Safety and efficacy of first-in-man intrathecal injection of human astrocytes (AstroRx®) in ALS patients: phase I/IIa clinical trial results.

BACKGROUND: Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients. METHODS: We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx® in patients with ALS. Five patients were injected intrathecally with a single dose of 100 × 106 AstroRx® cells and 5 patients with 250 × 106 cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3 months pre-treatment (run-in period) and 12 months post-treatment (follow-up period). RESULTS: A single administration of AstroRx® at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx® itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100 × 106 AstroRx® arm, the ALSFRS-R rate of deterioration was attenuated from - 0.88/month pre-treatment to - 0.30/month in the first 3 months post-treatment (p = 0.039). In the 250 × 106 AstroRx® arm, the ALSFRS-R slope decreased from - 1.43/month to - 0.78/month (p = 0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study. CONCLUSIONS: Overall, these findings suggest that a single IT administration of AstroRx® to ALS patients at a dose of 100 × 106 or 250 × 106 cells is safe. A signal of beneficial clinical effect was observed for the first 3 months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx®, e.g., every 3 months. TRIAL REGISTRATION: NCT03482050.

Long-term pituitary down-regulation pretreatment for endometriosis - chronicles of guidelines and recommendations.

It was suggested in the 1980s that long-term pituitary down-regulation by a gonadotrophin-releasing hormone agonist, termed the ultra-long protocol, inducing a hypo-oestrogenic state, might improve reproductive outcomes in women with endometriosis. Subsequently, international guidelines strongly supported the long-term pituitary down-regulation protocol in women with endometriosis based on a Cochrane review from 2006. The recently published European Society for Human Reproduction and Embryology guideline, based on the updated Cochrane review from 2019 and newer evidence, has reversed this recommendation. This paper explores the past and current evidence that led to these recommendations and calls for a consideration of refinement of the international guidelines to include additional factors and evaluate whether a paradigm shift is needed in the approach to endometriosis-related infertility. We believe that this can optimize evidence-based patient-centred care and benefit women worldwide and improve the design of future studies.

Endometrial compaction is associated with increased clinical and ongoing pregnancy rates in unstimulated natural cycle frozen embryo transfers: a prospective cohort study.

PURPOSE: To investigate the association between endometrial compaction and pregnancy rates in unstimulated natural cycle frozen embryo transfers. DESIGN: A single-center prospective cohort study. Endometrial thickness by transvaginal ultrasound and blood progesterone levels on the day of ovulation and the day of embryo transfer were evaluated in patients undergoing natural cycle frozen embryo transfer. Compaction was defined as > 5% decrease in endometrial thickness between ovulation day and day of transfer. Clinical and ongoing pregnancy rates in cycles with and without compaction were compared. RESULTS: Seventy-one women were included, of which 44% had endometrial compaction, with similar rates when subdividing the patients by day of transfer (day 3 or day 5). Clinical and ongoing pregnancy rates were higher in the compaction group compared to the non-compaction group (0.58 vs. 0.16, P < 0.001; 0.52 vs. 0.13, P < 0.001 respectively). Subdividing by degree of compaction > 10% and > 15% revealed similar pregnancy rates as > 5%, with no added benefit to higher degrees of compaction. CONCLUSIONS: About half the patients in our study undergoing unstimulated natural cycle frozen embryo transfer experienced compaction of the endometrium, occurring as early as day 3 post-ovulation. This was significantly correlated with increased clinical and ongoing pregnancy rates.

Establishment of a controlled slow freezing-based approach for experimental clinical cryopreservation of human prepubertal testicular tissues.

Objective: To develop an efficient, clinical-grade, freezing protocol toward experimental clinical cryopreservation of testicular tissues in prepubertal boys suffering from cancer. Design: Experimental cryopreservation of testicular tissue. Setting: University Medical Center. Patients: Adult patients undergoing orchiectomy for various tumors and prepubertal boys scheduled for gonadotoxic treatment. Interventions: None. Main Outcome Measures: Histopathological analysis of tissue architecture, structural integrity, and cellular morphology was performed for control and frozen-thawed cryopreserved tissues.The number of seminiferous tubules per testicular section was calculated. The survival of spermatogonial stem cells (SSCs) and Sertoli cells of the control and frozen-thawed cryopreserved tissues was analyzed by immunofluorescence staining. Results: Uncontrolled Slow Freezing, Controlled slow freezing, and vitrification similarly preserved the integrity of the adult testicular tissues and the survival of SSCs and Sertoli cells. Controlled slow freezing of prepubertal testicular tissues effectively preserved their architecture, the number of tubules, SSCs, and Sertoli cells. In addition, we observed SSC loss after chemotherapy in prepubertal boys, reemphasizing the importance of fertility preservation before gonadotoxic treatment. Conclusions: Future fertility restoration for male survivors of pediatric cancers depends on the development of an optimal prepubertal testicular tissue cryopreservation method. Our findings demonstrate the effectiveness of controlled slow freezing for cryopreservation of human prepubertal testicular tissues and may contribute to more effective banking of these tissues and potential fertility restoration. Clinical Trial Registration Number: NIH research clinical trials number: NCT02529826.

Astrocytes Downregulate Inflammation in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome: Applicability to COVID-19.

Background: An acute respiratory distress syndrome (ARDS) is caused by the increased amounts of pro-inflammatory cytokines and neutrophil-mediated tissue injury. To date, there is no effective treatment for the ARDS available, while the need for one is growing due to the most severe complications of the current coronavirus disease-2019 (COVID-19) pandemic. The human astrocytes (AstroRx) have shown immunomodulatory properties in the central nervous system (CNS). This study aimed to evaluate the capacity of astrocytes to decrease lung inflammation and to be applied as a treatment therapy in ARDS. Methods: First, we assessed the ability of clinical-grade AstroRx to suppress T-cell proliferation in a mixed lymphocyte reaction test. Next, we tested the therapeutical potential of AstroRx cells in a lipopolysaccharide (LPS)-based ARDS mouse model by injecting AstroRx intravenously (i.v). We determined the degree of lung injury by using a severity scoring scale of 0-2, based on the American Thoracic Society. The scoring measured the presence of neutrophils, fibrin deposits, and the thickening of alveolar walls. The state of inflammation was further assessed by quantifying the immune-cell infiltration to the bronchoalveolar lavage fluid (BALF) and by the presence of proinflammatory cytokines and chemokines in the BALF and serum. Results: We detected that AstroRx cells were capable to suppress T-cell proliferation in vitro after exposure to the mitogen concanavalin A (ConA). In vivo, AstroRx cells were able to lower the degree of lung injury in LPS-treated animals compared with the sham injected animals (P = 0.039). In this study, 30% of AstroRx treated mice showed no lung lesions (responder mice), these mice presented a steady number of eosinophils, T cells, and neutrophils comparable with the level of naïve control mice. The inflammatory cytokines and chemokines, such as TNFα, IL1b, IL-6, and CXCL1, were also kept in check in responder AstroRx-treated mice and were not upregulated as in the sham-injected mice (P < 0.05). As a result, the LPS-treated ARDS mice had a higher survival rate when they were treated with AstroRx. Conclusions: Our results demonstrate that the immunosuppressive activity of AstroRx cells support the application of AstroRx cells as a cell therapy treatment for ARDS. The immunoregulatory activity may also be a part of the mechanism of action of AstroRx reported in the amyotrophic lateral sclerosis (ALS) neurodegenerative disease.

Chemotherapy-based gonadotoxicity risk evaluation as a predictor of reproductive outcomes in post-pubertal patients following ovarian tissue cryopreservation.

BACKGROUND: The sterilizing effect of cancer treatment depends mostly on the chemotherapy regimen and extent of radiotherapy. Prediction of long-term reproductive outcomes among cancer survivors according to chemo-radiotherapy regimen may improve pre-treatment fertility preservation counseling and future reproductive outcomes. METHODS: The aim of this study was to evaluate long term reproductive outcomes in cancer survivors according to gonadotoxicity risk estimation of the chemo-radiotherapy regimens utilized. This retrospective cohort study was comprised of post-pubertal female patients referred for fertility preservation during 1997 and 2017 was performed. Eligible adult patients were addressed and asked to complete a clinical survey regarding their ovarian function, menstruation, reproductive experience and ovarian tissue auto-transplantation procedures. Results were stratified according to the gonadotoxic potential of chemotherapy and radiotherapy they received-low, moderate and high-risk, defined by the regimen used, the cumulative dose of chemotherapy administered and radiation therapy extent. RESULTS: A total of 120 patients were eligible for the survey. Of those, 92 patients agreed to answer the questionnaire. Data regarding chemotherapy regimen were available for 77 of the 92 patients who answered the questionnaire. Menopause symptoms were much more prevalent in patients undergoing high vs moderate and low-risk chemotherapy protocol. (51.4% vs. 27.3% and 16.7%, respectively; p < 0.05). Spontaneous pregnancy rates were also significantly lower in the high-risk compared with the low-risk gonadotoxicity regimen group (32.0% vs. 58.3% and 87.5%, respectively; p < 0.05). CONCLUSION: Patients scheduled for aggressive cancer treatment have significantly higher rates of menopause symptoms and more than double the risk of struggling to conceive spontaneously. Improving prediction of future reproductive outcomes according to treatment protocol and counseling in early stages of cancer diagnosis and treatment may contribute to a tailored fertility related consultation among cancer survivors.

'Luckily, I don't believe in statistics': survey of women's understanding of chance of success with futile fertility treatments.

RESEARCH QUESTION: Why are women who face poor prognoses for success in assisted reproductive technology (ART) treatment choosing to pursue procedures using their own eggs, despite receiving information that their chances of success are very low. DESIGN: Cross-sectional study based on an anonymous questionnaire distributed to women aged between 43 and 45 years, undergoing ART using their own oocytes, at six public outpatient fertility clinics and three public in-hospital IVF units in Israel between 2015 and 2016. The main outcome measure was personal estimation of chance to achieve a live birth after the current ART treatment cycle and the cumulative estimated rate after all the treatment cycles the patient intended to undergo. RESULTS: Response rate was 70.0%, with 91 participants of mean age 43.8 ± 0.7 years. Participants estimated their delivery rates after the next ART treatment cycle at 49.0 ± 31.8% (response rate 93.4%) and their cumulative delivery rates after all the ART treatments they would undergo at 57.7 ± 36.3% (response rate 90.1%). This is significantly higher than the predicted success rates of 5% and 15%, respectively (both P < 0.001), which are based on national register data. Nearly one-half of patients rated themselves as having a better than average chance of conception (47.3%). CONCLUSION: Women do not pursue futile treatments because they lack information. Despite being informed of the low success rates of conception using ART treatments, many patients of advanced maternal age have unrealistically high expectations from ART, essentially ignoring their estimated prognosis when deciding on treatment continuation. Future work should examine the psychological reasons behind continuing futile fertility treatments.

In vitro maturation rates in young premenarche patients.

OBJECTIVE: To evaluate in vitro maturation (IVM) efficacy and oocyte retrieval rates after ovarian tissue cryopreservation in young premenarche girls facing chemo- and radiotherapy. DESIGN: A retrospective cohort study. SETTING: University-affiliated tertiary medical center. PATIENT(S): A total of 84 chemotherapy-naïve patients ages 0-18 years referred for fertility preservation between 2004 and 2017: 33 premenarche and 51 postmenarche patients. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): IVM in the pre- and postmenarche groups and in the subgroups of very young (up to age 5 years) and older (5-10 years) premenarche girls. RESULTS: The number of oocytes retrieved did not significantly differ between the postmenarche and premenarche groups (10.8 ± 8.5 and 8.1 ± 6.8, respectively). However, the overall IVM rate was significantly higher in the postmenarche group (28.2% vs. 15.5%, respectively; odds ratio = 0.47). A separate analysis for patients up to 5 years of age demonstrated significantly lower oocyte yield compared with the older (5-10 years) premenarche girls (4.7 ± 5.2 vs.10.3 ± 7.0 oocytes, respectively) and much lower IVM rates (4.9% and 18.2%, respectively). Correlation of age with number of retrieved and matured oocytes showed a positive significant correlation (r = 0.45 and r = 0.64, respectively). CONCLUSIONS: IVM performed after ovarian tissue cryopreservation in premenarche girls and specifically in very young girls (4 years and younger) yields substantially decreased maturation rates compared with postmenarche patients, raising a question as to the utility of current IVM technique in this age group. Further studies are required to assess modification of the IVM technique for young girls.

Single-Incision Laparoscopic Surgery for Ovarian Tissue Cryopreservation.

STUDY OBJECTIVE: To present single-incision laparoscopic surgery (SILS) as an alternative to standard multiport laparoscopic surgery (MPLS) for ovarian tissue cryopreservation. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Tertiary medical center. PATIENTS: Two hundred thirty-one patients referred for oncologic fertility preservation. INTERVENTION: Non-inferiority comparison of SILS with MPLS for ovarian cryopreservation for future transplantation. MEASUREMENTS AND MAIN RESULTS: We compared duration of the procedure, intra- and postoperative complications, hospital stay, and time (days) from surgery to chemotherapy. We additionally compared number of ampules (each ampule contains 10 slivers of ovarian cortex tissue) preserved and number of oocytes retrieved during the preparation process. Adjustments for age, previous chemotherapy, and partial versus complete oophorectomy ratio were performed. MPLS was performed in 163 patients (71.2%) and SILS in 66 patients (28.8%). Ten patients (15.2%) in the SILS group and 32 (19.8%) in the MPLS group were prepubertal. Malignant conditions distribution was similar. Procedure duration and overall complication rates were similar. Number of ampules extracted from the preserved tissue was somewhat higher in the SILS group as compared with the MPLS group (14.7 vs 10.6, respectively; p < .01). CONCLUSION: Our findings suggest that SILS is an interesting alternative to MPLS. Future prospective trials may prove some benefit in ovarian tissue volume or time until chemotherapy initiation.

Transvaginal ultrasound to guide embryo transfer: a randomized controlled trial.

OBJECTIVE: To compare sonographic visualization and patient pain in conventional transabdominal ultrasound (TAUS) with transvaginal ultrasound (TVUS) sonographic-guided embryo transfer (ET). DESIGN: Prospective, randomized, controlled study. SETTING: Tertiary medical center, in vitro fertilization (IVF) unit. PATIENT(S): One hundred and twenty patients younger than 40 years old scheduled for ET. INTERVENTION(S): Patients (32.9 ± 4.5 years old) undergoing fresh cleavage-stage ET were randomly assigned to the study group (TVUS; n = 60) or control group (TAUS; n = 60). After ET each patient filled out a questionnaire based on a visual analogue scale (VAS) to evaluate pain and discomfort before, during, and after the procedure. The physician assessed the quality of sonographic visualization. The follow-up observation lasted 12 months and included pregnancy rates. MAIN OUTCOME MEASURE(S): Visualization of the uterus and ET location and pain before, during, and after the ET procedure. RESULT(S): Visualization of the uterus and the ET location by the physician was statistically significantly better in the TVUS than in the TAUS group (9.57 vs. 8.42 and 9.58 vs. 8.82, respectively). Pain sensation assessed by a visual analogue scale (VAS) before, during, and after the procedure was statistically significantly lower in the study group compared with the control group (5.45 vs. 1.48, 5.03 vs. 2.42 and 2.97 vs. 1.52). The implantation and live-birth rates did not differ between the two groups (32.9% vs. 23.4%, OR 1.61; 95% CI, 0.85-3.07; 31.6% vs. 25.0%, OR 1.39; 95% CI, 0.63-3.09, respectively). CONCLUSION(S): TVUS guidance to facilitate ET is superior to TAUS in visualization of ET location and in lessening the pain and discomfort of the patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT008263312.

In Vitro Fertilization Outcomes After Placement of Essure Microinserts in Patients With Hydrosalpinges Who Previously Failed In Vitro Fertilization Treatment: A Multicenter Study.

STUDY OBJECTIVE: To investigate whether hysteroscopic proximal tubal occlusion with Essure microinserts (Conceptus Inc.; Bayer, AG, North Rhine-Westphalia, Germany) can improve pregnancy rates in patients with hydrosalpinges who had failed in vitro fertilization (IVF) treatment. DESIGN: A prospective cohort study. SETTING: University-affiliated tertiary centers. PATIENTS: Twenty-four consecutive women with hydrosalpinges who had failed IVF treatment were included. INTERVENTIONS: Hysteroscopic placement of Essure microinserts for hydrosalpinx blockage followed by IVF treatment. MEASUREMENTS AND MAIN RESULTS: Ongoing pregnancy and live birth rates were recorded. Of the 24 patients undergoing a total of 42 IVF cycles after Essure insertion, 18 (75% of patients and 42.8% of IVF cycle attempts) conceived and 16 delivered live births (66.6% of patients and 38.1% of IVF cycle attempts). CONCLUSION: Hysteroscopic proximal occlusion of hydrosalpinges with Essure microinserts is a valuable alternative to laparoscopic salpingectomy, resulting in reasonable pregnancy rates.

Operative hysteroscopy for treatment of intrauterine pathologies does not interfere with later endometrial development in patients undergoing in vitro fertilization.

PURPOSE: Operative hysteroscopy procedure is extensively used for the treatment of intrauterine abnormalities that can potentially cause infertility. To date, there are little data addressing the effect of operative hysteroscopy that applies electrical current for excision and its subsequent effect on endometrial thickness. This study was aimed to assess the effect of thermal resection used in operative hysteroscopy on endometrial thickness and on fertility outcome in women undergoing in vitro fertilization (IVF). METHODS: A retrospective study conducted at Hadassah-Hebrew University Medical Center, a tertiary referral center. Included were IVF women who underwent an operative hysteroscopy throughout the years 2000-2010 for intrauterine pathologies. RESULTS: Throughout the years 2000-2010, 41 IVF women who underwent an operative hysteroscopy using electric current between their 82 IVF cycles were studied. The mean age of women at the time of the intervention was 37.1 years (36.7 and 37.5 at the IVF cycles before and after intervention, respectively). The maximal endometrial thickness before operative hysteroscopy was 10.7 mm compared to 9.5 mm after all procedures (P < 0.001). Excluding polypectomy cases (n = 24) the endometrial thickness was 9.9 mm before vs. 9.1 mm after operative hysteroscopy (P < 0.001). The clinical pregnancy rate was 19.5 % before as compared to 24.4 % after operative hysteroscopy (NS). The take home baby rate (THBR), however, was significantly increased following operative hysteroscopy for all indications from 2.4 to 12.2 % (P < 0.05). CONCLUSION: Despite the small change in endometrial thickness, our results indicate that using electric current is safe to treat intrauterine pathologies.

microRNAs and Endometrial Pathophysiology.

Embryo implantation requires a reciprocal interaction between the blastocyst and endometrium and is associated with complex regulatory mechanisms. Since their discovery, microRNAs became prominent candidates providing missing links for many biological pathways. In recent years, microRNAs were implicated as one of the important players in regulation of various biological and physiological endometrial related processes. This chapter aims to present recent knowledge pertaining to the diverse aspects of microRNAs in the embryo-endometrial relationship. We will focus on the role of microRNAs in decidualization and their part in natural and stimulated cycles. Next, we will present recent studies deliberating the role of microRNAs in recurrent pregnancy loss and in the important phenomenon of recurrent implantation failure. Lastly, demonstrating an important aspect of embryo implantation and invasion, we will outline few microRNA related shared pathways of implantation and carcinogenesis.

Assisted reproduction policies in Israel: a retrospective analysis of in vitro fertilization-embryo transfer.

OBJECTIVE: To analyze whether the results and effectiveness of the open-ended treatment with IVF in Israel justifies the policy of limitless nondonor IVF rounds. DESIGN: The research sample included 535 patients. The files of these patients were reviewed; data were extracted into a questionnaire, transferred into digital files, and analyzed with SPSS. SETTING: IVF clinics. PATIENT(S): Two hundred ten women who began IVF treatment in 2000 and 325 women who were in IVF treatment during 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Retrospective analysis of the success rates of live births resulting from cycles with IVF in women who started treatment in 2000, retrospective analysis of IVF results during 2010, and number of cycles in women who were in IVF treatment during 2010. RESULT(S): In the 2000 cohort, the rate of success with IVF was 54%. The success rate fell as the number of unsuccessful cycles and duration of infertility increased; age at the beginning of the treatment was influential. A similar pattern appeared in the group that was in treatment during 2010. The rate of success in the group that was in IVF treatment during 2010 was 16.6%; of the women in this group (2010, ongoing), 25% had already undergone more than five cycles and 12% of the women had already undergone more than seven cycles. CONCLUSION(S): Although limited in scope, this study suggests that the policy of limitless nondonor IVF-ET cycles in Israel should be further examined and assessed.

Emerging roles of microRNA in the embryo-endometrium cross talk.

Embryo implantation requires a reciprocal interaction between the blastocyst and endometrium and is associated with complex regulatory mechanisms. Since their discovery, microRNAs have become prominent regulatory candidates, providing missing links for many biological pathways. In recent years, microRNAs have been implicated as one of the important players in the regulation of multiple physiological functions of the endometrium. This review aims to present recent knowledge pertaining to the diverse aspects of microRNAs in the embryo-endometrial cross talk. We will focus on the role of microRNAs in decidualization. Next, we will review recent studies investigating the role of microRNAs in recurrent pregnancy loss. Finally, we will discuss the role of microRNAs in the tissue invasion of implantation and compare that with tissue invasion in cancers.

[Single incision laparoscopic combined cholecystectomy, bilateral salpingo-oophorectomy and omentectomy].

Single Incision Laparoscopic Surgery (SILS) is gaining popularity as a modality in surgery which reduces the number and size of skin incisions. General surgeons and urologists were the first to implement this technique, however, recently gynecologists have also started performing SILS procedures. We present the case of a 70 year old female who underwent a combined SILS procedure which included cholecystectomy, bilateral oophorectomy and omentectomy. The procedure lasted 100 minutes and the patient was discharged home the day after the operation. No operative or post-operative complications were noted. In this case report we present the technical details and demonstrate the collaboration between different disciplines which enables performing this complex and demanding procedure.

Women's post-chemotherapy parity is affected by offspring number and marital status.

Childbearing rates post-chemotherapy for breast cancer (BC) are affected by age and chemotherapy-type but may also depend on personal characteristics. In this single institution retrospective study we evaluated post-chemotherapy fertility and its association with offspring number and marital-status at the time of BC diagnosis. We identified 65 fertile BC patients under 38y, who received adjuvant-chemotherapy. Menses resumption and pregnancies along with offspring-number and marital-status were recorded. Menses resumed in 95.4% and 33.8% gave birth. Of those who did not give birth 46.5% had at least three children at diagnosis and of those without children 83% were unmarried. Our data associates multiparity with lower childbearing post-chemotherapy, suggesting it as a possible surrogate for women's preferences in retrospective studies. Unlike multiparity, marital status association with lower childbearing may be culture-dependent and not a universal surrogate for women's intentions and would be best investigated prospectively.

Defective endometrial receptivity.

The endometrium is one of the most fascinating tissues in the human body. Its sole purpose is to enable implantation of an embryo during a relatively short window of opportunity in the menstrual cycle. It is becoming clear that overcoming the current bottleneck in improvements to assisted reproductive techniques will require a closer look at the interface between uterus and embryo. Indeed, embryo implantation requires a cross talk with a receptive endometrium. Using sonography, hysteroscopy and endometrial biopsy we can learn about anatomical and functional markers of endometrial receptivity. This article reviews the factors which might cause defective endometrial receptivity. These include uterine polyps, septa, leiomyomata and adhesions. The effect of thin endometrium, endometriosis and hydrosalpinx is also described. Finally contemporary investigation of molecular markers of endometrial receptivity is described. Improving embryo implantation by a closer look inside the uterus is the key to increasing pregnancy rates in IVF.

Fertility preservation in girls.

Children that undergo treatment for cancer are at risk of suffering from subfertility or hormonal dysfunction due to the detrimental effects of radiotherapy and chemotherapeutic agents on the gonads. Cryopreservation of ovarian tissue prior to treatment offers the possibility of restoring gonadal function after resumption of therapy. Effective counseling and management of pediatric patients is crucial for preserving their future reproductive potential. The purpose of this article is to review recent literature and to revise recommendations we made in a 2007 article. Pediatric hemato-oncology, reproductive endocrinology, surgery, anesthesia and bioethics perspectives are discussed and integrated to propose guidelines for offering ovarian cryopreservation to premenarcheal girls with cancer.

Underdiagnosed menorrhagia in adolescents is associated with underdiagnosed anemia.

OBJECTIVE: To test the hypothesis that adolescent girls with menorrhagia rarely seek medical attention. STUDY DESIGN: A total of 705 adolescent girls attended a lecture on menorrhagia, completed an initial anonymous questionnaire, and were asked to participate in a more comprehensive study comprising a detailed bleeding questionnaire, a pictorial blood loss assessment chart, and blood tests. RESULTS: A total of 105 adolescents (15%) reported they had heavy periods on the initial questionnaire. Among the 94 girls who completed the full questionnaire, 34 reported menorrhagia (36%; 95% CI, 26.5%-46.7%). Almost one-third (11 of 34) of these girls did not perceive having menorrhagia according to their response to the initial questionnaire. Menorrhagia was not related to age, years since menarche, or family history of menorrhagia. Among the 62 girls who consented to blood testing, 6 had anemia (9.6%; 95% CI, 3.6%-19.6%), all of whom had bleeding symptoms. CONCLUSION: Using standardized questionnaires, we were able to identify adolescents with menorrhagia associated with anemia. Importantly, some of these adolescents were not aware of having menorrhagia and/or anemia. Screening programs for menorrhagia in schools could result in better detection of menorrhagia among adolescents and consequent appropriate referral for medical consultation.