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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.

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

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.

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.

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.

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., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.

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.

Human cytomegalovirus (HCMV) is the leading cause of congenital infection, associated with severe birth defects and intrauterine growth retardation. The mechanism of HCMV transmission via the maternal-fetal interface is largely unknown, and there are no animal models for HCMV. The initial stages of infection are believed to occur in the maternal decidua. Here we employed a novel decidual organ culture, using both clinically derived and laboratory-derived viral strains, for the ex vivo modeling of HCMV transmission in the maternal-fetal interface. Viral spread in the tissue was demonstrated by the progression of infected-cell foci, with a 1.3- to 2-log increase in HCMV DNA and RNA levels between days 2 and 9 postinfection, the expression of immediate-early and late proteins, the appearance of typical histopathological features of natural infection, and dose-dependent inhibition of infection by ganciclovir and acyclovir. HCMV infected a wide range of cells in the decidua, including invasive cytotrophoblasts, macrophages, and endothelial, decidual, and dendritic cells. Cell-to-cell viral spread was revealed by focal extension of infected-cell clusters, inability to recover infectious extracellular virus, and high relative proportions (88 to 93%) of cell-associated viral DNA. Intriguingly, neutralizing HCMV hyperimmune globulins exhibited inhibitory activity against viral spread in the decidua even when added at 24 h postinfection-providing a mechanistic basis for their clinical use in prenatal prevention. The ex vivo-infected decidual cultures offer unique insight into patterns of viral tropism and spread, defining initial stages of congenital HCMV transmission, and can facilitate evaluation of the effects of new antiviral interventions within the maternal-fetal interface milieu.

Objective: To study whether the sex of the offspring is related to increasing parental age, gravidity, and parity, hypothesizing an altered male-to-female sex ratio with the advancing parental age., Design: A large retrospective cohort study., Setting: The study analyzed birth records of Hadassah Hebrew University Medical Center in Jerusalem from June 2003 to December 2006., Patient(s): 35,837 birth records were analyzed including 941 multifetal deliveries, excluding foreign inhabitants (n = 744), missing data for the main study outcome (n = 2) and parturients over 50 years to control for egg donation (n = 26)., Intervention(s): None., Main Outcome Measure(s): Male-to-female sex ratio., Result(s): The male-to-female sex ratio of all the newborns was 1.05. This ratio did not change significantly with either maternal or paternal age. Neither gravidity nor parity affected the male-to-female ratio. The only factor that affected the regression of sex ratio was the length of gestation., Conclusion(s): Sex ratio at birth is remarkably constant. No association was found between parental age or birth order and neonatal sex ratio., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To examine traditional Jewish concepts and practices of reproduction, and define problems that may arise in members of Orthodox Jewish society that follows the Halachah (the Jewish codes of conduct)., Design: Expert opinion based on clinical experience., Setting: Academic-affiliated fertility clinic situated in an observant Jewish community., Patient(s): Orthodox and Ultraorthodox (Haredi) couples of the Jewish community., Interventions(s): We examined traditional Jewish concepts and practices of reproduction and defined problems that may arise in Jewish Orthodox society., Main Outcome Measure(s): None., Result(s): The concepts and practices of reproduction of Orthodox religious Jewish couples may lead to halachic subfertility and modification of the usual infertility workup. Treatments are limited to and determined largely by considerations related to religious doctrine., Conclusion(s): Understanding the religious, social, and cultural background of patients, particularly religious Orthodox women, enables appropriate fertility counseling and treatment., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To report a possible association between intracytoplasmic sperm injection (ICSI)-preimplantation genetic diagnosis (PGD) and monozygotic multiple gestation., Design: Small case series., Setting: In vitro fertilization unit in an academic medical center., Patient(s): Three patients were treated with ICSI-PGD for sexing as well as selection against a known translocation., Intervention(s): Transfer of day 4 embryos to the uterus., Main Outcome Measure(s): Clinical pregnancy., Result(s): Two pairs of monozygotic twins and a triplet pregnancy., Conclusion(s): Repeated manipulation of the zona pellucida as well as extended embryo culture during ICSI-PGD treatments may result in monozygotic twin and triplet pregnancies.

Objective: To report the occurrence of spontaneous regression of three endometrial polyps detected by hysteroscopy., Design: Case series., Setting: A uterine imaging unit in an academic medical center., Patient(s): Three patients diagnosed as having an endometrial polyp of 5-8 mm on hysteroscopy., Intervention(s): Patient deferral of the surgical procedure for several months., Main Outcome Measure(s): Presence of a uterine polyp in the next hysteroscopy., Result(s): The polyps disappeared spontaneously., Conclusion(s): Deferral of hysteroscopic polypectomy for a few months in asymptomatic women in the hope of spontaneous regression of the polyps may be justified.

To determine the predictive value of a previous testicular biopsy to the chance of sperm retrieval in the next testicular sperm extraction (TESE) procedure, we retrospectively analyzed the outcome of past sperm collection procedures and histopathology diagnoses of patients with nonobstructive azoospermia. Repeated TESE ensured a high recovery rate (96%) when the first recovery procedure had been successful and when hypospermatogenesis was diagnosed (77%); when no spermatozoa were found on the first attempt, a repeat TESE procedure was successful in one-third of the patients.

Reproductive concepts and practices among observant Orthodox Jews may Lead to Halachic subfertility in a significant portion of couples. According to Halachah [the Jewish code of law) sexual activity may not take place during the time a woman menstruates (Niddah) as well as for a full week thereafter (7 days of cleanliness). Coitus is allowed to resume after the woman has immersed herself in a ritual bath (mikvah). In the case of unexpected spotting or bleeding (Zavah), the woman should consult a rabbi and a doctor to determine the origin of the blood. Uterine bleeding entails that intercourse is forbidden for a minimum of 5 initial days plus 7 days thereafter. In practice, any minute bleeding or spotting, regardless of timing during the menstrual cycle, renders the woman ritually impure and invokes the stringencies of Niddah rulings. Even a physiologic occurrence such as midcycle ovulatory bleeding or spotting renders the woman Zavah and prohibits sexual intercourse at the optimal time for conception. The inability to conceive in this halachically mandated time period is not due to a biologic fault but rather to social, cultural and religious norms as defined by the rabbinate. Medically lengthening the pre-ovulatory phase is a common practice, as shortening the count of days of ritual impurity is often seen as nonnegotiable. Ethical issues concerning the role of the physician and the safety of such treatments are discussed.

Preeclampsia (PE), which affects 4-8% of human pregnancies, causes significant maternal and neonatal morbidity and mortality. Within the basal plate, placental cytotrophoblasts (CTBs) of fetal origin invade the uterus and extensively remodel the maternal vasculature. In PE, CTB invasion is often shallow, and vascular remodeling is rudimentary. To better understand possible causes, we conducted a global analysis of gene expression at the maternal-fetal interface in placental samples from women with PE (n = 12; 24-36 wk) vs. samples from women who delivered due to preterm labor with no evidence of infection (n = 11; 24-36 wk), a condition that our previous work showed is associated with normal CTB invasion. Using the HG-U133A&B Affymetrix GeneChip platform, and statistical significance set at log odds-ratio of B >0, 55 genes were differentially expressed in PE. They encoded proteins previously associated with PE [e.g. Flt-1 (vascular endothelial growth factor receptor-1), leptin, CRH, and inhibin] and novel molecules [e.g. sialic acid binding Ig-like lectin 6 (Siglec-6), a potential leptin receptor, and pappalysin-2 (PAPP-A2), a protease that cleaves IGF-binding proteins]. We used quantitative PCR to validate the expression patterns of a subset of the genes. At the protein level, we confirmed PE-related changes in the expression of Siglec-6 and PAPP-A2, which localized to invasive CTBs and syncytiotrophoblasts. Notably, Siglec-6 placental expression is uniquely human, as is spontaneous PE. The functional significance of these novel observations may provide new insights into the pathogenesis of PE, and assaying the circulating levels of these proteins could have clinical utility for predicting and/or diagnosing PE.

Objective: To determine the predictive value and the quality of supernatant sperm (SS) achieved by a simple laboratory technical modification after testicular sperm extraction (TESE)., Design: A retrospective analysis., Setting: An IVF unit in a university medical center., Patient(s): Azoospermic patients undergoing TESE between January 2001 and December 2006., Intervention(s): Before the mechanical shredding, the testicular specimen in toto was placed in medium. The medium was spun and the pellet resuspended and transferred for SS detection. Then a wet preparation of the testicular tissue was shredded roughly and inspected for tissue sperm (TS) as described., Main Outcome Measure(s): Detection of SS versus TS, fertilization and pregnancy rates (PR) after intracytoplasmic sperm injection (ICSI) with SS versus TS., Result(s): The SS was detected in all specimens where TS was eventually found, independent of their testicular pathology. When the supernatant was spermatozoa-negative, no spermatozoa were detected in the tissue. For embryos derived from ICSI the fertilization rate of SS was significantly higher than TS (52% vs. 44%), whereas the PR was comparable., Conclusion(s): The SS serves as an excellent predictor of TESE outcome and as a superior source for fertilization. This modified technique enables faster decision of TESE outcome and an easier switch to donor sperm when available.

Objective: To report a possible association between azoospermia and acute renal failure., Design: A case report., Setting: An in vitro fertilization unit in an academic medical center., Patient(s): A patient with high-gonadotropin azoospermia and a history of acute obstructive renal failure because of bilateral renal calculi, who was referred for testicular sperm extraction., Intervention(s): Deferral of the surgical procedure., Main Outcome Measure(s): Return of sperm into the patient's ejaculate., Result(s): Four months after normalization of his renal function tests, the sperm analysis showed reversal of the azoospermic state., Conclusion(s): Azoospermic patients with recent history of acute renal failure would be followed up for several months after renal function normalization, awaiting reappearance of sperm in the ejaculate.

Objective: To present the set of reasons for and against fertility treatment for a very young patient., Design: An expert opinion based on clinical experience., Setting: An academic-affiliated fertility clinic situated in East Jerusalem., Patient(s): A 16-year-old married teenager with 2 years' duration of infertility due to polycystic ovarian syndrome was referred to our infertility center after treatment with six cycles of clomiphene citrate and ovarian drilling., Intervention(s): Counseling of the options of fertility treatments, weight reduction, physical exercise, metformin intake, and an additional gonadotropins-intrauterine insemination cycle with IVF backup., Main Outcome Measure(s): Successful pregnancy while avoiding the risk of ovarian hyperstimulation syndrome., Result(s): The patient conceived a single embryo and on the 30th week of gestation suffered premature uterine contractions and gave birth to a 1,330-g preterm male newborn., Conclusion(s): Adolescent contraception and unintended pregnancies are prevalent issues in the Western world, whereas adolescent infertility is unheard of. Early age of marriage and conception imposes tremendous dilemma to the society of reproductive endocrinologists. This important cultural issue ought to be debated regarding the age at marriage, the age at first pregnancy, and the treatment of infertility in married "minors" who need treatment. Such a debate is likely to encourage development of formal guidelines for practitioners, which would clearly be beneficial.

NK cells populate the human endometrium before pregnancy. Unlike decidual NK cells that populate the decidua during pregnancy, the NK cells present in the human endometrium, before pregnancy, have not been fully characterized. In this study, we provide a detailed analysis of the origin, phenotype, and function of endometrial NK cells (eNK). We show that eNK cells have a unique receptor repertoire. In particular, they are negative for NKp30 and chemokine receptor expression, which distinguishes them from any other NK subset described so far. We further show that eNK cells lack NK-specific functional phenotype and activity such as cytokine secretion and cytotoxicity, before IL-15 stimulation. Following such stimulation, endometrial NK cells acquire phenotype and function that are similar to those of decidual NK cells. We therefore suggest that eNK cells are inactive cells (before IL-15 activation and in relation to the known NK activity) that are present in the endometrium before conception, waiting for pregnancy.

Objectives: To evaluate adverse effects of herbal remedies consumed by menopausal women for control of the climacteric syndrome., Methods: We examined the long term safety and herb-drug interactions of commonly used herbal therapy such as soy, black cohosh, dong quai, ginseng and vitamin E., Results: Even carefully designed studies on herbal treatments for vasomotor menopausal symptoms never addressed specifically safety issues. Sporadic reports show dangerous adverse effects of these herbal preparations as well as hazardous interactions between botanic compounds and conventional medications., Conclusions: The unrestricted sale of plant products constitutes a new situation for physicians with little training in phytotherapy. The qualitative and quantitative diversity of the commercially available preparations, the absence of precise prescribing guidelines, and the risk of self-prescribed medication justify the introduction of 'phyto-vigilance'. Physicians should warn their patients about the lack of evidence regarding safety and possible interactions of herbal remedies with concurrent medications.

Objective: Low initial serum beta hCG is a good predictor of early pregnancy failure. We sought to determine the contribution of treatment variables and the predictive value of early serum beta hCG after IVF on long-term pregnancy outcome., Design: A retrospective case-control study., Setting: An academic IVF unit., Patient(s): Five hundred thirty-three IVF cycles performed between 1999 and 2004, which resulted in a positive serum beta hCG level (> 10 mIU/mL) on day 13 after embryo transfer (ET)., Intervention(s): The study group included 281 pregnancies with initial beta hCG < or = 150 mIU/mL on day 13 after ET. Randomly selected 252 IVF cycles with initial beta hCG > 150 mIU/mL comprised the control group. Characteristics of the patients and the treatment protocols were analyzed using logistic regression, Pearson's chi-square, and Fisher's exact test., Main Outcome Measure(s): Primary pregnancy outcome was defined as favorable when a fetal pulse was detected, testifying to a viable gestation. Unfavorable outcome referred to chemical or ectopic pregnancies, as well as spontaneous abortions. Additionally, the two groups were followed throughout gestation. Secondary pregnancy outcome was based on the following parameters: gestational age at delivery, method of delivery, and birth weight., Result(s): Poor primary pregnancy outcome was encountered in 64.8% of the study group and in 22.2% of the control group. Predictors of unfavorable primary pregnancy outcome were older age, use of a short protocol, and shorter than anticipated crown-rump length. No difference was found in the secondary pregnancy outcome between the groups. Preterm labor was more prevalent in the study group, but the difference did not reach statistical significance., Conclusion(s): Pregnancy viability can be predicted by measuring serum beta hCG as early as on day 13 after ET. Older age, use of a short protocol, and shorter than anticipated crown-rump length are associated with early pregnancy loss. Of those who reach delivery, no significant adverse outcome is anticipated in IVF pregnancies with low initial serum beta hCG.

Due to temporary social trends, many women elect to postpone their first pregnancy to a later stage in life. Pregnancy and labor later in life entail major risks to both the mother and the neonate. Furthermore, a large part of this population will be infertile by the time they opt to conceive, mainly because of decreasing ovarian reserve and low oocyte quality. Assessment of the fertility potential of the elderly nullipara includes clinical measurements of early follicular FSH and estradiol, clomiphene citrate test and ultrasonographic evaluation of the ovaries. A fast track step-by-step fertility evaluation is the procedure for women above 35 years of age. Only empirical treatment modalities may be offered to the elderly infertile patient, with the exception of ovum donation.

Human placentation entails the remarkable integration of fetal and maternal cells into a single functional unit. In the basal plate region (the maternal-fetal interface) of the placenta, fetal cytotrophoblasts from the placenta invade the uterus and remodel the resident vasculature and avoid maternal immune rejection. Knowing the molecular bases for these unique cell-cell interactions is important for understanding how this specialized region functions during normal pregnancy with implications for tumor biology and transplantation immunology. Therefore, we undertook a global analysis of the gene expression profiles at the maternal-fetal interface. Basal plate biopsy specimens were obtained from 36 placentas (14-40 wk) at the conclusion of normal pregnancies. RNA was isolated, processed, and hybridized to HG-U133A&B Affymetrix GeneChips. Surprisingly, there was little change in gene expression during the 14- to 24-wk interval. In contrast, 418 genes were differentially expressed at term (37-40 wk) as compared with midgestation (14-24 wk). Subsequent analyses using quantitative PCR and immunolocalization approaches validated a portion of these results. Many of the differentially expressed genes are known in other contexts to be involved in differentiation, motility, transcription, immunity, angiogenesis, extracellular matrix dissolution, or lipid metabolism. One sixth were nonannotated or encoded hypothetical proteins. Modeling based on structural homology revealed potential functions for 31 of these proteins. These data provide a reference set for understanding the molecular components of the dialogue taking place between maternal and fetal cells in the basal plate as well as for future comparisons of alterations in this region that occur in obstetric complications.

Objectives: The evaluation of birth control issues among orthodox Jews who strictly follow the Halachah (the Jewish codes of conduct)., Methods: We examine traditional Jewish concepts and practices of reproduction, review various contraceptive methods, and define problems that may arise with their use in the Jewish orthodox society. We focus on the orthodox and ultra-orthodox (Haredi) elements of the Jewish community., Results: The choices of orthodox religious women are limited and determined largely by considerations related to religious doctrine., Conclusions: Understanding the religious, social and cultural background of patients, religious orthodox women in particular, enables to appropriately counsel them.

Background: The aim of this study was to determine the effectiveness of medical abortions with mifepristone and misoprostol following the approval of medical abortion in Israel., Methods: A retrospective review of 377 consecutive medical records at an ambulatory care unit of a university medical centre was performed, screening all women undergoing medical abortion with mifepristone and misoprostol. Transvaginal ultrasonographic study and serum beta hCG measurement were performed 14-20 days after the procedure. The clinical outcome was defined as complete expulsion of intrauterine contents with (failed group) or without (successful group) surgical intervention., Results: Surgical intervention was performed in 7.4% of patients. Residual products of conception were confirmed in 89%. Older age, previous spontaneous abortions, multigravidity, and earlier follow-up visit were independently associated with unsuccessful medical abortion. Significant differences were found in mean serum beta hCG and mean endometrial thickness in the successful versus failed procedure groups., Conclusions: Medical termination of pregnancy with mifepristone and misoprostol is >90% effective. High risk group for failure of the procedure can be characterised. An algorithm of follow up using follow-up visit date, serum beta hCG and sonographic endometrial stripe is suggested to define high risk patients for failed medical abortion.

The publication of the Women's Health Initiative (WHI) study had significant impact on the attitude of physicians and patients towards the use of hormones in the menopause. It has been estimated that 40-83% of patients using hormones ceased treatment on their own initiative following publication of the WHI results. While in the pre-WHI period, use of hormones in the menopause was termed 'hormone-replacement therapy' (HRT) with an emphasis on replacement; 'HRT' has now been replaced with the term 'hormone therapy' (HT), focusing on the therapy's status as a treatment with defined risks and benefits. Following the publication of the WHI study, many caregivers concluded that HT had absolutely no role in clinical practice. However, the decision to begin HT for the symptomatic, healthy, newly postmenopausal woman should be based on whether the WHI study addresses all the issues that must be taken into consideration before initiation of HT, whether there are effective alternatives available to relieve climacteric symptoms, and also whether HT is better able to prevent cardiovascular disease (CVD) and Alzheimer's disease (AD) than to halt atherosclerotic lesions. Every postmenopausal woman should have an individual risk-benefit evaluation to determine whether HT suits her needs. Until the effectiveness of HT for primary prevention of CVD and AD is established or disproved, there is no justification for HT use in the asymptomatic postmenopausal woman. However, symptomatic newly menopausal women might experience relief of their climacteric symptoms following HT use without exposing themselves to unreasonable risks.

The treasured ancient papyri provide a glimpse into understanding of common concepts and practices in ancient Egypt. The Kahun gynecological papyrus and other texts unveil the traditions of reproduction, conception and delivery. This article addresses the rationale of beliefs and practices of that era. Frequently, the reason for common traditions exercised at the time is based on medical knowledge of female anatomy and physiology during pregnancy. Surprisingly some of the remedies commonly used in ancient Egypt were recently explored and found intriguing. This paper was aimed to look at the reflection of archaic practices and concepts of ancient Egypt by the modern mirror of evidence-based medicine.

Background: Hot flashes are the most frequent symptoms of menopause and the most common reason for climacteric women seeking medical advice. Estrogen therapy is by far the most effective therapy. However, fears of side-effect of estrogen therapy urged many patients to seek alternative modalities for symptomatic relief., Methods: The MEDLINE database for the years 1975-2004 was searched for clinical placebo-controlled trials for the treatment of hot flashes with alternative therapy. Articles reporting the use of progesterone, alpha adrenergic agonists, anti-depressants, anti-convulsants, soy products, black cohosh (BC), red clover, dong quai, ginseng root, evening primrose oil, vitamin E, and wild yam were included., Results and Conclusions: A critical review of the literature shows that progesterone may have an independent effect on relieving hot flashes. New nonhormonal agents such as selective serotonin-uptake-inhibitor anti-depressants and a new anti-convulsant gabapentin yielded promising results on small well-conducted studies. Isoflavone's effect on hot flashes is variable and inconsistent, and only modest and delayed improvement of symptoms could be expected by BC and vitamin E. There are insufficient data on the other herbal alternative therapies at this time. Well-designed large studies are needed to further explore new modalities of treatment.

Growth factor signalling has important modulatory roles in the process of human follicular growth, oocyte maturation and corpus luteum (CL) formation. Recently, Sprouty-2, an inhibitor of receptor tyrosine kinase (RTK) signalling pathway was advocated as a marker of oocyte competence in the bovine ovary. We sought to study Sprouty-2 expression and regulation in the human ovary. RT-PCR was used to detect Sprouty-2 mRNA in human granulosa-lutein cells (GLC) collected from follicular aspiration of IVF patients. The effect of epidermal and fibroblast growth factors (EGF and FGF) on Sprouty-2 mRNA expression in GLC was studied using quantitative real-time PCR. Immunohistochemistry was performed on cultured GLC, human CL and stimulated rat ovary sections. Sprouty-2 mRNA was expressed in human GLC. EGF and basic FGF, but not FGF4 and FGF10, increased Sprouty-2 mRNA expression in GLC. The Sprouty protein was localized to GLC of early and late human CL but not to the theca cell layer. Immunostaining of developing rat CL confirmed the temporal and spatial expression of Sprouty in humans. The detection of Sprouty-2 mRNA and protein in human GLC may suggest a role for Sprouty-2 during the final stages of follicle maturation and CL formation.

Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs), major components of the basement membrane (BM) and extracellular matrix (ECM). Heparanase activity results in release of HSPG-bound molecules, including basic fibroblast growth factor (FGF2). Structural and functional development of the corpus luteum (CL) involves tissue remodeling, active angiogenesis, and steroid production. Heparanase-induced ECM and BM breakdown as well as FGF2-stimulated endothelial proliferation may have an important role in the regulation of luteal function. Heparanase mRNA was detected by reverse-transcription-polymerase chain reaction in granulosa cells recovered from follicular fluid of in vitro fertilization patients. Using sulfate-labeled ECM, heparanase enzymatic activity was determined in human luteinized granulosa cells. Employing immunohistochemistry, heparanase protein was localized predominantly in the theca interna cell layer of the mature antral follicle, whereas in human corpora lutea, both luteinized granulosa and theca cells were immunostained for heparanase. During luteolysis, heparanase was identified in macrophages surrounding the forming corpus albicans. In serially sectioned ovaries from unstimulated rats as well as from eCG-treated rats, expression of heparanase was noted exclusively in the ovarian steroid-producing interstitial tissue. Following an ovulatory dose of hCG, heparanase was immunostained also in lutein cells of the forming corpora lutea. Temporal expression of heparanase in granulosa cells during the luteal phase and in macrophages during luteal regression supports the hypothesis that heparanase plays a role in human ovarian ECM remodeling and may potentiate cellular migration and growth factor bioavailability.

Objective: To describe the success rate of intracytoplasmic sperm injection (ICSI) using thawed cryopreserved sperm in male cancer patients., Design: Retrospective consecutive study., Setting: IVF unit in a tertiary university hospital., Patient(s): Twenty-one couples treated by ICSI using the frozen-thawed sperm of husbands treated for cancer., Intervention(s): Follow-up of all treatments by ICSI., Main Outcome Measure(s): Pregnancy rate, sperm count, and fertilization rate., Result(s): Male patients being treated for cancer froze between one and 29 sperm samples. Post-thaw sperm count ranged from 1 x 10(5) to 106 x 10(6). The mean fertilization rate by ICSI was 60% (range, 33%-100%), and the pregnancy rate was 42%. Twenty-six pregnancies were obtained resulting in 23 children (13 singleton and 10 twins) and eight spontaneous abortions (31%). Delivery was obtained in 12 of the 21 treated couples (57%). The lowest total motile sperm count that resulted in a pregnancy was 1 x 10(5)., Conclusion(s): Male cancer patients should be encouraged to freeze numerous sperm samples even when sperm count and motility are poor. In these cases, ICSI is a powerful technique compared with intrauterine injection since thawed sperm samples with poor parameters can produce relatively high fertilization rates resulting in normal pregnancies and deliveries. The possibility to repeat treatments even in the face of a limited number of sperm samples appears to be of importance.

Many epidemiological studies have demonstrated an association between low birth weight and the subsequent development of hypertension, insulin resistance, type 2 diabetes and cardiovascular disease. This association appears to be independent of classic lifestyle risk factors such as smoking, overweight, social class, alcohol consumption and lack of exercise, which are additive to the effect. The association holds for the full range of birth weights, including those within the normal range. In addition, it was suggested that faster postnatal catch-up growth may also predict later risk of cardiovascular disease. 'Fetal programming' has been proposed as a mechanism underlying the link related to low birth weight, rapid neonatal growth and adult disease. The fetal programming hypothesis suggests that the intrauterine environment during critical periods of organogenesis and tissue growth may permanently alter organ structure and function in an epigenetic manner. Indeed, evidence from both human and animal studies suggests that diseases of adult life are induced by the fetal environment. This review describes epidemiological and physiological evidence that the programming phenomenon is a major factor in determining later life diseases. Better management of pregnancy in the present will have long term wide-scale effects on the health of our society.

In the maternal decidua, natural killer (NK) cells, characterized by lack of CD16, are found in direct contact with the fetal extravillous trophoblasts (EVTs). It is yet unknown which factors contribute to the specific homing of this unique NK subset to the decidua. In this study we analyze the chemokine receptor repertoire on various NK populations derived from the peripheral blood and decidua. We show that CXCR4 and CXCR3 receptors are preferentially expressed on CD16- NK subsets derived either from the peripheral blood or the decidua and that these receptors are involved in migration of all NK subsets to their ligands. We further demonstrate in vivo that invading EVTs that eventually perform endovascular invasion express CXCL12, the ligand for CXCR4, but not ligands for CXCR3. Indeed, specific accumulation of the CD16- NK cells at the expense of CD16+ cells was observed only when in vitro migration was performed with ligands for CXCR4. Finally, incubation of the peripheral blood CD16- NK cells with cytokines present in the decidua, especially interleukin 15 (IL-15), resulted in the expression of chemokine receptor repertoire similar to that observed on decidual NK cells, suggesting an additional important regulatory effect of local decidual cytokines.

Breast cancer is the most common malignancy in women and constitutes 18% of all cancers in women. Female gender, age and country of birth are the strongest determinants of disease risk. Family history and mutations in tumor suppressor genes BRCA1 and BRCA2 are important correlates of lifetime risk. Genetic polymorphisms associated with estrogen synthesis and metabolism are viewed as major factors in breast cancer prevalence in specific populations. Atypical hyperplasia and ductal/lobular carcinoma in situ although uncommon, are considered as pre-malignant conditions as well as markers for invasive breast cancer. Lately, increased bone density and high breast tissue density on mammogram in postmenopausal women have been reported in association with increased risk of breast carcinoma, probably attributable to increased levels of endogenous estrogen. Serum estrogen levels are higher in breast cancer cases as compared with controls. Current use of oral contraceptives and prolonged, current or recent use of postmenopausal hormonal replacement therapy are also considered as risk factors for breast cancer. Tamoxifen and raloxifene, selective estrogen receptor modulators, were shown to reduce breast cancer risk among high-risk women. Various nutrients were evaluated for their possible effect on breast cancer risk but further studies are needed. High socioeconomic status is found to be associated with increased risk of breast malignancy for as yet unestablished reasons. Studying breast cancer risk factors and further research into the molecular etiology of the disease will enable early diagnosis and detection of high-risk women and ultimately improve prognosis.

Preserved fertility status is frequently encountered in patients with Wilson's disease, and contraceptive counseling may, therefore, be a relevant issue. Yet, several contraceptive methods can adversely influence the hepatic function, and the efficacy of others may be affected by the liver disease. We describe a patient with Wilson's disease manifested by cirrhosis, portal hypertension, and bleeding esophageal varices who underwent termination of pregnancy at 9 weeks' gestation. Following the procedure, contraceptive advice was sought in order to postpone conception until portal hypertension was controlled and hepatic function improved. Intramuscular depot medroxyprogesterone acetate was administered and tolerated well by the patient. A detailed discussion of the contraceptive options for patients with chronic liver disease, in general, and Wilson's disease, in particular, follows the case report.

This study compared prophylactic administration of either intragastric misoprostol (200 micrograms four times a day), a prostaglandin E1 analog, or bolus intravenous cimetidine (300 mg every 6 hours) in preventing stress lesions and stress bleeding in 127 adult postoperative patients who required mechanical ventilation and also had developed hypotension or sepsis. Both drug treatments were equally effective in preventing the development of diffuse gastritis (greater than 10 gastric hemorrhagic lesions) and in preventing upper gastrointestinal hemorrhage (UGIH). The combined data from both groups showed that for the 44 (35%) patients who died, death was significantly associated with the presence at study entry of renal failure (64% of 25 patients with renal failure died), hepatic failure (57% of 23 patients) or coagulopathy (62% of 29 patients) (p less than 0.02 for each), and with the number of organ system failures at study entry (48% of 69 patients with multiple organ system failures died, p less than 0.001). Death was also significantly associated with the presence of adult respiratory distress syndrome (ARDS) at study entry or the development of ARDS (63% of 24 patients with ARDS died, p less than 0.001), and the development of UGIH (5% of 93 patients with known bleeding outcome died, p less than 0.05). The number of stress lesions that developed was significantly associated with subsequent UGIH (p less than 0.001). Additional organ system failure developed during the study in 31% of the 127 patients, as did diffuse gastritis in 20% of 111 patients who had a follow-up endoscopy. These results demonstrate that postoperative patients who require mechanical ventilation and have hypotension or sepsis are at significant risk for the development of stress gastric lesions and multiple organ system failure even when prophylaxis for stress ulcers is provided. Furthermore, the presence of ARDS, renal failure, hepatic failure, coagulopathy, and UGIH are significantly associated with death.

The effects of GABA on benzodiazepine receptor binding in cerebral cortical, hippocampal, and cerebellar membranes from 2-3 months old and 28-32 months old rats were studied. GABA modulation of agonist, antagonist, and inverse agonist binding to the receptor was examined using the displacement of 3H-Ro15-1788 by diazepam, Ro15-1788, and beta-carboline-3-carboxylate methyl ester, respectively, in the absence and presence of 100 microM GABA and 150 mM sodium chloride. GABA modulation was alike in old and young rats, with respect to the particular ligand and brain region. The results support the hypothesis that, in the brain regions studied, the allosteric modulation of benzodiazepine receptor binding by GABA remains intact as a function of aging.

Nickel (Ni+2) ions enhance the binding of 3H-diazepam, but decrease the binding of 3H-propyl beta-carboline-3-carboxylate to benzodiazepine receptors in mouse brain. Our experiments were performed to determine the locus for this action. In both control and Ca+2-depleted membranes, Ca+2 blocked the stimulatory effect of Ni+2 on 3H-diazepam binding in a concentration-dependent manner. In Ca+2-depleted membranes, physiological Ca+2 concentrations blocked this effect of Ni+2. In control membranes, Ca+2 did not reverse Ni+2 inhibition of 3H-propyl beta-carboline-3-carboxylate binding, but was effective at physiological concentrations in reversing Ni+2 inhibition in Ca+2-depleted membranes. The effects of Cd+2 ions on 3H-diazepam binding were similar to Ni+2 and were also reversed by Ca+2. The effects of Ni+2 were blocked by La+3 ions but not by Mg+2 ions, and were not due to interactions with the GABA receptor or Cl- ionophore. These data suggest that a Ca+2 binding site is associated with the brain benzodiazepine receptor.

We administered 2 g of cefoxitin to 25 patients before cataract surgery. An additional 23 patients received 500 mg of probenecid 30 minutes before the 2-g doses of cefoxitin. Average aqueous humor levels of 1.54, 3.16, 2.46, 1.22, and 0.82 microgram/ml were achieved at 30 minutes and one, two, four, and six hours, respectively, after the 2-g dose. The addition of probenecid prolonged significant aqueous humor levels. Therapeutic levels against common gram-positive pathogens were consistently achieved at two hours after injection without probenecid and from two to four hours after injection with probenecid. Therapeutic levels effective against Enterobacteriaceae were inconsistent.