Endometrial Receptivity Testing and Therapy in Assisted Reproductive Treatment.

Assisted reproductive treatment (ART) gave numerous couples the chance to have their biological child. Improvement in laboratory and culture conditions allows for selection of embryos with the best developmental potential, although replacement of these top-quality embryos does not, however, guarantee reproductive success. Endometrial receptivity is essential for pregnancy establishment and may be the limiting factor for the observed pregnancy rates with ART. Multiple modalities have been in use to assess endometrial receptivity, with ultrasound assessment of the endometrial morphology most commonly used due to its noninvasive nature and availability. Utilization of various "omics" increases our understanding of endometrial receptivity and selectivity; however, significantly more work is required to develop clinically relevant and validated tests of endometrial receptivity and treatments which could improve a suboptimal endometrial milieu. Current evidence for and against use of various tests of endometrial receptivity in women undergoing ART is presented in this article.

Efficacy of Dehydroepiandrosterone (DHEA) to overcome the effect of ovarian ageing (DITTO): A proof of principle double blinded randomized placebo controlled trial.

OBJECTIVE: To evaluate the effect of DHEA supplementation on In-Vitro Fertilisation (IVF) outcome as assessed by ovarian response, oocyte developmental competence and live birth rates in women predicted to have poor ovarian reserve (OR). The feasibility of conducting a large trial is also assessed by evaluating the recruitment rates and compliance of the recruited participants with DHEA/placebo intake and follow-up rates. STUDY DESIGN: A single centre, double blinded, placebo controlled, randomized trial was performed over two years with 60 women undergoing in-vitro fertilisation (IVF). Subjects were randomized, based on a computer-generated pseudo-random code to receive either DHEA or placebo with both capsules having similar colour, size and appearance. 60 women with poor OR based on antral follicle count or anti-Mullerian hormone thresholds undergoing IVF were recruited. They were randomised to receive DHEA 75mg/day or placebo for at-least 12 weeks before starting ovarian stimulation. They had long protocol using hMG 300 IU/day. Data analysed by "intention to treat". Ovarian response, live birth rates and molecular markers of oocyte quality were compared between the study and control groups. RESULTS: The recruitment rate was 39% (60/154). A total of 52 participants (27 versus 25 in the study and placebo groups) were included in the final analysis after excluding eight. While the mean (standard deviation) DHEA levels were similar at recruitment (9.4 (5) versus 7.5 (2.4) ng/ml; P=0.1), the DHEA levels at pre-stimulation were higher in the study group than in the controls (16.3 (5.8) versus 11.1 (4.5) ng/ml; P<0.01). The number (median, range) of oocytes retrieved (4, 0-18 versus 4, 0-15 respectively; P=0.54) and live birth rates (7/27, 26% versus 8/25, 32% respectively; RR (95% CI): 0.74 (0.22-2.48) and mRNA expression of developmental biomarkers in granulosa and cumulus cells were similar between the groups. CONCLUSION: Pre-treatment DHEA supplementation, albeit statistical power in this study is low, did not improve the response to controlled ovarian hyperstimulation or oocyte quality or live birth rates during IVF treatment with long protocol in women predicted to have poor OR.

Deregulation of the endometrial stromal cell secretome precedes embryo implantation failure.

STUDY QUESTION: Is implantation failure following ART associated with a perturbed decidual response in endometrial stromal cells (EnSCs)? SUMMARY ANSWER: Dynamic changes in the secretome of decidualizing EnSCs underpin the transition of a hostile to a supportive endometrial microenvironment for embryo implantation; perturbation in this transitional pathway prior to ART is associated with implantation failure. WHAT IS KNOWN ALREADY: Implantation is the rate-limiting step in ART, although the contribution of an aberrant endometrial microenvironment in IVF failure remains ill defined. STUDY DESIGN, SIZE, DURATION: In vitro characterization of the temporal changes in the decidual response of primary EnSCs isolated prior to a successful or failed ART cycle. An analysis of embryo responses to secreted cues from undifferentiated and decidualizing EnSCs was performed. The primary clinical outcome of the study was a positive urinary pregnancy test 14 days after embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS: Primary EnSCs were isolated from endometrial biopsies obtained prior to IVF treatment and cryopreserved. EnSCs from 10 pregnant and 10 non-pregnant patients were then thawed, expanded in culture, subjected to clonogenic assays, and decidualized for either 2 or 8 days. Transcript levels of decidual marker gene [prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP1) and 11ß-hydroxysteroid dehydrogenase (HSD11B1)] were analysed using real-time quantitative PCR and temporal secretome changes of 45 cytokines, chemokines and growth factors were measured by multiplex suspension bead immunoassay. The impact of the EnSC secretome on human blastocyst development was scored morphologically; and embryo secretions in response to EnSC cues analyzed by multiplex suspension bead immunoassay. MAIN RESULTS AND THE ROLE OF CHANCE: Clonogenicity and induction of decidual marker genes were comparable between EnSC cultures from pregnant and non-pregnant group groups (P > 0.05). Analysis of 23 secreted factors revealed that successful implantation was associated with co-ordinated secretome changes in decidualizing EnSCs, which were most pronounced on Day 2 of differentiation: 17 differentially secreted proteins on Day 2 of decidualization relative to undifferentiated (Day 0) EnSCs (P < 0.05); 11 differentially secreted proteins on Day 8 relative to Day 2 (P < 0.05); and eight differentially secreted proteins on Day 8 relative to Day 0 (P < 0.05). By contrast, failed implantation was associated with a disordered secretome response. Blastocyst development was compromised when cultured for 24 h in medium conditioned by undifferentiated EnSCs when compared to decidualizing EnSCs. Analysis of the embryo microdroplets revealed that human blastocysts mount a secretory cytokine response to soluble decidual factors produced during the early (Day 2) but not late phase (Day 8) of differentiation. The embryo responses to secreted factors from decidualizing EnSCs were comparable between the pregnant and non-pregnant group (P > 0.05). LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: Although this study uses primary EnSCs and human embryos, caution is warranted when extrapolating the results to the in vivo situation because of the correlative nature of the study and limited sample size. WIDER IMPLICATIONS OF THE FINDINGS: Our finding raises the prospect that endometrial analysis prior to ART could minimize the risk of treatment failure. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by funds from the Biomedical Research Unit in Reproductive Health, a joint initiative of the University Hospitals Coventry & Warwickshire NHS Trust and Warwick Medical School, the University of Nottingham and Nurture Fertility, and the National Medical Research Council, Singapore (NMRC/BNIG14NOV023), the "Instituut voor Innovatie door Wetenschap en Technologie" (IWT, Flanders, Belgium), the "Fonds voor Wetenschappelijk Onderzoek" (FWO, Flanders, Belgium) and the "Wetenschappelijk Fonds Willy Gepts" (WFWG, UZ Brussel). The authors have declared that no conflict of interest exists.

Endometrial spatio-temporal image correlation (STIC) and prediction of outcome following assisted reproductive treatment.

OBJECTIVE: The aim of this study was to correlate manual and spherical endometrial spatio-temporal image correlation (STIC) vascularity indices with assisted reproductive treatment (ART) outcomes. STUDY DESIGN: STIC ultrasound assessments of the endometrium were carried out at three time-points in 127 women in a prospective observational study. RESULTS: Biochemical pregnancy rate was 69% (88/127), with a biochemical and clinical pregnancy loss of 17%. Endometrial STIC vascularity indices in the assessed time-points did not differ between subjects who achieved a clinical pregnancy and those who did not (P>0.05). For first trimester miscarriage, minimal manual vascularization index (VI) at oocyte collection (cut-off value ≥0.7; sensitivity 80.0% and specificity 68.1%) demonstrated the highest area under the curve (AUC) of 0.8. CONCLUSION: In summary, STIC modality is not a useful tool to predict ART outcome, however manual STIC analysis of endometrial vascularity seems to be more accurate in predicting first trimester pregnancy loss.

4-D Assessment of Endometrial Vascularity Using Spatiotemporal Image Correlation: A Study Comparing Spherical Sampling and Whole-Tissue Analysis.

Our aim in the study described here was to assess the feasibility of spatiotemporal image correlation power Doppler quantification of the endometrium with two techniques: spherical samples and whole tissue. We scanned 51 women in the midluteal phase of the menstrual cycle: STIC assessment of the whole endometrium was not possible in 10% of cases, whereas spherical analysis was possible in all. The time taken for data set analysis was much longer for the whole endometrium compared with spherical analysis (1478.9 ± 291 s vs. 266.8 ± 39.3 s, p < 0.05). Intra-class correlation coefficients for the vascularization flow index (VFI) were similar for both methods. Volumetric vascularity indices were higher when spherical sampling was conducted. Significant cycle-to-cycle variability in the vascularity indices was present, with coefficients of variation exceeding 20% for both techniques. We found that STIC power Doppler quantification of the whole endometrium is possible in the majority of cases, however, it is time consuming and limited by significant cycle-to-cycle variability.

What exactly do we mean by 'recurrent implantation failure'? A systematic review and opinion.

Recurrent implantation failure (RIF) is an iatrogenic condition, being the result of repetitive unsuccessful cycles of IVF or intracytoplasmic sperm injection (ICSI) treatment. The aim of this review was to assess the definitions of RIF used in literature as well as suggest a uniform definition of this condition. A systematic search of MEDLINE, Embase and Cochrane Library was conducted. The most commonly stated definitions described RIF as 'three or more failed treatment cycles' or 'two or more failed cycles'. Other identified definitions were based solely on the number of embryos transferred in previous cycles or combined the number of previously failed cycles with the number of transferred embryos. Several other definitions were also identified. This review highlights the lack of uniformity of the definition of RIF. Based on the available literature and the expert opinion of the authors, RIF should be defined as the absence of implantation after two consecutive cycles of IVF, ICSI or frozen embryo replacement cycles where the cumulative number of transferred embryos was no less than four for cleavage-stage embryos and no less than two for blastocysts, with all embryos being of good quality and of appropriate developmental stage.

Influence of gain adjustment on 3-dimensional power Doppler indices and on spatiotemporal image correlation volumetric pulsatility indices using a flow phantom.

Spatiotemporal image correlation can be used to acquire 3-dimensional power Doppler information across a single cardiac cycle. Assessment and comparison of the systolic and diastolic components of the data sets allow measurement of the recently introduced "volumetric pulsatility index" (vPI) through algorithms comparable with those used in 2-dimensional Doppler waveform analysis. The vPI could potentially overcome the dependency on certain machine settings, such as power, color gain, pulse repetition frequency, and attenuation, since these factors would affect the power Doppler signal equally throughout the cardiac cycle. The objective of this study was to compare the effect of color gain on the vascularization index (VI), vascularization-flow index (VFI), and vPI using an in vitro flow phantom model. We separated gains into 3 bands: -8 to -1 (no noise), -1 to +5 (low noise), and +5 to +8 (obvious noise). The vPI was determined from the 3-dimensional VI or VFI using the formula vPI = (maximum - minimum)/mean. Using no-noise gains, we observed that although the VI and VFI increased linearly with gain, the vPI was substantially less dependent on this adjustment. The VI and VFI continued to increase linearly with gain, whereas the vPI decreased slightly using low-noise gains. When gain was increased above the lower limit of obvious noise (+5), the VI and VFI increased noticeably, and there were marked reductions in both vPI values. We conclude that the vPI is less affected by changes in color gain than the VI and VFI at no-noise gains.

Do dopamine agonists prevent or reduce the severity of ovarian hyperstimulation syndrome in women undergoing assisted reproduction? A systematic review and meta-analysis.

Controlled ovarian stimulation is an integral part of assisted reproduction treatment. This can result in ovarian hyperstimulation syndrome (OHSS), which is associated with significant morbidity and potentially mortality. Recent approaches to ovarian stimulation have led to a reduction in the prevalence of OHSS but it still occurs. Dopamine agonists (DAs) have been used with some success during the ovarian stimulation phase when there are early signs of OHSS but there is no consensus on when to start and stop treatment or on the dose and specific agonist to use. EMBRASE, MEDLINE and Cochrane were searched using the following terms: ovarian hyperstimulation syndrome, controlled ovarian hyperstimulation, DAs, cabergoline, quinagolide, bromocriptide, pergolide, talipexole, ropinirole and pranipexole. The search yielded 20 publications. In total 1646 woman were included and 914 received a DA. In the treated group 86 (9.41%) developed OHSS, compared with 157 (21.45%) in the non-treated group. Nine studies were suitable for meta-analysis. This showed a benefit to the use of DAs (RR 0.51 [0.33, 0.78], Chi² = 16.07). The use of DAs appears to be effective for the prevention of OHSS. DAs are useful but less effective for the treatment of OHSS. No conclusions can be made regarding the most effective drug, the optimal dose or the most appropriate drug regimen.

The social and psychological impact of endometriosis on women's lives: a critical narrative review.

BACKGROUND Endometriosis is a chronic condition affecting between 2 and 17% of women of reproductive age. Common symptoms are chronic pelvic pain, fatigue, congestive dysmenorrhoea, heavy menstrual bleeding and deep dyspareunia. Studies have demonstrated the considerable negative impact of this condition on women's quality of life (QoL), especially in the domains of pain and psychosocial functioning. The impact of endometriosis is likely to be exacerbated by the absence of an obvious cause and the likelihood of chronic, recurring symptoms. The aims of this paper are to review the current body of knowledge on the social and psychological impact of endometriosis on women's lives; to provide insights into women's experience of endometriosis; to provide a critical commentary on the current state of knowledge and to make recommendations for future psycho-social research. METHODS The review draws on a method of critical narrative synthesis to discuss a heterogeneous range of both quantitative and qualitative studies from several disciplines. This included a systematic search, a structured process for selecting and collecting data and a systematic thematic analysis of results. RESULTS A total of 42 papers were included in the review; 23 used quantitative methods, 16 used qualitative methods and 3 were mixed methods studies. The majority of papers came from just four countries: UK (10), Australia (8), Brazil (6) and the USA (5). Key categories of impact identified in the thematic analysis were diagnostic delay and uncertainty; 'QoL' and everyday activities; intimate relationships; planning for and having children; education and work; mental health and emotional wellbeing and medical management and self-management. CONCLUSIONS Endometriosis has a significant social and psychological impact on the lives of women across several domains. Many studies have methodological limitations and there are significant gaps in the literature especially in relation to a consideration of the impact on partners and children. We recommend additional prospective and longitudinal research utilizing mixed methods approaches and endometriosis-specific instruments to explore the impact of endometriosis in more diverse populations and settings. Furthermore, there is an urgent need to develop and evaluate interventions for supporting women and partners living with this chronic and often debilitating condition.

Obstetric outcome in donor oocyte pregnancies: a matched-pair analysis.

BACKGROUND: To investigate the obstetrical and perinatal impact of oocyte donation, a cohort of women who conceived after OD was compared with a matched control group of women who became pregnant through in vitro fertilisation with autologous oocytes (AO). METHODS: A matched-pair analysis has been performed at the Centre for Reproductive Medicine of the UZ Brussel, Dutch speaking Free University of Brussel. A total of 410 pregnancies resulted in birth beyond 20 weeks of gestation occurring over a period of 10 years, including 205 oocyte donation pregnancies and 205 ICSI pregnancies with autologous oocytes (AO). Patients in the OD group were matched on a one-to-one basis with the AO group in terms of age, ethnicity, parity and plurality. Matched groups were compared using paired t-tests for continuous variables and McNemar test for categorical variables. A conditional logistic regression analyses was performed adjusting for paternal age, age of the oocyte donor, number of embryos transferred, and singleton/twin pregnancy. RESULTS: Oocyte donation was associated with an increased risk of pregnancy induced hypertension (PIH) (matched OR: 1.502 CI: 1.024-2.204), and first trimester bleeding (matched OR: 1.493 CI: 1.036-2.15). No differences were observed between the two matched groups with regard to gestational age, mean birth weight and length, head circumference and Apgar scores. CONCLUSIONS: Oocyte donation is associated with an increased risk for PIH and first trimester bleeding independent of the recipients' age, parity and plurality, and independent of the age of the donor or the partner. However, oocyte donation has no impact on the overall perinatal outcome.

Administration of GnRH antagonists in case of elevated progesterone at initiation of the cycle: a prospective cohort study.

In patients with elevated progesterone levels at the beginning of an ART (assisted reproductive technology) treatment cycle, the outcome of controlled ovarian stimulation (COS) may be inappropriate. A prospective cohort study was conducted to investigate whether the administration of a GnRH antagonist prior to the start of COS in these patients could lead to a similar pregnancy rate than in case of normal progesterone. Four hundred eighty-four patients were included in this study between February 2009 and July 2009. COS was initiated on day 2 of the cycle when estradiol (E(2)) and progesterone (P) serum levels were normal (E(2) ≤ 80 pg/ml, P ≤ 1.5 ng/ml; 'normal P group'). When serum progesterone was > 1.5 ng/ml on day 2 of the cycle ('high P group'), stimulation was not initiated, instead a GnRH antagonist was administered at a dosage of 0.25 mg during three consecutive days. In both study groups, efficient ovarian stimulation ensued and pregnancy rates did not diverge significantly. The results of the study led us to conclude that administration of a GnRH antagonist normalizes progesterone levels in those cases with isolated elevated serum progesterone levels at the start of the ART treatment cycle, and that this pretreatment is compatible with adequate ovarian stimulation and results in acceptable pregnancy rates.