Search

BACKGROUND: The objective of this study was to assess the psychological implications of mild ovarian stimulation combined with single embryo transfer (SET) during a first IVF cycle. METHODS: We conducted a randomized controlled two-centre trial. Three hundred and ninety-one couples were randomized to undergo either mild ovarian stimulation with GnRH antagonist co-treatment and SET (n=199) or conventional GnRH agonist long protocol ovarian stimulation with double embryo transfer (DET) (n=192). Women completed the Hospital Anxiety and Depression Scale, the Hopkins Symptom Checklist and the Subjective Sleep Quality Scale at baseline, on the first day of ovarian stimulation and following embryo transfer. Affect was assessed daily with the Daily Record Keeping Chart from the first day of ovarian stimulation until the day treatment outcome became known. RESULTS: The conventional IVF group experienced elevated levels of physical and depressive symptoms during pituitary downregulation. At oocyte retrieval, this group experienced more positive affect and less negative affect than the mild IVF group. In the conventional IVF group, cycle cancellation was associated with less positive and more negative affect. CONCLUSIONS: During the first IVF treatment cycle, mild ovarian stimulation and SET does not lead to more psychological complaints than conventional IVF.

This meta-analysis was conducted to compare outcomes of conventional IVF in women presenting with polycystic ovary syndrome (PCOS) and non-PCOS patients. Studies in which PCOS patients undergoing IVF were compared with a matched--no male factor--control group were considered for this review. A definition consistent with the Rotterdam consensus criteria of PCOS was required, and all patients within a given study had to be treated with the same ovarian stimulation protocol. Information regarding patient characteristics and pregnancy outcome was also required. Nine out of 290 identified studies reporting data on 458 PCOS patients (793 cycles) and 694 matched controls (1116 cycles) fulfilled these inclusion criteria. PCOS patients demonstrated a significantly reduced chance of oocyte retrieval per started cycle, odds ratio (OR) = 0.5 [95% confidence interval (CI) = 0.2-1.0]. However, no difference was observed in chance of embryo transfer per oocyte retrieval between the groups (OR = 0.7, 95% CI = 0.4-1.3). Significantly more oocytes per retrieval were obtained in PCOS patients compared with controls [random effects estimate 3.4 [95% (CI) = 1.7-5.1)]. The number of oocytes fertilized did not differ significantly between PCOS patients and controls, weighted mean difference (WMD) 0.1 oocytes (95% CI = 21.4-1.6). No significant difference was observed in the clinical pregnancy rates per started cycle, OR = 1.0 (95% CI = 0.8-1.3). The incidence of ovarian hyperstimulation syndrome (OHSS) after oocyte retrieval was rarely reported. This meta-analysis demonstrates an increased cancellation rate, but more oocytes retrieved per retrieval and a lower fertilization rate in PCOS undergoing IVF. Overall, PCOS and control patients achieved similar pregnancy and live birth rates per cycle.

Infertility is an increasing problem all over the world, and it has been estimated that 10–15% of couples in fertile age have fertility problems. Likewise induced unsafe abortion is a serious threat to women’s health. Despite advances made in assisted reproduction techniques, little progress has been made in increasing the success rate during fertility treatment. This document describes a wide range of projects carried out to increase the understanding in the field of embryo implantation research. The ‘Fruitful’ research network was created to encourage collaborations within the consortium and to describe our different research potentials to granting agencies or private sponsors.

In modern fertility practice, much time and energy is devoted to controlling ovarian stimulation. Is this effort well directed? Does monitoring and dose adjustment prevent complications and improve outcomes? Or does it just provide clinicians with a false sense of security and power to influence ovarian function? Monitoring ovarian stimulation can identify excess response, and enable the clinician to prevent complications of hyperstimulation by terminating the cycle. However, subtle interventions such as dose adjustment to monitored response have little impact on outcomes. Poor responders are frequently subjected to increased doses of gonadotropins in the hope of improving chances of undergoing oocyte pick up and achieving pregnancy. However, the evidence supporting this approach is scarce. In the context of ovarian stimulation for IUI, interventions aimed at limiting response have little impact on the risk of multiple pregnancies. Why is the ovarian response so difficult to control? While recent studies suggest that batch variation in the bioactivity of gonadotropin preparations may be partially to blame, it is becoming increasingly evident that patient-related factors, rather than doctor-controlled factors are the primary determinants of outcome from ovarian stimulation.

Clomiphene citrate (CC) results in ovulatory cycles in about 75–90% of patients with PCOS and is particularly successful in the leaner, oligomenorrheic non-amenorrheic patient with only limited signs of hyperandrogenism. Of those that ovulate 60–70% conceive with 40–50% resulting in live births. Traditionally the method following unsuccessful ovulation induction with CC, either because anovulation persists or because no pregnancy occurs, is to administer gonadotropins directly. The gonadotropin step-down protocol for the PCOS patient is highly attractive from a physiological point of view. Nevertheless, practically and taking into account safety, the low-dose step-up protocol seems the first choice approach. Almost all patients become ovulatory after adequate dosages of gonadotropins with a high BMI, clomiphene resistance, higher IGF1 and FSH serum levels that indicate the need of higher doses of FSH. The overall conception rate is 50–60%. Pregnancy rates are lower in case of obesity, insulin resistance and higher age.

Assisted reproductive technologies (ARTs) aim to increase a woman's chances of becoming pregnant by bringing many female and male gametes into close proximity. Techniques to achieve this objective include ovarian hyperstimulation by maturation of several oocytes, intrauterine insemination (IUI) of concentrated sperm, or in-vitro fertilisation (IVF) by bringing gametes together outside the female body. The very nature of ovarian hyperstimulation--with or without IUI--enhances the risk of multiple pregnancy (eg, two or more babies). In most IVF cycles, more than one embryo is transferred, again resulting in an increased chance of multiple pregnancy. Developed societies have witnessed a large rise in prevalence of twin, triplet, and higher order multiple births, mainly resulting from ARTs. The primary aim of this Review is to increase awareness of the many implications of the present iatrogenic epidemic of multiple births. The background of ovarian hyperstimulation, trends supporting current practice, and strategies to reduce the chance of multiple pregnancy are highlighted.

Replacing GnRH agonist cotreatment for the prevention of a premature rise in LH during ovarian stimulation for in vitro fertilization (IVF) by the late follicular phase administration of GnRH antagonist may render supplementation of the luteal phase redundant, because of the known rapid recovery of pituitary function after antagonist cessation. This randomized two-center study was performed to compare nonsupplemented luteal phase characteristics after three different strategies for inducing final oocyte maturation. Forty patients underwent ovarian stimulation using recombinant (r-)FSH (150 IU/d, fixed) combined with a GnRH antagonist (antide; 1 mg/d) during the late follicular phase. When at least one follicle above 18 mm was observed, patients were randomized to induce oocyte maturation by a single injection of either r-human (h)CG (250 microg) (n = 11), r-LH (1 mg) (n = 13), or GnRH agonist (triptorelin; 0.2 mg) (n = 15). Retrieved oocytes were fertilized by either IVF or intracytoplasmatic sperm injection, depending on sperm quality. Embryo transfer was performed 3-4 d after oocyte retrieval. No luteal support was provided. Serum concentrations of FSH, LH, estradiol (E(2)), progesterone (P), and hCG were assessed at fixed intervals during the follicular and luteal phase. The median duration of the luteal phase was 13, 10, and 9 d for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.005). The median area under the curve per day (from 4 d post randomization until the onset of menses) for LH was 0.50, 2.34, and 1.07 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.001). The median area under the curve per day for P was 269 vs. 41 and 16 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P < 0.001). Low pregnancy rates (overall, 7.5%; range, 0-18% per started cycle) were observed in all groups. In conclusion, the nonsupplemented luteal phase was insufficient in all three groups. In the patients receiving r-hCG, the luteal phase was less disturbed, compared with both other groups, presumably because of prolonged clearance of hCG from the circulation and the resulting extended support of the corpus luteum. Despite high P and E(2) concentrations during the early luteal phase in all three groups, luteolysis started prematurely, presumably because of excessive negative steroid feedback resulting in suppressed pituitary LH release. Hence, support of corpus luteum function remains mandatory after ovarian stimulation for IVF with GnRH antagonist cotreatment.

Current approaches to ovarian stimulation for in vitro fertilization (IVF) are aimed at optimizing the number of oocytes retrieved in a treatment cycle. This approach is not without risks. Moreover, as the true costs of multiple pregnancy become clearer, the need to produce multiple embryos for transfer is increasingly questioned. Increasing knowledge of the physiological mechanisms involved in follicular development and dominance has led to new strategies in ovarian stimulation for IVF. The clinical availability of GnRH antagonists allows the normal cycle to be harnessed and manipulated by mild interventions to produce sufficient oocytes for successful IVF treatment. Recent evidence suggests that oocyte quality after mild stimulation may be superior to that after conventional stimulation regimens.

Item does not contain fulltext BACKGROUND: Specific subgroups of people planning IVF might be at risk of having more psychological or health-related problems. Identification of subgroups at risk may better enable allocation of appropriate counselling. METHODS: A group of 425 men and 447 women planning to undergo IVF treatment filled out a questionnaire. Four domains of health-related quality of life were measured, namely perceived emotional, physical, cognitive and social functioning. RESULTS: Young men and women (aged 21-30 years) planning IVF had more short-term social and emotional problems than people of the same age group in the general population. No substantial differences were found in cognitive and physical functioning for all age groups of men nor women planning IVF compared with the general population. A high level of irrational parenthood cognitions substantially accounted for a less optimal score on all the different domains of quality of life. These cognitions ('needing a child in order to live a happy life') were especially prevalent among younger women. CONCLUSIONS: Patients with high levels of irrational parenthood cognitions are at risk of a less optimal quality of life. A short cognitive counselling therapy is advised for patients with high levels of these cognitions.

BACKGROUND: Extending the period of in-vitro culture to the blastocyst stage may improve implantation rates in IVF treatment. Recognition of the dynamic nature of early embryo metabolism has led to the development of commercially available sequential culture systems. However, their improved efficacy over monoculture systems remains to be demonstrated in prospective studies. METHODS: Embryos obtained from 158 women undergoing IVF treatment were randomized by sealed envelopes to culture in one of three systems: (A) culture for 5 days in our own monoculture medium (Rotterdam medium); (B) culture for 3 days in Rotterdam medium followed by 2 days in fresh Rotterdam medium; (C) culture for 5 days using the commercially available G1/G2 sequential culture system. RESULTS: There were no significant differences in blastulation, implantation or pregnancy rates between the three tested culture systems. CONCLUSION: The employed monoculture system is as effective as the G1/G2 sequential system for the culture of blastocysts for IVF.

OBJECTIVE: To evaluate the ability of a prediction model to identify the individual starting dose of FSH for ovulation induction using a step-down regimen. DESIGN: Retrospective analysis of clinical data in an academic fertility unit. Fifty-six normogonadotropic anovulatory infertile patients who failed to ovulate or conceive with clomiphene citrate were included. They were treated with exogenous gonadotropins with a flexible starting dose for ovulation induction using a step-down regimen. The clinically applied starting dose of exogenous gonadotropins was compared with the calculated response-dose using a previously published prediction model. RESULTS: Patients were arbitrarily divided into three groups according to the day of the first decrease in gonadotropin dose: (a) early step-down (day 3 or earlier); (b) standard step-down (day 4 or later); (c) no step-down. These groups had average starting doses of 28.5 IU (group a) and 13 IU (group b) above the calculated response-dose, and 43 IU (group c) under the calculated response-dose. A significant correlation between day of first step-down and the difference between clinically applied and calculated response-dose was observed (P

The contemporary approach to ovarian stimulation for IVF treatment results in supraphysiological concentrations of steroids during the follicular and luteal phases of the menstrual cycle. These sex steroids act directly and indirectly to mature the endometrium, influencing receptivity for implantation. Corpus luteum function is distinctly abnormal in IVF cycles, and therefore luteal support is widely used. Various reasons may underlie the defective luteal phase, including (i) ovarian hyperstimulation per se, (ii) gonadotrophin-releasing hormone (GnRH) analogue co-treatment and (iii) the use of human chorionic gonadotrophin (HCG) to induce final oocyte maturation. The recent introduction of GnRH antagonist co-treatment for the prevention of a premature LH rise during the late follicular phase allows for different approaches to ovarian stimulation for IVF. However, a recent meta-analysis showed that implantation rates may be compromised by using GnRH antagonists in currently employed regimens. The development of endometrium receptive to embryo implantation is a complex process and may be altered by inappropriate exposure to sex steroids in terms of timing, duration and magnitude. New approaches to the assessment of endometrial receptivity are now required. Novel approaches to ovarian stimulation aimed at adjusted GnRH antagonist regimens and achieving a more physiological luteal phase endocrinology are now appearing in the literature and may represent an important step in the improvement of the overall health economics of IVF.

Even when conditions are optimal, the maximum chance of a clinically recognized pregnancy occurring in a given menstrual cycle is 30-40%. Increasing evidence points to preclinical pregnancy loss rather than failure of conception as the principal cause for the relatively low fecundity observed in humans. While sensitive assays for hCG have provided a glimpse of the events occurring between implantation and the missed menstrual period, new cytogenetic techniques have further opened this 'black box', providing novel insights into the causes of early pregnancy wastage. In this article, the evidence and causes of preclinical or 'occult' pregnancy are reviewed, and the implications for the infertile patient are addressed.

Purpose: To calculate the added benefit of a cryopreservation program to the cumulative ongoing pregnancy rate over a maximum of three cycles of IVF. Methods: A total of 1251 couples beginning their first IVF treatment between January 1995 and December 1999 were evaluated. Ongoing pregnancies from fresh and subsequent cryopreserved embryo transfer cycles were analyzed. Pregnancies arising from the cryopreservation cycle were considered to augment the cumulative pregnancy rate when no ongoing pregnancy arose from the fresh embryo transfer cycle. Results: The ongoing pregnancy rate per cryopreserved embryo transfer was 11.7%. The cumulative ongoing pregnancy rate following three successive started fresh IVF cycles was 42.5%. When pregnancies arising from the transfer of thawed cryopreserved embryos were included, the cumulative ongoing pregnancy rate increased to 43.8%, rising to 44.8% when extrapolated data from as yet unthawed embryos was included. Conclusions: When analyzed in these terms, the supplementary benefit of cryopreserving supranumerical embryos appears limited.

Human reproduction is characterized by a high degree of embryo wastage, which is largely ascribed to a high prevalence of embryo aneuploidy. It is proposed that maternal strategies have evolved that prevent inappropriate investment in invasive, but poorly viable embryos. Key to this is the emerging concept of the endometrium as biosensor, first identified in human in vitro embryo/decidualized stromal cell coculture systems and recently confirmed in an in vivo mouse model. In this review, the growing supporting experimental evidence for the biosensor component of decidualized endometrium is outlined, and recent insights into the nature of the embryo-derived signal detected by the endometrium and the biological processes by which this signal is thought to be converted into a go or no-go endometrial response are described. Finally, the clinical implications of this new paradigm of the choosy uterus are addressed.

Using endometrial secretion analysis, we assessed whether altered inflammatory cytokine levels can be detected in the uterine environment in asthma patients, thereby providing a possible cause of reduced fertility in asthmatics.Forty-four unexplained infertile women (aged 28-44) underwent asthma and allergy testing, questionnaires, endometrial secretion and blood samples in the mid-secretory phase of the menstrual cycle (day 19-23) during assisted reproduction. Differences in cytokines and growth factors were analyzed.Mean log-VEGF in uteri was lower in asthma patients compared with controls (2.29 versus 2.70, p = 0.028). This was mainly due to lower values of VEGF among women with non-atopic asthma compared with women with atopic asthma (1.86 versus 2.72, p = 0.009) and with healthy controls (1.86 versus 2.70, p = 0.01). Asthma treatment status had no effect on VEGF levels in uteri. Serum high sensitivity CRP was negatively correlated with VEGF in endometrial secretions. No other significant correlations were observed between peripheral blood values and markers found in utero.Asthma is associated with lower values of VEGF in uterine endometrial secretions, which might affect the receptiveness of the endometrium and thereby increase time to pregnancy. The effect appears to be associated with non-atopic asthma with general increased systemic inflammation.

Human reproduction is characterized by a high degree of embryo wastage, which is largely ascribed to a high prevalence of embryo aneuploidy. It is proposed that maternal strategies have evolved that prevent inappropriate investment in invasive, but poorly viable embryos. Key to this is the emerging concept of the endometrium as biosensor, first identified in human in vitro embryo/decidualized stromal cell coculture systems and recently confirmed in an in vivo mouse model. In this review, the growing supporting experimental evidence for the biosensor component of decidualized endometrium is outlined, and recent insights into the nature of the embryo-derived signal detected by the endometrium and the biological processes by which this signal is thought to be converted into a go or no-go endometrial response are described. Finally, the clinical implications of this new paradigm of the choosy uterus are addressed.

Approximately one in six couples suffer from subfertility, and many seek treatment with artificial reproductive technologies (ART). Despite improvements in laboratory techniques and ovarian stimulation, ongoing pregnancy rates per cycle remain at ~25%. Couples wanting to improve their chances may turn to adjuvant therapies, such as nutritional supplements. There is growing evidence that periconceptional nutritional status is a key determinant of fertility and long-term health of the offspring, and a lucrative market has developed to meet the demand based on these benefits. However, the practice of routine dietary supplementation before and during IVF treatment has not been subject to well-powered prospective randomised trials. In this article, the potential roles of specific nutritional supplements in the context of improving IVF outcomes are reviewed and an assessment is made of the evidence base supporting their clinical use in this context. Finally, current research needs in the field are outlined.

BACKGROUND: In vitro fertilisation (IVF) treatment provides an opportunity to study early developmental responses to periconceptional dietary interventions. Retrospective studies have suggested links between preconception diet and fertility, and more recently, a "Mediterranean" diet has been reported to increase pregnancy rates by up to 40%. In addition, a prospective study examining increased intake of omega-3 polyunsaturated fats demonstrated a quickened rate of embryo development after IVF. However, up to now, few prospective randomised controlled trials have investigated the impact of periconceptional dietary interventions on fertility outcomes.METHODS AND DESIGN: The study is a randomised controlled trial of a dietary intervention consisting of olive oil for cooking, an olive oil based spread, and a daily supplement drink enriched with Vitamin D (10 microgram daily) and marine omega-3 fatty acids (2 g daily) for 6 weeks preconception versus a control diet of sunflower seed oil for cooking, a sunflower oil based spread, and a daily supplement drink without added Vitamin D or marine omega-3 fatty acids. Couples undergoing IVF will be randomised to either the intervention or control group (55 in each arm). The primary endpoint is embryo developmental competency in vitro, measured by validated morphokinetic markers. Secondary outcomes will include the effect of the dietary intervention on the nutritional content of the intrauterine environment.DISCUSSION: This approach will enable rigorous examination of the impact of the dietary intervention on early embryo development, together with the influence of the peri-implantation intra-uterine nutritional environment.

Human embryos frequently harbor large-scale complex chromosomal errors that impede normal development. Affected embryos may fail to implant although many first breach the endometrial epithelium and embed in the decidualizing stroma before being rejected via mechanisms that are poorly understood. Here we show that developmentally impaired human embryos elicit an endoplasmic stress response in human decidual cells. A stress response was also evident upon in vivo exposure of mouse uteri to culture medium conditioned by low-quality human embryos. By contrast, signals emanating from developmentally competent embryos activated a focused gene network enriched in metabolic enzymes and implantation factors. We further show that trypsin, a serine protease released by pre-implantation embryos, elicits Ca(2+) signaling in endometrial epithelial cells. Competent human embryos triggered short-lived oscillatory Ca(2+) fluxes whereas low-quality embryos caused a heightened and prolonged Ca(2+) response. Thus, distinct positive and negative mechanisms contribute to active selection of human embryos at implantation.

Item does not contain fulltext OBJECTIVE: To assess the impact of elevated early follicular progesterone (P) levels in gonadotropin-releasing hormone (GnRH) antagonist cycles on clinical outcome using prospective data in combination with a systematic review and meta-analysis. DESIGN: Nested study within a multicenter randomized controlled trial and a systematic review and meta-analysis. SETTING: Reproductive medicine center in an university hospital. PATIENT(S): 158 in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) patients. INTERVENTION(S): Recombinant follicle-stimulating hormone (FSH) (150-225 IU) administered daily from cycle day 2 onward; GnRH antagonist treatment randomly started on cycle day 2 or 6; assignment into two groups according to P level on cycle day 2: normal or elevated (>4.77 nmol/L or >1.5 ng/mL, respectively). MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (OPR) per started cycle. RESULT(S): The incidence of elevated P was 13.3%. A non-statistically-significant difference in OPR was present between the normal and elevated P groups (27.0% vs. 19.0%). No differential impact of early or late GnRH antagonist initiation on the effect of elevated or normal P on OPR was observed. A systematic search of Medline and EMBASE from 1972-2013 was performed to identify studies analyzing elevated early P levels in GnRH antagonists. The meta-analysis (n=1,052) demonstrated that elevated P levels statistically significantly decreased the OPR with 15% (95% CI -23, -7 %). Heterogeneity across the studies, presumably based on varying protocols, may have modulated the effect of elevated P. CONCLUSION(S): From the present meta-analysis it appears that early elevated P levels are associated with a lower OPR in GnRH antagonists. The incidence of such a condition, however, is low. CLINICAL TRIAL REGISTRATION NUMBER: NCT00866034.

Objective To examine the effects of high-fat (HF) diet-induced maternal obesity on follicular population and gene expression in adult offspring ovaries. Design Experimental mouse study. Setting Laboratory. Animal(s) Mice on HF diet. Intervention(s) Female C57BL/6J mice were fed an HF or standard chow (C) diet 6 weeks before conception, through pregnancy and lactation. Offspring were fed the C or HF diet from weaning, creating the HF/HF, HF/C, C/HF, C/C offspring groups. Main outcome measure(s) Follicular counts and gene expression in adult offspring ovaries. Result(s) Prenatal exposure to maternal HF nutrition resulted in the reduction of primordial, antral, and Graafian follicle numbers in offspring ovaries (both HF/C and HF/HF). Expression levels of genes involved in apoptosis (FoXO3a), follicular growth and development (Gdf9), and circadian rhythms generation (Clock and Bmal1) were elevated in the ovaries of HF/C and HF/HF offspring, while expression of the circadian clock genes Cry1 and Per1 were lower in HF/HF ovaries. Conclusion(s) Maternal obesity during pregnancy has long-term deleterious consequences on follicular growth and development in the adult offspring ovaries, which may impact their reproductive potential.

Background: 'Omics' high-throughput analyses, including genomics, epigenomics, transcriptomics, proteomics and metabolomics, are widely applied in human endometrial studies. Analysis of endometrial transcriptome patterns in physiological and pathophysiological conditions has been to date the most commonly applied 'omics' technique in human endometrium. As the technologies improve, proteomics holds the next big promise for this field. The 'omics' technologies have undoubtedly advanced our knowledge of human endometrium in relation to fertility and different diseases. Nevertheless, the challenges arising fromthe vast amount of data generated and the broad variation of 'omics' profiling according to different environments and stimuli make it difficult to assess the validity, reproducibility and interpretation of such 'omics' data.With the expansion of 'omics' analyses in the study of the endometrium, there is a growing need to develop guidelines for the design of studies, and the analysis and interpretation of 'omics' data. methods: Systematic review of the literature in PubMed, and references from relevant articles were investigated up to March 2013. results: The current review aims to provide guidelines for future 'omics' studies on human endometrium, together with a summary of the status and trends, promise and shortcomings in the high-throughput technologies. In addition, the approaches presented here can be adapted to other areas of high-throughput 'omics' studies. conclusion: A highly rigorous approach to future studies, based on the guidelines provided here, is a prerequisite for obtaining data on biological systems which can be shared among researchers worldwide and will ultimately be of clinical benefit. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

The great majority of human oocytes is destined to undergo atresia. Only follicles able to respond to stimulation by follicle-stimulating hormone (FSH) will enter the final stage of development and ovulate. While the role of FSH in early follicle development is unclear, late follicular development is FSH-dependent. FSH levels increase during the luteo-follicular transition and give rise to continued growth of a cohort of follicles. In the normo-ovulatory cycle, one follicle achieves a diameter of >8 mm and produces high concentrations of estradiol. In response to negative feedback from rising estradiol and inhibin levels, FSH levels fall in the late follicle phase. The dominant follicle has increased sensitivity to the falling FSH levels and continues growing. Follicles that initiate the latter stages of development after FSH levels begin to fall undergo atresia. The duration of this FSH window during which FSH levels are above the threshold required to stimulate ongoing development determines the number of follicles that can develop to the pre-ovulatory stage. Recognition of this concept has resulted in new approaches in ovulation induction treatment and ovarian hyperstimulation therapy for in vitro fertilization (IVF).

Objective: To investigate relations between dose of GnRH antagonist and follicular phase characteristics. Design: Randomized controlled multicenter trial. Setting: Tertiary referral fertility centers. Patient(s): Three hundred and twenty-nine IVF patients. Intervention(s): Ovarian stimulation for IVF with recombinant FSH starting on cycle day 2. From cycle day 7 onwards, cotreatment was provided with 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0 mg/d GnRH antagonist. Main Outcome Measure(s): Number of follicles, total follicular surface area, gonadotropin, and serum steroid concentrations. Result(s): In 311 patients, similar follicular growth was observed in all treatment groups. FSH levels increased during the follicular phase. Late follicular phase LH, androstenedione (AD), and E 2 levels showed a GnRH antagonist dose-related decrease ( P 2 levels correlated with total follicular surface area, AD, LH, and FSH (all P 2 levels. Conclusion(s): Follicular growth was unaffected by the dose of GnRH antagonist. A rise in follicular phase FSH serum concentrations during the follicular phase, largely related to exogenous FSH, enabled ongoing follicular growth in all treatment groups. The effect of GnRH antagonist on late follicular phase E 2 levels could not be exclusively attributed to suppression of LH.

Ovarian stimulation protocols applied world-wide today may take several weeks per stimulated cycle, are complex, expensive and associated with a certain degree of risk. Gonadotrophin preparations are administered to stimulate multiple follicle development usually at daily doses of 150–300 IU (and sometimes higher) for one to three weeks. A premature rise in serum luteinizing hormone (LH) levels, generally believed to be detrimental for in vitro fertilization (IVF) outcome, is prevented by the co-administration of a gonadotrophin-releasing hormone (GnRH) agonist. This is usually initiated in the preceding cycle to allow for pituitary downregulation to occur before the initiation of exogenous follicle-stimulating hormone (FSH). Finally, the resumption of oocyte meiotic maturation is induced by a single bolus injection of human chorionic gonadotrophin (hCG) during the late follicular phase. In addition, the corpus luteum is supported during the luteal phase by repeated administration of hCG or supplemented by exogenous progesterone.

Objective: To establish the influence of fetal behavior states on venous and arterial pulmonary blood flow velocity waveforms in the normally developing term fetus. Methods: The relation between venous and arterial pulmonary blood flow velocity waveforms and fetal behavior states was investigated in 18 normal term fetuses. Recordings of the venous pulmonary blood flow velocity waveforms were obtained just proximal to the entrance in the left atrium, and the arterial pulmonary blood flow velocity waveforms were taken from the most proximal branch of the pulmonary artery in the same lung using color Doppler imaging. Time-averaged peak systolic, peak diastolic, and end-diastolic flow velocity; peak systolic to peak diastolic ratio; pulsatility index; and fetal heart rate were calculated from both venous and arterial Doppler recordings obtained during behavior states 1F (quiet sleep) and 2F (active sleep). Fetal behavior states were determined from combined recordings of fetal eye and body movements. Results: Recordings of sufficient quality for analysis were obtained from ten fetuses. Venous pulmonary blood flow velocity waveforms demonstrated a statistically significant increase in time-averaged peak diastolic and end-diastolic velocity during fetal behavior state 2F. No behavior-state-related changes were observed for the arterial pulmonary blood flow velocity waveform. Conclusion: The data suggest an increased pressure gradient between the pulmonary venous system and the left atrium during behavior state 2F. Flow velocity waveforms from the proximal arterial pulmonary branch are independent of behavioral state.

Accurate diagnosis of deep venous thrombosis (DVT) and pulmonary embolism (PE) is required because treatment can be life-saving, while inappropriate anticoagulation exposes the mother and fetus to haemorrhage and other hazards. Clinicians must be aware of which patients are at risk because DVT is frequently asymptomatic. Clinical diagnosis is unreliable for DVT and PE so objective tests are required. Venography is the gold standard test for DVT but is invasive and has been superseded by less invasive tests such as duplex ultrasound which is now the first-line investigation in pregnancy. However, where doubt remains, venography, CT and MRI have a role. Ventilation-perfusion scanning is the pivotal test for PE in pregnancy, and need not expose the fetus to excess radiation. If the result is unclear deep venous ultrasound can guide management of suspected PE, thus avoiding pulmonary angiography, the invasive gold standard test.

Objective To investigate gestational and postural changes in diameter and blood flow in the proximal deep leg veins during pregnancy. Design A longitudinal, prospective observational study. Setting The ultrasound department of a teaching maternity hospital. Population Twenty-four healthy women with uncomplicated singleton pregnancies. Methods Real-time and duplex Doppler ultrasound assessments of the vessel diameter, flow velocity and respiratory flow fluctuation in the proximal deep leg veins of women serially measured from the first trimester of pregnancy to six weeks postnatally. Main outcome measures The effects of increasing gestation and the adoption of the left lateral position on the above parameters. Results An increase in vessel diameter and a fall in flow velocity with increasing gestation was observed. However, no change in venous flow variation was observed. Delivery had reverse effects. Flow velocity was slower in the left than the right legs, but on adoption of the left lateral position an increase in flow velocity and venous flow variation was observed in both legs during pregnancy. Conclusions These data are consistent with the observed increase in incidence and pattern of deep venous thrombosis in pregnancy and may aid interpretation of duplex Doppler ultrasound examinations for deep venous thrombosis in pregnancy. Postural changes should be part of this evaluation. The gravid uterus may not be the sole cause for postural changes in deep venous flow velocity.

BACKGROUND Oocyte number is established early in life before a gradual loss of this ovarian reserve during reproductive life until oocyte availability becomes limiting at the menopause. Although there is a large genetic component to the ovarian reserve achieved before birth, other influences including the maternal endocrine and nutritional milieu, and environmental factors may represent important developmental determinants. Environmental and nutritional factors may also modify the downward trajectory of ovarian reserve in adult life. The combination of these early and later life influences has the potential to lead to diminished ovarian reserve, compromising fertility in later reproductive years and altering age at natural menopause. METHODS Literature searches of the ISI Web of Knowledge database were carried out using the main terms 'ovarian reserve' and 'menopause AND age' in conjunction with a range of other terms encompassing a variety of factors with potential effects on ovarian reserve. The various searches were inspected manually and the relevant papers selected for critical analysis and interpretation. RESULTS Evidence was identified supporting the view that elevated prenatal androgens have an adverse effect on the early establishment of ovarian reserve, although the implications for ovarian reserve in the polycystic ovary syndrome (which may also be programmed through prenatal androgen exposure) remain uncertain. Recent evidence is cited suggesting that effects of maternal nutrient restriction on ovarian reserve may also involve changes in prenatal androgen exposure. A general rationale is developed through examination of evidence which emphasizes the roles of the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER) systems in ovarian reserve modulation. Because of their similarity to the natural ligands, many environmental compounds have the ability to bind to these receptors (albeit at lower affinities) and thereby have the potential to influence either the initial setting of ovarian reserve during development or the trajectory of ovarian reserve during adult life. For example, exposure to compounds in cigarette smoke may accelerate loss of ovarian reserve in smokers leading to diminished ovarian reserve, earlier age at last child and earlier menopause. Socioenocomic factors are clearly associated with age at natural menopause, with correlations with economic status and education level. However, such effects in western societies are in general small, and the underlying mechanisms remain unclear. CONCLUSIONS Exposure to many environmental compounds, particularly to those that leach from plastics and other synthetic materials, is commonplace in modern societies to the extent that many are found at measurable concentrations in body fluids within most of the population. Relating fluid levels of individual compounds to parameters reflecting ovarian reserve in selected populations appears to be an effective way forward and, indeed, some early-stage findings do show some cause for concern. There is a pressing need for the development of practical advice enabling women to minimize their intake of AHR/ER ligands, perhaps through dietary/cosmetic choices or improved food packaging.

Implantation requires highly orchestrated interactions between the developing embryo and maternal endometrium. The association between abnormal implantation and reproductive failure is evident, both in normal pregnancy and in assisted reproduction patients. Failure of implantation is the pregnancy rate-limiting step in assisted reproduction, but, as yet, empirical interventions have largely failed to address this problem. Better understanding of the mechanisms underlying human embryo-endometrium signalling is a prerequisite for the further improvement of assisted reproduction outcomes and the development of effective interventions to prevent early pregnancy loss. Studying human embryo implantation is challenging since in-vivo experiments are impractical and unethical, and studies in animal models do not always translate well to humans. However, in recent years in-vitro models have been shown to provide a promising way forward. This review discusses the principal models used to study early human embryo development and initial stages of implantation in vitro. While each model has limitations, exploiting these models will improve understanding of the molecular mechanisms and embryo-endometrium cross-talk at the early implantation site. They provide valuable tools to study early embryo development and pathophysiology of reproductive disorders and have revealed novel disease mechanisms such as the role of epigenetic modifications in recurrent miscarriage.

Although embryo implantation is essential for human survival, it remains an enigmatic biological phenomenon. Following fertilization, the resulting blastocyst must signal its presence to the mother, attach to the luminal epithelium of the endometrium and embed into the decidualising stroma. Failure to do so results in infertility, which affects around 9% of women. Subsequent placental development requires remodelling of maternal blood vessels by trophoblast cells from the placenta, that invade deep into the decidua. Failure in these very early stages can compromise fetal development, resulting in diseases of pregnancy such as intrauterine growth restriction or pre-eclampsia which can also impact on health in adulthood. Abnormal implantation therefore constitutes a significant disease burden in humans. Although we have known for many years that successful implantation requires an embryo that is competent to implant and an endometrium that is receptive, the molecular basis of these processes remains poorly understood. Our inability to identify implantation-competent embryos or to diagnose/treat the non-receptive endometrium therefore limits our ability to intervene through assisted reproduction techniques. This Implantation Symposium aims to review recent exciting developments in our understanding of the biology of early implantation and to highlight the rapid progress being made to translate these into improved diagnosis and treatment. Although embryo implantation is essential for human survival, it remains an enigmatic biological phenomenon. Following fertilization, the resulting blastocyst must signal its presence to the mother, attach to the luminal epithelium of the endometrium and embed into the decidualising stroma. Failure to do so results in infertility, which affects around 9% of women. Subsequent placental development requires remodelling of maternal blood vessels by trophoblast cells that invade deep into the decidua. Failure in these very early stages can compromise fetal development, resulting in diseases of pregnancy such as intrauterine growth restriction or pre-eclampsia which can also impact on health in adulthood. Abnormal implantation therefore constitutes a significant disease burden in humans. Although we have known for many years that successful implantation requires an embryo that is competent to implant and an endometrium that is receptive, the molecular basis of these processes remains poorly understood. Our inability to identify implantation-competent embryos or to diagnose/treat the non-receptive endometrium therefore limits our ability to intervene through assisted reproduction techniques. This Implantation Symposium aims to review recent exciting developments in our understanding of the biology of early implantation and to highlight the rapid progress being made to translate these into improved diagnosis and treatment.

BACKGROUND Mechanisms underlying early reproductive loss in the human are beginning to be elucidated. The migratory and invasive capacity of human endometrial stromal cells (ESCs) is increasingly recognized to contribute to the intense tissue remodelling associated with embryo implantation, trophoblast invasion and endometrial regeneration. In this review, we examine the signals and mechanisms that control ESC migration and invasion and assess how deregulation of these cell functions contributes to common reproductive disorders. METHODS The PubMed database was searched for publications on motility and invasiveness of human ESCs in normal endometrial function and in reproductive disorders including implantation failure, recurrent pregnancy loss (RPL), endometriosis and adenomyosis, covering the period 2000-2012. RESULTS Increasing evidence suggests that implantation failure and RPL involve abnormal migratory responses of decidualizing ESCs to embryo and trophoblast signals. Numerous reports indicate that endometriosis, as well as adenomyosis, is associated with increased basal and stimulated invasiveness of ESCs and their progenitor cells, suggesting a link between a heightened menstrual repair response and the formation of ectopic implants. Migration and invasiveness of ESCs are controlled by a complex array of hormones, growth factors, chemokines and inflammatory mediators, and involve signalling through Rho GTPases, phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways. CONCLUSIONS Novel concepts are extending our understanding of the key functions of ESCs in effecting tissue repair imposed by cyclic menstruation and parturition. Migration of decidualizing ESCs also serves to support blastocyst implantation and embryo selection through discriminate motile responses directed by embryo quality. Targeting regulatory molecules holds promise for developing new strategies for the treatment of reproductive disorders such as endometriosis and recurrent miscarriage; and harnessing the migratory capacity of progenitor mesenchymal stem cells in the endometrium may offer new opportunities in regenerative medicine.

Purpose of review: implantation is an essential step in the development of a pregnancy, but often fails in humans. In assisted reproductive technologies, implantation failure continues to impair treatment outcomes, with distressing results for patients and physicians. Recent findings: morphokinetics, comprehensive chromosome screening, and the analysis of embryo-derived products detectable in spent culture media offer new means of assessing embryo viability. However, all await validation in randomized controlled trials. Genomic, transcriptomic, and secretomic technologies are similarly being exploited to define specific biomarkers of endometrial receptivity with the aim of identifying novel therapeutic interventions. However, to date no single, clinically relevant molecular marker capable of indicating endometrial receptivity has been reported. Recent work continues to describe the key signalling pathways which result in acceptance or rejection of the implanting embryo. In-vitro studies have revealed that the decidualized endometrium plays an important role in natural embryo selection, which could change our understanding of the aetiology and treatment of reproductive failure. Summary: recent developments in analytical techniques have initiated a search for biomarkers of embryo quality and endometrial receptivity, and in-vitro studies have revealed novel roles for the decidualized endometrium as a biosensor of embryo quality

For anovulatory women who fail to ovulate or conceive with clomiphene citrate, gonadotrophin ovulation induction has been the conventional second-line therapy. The aim of treatment is to achieve monofollicular development and ovulation. This differs fundamentally from the aim of ovarian stimulation for IVF, in which multiple follicular development is the goal. The small therapeutic window of ovulation induction requires a rigorous approach to monitoring, and willingness to cancel the cycle when multiple follicle development occurs. The two most widely used approaches are the low-dose step-up and the step-down protocols. While the latter more closely mimics the normo-ovulatory cycle, outcomes are similar. For safety reasons, the step-down protocol has not been widely adopted. The principle risks of ovulation induction are ovarian hyperstimulation syndrome and multiple pregnancy. There is a need to individualize treatment if outcomes are to be optimized. The role of adjuvant therapies remains unclear. However, prediction models based on initial screening parameters enable the optimal dose of FSH to be determined, and the identification of patients with a poor prognosis for successful treatment.

Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration. Among local growth factors known to be present at the time of implantation, heparin-binding epidermal growth factor-like growth factor (HB-EGF) triggered chemotaxis (directed locomotion), whereas platelet-derived growth factor (PDGF)-BB elicited both chemotaxis and chemokinesis (non-directed locomotion) of endometrial stromal cells. Supernatants of the trophoblast cell line AC-1M88 and of first trimester villous explant cultures stimulated chemotaxis but not chemokinesis. Proteome profiling for cytokines and angiogenesis factors revealed neither PDGF-BB nor HB-EGF in conditioned media from trophoblast cells or villous explants, while placental growth factor, vascular endothelial growth factor and PDGF-AA were identified as prominent secretory products. Among these, only PDGF-AA triggered endometrial stromal cell chemotaxis. Neutralization of PDGF-AA in trophoblast conditioned media, however, did not diminish chemoattractant activity, suggesting the presence of additional trophoblast-derived chemotactic factors. Pathway inhibitor studies revealed ERK1/2, PI3 kinase/Akt and p38 signaling as relevant for chemotactic motility, whereas chemokinesis depended primarily on PI3 kinase/Akt activation. Both chemotaxis and chemokinesis were stimulated upon inhibition of Rho-associated, coiled-coil containing protein kinase. The chemotactic response to trophoblast secretions was not blunted by inhibition of isolated signaling cascades, indicating activation of overlapping pathways in trophoblast-endometrial communication. In conclusion, trophoblast signals attract endometrial stromal cells, while PDGF-BB and HB-EGF, although not identified as trophoblast-derived, are local growth factors that may serve to fine-tune directed and non-directed migration at the implantation site.

study question: what is the impact of initiating GnRH antagonist co-treatment for in vitro fertilization (IVF) on cycle day (CD) 2 compared with CD 6 on live birth rate (LBR) per started cycle and on the cumulative live birth rate (CLBR)? Summary answer: early initiation of GnRH antagonist does not appear to improve clinical outcomes of IVF compared with midfollicular initiation. What is known already: during ovarian stimulation for IVF, GnRH antagonist co-treatment is usually administered from the midfollicular phase onwards. Earlier initiation may improve the follicular phase hormonal milieu and therefore overall clinical outcomes. Study design, size, duration: this open-label, multicentre randomized controlled trial was conducted between September 2009 and July 2011. A web-based program was used for randomization and 617 IVF-intracytoplasmic sperm injection (ICSI) patients were included. Participants/materials, setting, methods: recombinant FSH (150–225 IU) was administered daily from CD 2 onwards in both groups. The study group (CD2; n = 308) started GnRH antagonist co-treatment on CD 2, whereas the control group (CD6; n = 309) started on CD 6. Main results and the role of chance: there were no significant differences in clinical outcomes between the two groups. A non-significant trend towards a higher LBR per started cycle and CLBR was observed in the CD6 group compared with the CD2 group (LBR: 24.0 versus 21.5%, P = 0.5; CLBR: 29.9 versus 26.7%, P = 0.6). Limitations, reasons for caution: the study was terminated prematurely because no significant difference was observed in clinical outcomes after 617 inclusions. A much larger study population would be needed to detect a small significant difference in favour of either study arm, which raises the question of whether this would be relevant for clinical practice. Wider implications of the findings: the present study shows that the additional treatment burden and costs of starting GnRH antagonist on CD 2 instead of on CD 6 are not justified, as early initiation of GnRH antagonist does not improve LBRs. Study funding/competing interests: this study was partially supported by a grant from Merck Serono. O.H., M.J.C.E, A.V., P.A.D., R.E.B., G.J.E.O., C.A.G.H., G.C.D.M., H.J.V., P.F.M.H. and A.B. have nothing to declare. F.J.B. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gedeon Richter, Merck Serono, MSD and Roche. B.J.C. has received fees and grant support from the following companies (in alphabetic order): Ferring, Merck Serono and MSD. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, Ferring, Merck Serono and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, MSD, Merck Serono, Organon, Schering Plough and Serono. N.S.M. has received fees and grant support from the following companies (in alphabetic order): Anecova, Ferring, Merck Serono, MSD, Organon and Serono

Changing the way in which successful IVF treatment is defined offers a tool to improve efficacy while reducing costs and complications of treatment. Crucial to this paradigm shift is the move away from considering outcomes in terms of the single IVF cycle, and towards the started IVF treatment as a whole. We propose the most informative end-point of success in IVF to be the term singleton birth rate per started IVF treatment (or per given time period) in the overall context of patient discomfort, complications and costs. These end-points are important not only for patients, but also for clinicians, health economists and policy makers. Such an approach would encourage the development of patient-friendly and cheaper stimulation protocols with less stress, discomfort and side effects. The combination of mild ovarian stimulation with single embryo transfer may provide the same overall pregnancy rate per total IVF treatment, achieved in the same amount of time for similar direct costs, but with reduced patient stress and discomfort, and the near complete elimination of multiple pregnancies. This would offer major health and indirect cost benefits. If IVF success rates were to be expressed in terms of delivery of a term single baby per IVF treatment (or in a given treatment period), the introduction of single embryo transfer on a large scale would be facilitated.

Pregnancy limits the therapeutic options for managing thrombocytopenia which occurs in 5% of patients on heparin. We describe a case of extensive thromboembolism associated with antithrombin (AT) deficiency complicated by thrombocytopenia which resolved when low-molecular-weight heparin was instituted. A primigravid woman presented at 11 weeks gestation with bilateral femoral occlusive thrombi extending above the renal veins. Investigations revealed AT deficiency, thrombocytopenia and renal infarction. After low-molecular-weight heparin was substituted for unfractionated heparin, the thrombocytopenia resolved and although the pregnancy was lost, the patient made a full recovery.

Implantation requires highly orchestrated interactions between the developing embryo and maternal endometrium. The association between abnormal implantation and reproductive failure is evident, both in normal pregnancy and in assisted reproduction patients. Failure of implantation is the pregnancy rate-limiting step in assisted reproduction, but, as yet, empirical interventions have largely failed to address this problem. Better understanding of the mechanisms underlying human embryo-endometrium signalling is a prerequisite for the further improvement of assisted reproduction outcomes and the development of effective interventions to prevent early pregnancy loss. Studying human embryo implantation is challenging since in-vivo experiments are impractical and unethical, and studies in animal models do not always translate well to humans. However, in recent years in-vitro models have been shown to provide a promising way forward. This review discusses the principal models used to study early human embryo development and initial stages of implantation in vitro. While each model has limitations, exploiting these models will improve understanding of the molecular mechanisms and embryo-endometrium cross-talk at the early implantation site. They provide valuable tools to study early embryo development and pathophysiology of reproductive disorders and have revealed novel disease mechanisms such as the role of epigenetic modifications in recurrent miscarriage.

Background Frozen thawed embryo transfer (FET) is a cost- effective adjunct to IVF or IVF-ICSI treatment. In order to optimize treatment outcome, FET should be carried out during a period of optimal endometrial receptivity. To optimize implantation several methods for endometrium preparation have been proposed. In natural cycle FET (NC-FET), the endometrium develops under endogenous hormonal stimulation. The development of the dominant follicle and endometrium is monitored by ultrasound and FET is timed after triggering ovulation induction or determination of the spontaneous LH surge. In an artificial cycle FET (AC-FET) estrogens and progesterone are administered to prepare the endometrium for implantation. While the currently available data show no significant difference in pregnancy rates between these methods, well designed randomized controlled trials are lacking. Moreover there is little literature on difference in cancellation rates, cost-efficiency and adverse events. Methods and design In this randomized, multi-centre, non-inferiority trial we aim to test the hypothesis that there is no significant difference in live birth rates between patients undergoing NC-FET versus AC-FET. The primary outcome will be live birth rate per embryo transfer procedure. Secondary outcomes will be ongoing and clinical pregnancy rate, cancellation rate, (serious) adverse events and cost-efficiency. Based on a live birth rate of 20% and a minimal clinical important difference of 7,5% (one-sided alpha 2,5%, beta 20%) a total of 1150 patients will be needed. Analyzes will be performed using both per protocol as well as intention to treat analyses. Discussion This prospective, randomized, non –inferiority trial aims to address the hypothesis that there is no significant difference in live birth rates between patients undergoing NC-FET versus patients undergoing AC-FET. Moreover it addresses cost-efficiency as well as the perceived burden of both treatments. Trial register Netherlands trial register (NTR): 1586

Despite expanding global experience with advanced reproductive technologies, the majority of IVF attempts do not result in a successful pregnancy, foremost as a result of implantation failure. The process of embryo implantation, a remarkably dynamic and precisely controlled molecular and cellular event, appears inefficient in humans and is poorly understood. However, insights gained from clinical implantation failure, early pregnancy loss, and emerging techologies that enable molecular interrogation of endometrial–embryo interactions are unravelling this major limiting step in human reproduction. We review current molecular concepts thought to underlie implantation failure, consider the contribution of embryonic and endometrial factors, and discuss the clinical value of putative markers of impaired endometrial receptivity. Finally we highlight the nature of the dialogue between the maternal endometrium and the implanting embryo and discuss the concept of natural embryo selection. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.

LH surges are the start of a period of optimal endometrial receptivity. Missing these surges in an unstimulated-cycle frozen-thawed embryo transfer (FET) based on ultrasound alone might lead to incorrect timing of embryo transfer. This prospective, non-randomized trial established the incidence and effect of spontaneous LH surges on ongoing pregnancy rates and assessed the use of ultrasound without LH monitoring in planning FET. All patients undergoing unstimulated-cycle FET in the study centre over a 2-year period were included in this analysis (n = 233). All patients had regular menstrual cycles. Serum LH analysis took place before human chorionic gonadotrophin administration. The main outcome measure was ongoing pregnancy. LH surges occurred in over half of patients. Overall pregnancy rate was 34.3%. Relative risks for ongoing pregnancy for cycles with or without a spontaneous LH surge were not significantly different (ongoing pregnancy rate 33.4% versus 34.8%; RR 1.02, 95% CI 0.7-1.5). Based on these results, it was concluded that LH surges >= 10 IU/l occurred in over 50% of patients, but LH surges demonstrated no significant effect on pregnancy rates. Single LH determination prior to ovulation induction in unstimulated-cycle FET does not seem to have added clinical value. (C) 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.