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Colchicine is used for the treatment of various diseases including gouty arthritis, familial Mediterranean fever (FMF) and Behcet's disease. As a modulator of the microtubules at the cytoskeleton level, it arrests cell division at metaphase and inhibits microtubular-dependent cell motility. Controversy exists as to the adverse effect of colchicine on sperm production and function in healthy subjects as well as in gout, FMF and Behcet's patients. Sperm analysis shows a spectrum of pathology, from oligo- and azoospermia to normospermia with disturbances in sperm motility. These inconsistent sperm pathologies can be explained in part by the variability of the pathophysiology of the underlying disease. Thus, it seems that colchicine by itself may not have a significant direct adverse effect on sperm production and function. [ABSTRACT FROM PUBLISHER]

Focuses on the effects of the drug colchicine which is used to treat patients diagnosed with Familial Mediterranean fever (FMF). Reference to the disease amyloidosis, a main complication associated with FMF; What is FMF; Symptoms of FMF; Information on the use of colchicine in the treatment of FMF; Details on the long term preventive colchicine therapy for patients with FMF.

Premature telomere shortening or telomere instability is associated with a group of rare and heterogeneous diseases collectively known as telomere biology disorders (TBDs). Here we identified two unrelated individuals with clinical manifestations of TBDs and short telomeres associated with the identical monoallelic variant c.767A>G; Y256C in RPA2 Although the replication protein A2 (RPA2) mutant did not affect ssDNA binding and G-quadruplex-unfolding properties of RPA, the mutation reduced the affinity of RPA2 with the ubiquitin ligase RFWD3 and reduced RPA ubiquitination. Using engineered knock-in cell lines, we found an accumulation of RPA at telomeres that did not trigger ATR activation but caused short and dysfunctional telomeres. Finally, both patients acquired, in a subset of blood cells, somatic genetic rescue events in either POT1 genes or TERT promoters known to counteract the accelerated telomere shortening. Collectively, our study indicates that variants in RPA2 represent a novel genetic cause of TBDs. Our results further support the fundamental role of the RPA complex in regulating telomere length and stability in humans., (© 2024 Kochman et al.; Published by Cold Spring Harbor Laboratory Press.)

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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 apo lipoprotein B e diting c atalytic 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., (Copyright © 2017 American Society for Microbiology.)

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., (Copyright © 2017 American Society for Microbiology.)

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., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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.)

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: 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.

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.

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.

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.

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.

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.