Luk Rombauts

Priorities for Endometriosis Research: Recommendations From an International Consensus Workshop

Endometriosis is an estrogen-dependent disorder where endometrial tissue forms lesions outside the uterus. Endometriosis affects an estimated 10% of women in the reproductive-age group, rising to 30% to 50% in patients with infertility and/or pain, with significant impact on their physical, mental, and social well-being. There is no known cure, and most current medical treatments are not suitable long term due to their side-effect profiles. Endometriosis has an estimated annual cost in the United States of

Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence

18.8 to

Analysis of Fertility-Related Soluble Mediators in Human Uterine Fluid Identifies VEGF as a Key Regulator of Embryo Implantation

22 billion (2002 figures). Although endometriosis was first described more than 100 years ago, current knowledge of its pathogenesis, spontaneous evolution, and the pathophysiology of the related infertility and pelvic pain, remain unclear. A consensus workshop was convened following the 10th World Congress on Endometriosis to establish recommendations for priorities in endometriosis research. One major issue identified as impacting on the capacity to undertake endometriosis research is the need for multidisciplinary expertise. A total of 25 recommendations for research have been developed, grouped under 5 subheadings: (1) diagnosis, (2) classification and prognosis, (3) treatment and outcome, (4) epidemiology, and (5) pathophysiology. Endometriosis research is underfunded relative to other diseases with high health care burdens. This may be due to the practical difficulties of developing competitive research proposals on a complex and poorly understood disease, which affects only women. By producing this consensus international research priorities statement it is the hope of the workshop participants that researchers will be encouraged to develop new interdisciplinary research proposals that will attract increased funding support for work on endometriosis.

2D-DiGE analysis of the human endometrial secretome reveals differences between receptive and nonreceptive states in fertile and infertile women.

BACKGROUND Improvements in vitrification now make frozen embryo transfers (FETs) a viable alternative to fresh embryo transfer, with reports from observational studies and randomized controlled trials suggesting that: (i) the endometrium in stimulated cycles is not optimally prepared for implantation; (ii) pregnancy rates are increased following FET and (iii) perinatal outcomes are less affected after FET. METHODS This review integrates and discusses the available clinical and scientific evidence supporting embryo transfer in a natural cycle. RESULTS Laboratory-based studies demonstrate morphological and molecular changes to the endometrium and reduced responsiveness of the endometrium to hCG, resulting from controlled ovarian stimulation. The literature demonstrates reduced endometrial receptivity in controlled ovarian stimulation cycles and supports the clinical observations that FET reduces the risk of ovarian hyperstimulation syndrome and improves outcomes for both the mother and baby. CONCLUSIONS This review provides the basis for an evidence-based approach towards changes in routine IVF, which may ultimately result in higher delivery rates of healthier term babies.

Recruitment of follicles by recombinant human follicle-stimulating hormone commencing in the luteal phase of the ovarian cycle

Embryo implantation requires synchronized dialogue between the receptive endometrium and activated blastocyst via locally produced soluble mediators. During the midsecretory (MS) phase of the menstrual cycle, increased glandular secretion into the uterine lumen contains important mediators that modulate the endometrium and support the conceptus during implantation. This study aimed first to identify the growth factor and cytokine profile of human uterine fluid from fertile women during the midproliferative (MP; nonreceptive) and MS (receptive) phases of the cycle, and from women with unexplained infertility during the MS phase. The second aim was to determine important functions of endometrial secretions for embryo implantation. Analysis of uterine fluid using quantitative Luminex assays revealed the presence of over 30 cytokines and growth factors, of which eight [platelet-derived growth factor-AA, TNF-B, soluble IL-2 receptor-A, Fms-like tyrosine kinase 3 ligand, soluble CD40 ligand, IL-7, interferon-A2, and chemokine (C-X-C motif) ligand 1-3] were previously unknown in human uterine fluid. Comparison of the fertile MP, MS, and infertile MS cohorts revealed vascular endothelial growth factor (VEGF) levels are significantly reduced in uterine fluid during the MS phase in women with unexplained infertility compared with fertile women. Functional studies demonstrated that culturing mouse embryos with either MS-phase uterine fluid from fertile women or recombinant human VEGF significantly enhanced blastocyst outgrowth. Furthermore, treatment of human endometrial epithelial cells with uterine fluid or recombinant human VEGF-A significantly increased endometrial epithelial cell adhesion. Taken together, our data support the concept that endometrial secretions, including VEGF, play important roles during implantation. Identifying the soluble mediators in human uterine fluid and their actions during implantation provides insight into interactions essential for establishing pregnancy, fertility markers, and infertility treatment options.

Aromatase inhibitors for PCOS: a systematic review and meta-analysis

Endometrial secretions in the uterine cavity contain mediators important for endometrial receptivity and embryo implantation. Unbiased analysis of uterine fluid from a receptive versus nonreceptive time of the menstrual cycle and in fertile and infertile women will provide new insights into uterine receptivity. We hypothesized that proteomic analysis of human uterine lavages would identify proteins important for the establishment of pregnancy in humans. Lavages collected from fertile (n = 7) and infertile (n = 8) women during the midsecretory (MS) phase, and from fertile women during the midproliferative (MP) (n = 7) phase, were assessed using 2D-differential in gel electrophoresis (2D-DiGE) over a pI 4-7 range. Statistical analysis revealed 7 spots that were significantly decreased in the MP compared to the MS phase, while 18 spots showed differential expression between fertile and infertile women. A number of proteins were identified by mass spectrometry, including antithrombin III and alpha-2-macroglobulin, whose production was confirmed in endometrial epithelium. Their staining pattern suggests roles during embryo implantation. Assessment of the human endometrial secretome has identified differences in the protein content of uterine fluid with respect to receptivity and fertility.

Post-translational modifications and protein-specific isoforms in endometriosis revealed by 2D DIGE.

OBJECTIVE To investigate, in patients who previously had a suboptimal ovarian stimulation cycle, the benefit of starting ovarian stimulation before the onset of menses. DESIGN Prospective, randomized, controlled study. SETTING A tertiary referral center for infertility treatment. PATIENT(S) Forty patients undergoing IVF or GIFT from whom only 3-6 oocytes were retrieved in their last cycle. INTERVENTION(S) Recombinant human FSH was administered before the onset of the menstrual period (experimental group) or in the early follicular phase after the onset of menses (control group). MAIN OUTCOME MEASURE(S) The number of oocytes retrieved. RESULT(S) Patients in the experimental group were ready for oocyte retrieval on menstrual cycle day 11 instead of cycle day 14. The number of oocytes retrieved was not significantly different between the two groups. CONCLUSION(S) Poor responders do not benefit from commencing recombinant human FSH therapy in the luteal phase.

Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis

BACKGROUND The effectiveness of aromatase inhibitors (AIs) in the treatment of anovulatory polycystic ovary syndrome (PCOS) remains unclear. The objective was to determine whether AIs are effective in improving fertility outcomes in women with PCOS. METHODS Databases were searched until July 2011. Inclusion criteria were women with PCOS, who are infertile, receiving any type, dose and frequency of AI compared with placebo, no other treatment or other infertility treatment. Outcomes were rates of: ovulation, pregnancy, live birth, multiple pregnancies, miscarriage and adverse events, as well as quality of life and cost effectiveness. Data were extracted and risk of bias was assessed. A random-effects model was used for the meta-analyses, using odds ratios (ORs) and rate ratios (RRs). RESULTS The search returned 4981 articles, 78 articles addressed AIs and 13 randomized controlled trials (RCTs) met the inclusion criteria. No RCTs compared AIs versus placebo or no treatment, in therapy naïve women with PCOS. Meta-analyses of six RCTs comparing letrozole with clompihene citrate (CC) demonstrated that letrozole improved the ovulation rate per patient [OR 2.90 (95% confidence interval (CI) 1.72, 4.88), I(2) = 0%, P < 0.0001]; however, there was no statistical difference for the ovulation rate per cycle or the pregnancy, live birth, multiple pregnancy or miscarriage rates. Letrozole also did not improve pregnancy or live birth rates compared with placebo or with CC plus metoformin in women with CC-resistant PCOS. Results of comparisons of letrozole and anastrozole in women with CC-resistant PCOS were conflicting in terms of ovulation and pregnancy rates. CONCLUSIONS In the absence of supportive high-quality evidence, AIs should not be recommended as the first-line pharmacological therapy for infertility in women with PCOS, and further research is needed.

World Endometriosis Research Foundation Endometriosis Phenome and biobanking harmonization project: II. Clinical and covariate phenotype data collection in endometriosis research

Endometriosis is a chronic disorder affecting approximately 10% of women in whom endometrial tissue forms painful lesions outside the uterus. It has a major impact on their physical, mental and social well-being but has no known cure, and there is no nonsurgical means of diagnosis. We have used a proteomic approach to identify proteins with altered abundance in the eutopic endometrium of endometriosis patients in the midsecretory phase of the menstrual cycle. 2D-differential in gel electrophoresis (DIGE) and mass spectrometry identified 20 proteins that were present at different levels in endometriosis patients (p < 0.05), many of which have not previously been associated with endometriosis. Protein abundance changes did not correlate well with published gene array data, emphasizing the extensive post-translational modification that occurs in this tissue. Abundance or localization changes in endometrial tissue were validated by immunohistochemistry and Western blotting for three proteins, vimentin (VIM), peroxiredoxin 6 (PRDX6), and ribonuclease/angiogenin inhibitor 1 (RNH1), while observed changes could not be confirmed for coronin 1A (CORO1A) or transgelin (TAGLN2). In addition, multiple charge and size isoforms were observed for PDRX6 and vimentin (VIM), and an additional PDRX6 isoform was observed in endometriosis patients that was below the level of detection in healthy women. Biological pathway analysis identified that cytoskeletal remodeling via keratin intermediate filaments, processing of the cystic fibrosis transmembrane receptor (CFTR), the glucocorticoid receptor subunit alpha (GCR), and heat shock factor 1 (HSF1) were all significantly over-represented features in endometriosis patients. This study highlights the highly dynamic nature of endometrial tissue and suggests that considerable post-translational modification of proteins is a key factor in the pathology of endometriosis.

Different influence of incongruent follicular development on in vitro fertilization–embryo transfer and gamete intrafallopian transfer pregnancy rates

UNLABELLED BACKGROUND Recent studies suggest that metformin may be more effective in women with polycystic ovary syndrome (PCOS) who are non-obese. The objective here is to determine and compare the effectiveness of metformin and clomiphene citrate for improving fertility outcomes in women with PCOS and a BMI < 32 kg/m(2) (BMI 32 kg/m(2) was used to allow for international differences in BMI values which determine access to infertility therapy through the public health system). METHODS Databases were searched for English language articles until July 2011. INCLUSION CRITERIA women of any age, ethnicity and weight with PCOS diagnosed by all current criteria, who are infertile; at least 1000 mg of any type of metformin at any frequency, including slow release and standard release, compared with any type, dose and frequency of clomiphene citrate. OUTCOMES rates of ovulation, live birth, pregnancy, multiple pregnancies, miscarriage, adverse events, quality of life and cost effectiveness. Data were extracted and risk of bias assessed. A random effects model was used for meta-analyses of data, using risk ratios (relative risk). RESULTS The search returned 4981 articles, 580 articles addressed metformin or clomiphene citrate and four randomized controlled trials (RCTs) comparing metformin with clomiphene citrate were included. Upon meta-analysis of the four RCTs, we were unable to detect a statistically significant difference between the two interventions for any outcome in women with PCOS and a BMI < 32 kg/m(2), owing to significant heterogeneity across the RCTs. CONCLUSIONS Owing to conflicting findings and heterogeneity across the included RCTs, there is insufficient evidence to establish a difference between metformin and clomiphene citrate in terms of ovulation, pregnancy, live birth, miscarriage and multiple pregnancy rates in women with PCOS and a BMI < 32 kg/m(2). However, a lack of superiority of one treatment is not evidence for equivalence, and further methodologically rigorous trials are required to determine whether there is a difference in effectiveness between metformin and placebo (or no treatment) or between metformin and clomiphene citrate for ovulation induction in women with PCOS who are non-obese. Until then, caution should be exercised when prescribing metformin as first line pharmacological therapy in this group of women.