Newborn infant urinary cotinine and birth outcomes in the Jerusalem Environment Mother and Child Cohort Study.

BACKGROUND: Environmental tobacco smoke (ETS) exposure during pregnancy can cause preterm delivery and childhood cancer. The aim of this study was to measure ETS exposure in pregnant women and in newborn infants in Israel using urinary cotinine measurements, to assess predictors of ETS exposure in these vulnerable groups, and to assess associations with birth effects (birth weight, birth length, head circumference) in newborn infants. METHODS: We analyzed urinary cotinine and creatinine in 265 non-smoking pregnant women and 97 newborns, and analyzed associations with self-reported exposure to ETS, paternal smoking, sociodemographic variables and with birth outcomes (birth weight, birth length, head circumference). RESULTS: 37.7% of pregnant women and 29.0% of infants had urinary cotinine concentrations above the level of quantification (LOQ) of 1 µg/L, whereas 63.8% and 50.5%, respectively, had urinary cotinine concentrations above the level of detection (LOD) of 0.5 µg/L. Median unadjusted and creatinine adjusted urinary concentrations of cotinine in pregnant women were 0.7 µg/L, and 0.9 µg/g creatinine, respectively, and in newborn infants were 0.5 µg/L, and 1.3 µg/g creatinine, respectively. We did not find an association between maternal and infant urinary cotinine level. Maternal (but not infant) urinary cotinine was significantly associated with paternal smoking (p < 0.05). Infant (but not maternal) cotinine above the LOQ was negatively associated with birth weight (p < 0.05). CONCLUSIONS: In this high socioeconomic cohort, almost a third of newborn infants born to non-smoking mothers had quantifiable levels of urinary cotinine. This is the first study showing that newborns with quantifiable urinary cotinine levels have lower birth weight.

Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies.

Natural killer cells (NKs) are abundant in the human decidua, regulating trophoblast invasion and angiogenesis. Several diseases of poor placental development are associated with first pregnancies, so we thus looked to characterize differences in decidual NKs (dNKs) in first versus repeated pregnancies. We discovered a population found in repeated pregnancies, which has a unique transcriptome and epigenetic signature, and is characterized by high expression of the receptors NKG2C and LILRB1. We named these cells Pregnancy Trained decidual NK cells (PTdNKs). PTdNKs have open chromatin around the enhancers of IFNG and VEGFA. Activation of PTdNKs led to increased production and secretion of IFN-γ and VEGFα, with the latter supporting vascular sprouting and tumor growth. The precursors of PTdNKs seem to be found in the endometrium. Because repeated pregnancies are associated with improved placentation, we propose that PTdNKs, which are present primarily in repeated pregnancies, might be involved in proper placentation.

Decreasing urinary organophosphate pesticide metabolites among pregnant women and their offspring in Jerusalem: Impact of regulatory restrictions on agricultural organophosphate pesticides use?

INTRODUCTION: Maternal urinary levels of dialkyl phosphate (DAP) metabolites of organophosphate pesticides (OP) during pregnancy are associated with adverse outcomes in the offspring. Between 2012 and 2014, eighteen active OP ingredients were restricted or banned in Israel for agricultural use. AIM: We aimed to study trends of urinary DAP metabolites among pregnant women and their offspring in the era of the new regulations. METHODS: Pregnant women were recruited at 11-18 weeks of gestation and provided spot urine samples (n = 273). Soon after birth, neonatal urine samples were collected (n = 107). All urine specimens analyzed for DAP metabolites. Trends in DAP metabolites were tested using Mann-Kendall trend statistic (M-K S) and linear regression models were constructed to estimate the association between calendar period and DAP levels between September 2012 and March 2016. RESULTS: Over the study period, median maternal ∑DAP levels decreased from 248 nmol/L to 148 nmol/L. Time of recruitment was associated with a statistically significant decrease in DAP metabolites, which remained significant after multivariate adjustment. Overall, the results for the analysis of before and after June 2014 showed a significant decrease in ∑DAP of -0.198 log10 nmol/L (95%CI: -0.311,-0.084) which corresponds with a decrease of 36.6% in ∑DAP. A similar trend was found for DAP metabolites in neonatal urine. Compared to other studies, pregnant women in Jerusalem had higher ∑DAP levels, even at the end of the study period. CONCLUSION: We observed significant reductions in maternal and neonatal DAP urinary levels during the period of 2012-2016. Regulations restricting agricultural use of OP seem to be effective in reducing population exposure to OP, in an era when residential use of OP is banned.

APOBEC3A Is Upregulated by Human Cytomegalovirus (HCMV) in the Maternal-Fetal Interface, Acting as an Innate Anti-HCMV Effector.

Human cytomegalovirus (HCMV) is the leading cause of congenital infection and is associated with a wide range of neurodevelopmental disabilities and intrauterine growth restriction. Yet our current understanding of the mechanisms modulating transplacental HCMV transmission is poor. The placenta, given its critical function in protecting the fetus, has evolved effective yet largely uncharacterized innate immune barriers against invading pathogens. Here we show that the intrinsic cellular restriction factor apolipoprotein B editing catalytic subunit-like 3A (APOBEC3A [A3A]) is profoundly upregulated following ex vivo HCMV infection in human decidual tissues-constituting the maternal aspect of the placenta. We directly demonstrated that A3A severely restricted HCMV replication upon controlled overexpression in epithelial cells, acting by a cytidine deamination mechanism to introduce hypermutations into the viral genome. Importantly, we further found that A3 editing of HCMV DNA occurs both ex vivo in HCMV-infected decidual organ cultures and in vivo in amniotic fluid samples obtained during natural congenital infection. Our results reveal a previously unexplored role for A3A as an innate anti-HCMV effector, activated by HCMV infection in the maternal-fetal interface. These findings pave the way to new insights into the potential impact of APOBEC proteins on HCMV pathogenesis.IMPORTANCE In view of the grave outcomes associated with congenital HCMV infection, there is an urgent need to better understand the innate mechanisms acting to limit transplacental viral transmission. Toward this goal, our findings reveal the role of the intrinsic cellular restriction factor A3A (which has never before been studied in the context of HCMV infection and vertical viral transmission) as a potent anti-HCMV innate barrier, activated by HCMV infection in the authentic tissues of the maternal-fetal interface. The detection of naturally occurring hypermutations in clinical amniotic fluid samples of congenitally infected fetuses further supports the idea of the occurrence of A3 editing of the viral genome in the setting of congenital HCMV infection. Given the widely differential tissue distribution characteristics and biological functions of the members of the A3 protein family, our findings should pave the way to future studies examining the potential impact of A3A as well as of other A3s on HCMV pathogenesis.

Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface.

Zika virus (ZIKV) has emerged as a cause of congenital brain anomalies and a range of placenta-related abnormalities, highlighting the need to unveil the modes of maternal-fetal transmission. The most likely route of vertical ZIKV transmission is via the placenta. The earliest events of ZIKV transmission in the maternal decidua, representing the maternal uterine aspect of the chimeric placenta, have remained unexplored. Here, we show that ZIKV replicates in first-trimester human maternal-decidual tissues grown ex vivo as three-dimensional (3D) organ cultures. An efficient viral spread in the decidual tissues was demonstrated by the rapid upsurge and continued increase of tissue-associated ZIKV load and titers of infectious cell-free virus progeny, released from the infected tissues. Notably, maternal decidual tissues obtained at midgestation remained similarly susceptible to ZIKV, whereas fetus-derived chorionic villi demonstrated reduced ZIKV replication with increasing gestational age. A genome-wide transcriptome analysis revealed that ZIKV substantially upregulated the decidual tissue innate immune responses. Further comparison of the innate tissue response patterns following parallel infections with ZIKV and human cytomegalovirus (HCMV) revealed that unlike HCMV, ZIKV did not induce immune cell activation or trafficking responses in the maternal-fetal interface but rather upregulated placental apoptosis and cell death molecular functions. The data identify the maternal uterine aspect of the human placenta as a likely site of ZIKV transmission to the fetus and further reveal distinct patterns of innate tissue responses to ZIKV. Our unique experimental model and findings could further serve to study the initial stages of congenital ZIKV transmission and pathogenesis and evaluate the effect of new therapeutic interventions. IMPORTANCE: In view of the rapid spread of the current ZIKV epidemic and the severe manifestations of congenital ZIKV infection, it is crucial to learn the fundamental mechanisms of viral transmission from the mother to the fetus. Our studies of ZIKV infection in the authentic tissues of the human maternal-fetal interface unveil a route of transmission whereby virus originating from the mother could reach the fetal compartment via efficient replication within the maternal decidual aspect of the placenta, coinhabited by maternal and fetal cells. The identified distinct placental tissue innate immune responses and damage pathways could provide a mechanistic basis for some of the placental developmental abnormalities associated with ZIKV infection. The findings in the unique model of the human decidua should pave the way to future studies examining the interaction of ZIKV with decidual immune cells and to evaluation of therapeutic interventions aimed at the earliest stages of transmission.

Elevated circulating micro-ribonucleic acid (miRNA)-200b and miRNA-429 levels in anovulatory women.

OBJECTIVE: To study the role of micro-RNA (miRNA)-200b and miRNA-429 in human ovulation and to measure their expression levels in ovulatory and anovulatory patients. DESIGN: Micro-RNA-200b and miRNA-429 expression analysis in human serum and granulosa cells at different phases of the ovulation cycle in normal cycling women and women undergoing assisted reproductive technology cycles. SETTING: University-affiliated hospital and academic research laboratory. PATIENT(S): Forty women (7 normally ovulating, 15 normally ovulating with pure male infertility factor, and 18 with polycystic ovary syndrome) were included in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The expression profile of circulating miRNAs and granulosa cells was assessed by means of real-time quantitative reverse transcription-polymerase chain reaction analysis. RESULT(S): We identified miRNA-200b and miRNA-429 in the sera of all women tested. These miRNA expression levels were elevated during the early follicular phase of the cycle compared with serum levels during the early luteal phase. Anovulatory women, diagnosed with polycystic ovary syndrome, expressed significantly higher levels of miRNA-200b and miRNA-429 compared with spontaneously ovulating women. Ovulation induction with exogenous gonadotropins during an IVF cycle reduced these levels to the levels measured in normal ovulating women. CONCLUSION(S): Our findings suggest an involvement of miRNA-200b and miRNA-429 in the pituitary regulation of human ovulation. Although it is unclear whether this altered miRNA expression profile is a cause or a result of anovulation, the levels of these molecules in the serum of anovulatory women may serve as serum biomarkers for the ovulation process.

Three Giants in the Cradle of Reproductive Medicine; Reproduction Theories of the Seventeenth Century as Discerned by Pregnancy Portraiture in the Oeuvre of Jan Vermeer.

Portraits of pregnant women are rare in Catholic Renaissance art. In seventeenth-century Holland, the Catholic rule of Spain had been thrown off and a Protestant Calvinistic republic emerged, freeing Dutch artists to choose an unorthodox subject matter for their paintings. The Golden Age of Holland was characterized by extreme wealth, originating from overseas trade, which fostered a marked interest in philosophy, science, medicine, as well as art. Despite this, portraiture of pregnancy remained uncommon. An exception to this rule was Jan Vermeer of Delft, who lived during the zenith of this era. Jan Vermeer painted fewer than 40 pictures, fathered 15 children, and died bankrupt and little appreciated at the age of 43. Vermeer confined himself almost entirely to images of women in various domestic situations, including three figures of pregnant women. In this framework, pregnancy could be viewed as an icon for fidelity and conformism to social expectations. In this paper we investigate the roots of this unusual icon in Vermeer's oeuvre, and suggest that the use of pregnancy in his paintings could have been inspired by his Delft-resident contemporaries Antony van Leeuwenhoek and Reinier de Graaf, fathers of well-known and opposing theories of reproduction. These eminent scientists and Vermeer's pregnant wife, who frequently served as his model, might have made pregnancy less mysterious and more realistic to the painter.

Human cytomegalovirus induces a distinct innate immune response in the maternal-fetal interface.

The initial interplay between human cytomegalovirus (HCMV) and innate tissue response in the human maternal-fetal interface, though crucial for determining the outcome of congenital HCMV infection, has remained unknown. We studied the innate response to HCMV within the milieu of the human decidua, the maternal aspect of the maternal-fetal interface, maintained ex vivo as an integral tissue. HCMV infection triggered a rapid and robust decidual-tissue innate immune response predominated by interferon (IFN)γ and IP-10 induction, dysregulating the decidual cytokine/chemokine environment in a distinctive fashion. The decidual-tissue response was already elicited during viral-tissue contact, and was not affected by neutralizing HCMV antibodies. Of note, IFNγ induction, reflecting immune-cell activation, was distinctive to the maternal decidua, and was not observed in concomitantly-infected placental (fetal) villi. Our studies in a clinically-relevant surrogate human model, provide a novel insight into the first-line decidual tissue response which could affect the outcome of congenital infection.

Ovarian stimulation for oocyte cryopreservation for prevention of age-related fertility loss: one in five is a low responder.

Oocyte cryopreservation for age-related fertility loss is gaining interest considering the tendency to postpone motherhood in many societies. Little is currently known about the actual efficiency of this approach. We aimed to explore ovarian response of presumably fertile women undergoing in vitro fertilization for this indication. A total of 105 women underwent 151 stimulation cycles at mean age 37.7 ± 2.4. None had known infertility. Mean daily starting FSH dose was 371 ± 110 (225-600). Mean number of mature oocytes cryopreserved at the first completed cycle was 9.7 ± 7.5 (0-43). However, 21% of started cycles were either cancelled before egg retrieval or resulted in 0-3 mature oocytes retrieved. Therefore, women considering oocyte cryopreservation for prevention of age-related fertility decline should be encouraged to perform this procedure at younger age than, preferably before 35.

Models of vertical cytomegalovirus (CMV) transmission and pathogenesis.

Despite the considerable clinical impact of congenital human cytomegalovirus (HCMV) infection, the mechanisms of maternal-fetal transmission and the resultant placental and fetal damage are largely unknown. Here, we discuss animal models for the evaluation of CMV vaccines and virus-induced pathology and particularly explore surrogate human models for HCMV transmission and pathogenesis in the maternal-fetal interface. Studies in floating and anchoring placental villi and more recently, ex vivo modeling of HCMV infection in integral human decidual tissues, provide unique insights into patterns of viral tropism, spread, and injury, defining the outcome of congenital infection, and the effect of potential antiviral interventions.

Cognitive functions of regularly cycling women may differ throughout the month, depending on sex hormone status; a possible explanation to conflicting results of studies of ADHD in females.

Attention Deficit/Hyperactivity Disorder (ADHD) is considered as a model of neuro-developmental cognitive function. ADHD research previously studied mainly males. A major biological distinction between the genders is the presence of a menstrual cycle, which is associated with variations in sex steroid hormone levels. There is a growing body of literature showing that sex hormones have the ability to regulate intracellular signaling systems that are thought to be abnormal in ADHD. Thus, it is conceivable to believe that this functional interaction between sex hormones and molecules involved with synaptic plasticity and neurotransmitter systems may be associated with some of the clinical characteristics of women with ADHD. In spite of the impact of sex hormones on major neurotransmitter systems of the brain in a variety of clinical settings, the menstrual cycle is usually entered to statistical analyses as a nuisance or controlled for by only testing male samples. Evaluation of brain structure, function and chemistry over the course of the menstrual cycle as well as across the lifespan of women (premenarche, puberty, cycling period, premenopause, postmenopause) is critical to understanding sex differences in both normal and aberrant mental function and behavior. The studies of ADHD in females suggest confusing and non-consistent conclusions. None of these studies examined the possible relationship between phase of the menstrual cycle, sex hormones levels and ADHD symptoms. The menstrual cycle should therefore be taken into consideration in future studies in the neurocognitive field since it offers a unique opportunity to understand whether and how subtle fluctuations of sex hormones and specific combinations of sex hormones influence neuronal circuits implicated in the cognitive regulation of emotional processing. The investigation of biological models involving the role of estrogen, progesterone, and other sex steroids has the potential to generate new and improved diagnostic and treatment strategies that could change the course of cognitive-behavioral disorders such as ADHD.

Serum amyloid A: expression throughout human ovarian folliculogenesis and levels in follicular fluid of women undergoing controlled ovarian stimulation.

BACKGROUND: Serum amyloid A (SAA) is an acute phase protein expressed primarily in the liver in response to various injuries and inflammatory stimuli and is recognized as a modulator of inflammation. Ovarian reproductive functions including folliculogenesis and ovulation use inflammatory processes; thus, studying SAA in this context is of interest. OBJECTIVES: We investigated the expression and localization of SAA in ovarian developing follicles and its levels in follicular fluids. METHODS AND PARTICIPANTS: Nonradioactive in situ hybridization and immunohistochemical staining were applied on ovarian paraffin tissue sections. ELISA and RT-PCR were applied on follicular aspirates and blood samples from women undergoing controlled ovarian stimulation for in vitro fertilization. RESULTS: Expression of SAA mRNA and protein was found in follicular cells at all stages of follicular development, from primordial and primary follicles through antral follicles and corpora lutea. Expression was observed in granulosa, theca and luteal cells, and oocytes. Expression of SAA was also found in granulosa cells recovered from follicular aspirates. The SAA protein was detected in follicular fluids. Its levels were somewhat lower than in peripheral blood with strong correlation between the two compartments and with significant correlation with patient's body mass index. High follicular fluid SAA levels were associated with reduced pregnancy rate. CONCLUSIONS: SAA is locally produced in ovarian developing follicles and is a constituent of follicular fluids, suggesting its role within the follicular environment. Elevated follicular SAA levels are associated with decreased pregnancy rate and may signify lower reproductive performance.

The clinical significance of small endometrial polyps.

OBJECTIVE: Small endometrial polyps are relatively common in asymptomatic women and may regress spontaneously. In symptomatic women, the finding of a small polyp (<1cm diameter) raises the question of the clinical pertinence and necessity of excision. Sparse data are available on the effectiveness of hysteroscopic excision of small polyps to manage abnormal uterine bleeding. The aim of this study was to assess outcome after hysteroscopic excision of small endometrial polyps in symptomatic patients. STUDY DESIGN: This was an observational cohort study enrolling 255 premenopausal women presenting with abnormal uterine bleeding and a small endometrial polyp on office hysteroscopy, undertaken between January 2004 and February 2007. The study group was referred for polypectomy by operative hysteroscopy. The outcome of the procedure was reviewed 6-12 months later by a telephone interview to assess the pattern of uterine bleeding after the procedure and overall satisfaction. RESULTS: Significant improvement in the magnitude of bleeding was experienced by 70% of participants, but only 30% of them reported return to regular menses. Satisfaction with the procedure was reported by 80%. Younger patients reported a less favorable bleeding pattern and were found to be less satisfied with the outcome of the procedure. CONCLUSIONS: Symptomatic women with small endometrial polyps can be treated safely and efficiently with hysteroscopic excision. In the younger age group of patients, however, the outcome of the procedure may be less favorable and may necessitate the addition of endometrial ablation to improve outcome and increase patient satisfaction.

snRNAs are reduced in the syncytiotrophoblast: a possible mechanism for regulation of human placental protein production.

The multinucleate syncytiotrophoblast of the human placenta is formed by fusion of the underlying cytotrophoblast progenitor cells. The large surface area of the syncytiotrophoblast is necessary for transport functions while it also serves as the site of synthesis of hormones and steroids. Studies of syncytiotrophoblast transcription are puzzling, demonstrating that many of the nuclei in the multinucleated syncytium are transcriptionally inactive. To further elucidate RNA activity in the syncytiotrophoblast, we investigated expression of snRNAs involved in RNA splicing. Using RNA in situ hybridization, we observed that snRNAs were markedly reduced in the syncytium throughout the course of pregnancy. Recapitulating these results in primary trophoblasts and in trophoblast cell lines in vitro, we found, using qRT-PCR and RNA in situ hybridization, that snRNA expression is reduced in trophoblasts cultured under fusion conditions. Our finding that snRNA is markedly reduced in the syncytiotrophoblast suggests that the placenta has evolved a balance between the large surface area essential for its transport function and the need to regulate protein production in the multinucleated syncytium.

Regular exercise is the most significant lifestyle parameter associated with the severity of climacteric symptoms: a cross sectional study.

OBJECTIVE: To assess the association between demographic and lifestyle parameters and perceived severity of the climacteric syndrome in perimenopausal women. STUDY DESIGN: A cross-sectional study of 151 healthy women aged 45-55 years who attended the University Medical Center affiliated menopause clinics. The analysis was based on self completion of the Greene climacteric score, consisting of psychological, somatic/physical, sexual and vasomotor subscores. The Greene total score and subscores were the main outcomes of the study. RESULTS: Of all demographic, anthropometric and lifestyle parameters recorded, the correlates with reduced total Greene score were high-order maternity and regular physical exercise. Mothers of 3 or more children reported significantly lower total Greene score (18±12.8 vs. 22.1±8.1) (p=0.01) as well as lower psychological subscore (8.7±6.8 vs. 11.5±5.4) (p=0.01). Regular physical activity was also associated with significantly lower total Greene score (17.0±11.0 vs. 22.6±11.3) (p=0.01) and specifically lower psychological subscore (9.5±6.6 vs. 12.8±7.7) (p=0.03) and sexual subscore (1.1±0.99 vs. 1.61±1.05) (p=0.03). Linear regression models showed that regular exercise was the lifestyle parameter most significantly correlated with a lower total Greene score (p=0.006) independent of menopausal status. Of particular note, regular exercise was significantly correlated with lower psychological (p=0.006) and physical subscores (p=0.06). Moreover, the higher the frequency of exercise (both aerobic and non aerobic), the lower the severity of the climacteric symptoms reported, yet the vasomotor and sexual subscores remained unchanged. CONCLUSIONS: Regular exercise of at least 3 times a week was the most significant lifestyle parameter to be associated with the severity of climacteric symptoms.

Is the quality of donated semen deteriorating? Findings from a 15 year longitudinal analysis of weekly sperm samples.

BACKGROUND: Studies suggest that global semen quality is declining, but the debate remains open owing to geographic variation. OBJECTIVES: To evaluate temporal trends of sperm parameters - namely concentration, motility and total motile sperm count - in sperm donated during the period 1995-2009. METHODS: In a retrospective longitudinal cohort study we analyzed the sperm count and motility of 2182 semen samples provided on a weekly basis by 58 young, healthy, fertile, university-educated, paid donors. RESULTS: Despite the lowering of criteria for sperm parameters satisfactory for donation that were implemented in 2004, 38% of applicants for sperm donation are now rejected based on semen quality as compared to a third of applicants 10-15 years ago (P < 0.001). If the old strict criteria were in place 88% of candidates would be rejected today (P < 0.0001). Over the study period, the average sperm parameters dropped from a concentration of 106 +/- 25 million spermatozoa/ml with 79% +/- 4.3% motility to 68 +/- 14 million/ ml with 66% +/- 4.5% motile sperm (P < 0.0001, P < 0.0001, respectively). The total motile sperm count per ejaculate also decreased, from 66.4 +/- 18.2 million to 48.7 +/- 12 million (P < 0.005). When the previous criteria were implemented for the analysis of the latest group of sperm donors, only 18% of donors had an acceptable sperm quality, with an average concentration of 87 +/- 12 million spermatozoa/ml, 73% +/- 2.6% motile sperm and total motile sperm count of 53.1 +/- 3.8 million per ejaculate - still significantly lower than 15 years ago (P= 0.01, P= 0.003, P= 0.058 respectively). CONCLUSIONS: The rapid deterioration of sperm quality among fertile semen donors is alarming and may lead to cessation of sperm donation programs.

Infertility associated with precoital ovulation in observant Jewish couples; prevalence, treatment, efficacy and side effects.

BACKGROUND: Religious (halachic*) infertility' results from precoital ovulation prior to immersion in a ritual bath (mikveh) 7 days after menstruation, as mandated by Jewish religious law. Previous authors recommended treatment with estradiol to postpone ovulation and enhance pregnancy rates. OBJECTIVES: To evaluate the prevalence of halachic infertility in an ultra-Orthodox jewish community, and assess the efficacy of estradiol treatment in postponing ovulation and increasing pregnancy rates. METHODS: We reviewed 88 cycles, of which 23 were control cycles and 65 estradiol-treated cycles, and analyzed the files of 23 women who were treated with 6 mg estradiol/day from day 1 for 5 days of the cycle. RESULTS: The prevalence of precoital ovulation in the infertile population was 21%. Most of the patients (94%) ovulated before day 13 of the cycle. A short follicular phase due to low ovarian reserve orthyroid endocrinopathy was noted in 12% of the patients. While 64% of the women reported consultation with a Rabbinate authority, 68% of the patients sought medical therapy. Estradiol postponed ovulation for at least one day in 89% of the treatment cycles. Ovulation post-mikveh occurred in 73% of estradiol-treated cycles. The pregnancy rate was 12.5% per cycle and the cumulative pregnancy rate 35% per woman. Half the patients reported spotting during estradiol-treated cycles, and this postponed coitus. CONCLUSIONS: Precoital ovulation is a major reason for infertility among observant couples attending fertility clinics. Estradiol treatment is effective in delaying ovulation and restoring fecundity; however, it causes some adverse effects that may decrease its effectiveness.

Altered endothelin expression in granulosa-lutein cells of women with polycystic ovary syndrome.

AIMS: To examine the levels of endothelin system components in granulosa lutein cells (GLCs) of women with PCOS and compare them to normally ovulating women undergoing In Vitro Fertilization (IVF). Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age. Endothelins are locally produced by endothelial and granulosa cells of the preovulatory follicle. Abnormal expression or production of endothelins may be a contributing factor in PCOS pathogenesis. MAIN METHODS: Follicular aspirates containing GLCs were obtained from PCOS and normally ovulating patients undergoing oocyte retrieval during the IVF cycle. RNA was extracted and endothelin system components were quantified using real-time PCR. GLCs were cultured in basal media for 7 days, and then challenged with various luteinizing agents (luteinizing hormone, hCG, or forskolin) for 24 h. KEY FINDINGS: In GLCs from women with PCOS, Endothelin-1 mRNA expression was elevated (2.2-fold) as compared with normally ovulating women, whereas endothelin-2 mRNA was reduced (1.8-fold). ET receptors and endothelin-converting enzyme showed the same expression levels in the two groups. In vitro modeling showed that although the steroidogenic response was preserved in GLC, endothelin expression levels were not exhibited in vitro in their original pattern. SIGNIFICANCE: Dysregulation of ovarian endothelin expression may induce a pathologic ovulation pattern characteristic of PCOS.