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Research Question: What is the involvement of pigment epithelium-derived factor (PEDF), expressed in granulosa cells, in folliculogenesis?, Design: mRNA expression of PEDF and other key factors [Cyp19, anti-Müllerian hormone receptor (AMHR) and vascular endothelial growth factor (VEGF)] in mice follicles was examined in order to typify the expression of PEDF in growing follicles and in human primary granulosa cells (hpGC), and to follow the interplay between PEDF and the other main players in folliculogenesis: FSH and AMH., Results: mRNA expression of PEDF increased through folliculogenesis, although the pattern differed from that of the other examined genes, affecting the follicular angiogenic and oxidative balance. In hpGC, prolonged exposure to FSH stimulated the up-regulation of PEDF mRNA. Furthermore, a negative correlation between AMH and PEDF was observed: AMH stimulation reduced the expression of PEDF mRNA and PEDF stimulation reduced the expression of AMHR mRNA., Conclusions: Folliculogenesis, an intricate process that requires close dialogue between the oocyte and its supporting granulosa cells, is mediated by various endocrine and paracrine factors. The current findings suggest that PEDF, expressed in granulosa cells, is a pro-folliculogenesis player that interacts with FSH and AMH in the process of follicular growth. However, the mechanism of this process is yet to be determined., (Copyright © 2024 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: Do preimplantation genetic testing (PGT) pregnancies have higher post-partum complications compared with naturally conceived pregnancies?, Design: 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 birth >24 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., Results: 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., Conclusions: 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., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: What are the reproductive choices and retrospective reflections of women at least 4 years after planned oocyte cryopreservation (POC)?, Design: This was an internet survey, using the REDCap application, of women who underwent POC, at a single-centre university-affiliated IVF unit, 4-8 years before the survey. The questionnaire addressed reproductive choices and outcomes following POC., Results: Seventy-nine women who underwent POC during 2011-2014 were invited to participate, and 70 (89%) responded. Mean age at cryopreservation was 37.1 ± 2.4 (range 30-41) years, mean age at study participation 42.6 ± 2.6 (range 35-48) years, and mean time from first cryopreservation cycle to study participation 5.5 ± 1.3 (range 4-8) years. The main retrospectively reported reason for POC was not wanting to become pregnant without a partner (59, 84%). During the follow-up period, 44 women (63%) attempted to conceive either naturally or by assisted reproductive technology using fresh or cryopreserved oocytes. Of those, 28 women achieved a live birth (64% of those who tried to conceive). Fourteen respondents (20% of all respondents) reported using their cryopreserved oocytes, and three (21%) achieved a birth using those oocytes. Fifteen women (34%) of those who tried to conceive used donor spermatozoa., Conclusions: The most common reasons for not using frozen oocytes were achieving pregnancy without frozen oocytes or preferring not to have a child without a partner. A considerable proportion of women who had POC and were not interested in being a single parent by choice eventually try to conceive using donor spermatozoa several years later., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: The objective was to explore the prevalence of and risk factors for inadequate cervical dilation following insertion of a single set of laminaria in women scheduled for dilation & evacuation (D&E) at 14-24 weeks' gestation., Study Design: We retrospectively reviewed all cases of women who underwent pregnancy termination by D&E at 14-24 weeks' gestation between January 2003 and December 2013. All cases in which the surgical procedure was cancelled due to failure to achieve adequate cervical dilation after a single set of laminaria inadequate cervical dilation were included. The control group was women who underwent D&E following adequate cervical dilation after a single set of laminaria, and were matched according to gestational week in a ratio of 1:3., Results: The overall dilation failure rate was 3.2%, with 4.0% among the induced-abortion patients and 1.5% among the patients with fetal demise (p=.002). Patients who had inadequate cervical dilation had lower rates of gravidity (p=.002) and previous spontaneous vaginal delivery (p<.001), along with higher rates of primigravidity, nulliparity (p<.001), previous cesarean section/s (p=.041), previous abdominal surgeries (p=.001) and previous cervical procedures (p=.003), compared to controls. A multivariable logistic regression analysis revealed two risk factors for inadequate cervical dilation following laminaria insertion, namely, previous cesarean section (p=.002) and previous cervical procedure (p<.001), whereas increased gravidity was found to protect against inadequate cervical dilation (p=.002)., Conclusions: Previous cesarean section/s, cervical procedures and primigravidity were found to be risk factors for failure to achieve adequate cervical dilation after a single set of laminaria. Women who are scheduled for D&E, and in whom one of these risk factors exists, might benefit from additional interventions to achieve better cervical preparation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 AAGL. Published by Elsevier Inc. All rights reserved.)

Iatrogenic twinning has become the main side-effect assisted reproduction treatment. We have evaluated the evidence for additional care that assisted-reproduction twins may require compared with spontaneous twins. Misacarriages are increased in women with tubal problems and after specific treatments. Assisted-reproduction twin pregnancies complicated by a vanishing twin after 8 weeks have an increased risk of preterm delivery and of low and very low birthweight compared with singleton assisted-reproduction pregnancies. Monozygotic twin pregnancies occur at a higher rate after assisted reproduction treatment and are associated with a higher risk of perinatal complications. The incidence of placenta praevia and vasa praevia is increased in assisted-reproduction twin pregnancies. Large cohort studies do not indicate a higher rate of fetal congenital malformations in assisted-reproduction twins. Overall, assisted-reproduction twins in healthy women <45 years of age are not associated with a notable increase in antenatal complication rates and thus do not require additional antenatal care compared with spontaneous twins. The risks of maternal and fetal morbidity and mortality associated with assisted-reproduction twins is only increased in women with a pre-existing medical condition such as hypertensive disorders and diabetes and most of these risks can be avoided with single-embryo transfer. Following the birth of the first IVF baby, rumours started to spread in both the medical literature and the media about the long-term health effects for children born following assisted reproduction treatment. However, after more than 30 years, the most common complications associated with IVF treatment remain indirect and technical such as the failure of treatment and ovarian hyperstimulation. Iatrogenic twinning has become the main side-effect of assisted reproduction treatment and the increasing number of twin pregnancies, in particular in older women, has generated numerous debates on the need for additional healthcare provision. In this review, we have evaluated the evidence for additional care that assisted-conception twin pregnancies may require compared with spontaneous twin pregnancies. Twin pregnancies are obviously at higher risk of perinatal complications than singletons due to a natural increase in the incidence of fetal anomalies, antenatal disorders and obstetric and neonatal complications associated with the development of two fetuses instead of one. Overall, our review indicates that some antenatal complications are more frequent in assisted-conception twin pregnancies than in spontaneous twin pregnancies but their prevalence is low and thus their impact on the morbidity and mortality of an individual assisted-conception twin pregnancy is limited. Assisted reproduction treatment has become available to older women with pre-existing maternal medical conditions such as chronic hypertension and diabetes. The increased obstetrical risks in this population must be considered prior to attempts at assisted conception, and the transfer of more than one embryo should be avoided in women with a pre-existing maternal medical condition., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: We sought to investigate the reproductive outcomes of women who underwent laparoscopic removal of benign cystic teratoma with or without intraoperative spillage., Study Design: The reproductive outcomes of reproductive age women following laparoscopic removal of benign cystic teratoma from 1997 through 2007 were investigated by a telephone questionnaire., Results: In all, 128 reproductive age women underwent benign cystic teratoma removal, and reproductive outcomes were available for 45. Among those 45 women, intraoperative spillage occurred in 16 (35.6%). The rate of spontaneous pregnancies was significantly lower for the nonspillage compared to the intraoperative spillage groups (20/29 [68.9%] vs 16/16 [100%], respectively; P = .01). However, the median time from surgery to the first pregnancy was similar (22 and 18.5 months, respectively; P = .9). From the 9 remaining women in the nonspillage group, 4 conceived with ovulation induction, 2 conceived with in vitro fertilization, and 3 were infertile., Conclusion: Intraoperative spillage of benign cystic teratomas does not lead to long-term infertility., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Study Objective: To assess the efficacy of oophoropexy in obviating recurrent torsion and its possible long-term effects., Design: Case series and review of the literature (Canadian Task Force classification III)., Setting: University hospital., Patients: Women who underwent oophoropexy for recurrent torsion of normal adnexa between 2003 and 2008., Measurements and Main Results: Retrieved information included the indication for oophoropexy, surgical methods, recurrence, and follow-up. Seven women underwent oophoropexy during the study period because of recurrent torsion of normal adnexa. One additional patient had experienced 3 torsion events of cystic adnexa. Surgical methods included suturing of the ovary to the pelvic sidewall or to the round ligament and plication of the utero-ovarian ligaments. Recurrence occurred in 1 of 6 patients for whom follow-up was available. All 6 patients reported spontaneous menstruation, and 2 conceived spontaneously and gave birth. Ultrasound at long-term follow-up (9-58 months) demonstrated normal ovaries., Conclusion: Oophoropexy seems to be efficacious in preventing recurrent torsion. It is our impression that plication of the utero-ovarian ligaments has advantages over other approaches insofar as surgical feasibility and anatomical conservation., (Copyright 2010 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: To report a higher than estimated recurrence rate of benign mucinous cystadenomas after complete resection of the first one, and to assess potential risk factors for recurrence after complete surgical excision., Study Design: We retrospectively reviewed all cases of women who underwent either laparoscopic or laparotomic removal of benign mucinous adnexal cysts by either adnexectomy or cystectomy in our institution between 1996 and 2006., Results: Included were the data of 42 women who fulfilled study entry criteria. Three of them (7.1%) underwent a second operation because of a recurrence of the lesion. A significantly higher rate of women who had cyst recurrence had undergone cystectomy as opposed to adnexectomy (P < .05). Intraoperative rupture of cysts during cystectomy was also significantly associated with cyst recurrence (P < .03)., Conclusion: Mucinous cystadenoma recurrence is apparently not as rare as reported in the literature. Intraoperative cyst rupture and cystectomy instead of adnexectomy emerged as being two risk factors for recurrence., (Copyright 2010 Mosby, Inc. All rights reserved.)

Study Objectives: To investigate the phenomenon of recurrent adnexal torsion during the same pregnancy, describe its risk factors, and suggest possible management of this entity., Design: Retrospective case-control study (Canadian Task Force classification II-3)., Setting: Gynecologic endoscopy unit in a university hospital., Patients and Interventions: Pregnant women with surgically proved adnexal torsion were retrospectively identified from 1993 to 2007. Details of clinical presentation, method of conception, preoperative ultrasound findings, and operative findings were analyzed., Intervention: Comparison of characteristics of patients with recurrent episodes of adnexal torsion during the same pregnancy vs a single episode of torsion., Measurements and Main Results: Thirty-three pregnant women with 38 episodes of adnexal torsion were included in the study. Seventeen pregnancies (51.5%) were spontaneously conceived. Twenty-eight women had a single episode of torsion, and 5 women (15.1%) had recurrent episodes of torsion during the same pregnancy. No significant differences were found between the 2 groups in age, method of conception, and gestational age at time of torsion. However, ultrasound studies demonstrated that multicystic ovaries were significantly more common in women with recurrent torsion compared with women with a single episode of torsion (80% vs 25%; p =.02). The interval between the first and second episodes of torsion ranged from 1 to 4 weeks., Conclusion: Pregnant women are at risk for recurrent torsion, especially when the ovaries are enlarged and ultrasound studies demonstrate multiple cysts. Cyst aspiration may prevent recurrent torsion during the same pregnancy.

Objective: To assess whether there is an increased perioperative risk in termination of late second-trimester pregnancy after multiple cesarean sections by laminaria dilatation and evacuation., Study Design: During the period between January 2002 and June 2008, 636 consecutive patients underwent late second-trimester (17-24 weeks) pregnancy terminations by dilatation and evacuation. Patients were divided into 3 subgroups: those with no previous cesarean section (n = 545), those with 1 previous cesarean section (n = 59), and those with several previous cesarean sections (n = 32)., Results: There were no significant differences in major perioperative complications, such as anesthetic complications, need for blood transfusion, and cervical lacerations comparing the 3 subgroups. Importantly, there were neither cases of uterine perforation nor retained products of conception in the 3 subgroups., Conclusion: Late second-trimester pregnancy termination after multiple cesarean sections by laminaria dilatation and evacuation is probably not associated with an increased perioperative risk. Larger studies are needed to empower this study.

We have demonstrated previously that the synthesis of epiregulin and amphiregulin, of the EGF-like growth factor family, is stimulated by luteinizing hormone in human follicular (granulosa) cells obtained from in vitro fertilization program. In the present work, we demonstrate that H89, a PKA inhibitor, attenuated the expression of these growth factors both in the mRNA and the protein levels, suggesting PKA involvement in this signaling pathway. SV40-transformed human granulosa cells showed higher basal levels of epiregulin and amphiregulin than normal cells, which were still elevated following cAMP stimulation by Forskolin. Cleavage by a disintegrin and metalloproteinases (ADAMs) is essential for activation of these growth factors, allowing their interaction with EGF receptor. Expression of ADAMTS1 and ADAM12 was downregulated by cAMP in normal, but not in SV40-transformed cells, suggesting that in normal cells epiregulin and amphiregulin activity is downregulated by a feedback mechanism that may be lost in SV40-transformed cells and their loss of downregulation may be involved in the development of ovarian tumors.

Gonadotropic hormone, luteinizing hormone, and follicle-stimulating hormone exert their effect via activation of G-coupled receptors, which activate the hormone sensitive adenylyl cyclase, protein kinase A, and cyclic AMP responsive elements. This activation leads to specific de novo synthesis of steroidogenic factors and steroidogenic enzymes. In normal cells and following activation of this signaling pathway, desensitization period will be followed. This down-regulation, which was studied in detail for the last three decays, was found to take place at various steps of these signal transduction pathways as well as at different kinetics. A common and diverse feature of the mechanism of desensitization in other G-coupled-7-transmembrane receptor system is also discussed.

Epiregulin and amphiregulin are growth factors involved in cancer development, but their potential role in signaling in the gonads is still obscure. We report here that basal expression of these growth factors is evident in human granulosa cells obtained from women treated for in vitro fertilization, when examined by RT-PCR using RNA isolated from primary cultures of ovarian granulosa cells. Expression of these factors was elevated concomitantly with elevation of progesterone production in these cells upon stimulation with luteinizing hormone (LH), and to a lesser extent with follicle stimulating hormone (FSH), both essential stimulants for ovulation and luteinization. Epiregulin and amphiregulin gene expression was dose- and time-dependent when measured subsequent to LH stimulation. Moreover, forskolin, which activates adenylate cyclase, was as efficient as LH in stimulating expression of these growth factors. It is suggested that upregulation of the epiregulin and amphiregulin expression is part of the signal transduction pathway which leads to ovulation and luteinization in the human ovary.