (49.6%) cycles were treated with GnRH-agonist or progesterone respectively as sole luteal phase support. A significantly higher pregnancy rate was demonstrated in the GnRH-agonist group compared with the progesterone group. After adjustment of several potential confounders such as age, body mass index, past obstetric history, number of IVF cycles, oocyte retrieved and embryos transferred, GnRH-agonist was still associated with a higher pregnancy rate (odds ratio 3.4, 95% confidence interval 1.4-8.3). Ovarian hyperstimulation syndrome rates were similar between the groups. Conclusions: This prospective study suggests that nasal GnRH-agonist for luteal phase support is associated with higher pregnancy rates compared with standard progesterone support in an antagonist-based protocol triggered with hCG, while maintaining a similar safety profile.

Purpose We previously developed Haploseek, a method for comprehensive preimplantation genetic testing (PGT). However, some key features were missing, and the method has not yet been systematically validated. Methods We extended Haploseek to incorporate DNA from embryo grandparents and to allow testing of variants on chromosome X or in regions where parents share common haplotypes. We then validated Haploseek on 151 embryo biopsies from 27 clinical PGT cases. We sequenced all biopsies to low coverage (0.2×), and performed single-nucleotide polymorphism (SNP) microarray genotyping on the embryos' parents and siblings/grandparents. We used the extended Haploseek to predict chromosome copy-number variants (CNVs) and relevant variant-flanking haplotypes in each embryo. We validated haplotype predictions for each clinical sample against polymerase chain reaction (PCR)-based PGT case results, and CNV predictions against established commercial kits. Results For each of the 151 embryo biopsies, all Haploseek-derived haplotypes and CNVs were concordant with clinical PGT results. The cases included 17 autosomal dominant, 5 autosomal recessive, and 3 X-linked monogenic disorders. In addition, we evaluated 1 Robertsonian and 2 reciprocal translocations, and 17 cases of chromosome copy-number counting were performed. Conclusion Our results demonstrate that Haploseek is clinically accurate and fit for all standard clinical PGT applications.

Do preimplantation genetic testing (PGT) pregnancies have higher post-partum complications compared with naturally conceived pregnancies?Retrospective cohort study conducted in 2008-2020 at the Shaare Zedek Medical Center (SZMC), including all patients aged 18-45 years old who conceived following PGT with a singleton live birth24 weeks. Data were collected from computerized hospital databases and patient files. There were two control groups: (i) pregnancies following IVF-ICSI (intracytoplasmic sperm injection); (ii) four neighbourhood controls for each case delivery (two women delivered before and two after) of women with naturally conceived pregnancies.Overall, 120 PGT, 779 IVF-ICSI and 3507 naturally conceived deliveries were included. Demographic variables were similar apart from slightly higher age in the PGT (P = 0.003) and ICSI (P = 0.002) groups (31.07 ± 4.38 PGT, 31.66 ± 5.03 ICSI, 28.77 ± 5.72 naturally conceived). Composite post-partum placental-related complications (manual lysis of placenta, revision of uterine cavity, haemoglobin drop ≥3 g/dl, post-partum haemorrhage, need for blood transfusion) were more prevalent in both the PGT and IVF-ICSI groups as opposed to naturally conceived (20.0% versus 18.9% versus 10.3%, respectively, P 0.001, P = 0.007). In a multivariate regression model PGT was not found to be independently associated with composite post-partum placental-related complications (adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 0.83-2.15), while IVF-ICSI pregnancies had increased risk (aOR 1.52, 95% CI 1.20-1.97) compared with natural conception. No difference was found between fresh and frozen cycles or between day 3 and day 5 embryo transfer.PGT pregnancies have a comparable risk of post-partum placental-related complications to naturally conceived pregnancies, unlike IVF-ICSI pregnancies. It is possible that infertility itself is the main mediator for post-partum complications in IVF-ICSI pregnancies.

To report outcome of planned oocyte cryopreservation (POC) in the first 8 years of this treatment in our center.A retrospective study in a university-affiliated medical center.A total of 446 women underwent POC during 2011-2018. Fifty-seven (13%) women presented to use these oocytes during the study period (until June 2021). POC was performed at a mean age of 37.9 ± 2.0 (range 33-41). Age at thawing was 43.3 ± 2.1 (range 38-49). A total of 34 (60%) women transferred their oocytes for thawing at other units. Oocyte survival after thawing was significantly higher at our center than following shipping to ancillary sites (78 vs. 63%, p = 0.047). Forty-nine women completed their treatment, either depleting their cryopreserved oocytes without conceiving (36) or attaining a live birth (13)-27% live birth rate per woman. Only one of eleven women who cryopreserved oocytes aged 40 and older had a live birth using thawed oocytes.Women should be advised to complete planned oocyte cryopreservation before age 40, given low success rates in women who underwent cryopreservation at advanced reproductive age. In this study, oocyte shipping was associated with lower survival rate. These findings may be relevant for women considering POC and utilization of cryopreserved oocytes.

Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant aneuploidy (9M in mouse), heterochromatin histone marks are lost, and oocyte maturation is impaired. This loss occurs in both constitutive and facultative heterochromatin marks but not in euchromatic active marks. We show that heterochromatin loss with age also occurs in human prophase I-arrested oocytes. Moreover, heterochromatin loss is accompanied in mouse oocytes by an increase in RNA processing and associated with an elevation in L1 and IAP retrotransposon expression and in DNA damage and DNA repair proteins nuclear localization. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and oocyte maturation defects. Inhibiting retrotransposon reverse-transcriptase through azidothymidine (AZT) treatment in older oocytes partially rescues their maturation defects and activity of the DNA repair machinery. Moreover, activating the heterochromatin machinery via treatment with the SIRT1 activating molecule SRT-1720, or overexpression of Sirt1 or Ezh2 via plasmid electroporation into older oocytes causes an upregulation in constitutive heterochromatin, downregulation of retrotransposon expression, and elevated maturation rates. Collectively, our work demonstrates a significant process in oocyte aging, characterized by the loss of heterochromatin-associated chromatin marks and activation of specific retrotransposons, which cause DNA damage and impair oocyte maturation.

Study question What are the success rates of social oocyte cryopreservation (SOC) at advanced age? Summary answer In this study, one in four women who underwent SOC above age 35 had a delivery. What is known already While SOC is gaining popularity, reports on delivery rates are limited due to low utilization rates. Study design, size, duration Retrospective data collection of all woman who underwent SOC between 2011–2018, and presented for treatment using cryopreserved oocytes until January 2021. Participants/materials, setting, methods: Review of patient records (including both IVF and antenatal/postnatal) and laboratory data in a university affiliated hospital-based IVF unit. Main results and the role of chance: A total of 448 women underwent SOC during 2011–2018. 50 (11.2%) women returned to use these oocytes until the end of January 2021. Women who returned to use their oocytes underwent cryopreservation at mean age of 38.2±2.2. 46 (92%) of participants were above 35 at time of cryopreservation. Number of oocytes cryopreserved was 11.3±9.7. Mean time from cryopreservation to thawing was 5.5±1.8years (range 1–9 years). and age at thawing was 43.4±2.1 (range 40–49). Nearly half of patients initially attempted to conceive before using their cryopreserved oocytes, mostly by ART using fresh oocytes. Mean number of oocytes thawed and oocytes survived per women was 9.7±6.2 and 6.1±4.9 respectively (post thawing survival rate 65.4±35%). Mean number of embryos transferred, at one or more attempts was 2.6±2.1 per women. Eleven women gave birth or had an ongoing pregnancy > 20 weeks at time of analysis. All deliveries resulted from cryopreservation at age 36 and older (delivery rate 23.9% per women). Limitations, reasons for caution: We report our initial experience of women who underwent SOC at a single center. Most women who returned to use their oocytes had undergone SOC at advanced age, therefore not necessarily reflecting outcome for younger patients attempting to preserve fertility using this technology. Wider implications of the findings: Considering modest success rates of SOC in our cohort, women considering SOC are advised to do so at an earlier age. Trial registration number Not applicable

Molecular changes, caused by various environmental factors, affect the quality and developmental potential of oocytes. Oxidative stress (OS) is a major factor involved in various gynecologic disorders and/or in aging. Recent studies suggest that elevated reactive oxygen species (ROS) hamper oocyte quality and future embryonic development. Pigment epithelium-derived factor (PEDF) is a pleiotropic protein, known for its antiangiogenic, anti-inflammatory, and antioxidative properties. Our previous findings demonstrate the antioxidative role of rPEDF in maintaining granulosa cell viability. In the current study, we examined the ability of PEDF to negate the adverse impact of OS on oocytes. Maturation rate of oocytes exposed to OS was significantly lower than that of control oocytes. The number of mtDNA copies in OS-exposed oocytes was significantly higher than in control oocytes (>3 times), whereas ATP concentration was significantly lower. Oocytes exposed to OS demonstrated impaired chromosome arrangement at the metaphase plate. PEDF significantly improved maturation rate of untreated OS-exposed oocytes. Moreover, mtDNA copy number, ATP concentration, and chromosome arrangement at the metaphase plate in rPEDF-treated OS-exposed oocytes were restored to the level of control oocytes. Our findings demonstrate that OS hampers the ability of oocytes to undergo proper in vitro maturation. The energetic balance of OS-exposed oocyte is characterized by excessive mtDNA replication and reduced ATP concentration; it hampers the ability of oocytes to perform high fidelity chromosome segregation. PEDF alleviates this damage, improves the rate of oocyte maturation, and preserves mtDNA level and ATP content, thus enabling oocytes to form proper metaphase plate and improve oocyte competence.

The posthumous retrieval and use of gametes is socially, ethically, and legally controversial. In the countries that do not prohibit the practice, posthumous assisted reproduction is usually permitted only at the request of the surviving spouse and only when the deceased left written consent. This paper presents the recommendations of an ethics committee established by the Israeli Fertility Association. In its discussions, the committee addressed the ethical considerations of posthumous use of sperm—even in the absence of written consent from the deceased—at the request of either the spouse or the deceased’s parents who wish to become the offspring’s parents or grandparents. It is concluded that under certain conditions, a request by the deceased’s parents to posthumously use the deceased’s sperm is justified and should be granted.

Mammalian oocyte quality reduces with female age. A well-studied aspect of this deterioration is an age-associated rise in oocyte aneuploidy. We show that prior to the occurrence of significant aneuploidy (at the age of 9 months in mouse females), epigenetic changes occur and impact oocyte quality and maturation ability. At this age- we observe a reduction in heterochromatin marks in mouse oocytes. This decrease is apparent in both constitutive heterochromatin and facultative heterochromatin marks but is absent in active euchromatic marks which remain constant. A decrease of heterochromatin marks with age is also observed in human GV oocytes from IVF treatments. Heterochromatin loss with age is associated with an elevation in retrotransposon RNA transcription and processing, an elevation in retrotransposon protein expression, elevation in DNA repair proteins nuclear localization and oocyte maturation defects. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and processing and oocyte maturation defects. Collectively, our work demonstrates an early stage of oocyte aging, characterized by the loss of heterochromatin associated chromatin marks and activation of retrotransposons which cause DNA damage and impair oocyte maturation. We hypothesize that this heterochromatin loss serves as an oocyte associated “epigenetic clock” and is exploited by the cell as an oocyte QC mechanism.One Sentence SummaryOocyte aging includes an early pre-aneuploidy phase when loss of repressive chromatin marks occurs as well as retrotransposon activation and egg maturation defects.

Polycystic ovary syndrome (PCOS), one of the most common female endocrine disorder, is a prevalent cause of infertility. Hyperandrogenism is a key feature in PCOS and is correlated with increased expression of VEGF and cytokines in the ovaries. We have previously shown that pigment epithelium-derived factor (PEDF), an endogenous protein, presents potent anti-angiogenic and anti-inflammatory activities in the ovary and negates the effects of cytokines and VEGF. Additionally, PEDF plays a role in both pathophysiology and treatment of ovarian-hyperstimulation syndrome (OHSS), frequently seen in PCOS patients. We established hyperandrogenic-PCOS models, both in vivo, using mice exposed prenatally to dihydrotestosterone (DHT) and, in vitro, using human primary granulosa cells (hpGCs) and human granulosa cell line (KGN). In PCOS-induced mice, the mRNA levels of I l-6, V egf and Amh were higher than those of control; yet, treatment with rPEDF decreased these levels. Moreover, treating OHSS-induced PCOS-mice with rPEDF alleviated all OHSS symptoms. Stimulation of hpGCs with DHT resulted in downregulation of PEDF mRNA expression, concomitantly with a significant increase in IL-6 and IL-8 mRNAs expression. However, co-stimulation of DHT with rPEDF attenuated the increase in cytokines expression. The anti-inflammatory effect of PEDF was found to be mediated via PPARγ pathway. Our findings suggest that rPEDF treatment may normalize the ovarian angiogenic-inflammatory imbalance, induced by PCOS-associated hyperandrogenism. Moreover, the therapeutic potency of PEDF in preventing OHSS symptomes offers a rationale for using PEDF as novel physiological treatment for PCOS sequels.

Research question Does recombinant pigment epithelium derived factor (PEDF) have potential in treating uterine fibroids? Design In-vitro models that used human leiomyoma and Eker rat uterine leiomyoma (ELT-3) cell lines. The ELT-3 cell line was used to examine cellular targets after adding recombinant PEDF to the culture media. Athymic nude female mice were used as an in-vivo model. They were injected with ELT-3 cells to induce ectopic fibroid lesions, then treated with recombinant PEDF. Results RNA expression of PEDF and its receptors was found in both leiomyoma cell lines, as well as the expression of PEDF receptors. Addition of recombinant PEDF to the culture medium of leiomyoma cell lines activated ERK in a time-dependent manner, induced down-regulation of vascular endothelial growth factor mRNA and protein, as well as the mRNAs of oestrogen receptors alpha and beta and inhibited cellular proliferation. Treatment of mice-bearing fibroids with recombinant PEDF reduced fibroid growth rate and resulted in smaller tumours. Conclusions This study suggests that recombinant PEDF is a putative novel potent physiological treatment for uterine fibroids. It targets several cornerstones of fibroid pathobiology in parallel, including vascular endothelial growth factor and oestrogen receptors, which are needed for vascularization, and restricts fibroid growth and final size in an animal model.

To assess fetal central nervous system (CNS) abnormalities presenting as major findings leading to late termination of pregnancy (late TOP) performed ≥ 24 weeks’ gestation. The study population included 2789 pregnant women that underwent late TOP in our institute between the years 1998 and 2015. Fifty-seven cases (2.0%) underwent late TOP because of fetal CNS indications and are the subjects of the current study. Those cases were subdivided into four categories (1) no routine prenatal screening with an incidental finding discovered ≥ 24 weeks’ gestation (25 patients, 43.8%); (2) developmental or acquired findings detected during late second and third trimester (22 patients, 38.6%); (3) apparently normal routine screening with abnormal findings that could have been detected earlier (six patients, 10.6%); (4) routine prenatal care raised suspicion of abnormalities, and the final diagnosis was established only following additional tests (four patients, 7.0%). Combining the two categories of CNS abnormalities, i.e., pregnant women who did not undergo any fetal evaluation (group 1) and those that could have been detected earlier (group 3) consists 54% from our cohort in which late TOP could have been avoided. On contrary, 39% fetuses from our study population had CNS developmental findings which could be detected only at advanced stage of gestation.

Objective To assess the risk of adverse pregnancy outcomes in subsequent pregnancies among women treated with methotrexate for ectopic pregnancy. Methods In a retrospective single-center study, data were assessed for women treated with methotrexate for ectopic pregnancy at Asaf Harofe Medical Center, Zerifin, Israel, between May 2004 and May 2014. Results Overall, 226 women were treated with methotrexate for ectopic pregnancy and subsequently conceived. The median time from treatment to conception was 10 months (range 1–120 months), and 127 women conceived within 12 months of treatment. Except for early missed abortion—which affected 23 (10.2%) pregnancies—adverse pregnancy outcomes such as fetal malformations were rare. The frequency of early abortion was lowest for women who conceived within 6 months of treatment with methotrexate (3/93, 3.2%), increased between 6 and 23 months (15/83, 18.1%), and remained high thereafter (7/50, 14.0%; P=0.006). Conclusion The frequency of fetal malformation in a subsequent pregnancy was low among women treated with methotrexate for ectopic pregnancy. The frequency of early missed abortion was lowest during the first 6 months after treatment with methotrexate. This article is protected by copyright. All rights reserved.

Objective The article aimed to assess the spectrum of fetal renal tract abnormalities as a major finding leading to termination of pregnancy (TOP). Method The study population included all pregnant women with singleton pregnancy who underwent TOP in our institute because of fetal renal tract indications between 1998 and 2015. We specifically excluded TOPs performed because of multiple pregnancies, multisystem defects, abnormal karyotype and chromosomal or genetic defect not related to renal tract abnormalities. The patients were stratified into late TOP (≥24 weeks' gestation) and early TOP (

PCOS is the most common endocrinopathy in women; associated with obesity and insulin resistance (IR). IR leads to accumulation of advanced-glycation-end-products (AGEs) and their receptor, RAGE. PCOS patients have increased levels of vascular endothelial growth factor (VEGF), interleukin 6/8 (IL-6/8) and anti-Mϋllerian-hormone (AMH). PEDF is a secreted-glycoprotein known for its anti-angiogenic and anti-inflammatory properties. We aimed to elucidate the role of PEDF in the pathogenesis and treatment of PCOS. We used a prenatal PCOS mouse model and fed the female offspring a high-fat diet, inducing metabolic PCOS (met.PCOS) characteristics. Female offspring were divided into three groups: control; met.PCOS; met.PCOS + recombinant PEDF (rPEDF). Met.PCOS mice gained more weight, had elevated serum IL-6 and higher mRNA levels of AMH, PEDF and RAGE in their granulosa cells (GCs) than met.PCOS + rPEDF mice. An in vitro Met.PCOS model in human GCs (KGN) line was induced by prolonged incubation with insulin/AGEs, causing development of IR. Under the same conditions, we observed an elevation of VEGF, IL-6/8 mRNAs, concomitantly with an increase in PEDF mRNA, intracellular protein levels, and an elevation of PEDF receptors (PEDF-Rs) mRNA and protein. Simultaneously, a reduction in the secretion of PEDF from GCs, was measured in the medium. The addition of rPEDF (5 nM) activated P38 signaling, implying that PEDF-Rs maintained functionality, and negated AGE-induced elevation of IL-6/8 and VEGF mRNAs. Decreased PEDF secretion may be a major contributor to hyperangiogenesis and chronic inflammation, which lie at the core of PCOS pathogenesis. rPEDF treatment may restore physiological angiogenesis inflammatory balance, thus suggesting a potential therapeutic role in PCOS.

Study Objective: To investigate the use of operative hysteroscopy instead of traditional curettage in women with retained products of conception (RPOC) following first trimester medical abortion, with the aim of reducing post-operative intrauterine adhesions. Design: Retrospective study. Setting: Gynecology department in a University affiliated hospital. Patients: All women treated by hysteroscopy for RPOC following first trimester medical abortion using the mifepristone-misoprostol protocol for pregnancy termination or the misoprostol protocol for early missed abortion from January 2013 to August 2016. Intervention: Operative hysteroscopy for removal of RPOC. Post-operative intrauterine adhesions were assessed by diagnostic office hysteroscopy after 6â8 weeks. Measurements and Main Results: 50 cases were identified. The mean time from medication administration to the operative hysteroscopy was 1.7 ± 0.7 months. Operative hysteroscopy with blunt use of the resectoscopic loop was used to remove all specimens, and all procedures were completed without intra-operative complications. Two patients (4.0%) were readmitted for fever. Pathology confirmed the presence of RPOC in 45 (90.0%) cases. On follow-up office hysteroscopy, a normal uterine cavity without evidence of intrauterine adhesions was seen in 29/29 (100%) women. Conclusion: Hysteroscopy for removal of RPOC following medical abortion is associated with low rates of complications and post-operative intrauterine adhesions. Keywords: abortion, hysteroscopy, intrauterine adhesions, retained products of conception

Objective To compare the incidence of twin-to-twin transfusion syndrome (TTTS) in spontaneous versus IVF-conceived twin pregnancies. Design Retrospective multicenter study. Setting University-affiliated tertiary medical centers. Patient(s) Women admitted for 11–14 week's scan between January 1997 and July 2013 who were diagnosed with monochorionic (MC) diamniotic twin pregnancies. Intervention(s) None. Main Outcome Measure(s) Mode of conception, TTTS. Result(s) The study cohort included 327 pregnant women with live MC diamniotic twins. Of them, 284 (86.9%) and 43 (13.1%) were spontaneous and IVF conceived, respectively. The mean maternal age was significantly higher in IVF compared with in spontaneously conceived pregnancies (33.8 ± 5.5 vs. 31.6 ± 5.4, respectively). Thirty-seven twins (11.3%) had TTTS, of whom 36/284 (12.7%) versus 1/43 (2.3%) were spontaneously and IVF conceived, respectively. The mean week of delivery was significantly lower in MC twins diagnosed with TTTS compared with those without TTTS (32.7 ± 3.3 vs. 35.5 ± 2.5, respectively). Furthermore, there was a significantly higher birthweight discordancy in twins diagnosed with TTTS compared with those without (20.6% vs. 11%, respectively). Conclusion(s) The significantly lower proportion of TTTS found in IVF-conceived twins may suggest a different embryological process that lies at the core of IVF conception of monozygotic twinning.

Human chorionic gonadotropin (hCG) is a known trigger of ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening complication of assisted reproduction. Administration of hCG results in the release of vascular endothelial growth factor (VEGF) from the ovary. We have previously shown that expression of pigment epithelium-derived factor (PEDF) in granulosa cell line is regulated by hCG, reciprocally to VEGF, and that the PEDF–VEGF balance is impaired in OHSS. Our aim was to explore the signaling network by which hCG downregulates the expression of PEDF mRNA and protein in granulosa cells. We applied specific chemical inhibitors and stimuli to human primary granulosa cells and rat granulosa cell line. We found that PKA and protein kinase C, as well as EGFR, ERK1/2 and PI3K, participate in the signaling network. The finding that hCG-induced PEDF downregulation and VEGF upregulation are mediated by similar signaling cascades emphasizes the delicate regulation of ovarian angiogenesis.

GnRH agonist (GnRH-a) triggering is associated with a reduced risk of ovarian hyperstimulation syndrome (OHSS) compared with human chorionic gonadotropin (hCG) in assisted reproduction technology cycles. We have shown that ovarian pigment epithelium derived factor (PEDF), a potent antiangiogenic factor, counteracts vascular endothelial growth factor (VEGF) expression and that OHSS is correlated with hCG-induced impaired PEDF to VEGF ratio.The objective of the study was to explore whether GnRH-a triggering could directly modulate PEDF/VEGF balance in granulosa cells.The design of the study was a mouse model and cultured granulosa cells.Changes in PEDF and VEGF were measured by quantitative PCR and Western blot analysis. OHSS symptoms were recorded by changes in body weight and in peritoneal vascular leakage, quantified by the modified Miles vascular permeability assay.GnRH-a stimulation significantly increased PEDF and decreased VEGF mRNA and protein levels both in rat granulosa cell line and human primary granulosa cells in vitro. GnRH-a and hCG triggering inversely modulated PEDF mRNA and protein level in human granulosa cells in vivo. In the GnRH-a triggering mouse model, we showed similar increase in PEDF to VEGF ratio as in the in vitro results. OHSS-predisposed mice did not develop OHSS parameters after GnRH-a triggering, opposed to hCG-triggered mice. Finally, GnRH-a triggering of OHSS-predisposed mice significantly increased ovarian PEDF to VEGF ratio compared with hCG-triggered mice and control mice.GnRH-a triggering induces a direct effect on PEDF/VEGF balance in granulosa cells inversely to hCG. Our results suggest a novel elucidation to the GnRH-a triggering-mediated risk reduction of OHSS and may clarify the pros and cons of this triggering method.

Background/Aims: Gq protein-coupled receptors (GqPCRs) regulate various cellular processes including mainly proliferation and differentiation. In a previous study, we found that in prostate cancer cells, the GqPCR of GnRH induces apoptosis by reducing the PKC-dependent AKT activity and elevating JNK phosphorylation. Since it was thought that GqPCR induces mainly activation of AKT, we undertook to examine how general is this phenomenon and understand its signaling. Methods: We used various cells to follow the phosphorylation of signaling components using western blotting. Results: In a screen of 21 cell lines, we found that PKC activation results in the reduction of AKT activity, which correlates nicely to JNK activation and in some cases to apoptosis. To further understand the signaling pathways involved in this stimulation, we studied in detail the SVOG-4O and αT3-1 cells. We found that PGF2α and GnRH agonist (GnRH-a) indeed induce significant Gq- and PKC- dependent apoptosis in these cells. This is mediated by two signaling branches downstream of PKC, which converge at the level of MLK3 upstream of JNK. One branch consists on c-Src activation of the JNK cascade and the second involves reduction of AKT activity that alleviates its inhibitory effect on MLK3, to allow the flow of the c-Src signal to JNK. At the MAPKK level, we found that the signal is transmitted by MKK7 and not MKK4. Conclusion: Our results present a general mechanism that mediates a GqPCR-induced, death receptors-independent, apoptosis in physiological, as well as cancer-related systems.

OBJECTIVE The objective of this study was to compare the associations of crown-rump length (CRL) discrepancy with birthweight discordance in spontaneous versus in vitro fertilization (IVF) monochorionic (MC) twin pregnancies. METHOD This is a multicenter retrospective study on women with twin pregnancies assessed for nuchal translucency between January 1997 and July 2013. The study group was subdivided into MC twins conceived spontaneously and after IVF. Pregnancies with later fetal death or twin transfusion syndrome were excluded. A large-weight discordance was defined as a difference of birthweights of >15%. RESULTS The study group included 171 pregnancies; of them, 142 (83%) were spontaneous and 29 (17%) were IVF conceived. In the entire cohort, we found a significant correlation between birthweight discordance and CRL discrepancy (r = 0.173, P

Objective: To compare the reproductive outcomes of women with pathologically confirmed retained products of conception (RPOC) following spontaneous vaginal delivery versus first-trimester pregnancy termination. Methods: We retrospectively reviewed all cases of women who underwent uterine re-evacuation due to pathologically confirmed RPOC between January 1, 2000 and December 31, 2010. Reproductive outcomes were compared between women with RPOC following spontaneous vaginal delivery and those who underwent dilatation and curettage (D&C) due to first-trimester abortion. Results: The study group consisted of 176 patients with pathologically confirmed RPOC. Of those, 83 (47.1%) were admitted after spontaneous vaginal delivery and 93 (52.9%) following D&C due to first-trimester abortion. There were no significant differences in the conception rate, the mean time to conception and the rate of a new infertility problem between women with RPOC after vaginal delivery compared to those following pregnancy termination (p > 0.05). Furthermore, there were no significant differences between the groups in pregnancy outcomes following RPOC. Conclusion: Pathologically confirmed RPOC harbors the same reproductive outcomes following spontaneous vaginal delivery and first-trimester pregnancy termination.

The physiological function of the female reproductive organs is hormonally controlled. In each cycle, the reproductive organs undergo tissue modifications that are accompanied by formation and destruction of blood vessels. Proper angiogenesis requires an accurate balance between stimulatory and inhibitory signals, provided by pro- and anti-angiogenic factors. As with many other tissues, vascular endothelial growth factor (VEGF) appears to be one of the major pro-angiogenic factors in the female reproductive organs. Pigment epithelium-derived factor (PEDF) is a non-inhibitory member of the serine protease inhibitors (serpin) superfamily, possessing potent physiologic anti-angiogenic activity that negates VEGF activity. The role of PEDF in decreasing abnormal neovascularization by exerting its anti-angiogenic effect that inhibits pro-angiogenic factors, including VEGF, has been investigated mainly in the eye and in cancer. This review summarizes the function of PEDF in the reproductive system, showing its hormonal regulation and its anti-angiogenic activity. Furthermore, some pathologies of the female reproductive organs, including endometriosis, ovarian hyperstimulation syndrome, polycystic ovary syndrome, and others, are associated with a faulty angiogenic process. This review illuminates the role of PEDF in their pathogenesis and treatment. Collectively, we can conclude that although PEDF seems to play an essential role in the physiology and pathophysiology of the reproductive system, its full role and mechanism of action still need to be elucidated.

Despite the large volume of evidence on the management of retained products of conception (RPOC), there are virtually no data regarding the optimal time frame of surgical intervention in case of RPOC.To examine whether the time interval between spontaneous vaginal delivery or pregnancy termination and the uterine evacuation due to pathologically confirmed RPOC influences the reproductive outcome.We retrospectively reviewed all the records of women who were admitted to our department due to pathologically confirmed RPOC following either spontaneous vaginal delivery or pregnancy termination between January 2000 and December 2010. Based on the median time from delivery or pregnancy termination until the operative intervention in the study group, patients were stratified into two groups: early intervention (3 weeks) and late intervention (3 weeks). Reproductive outcomes were compared between the two study groups.Reproductive outcomes were analyzed in 172 patients with pathologically confirmed RPOC. Of them, 95 (55.2%) were included in the early intervention group and 77 (44.8%) in the late intervention group. There were no significant differences in the conception rate, mean time to conception, and the occurrence rate of a new infertility problem in women with early surgical intervention compared to those with late surgical intervention (P0.05). Furthermore, there was no significant difference between the groups in the pregnancy outcomes following RPOC.Early surgical intervention in women with pathologically confirmed RPOC following spontaneous vaginal delivery or pregnancy termination yields the same reproductive outcomes as late surgical intervention.

Umbilical vein varix (UVV) is defined as a focal enlargement of the umbilical vein and represents approximately 4% of fetal umbilical cord malformations. The reported neonatal outcome of fetuses with UVV varies widely due to its rarity, hence the small sample sizes of the case series in the literature. Earlier studies reported high fetal mortality, but more recent reports have demonstrated no association between UVV and intrauterine fetal death. A recent study has described a possible association between UVV diagnosed prenatally and child developmental delay. The present study of fetuses with UVV was done to evaluate and compare the levels of triple test serum biomarkers used for Down syndrome screening (human chorionic gonadotropin, α-fetoprotein, and unconjugated estriol) between a group of fetuses with uneventful obstetric outcome versus a subgroup of children with developmental delay.

Objective This study aims to evaluate the distribution of mean arterial pressure (MAP) and uterine artery Doppler pulsatility index (PI) in first trimester twins with and without preeclampsia. Method A total of 147 twins were recruited from a specialist clinic and 110 unaffected singleton pregnancies attending the same institution served as controls. MAP and Doppler PI values were expressed in multiples of the gestation-specific median using published equations. Results Among the twins, 12 had preeclampsia and two had pregnancy-induced hypertension. Among unaffected pregnancies, there was no significant difference in MAP levels between twins and singletons (P = 0.17, Wilcoxon rank sum test, two-tail). However, the Doppler PI levels were highly statistically significantly lower than in singletons (P

Objective This study aimed to compare the associations of crown–rump length (CRL) discrepancy with birthweight discordance in spontaneous versus vitro fertilization (IVF) conceived dichorionic twin pregnancies. Method A computerized retrospective study of women referred to our ultrasonographic unit for nuchal translucency examination between January 1997 and December 2011. The study group was subdivided into twins conceived after IVF, non-IVF fertility treatment and spontaneously conceived twins. Birthweight discordance was defined as a difference of birthweights of >20%. Results A total of 688 dichorionic twin pregnancies were included, all of them ending in live birth of both twins. IVF-conceived pregnancies were associated with a significant increased risk of extreme birthweight discordance compared with spontaneous-conceived twin pregnancies (OR = 2.3; CI = 1.4–3.8, P

Study Objective To evaluate the safety and effectiveness of Oxiplex/AP gel (Intercoat) in reducing intrauterine adhesion formation after hysteroscopic treatment because of retained products of conception (RPOC). Design Prospective double-blind, randomized, controlled pilot study (Canadian Task Force classification I). Setting Tertiary medical center. Patients All women who underwent hysteroscopic treatment because of RPOC at our institution between September 2009 and June 2012 were invited to participate. After operative hysteroscopy, participants were randomized to either have their uterine cavity filled with Oxiplex/AP gel (study group, n = 26) or not (control group, n = 26). Interventions Diagnostic office hysteroscopy to assess for adhesion formation was performed after 6 to 8 weeks. Findings were graded according to the American Fertility Society classification. Rates of subsequent pregnancy in the 2 groups were assessed. Measurements and Main Results Intraoperative complication rates were similar between the 2 groups. There were no postoperative complications after Oxiplex/AP gel application. Moderate to severe adhesions developed in 1 woman (4%) in the study group and 3 (14%) in the control group (p = .80). During follow-up of 20 months (range, 2–33 months), 7 women (27%) in the treatment group conceived, compared with 3 (14%) in the control group (p = .50). Conclusion Intrauterine application of Oxiplex/AP gel after hysteroscopic removal of RPOC is safe. In this small sample, the difference in the rate of intrauterine adhesions was not statistically significant. A larger study would enable further establishment of the safety and efficacy of use of this gel.

The objective of this study was to provide a critical analysis of the impact of assisted conception on prenatal screening for Down syndrome (DS) in twin pregnancies and the value of various screening modalities for early detection of anomalies.The literature was searched using PubMed and the Cochrane Library focusing on prenatal screening and antenatal care of assisted-conception twin pregnancies.Serum screening alone is of limited value in detecting aneuploid twins, because the unaffected cotwin can "mask" the abnormal serum results of an affected one. In addition, this test can designate the pregnancy as at high risk but not identify the affected fetus. Nuchal translucency (NT) screening is the best available modality and a highly effective screening method for twin pregnancies. Among twins, NT alone has a 69% DS detection rate, first-trimester combined NT and serum biochemistry has a 72% DS detection rate, and an integrated screen will have an 80% DS detection rate at a 5% FPR. The data in the literature concerning the effect of assisted conception on maternal serum screening markers in twin pregnancies are scarce.Down syndrome screening in assisted-conception twins presents clinical and technical challenges. Therefore, assisted-conception twins need close monitoring from conception to delivery, by a practitioner familiar with the available screening modalities and their relative accuracy.

To study whether intravaginal application of seminal plasma after follicle aspiration has the potential to increase implantation and clinical pregnancy rates after IVF-ET.We conducted a prospective, double-blind, placebo-controlled randomized study of 230 patients undergoing IVF-ET cycles. 500 μL of Fresh seminal plasma from the patient's partner or culture medium (placebo) were injected in the vaginal vault just after follicle aspiration. The main outcome measured was ongoing clinical-pregnancy rate.After ET cancellation in ten patients due to lack of fertilization or embryo cleavage, 220 embryo transfers (103 and 117 in the study and control groups) resulted in a clinical pregnancy rate of 36.9 % and 29.1 % for the study and control groups, corresponding to a relative increase of 26.8 %. After an early pregnancy loss of 13.1 % (5/38) and 23.5 % (8/34) in the study and control groups respectively an ongoing pregnancy rate of 32.0 % (33/103) and 22.2 % (26/117) was achieved corresponding to a relative increase of 44.1 %. Multivariate logistic regression analysis adjusted for study group, age, infertility, and cycle characteristics did not demonstrate any parameter that could predict occurrence of clinical pregnancy rates after IVF-ET.Patients who underwent SP intravaginal insemination after oocyte pick-up reached higher implantation and clinical pregnancy rates following ET compared to controls, although the difference did not reach statistical significance. More studies and variable methodologies may clarify the potential clinical effect of SP in improving live birth rates after ART.

Objective To compare intracytoplasmic sperm injection (ICSI) outcome of patients with cryptozoospermia after use of ejaculated versus testicular sperm in different cycles of the same patients. Design Retrospective cohort study. Setting University-affiliated infertility center. Patient(s) A total of 17 patients with cryptozoospermia who underwent a total of 116 ICSI cycles. Intervention(s) The patients initially underwent several ICSI cycles using ejaculated sperm (n = 68, 58.6%) that were followed by ICSI cycles using testicular sperm (n = 48, 41.4%). Main Outcome Measure(s) Fertilization rate, pregnancy rate (PR). Result(s) There were no significant differences in fertilization rates between the two subgroups. A comparison between testicular sperm extraction (TESE) versus ejaculated sperm cycles revealed significantly higher implantation rate (20.7% vs. 5.7%), higher PR (42.5% vs. 15.1%), and higher take home baby rate (27.5% vs. 9.4%). A multivariable logistic regression analysis showed three significant predictors for pregnancy, namely the use of testicular sperm (odds ratio [OR] 5.1, 95% confidence interval [95% CI] 1.8–14.8), use of motile sperm (OR 12.9, 95% CI 2.1–79.1), and female age (OR 0.83, 95% CI 0.7–0.9). Conclusion(s) Testicular sperm extraction is justified in patients with cryptozoospermia who fail to conceive by ICSI using ejaculated spermatozoa, as it offers higher PR.

Objectives The current study aims were to assess the long-term outcomes of children who were diagnosed with umbilical vein varix (UVV) prenatally. Methods The study included fetuses with UVV diagnosed in the community between the years 2005 and 2011. They all have been refereed to our Ultrasound Unit for diagnosis' confirmation. This has been conducted locally by a single operator. After delivery, they were matched by gestational age at birth with a set of newborns from a random list. Developmental delay was assessed by telephone interview using a questionnaire based on Ages and Stages Questionnaire. If the child's score (both in the study and control group) was below the cut-off in one or more domain(s), the families were offered an examination by a child developmental health care team. Results There was no perinatal mortality in both groups. A low-development score was found in 41.7% (15/36) and 3.7% (4/108) in UVV and control group, respectively (P

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproduction. OHSS is induced by an ovarian release of vasoactive, angiogenic substances that results in vascular hyperpermeability, leakage, and shift of fluids from blood vessels into the extravascular space with consequent ascites and edema that are attributed to vascular endothelial growth factor (VEGF).Our objective was to examine a physiological approach for preventing and treating OHSS, based on negating the VEGF network.We used a mouse OHSS model and cultured granulosa cells.Changes in pigment epithelium-derived factor (PEDF) and VEGF were measured by quantitative PCR and Western blot analysis. OHSS was recorded by changes in body weight and in peritoneal vascular leakage, quantified by the modified Miles vascular permeability assay.Granulosa cells produced and secreted the anti-angiogenic factor, PEDF, in an inverse fashion to VEGF. The physiological PEDF-VEGF counterbalance was found to be impaired in the mouse OHSS model. Treatment of OHSS-induced mice with low doses of recombinant PEDF (rPEDF) alleviated OHSS signs including edema (P.001) and vascular leakage (P.001) and reduced the level of ovarian VEGF mRNA. Low doses of rPEDF also reduced VEGF mRNA levels in granulosa cells in vitro. However, these effects were not seen at higher doses of rPEDF, suggesting a hormetic mechanism of rPEDF action.These observations provide a new perspective into the pathophysiology of OHSS, namely, high expression level of VEGF together with a nearly undetectable level of PEDF. A replacement therapy with rPEDF is suggested as an innovative physiological treatment for OHSS. Finally, control of the PEDF-VEGF reciprocal relationship could open new therapeutic avenues for other angiogenic-related fertility pathologies.

This study compares the fertilization rate and embryonic development of oocytes randomly inseminated by conventional IVF or ICSI in patients with endometriosis and normozoospermic semen during IVF cycles.Sibling oocytes were randomized to be inseminated either by ICSI or IVF. Rates of fertilization, cleavage, blastulation and embryonic morphology were assessed.A total of 786 sibling cumulus-oocyte complexes (COC) were randomized between insemination by conventional IVF (387 COC) or ICSI (399 COC). A significantly higher fertilization rate was found in the ICSI group (ICSI versus IVF, 73.3±23 % versus 54.7±31.9 % respectively; P=0.003), yielding a higher mean number of day 2 embryos (5.2±3.4 versus 3.6±2.9 respectively; P=0.002). Triploid fertilization rate (3PN/COC) was significantly higher in the IVF group compared to the ICSI group (3.9±8.7 % versus 0.9±3.1 % respectively; P=0.02). The morphology score and rate of development of day 2 and 3 embryos were not different between the two groups. Comparison of embryo transfer cycles in which either IVF or ICSI only embryos were transferred did not reveal any statistically significant differences in pregnancy or implantation rates.ICSI appears to be a better treatment option than conventional IVF in endometriosis-associated infertility, since it offers the advantages of higher fertilization rate and mean number of embryos and lower rate of total fertilization failure and triploid fertilization.

Objective. To characterize the clinical and laboratory features of coagulopathy following second-trimester surgical abortions. Design. Retrospective study. Setting. Gynecologic unit of a university-affiliated medical center. Population. 1249 consecutive women underwent late second-trimester (16–24 weeks) surgical abortions between January 2002 and June 2010. Of those, 20 women (1.6%) were diagnosed with excessive bleeding accompanied by coagulopathy. Methods. Women were divided into two groups based on whether the abortion was performed for fetal demise (n=14) or pregnancy termination (n=6). Main outcome measures. Gestational age, indication for abortion, blood clotting tests, number of blood products and coagulation factors administered. Results. Women who had pregnancy termination began to bleed significantly earlier than those with fetal demise (p

background: In vitro maturation (IVM) of oocytes is a promising technique to reduce the costs and avert the side effects of gonadotrophin stimulation for IVF. The pregnancy rates from oocytes matured in vitro are still lower than those of in vivo stimulation cycles, indicating that optimization of IVM remains a challenge. Recently, it was demonstrated that LH exerts its action on ovulation, at least in part, through stimulation of the production of the epidermal growth factor family members amphiregulin (Areg) and epiregulin (Ereg) in pre-ovulatory follicles, and they, in turn, serve as paracrine mediators of LH. We aimed to investigate the effect of supplementation of the medium with Areg and Ereg on the maturation rate of immature oocytes. methods: A total of 105 sibling human germinal vesicle (GV) oocytes obtained after gonadotrophin stimulation were cultured in a complex defined medium either with or without supplemented recombinant human Areg (75 ng/ml) and Ereg (75 ng/ml) for 24 h. results: Significantly more oocytes reached the metaphase II stage at 24 h in media supplemented with Areg and Ereg (75.5 versus 36.5%, P , 0.001). In vitro matured oocytes retrieved from the two subgroups had no statistically significant difference in fertilization and cleavage rates or morphology scores. Overall, a significantly higher number of Day 2 (52.8 versus 26.9% P , 0.01) and Day 3 (45.2 versus 23%, P , 0.05) embryos originated from GV oocytes cultured in the Areg- and Ereg-enriched medium. conclusions: Supplementation of the maturation medium with Areg and Ereg improves the maturation of human GV oocytes in vitro.