Endometrial receptivity tests in reproduction: a SWOT analysis.

Endometrial receptivity and its management in assisted reproduction is now a significant focus of research interest. Endometrial receptivity tests, which analyze different panels of gene expression, are usually offered in fertility clinics to determine the women's individual 'window of implantation', providing a personalized timing for embryo transfer. However, there are still no definite indications on whether its inclusion in the study of the infertile couple or the study of patients with repeated implantation failure is essential.

Endometrial whole metabolome profile at the receptive phase: influence of Mediterranean Diet and infertility.

Introduction: Several metabolite classes have been identified in human endometrium, including lipids, nucleotides, amino acids, organic acids, and sugars. The first studies suggest the importance of metabolites in endometrial functions, as imbalance in uterine metabolites has been associated with low implantation rate and endometriosis. Nevertheless, most of studies have put emphasis on specific metabolite classes, and we lack the knowledge of the whole metabolome composition in human uterus. Further, a healthy dietary pattern has been shown to potentially protect against different endometrial dysfunctions and is a potential modulator of metabolomic composition and, consequently, the intrauterine microenvironment. The Mediterranean Diet (MD), characterized by a high intake of fruits, vegetables, cereals, nuts, legumes, fish, and olive oil, and a low consumption of meat, dairy products, and processed foods, has been associated with a wide range of benefits for health. Indeed, the MD pattern has displayed a beneficial role in endometriosis management and fertility; however, the relationship between the MD and the endometrial metabolome is still unknown. In our study, we set out to analyze receptive-phase endometrial metabolome profiles among women with infertility and their associations with MD. Methods: The study included women with male factor infertility (n=8), unexplained infertility (n=10), recurrent implantation failure (n=14), and endometriosis (n=13). The endometrial metabolome was analyzed with ultrahigh-performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS). The MD adherence of the participants was assessed using the 14-point MEDAS questionnaire of adherence to the MD. Results: We provide the whole metabolome profile of the endometrium, where 925 different metabolites were identified. Among these metabolites, lipids comprised the largest part, where polyunsaturated fatty acids (PUFAs) prevailed. Women with endometriosis and recurrent implantation failure were found to have lower levels of PUFAs compared to women with male factor and unexplained infertility (i.e., no clear endometrial alterations), identifying a metabolome profile associated with infertility diagnoses where altered endometrial functions are suspected. Moreover, MD adherence seemed to be associated with the endometrial metabolomic profile in a manner dependent on the health status of the uterus. Conclusion: The study findings provide insight into the molecular background of female infertility and lead to identification of potential molecular biomarkers and possibilities for modulating the endometrial microenvironment and, thereby, endometrial functions involved in embryo implantation and infertility.

Impact of chronic endometritis in infertility: a SWOT analysis.

Chronic endometritis is a pathology often associated with reproductive failure, but there are still no clear recommendations on whether its inclusion in the initial study of infertile couples is necessary. In this discussion paper, based on a SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis, the different aspects of the repercussions of chronic endometritis in fertility are evaluated. To avoid possible subjectivity in the analysis and results of this study, the researchers followed the Oxford criteria for the evaluation of evidence. The results from the evaluation of the reviewed literature seem to indicate that, pending new evidence, it would be advisable not to include chronic endometritis in the initial baseline study before assisted reproduction in order not to delay other assisted reproduction treatments. However, it would be advisable in cases of repetitive implantation failure and pregnancy loss after having undergone IVF with viable embryos and before continuing with costly reproductive processes, since results could be improved. The development of randomized studies assessing the impact of antibiotic treatment as a possible therapeutic option in infertile women with chronic endometritis, as well as the possible impact on endometrial microbiota and receptivity/implantation, would allow for the establishment of more precise clinical guidelines in this regard.

New Opportunities for Endometrial Health by Modifying Uterine Microbial Composition: Present or Future?

Current knowledge suggests that the uterus harbours its own microbiota, where the microbes could influence the uterine functions in health and disease; however, the core uterine microbial composition and the host-microbial relationships remain to be fully elucidated. Different studies are indicating, based on next-generation sequencing techniques, that microbial dysbiosis could be associated with several gynaecological disorders, such as endometriosis, chronic endometritis, dysfunctional menstrual bleeding, endometrial cancer, and infertility. Treatments using antibiotics and probiotics and/or prebiotics for endometrial microbial dysbiosis are being applied. Nevertheless there is no unified protocol for assessing the endometrial dysbiosis and no optimal treatment protocol for the established dysbiosis. With this review we outline the microbes (mostly bacteria) identified in the endometrial microbiome studies, the current treatments offered for bacterial dysbiosis in the clinical setting, and the future possibilities such as pro- and prebiotics and microbial transplants for modifying uterine microbial composition.

Second-generation preimplantation genetic testing for aneuploidy in assisted reproduction: a SWOT analysis.

Second-generation preimplantation genetic testing for aneuploidy (PGT-A 2.0) in patients with an unfavourable reproductive and IVF prognosis is becoming common practice, with the aim of improving reproductive outcomes. However, there is still no clear evidence on the possible advantages and drawbacks with regard to this procedure. In this discussion paper, based on a SWOT (strengths, weaknesses, opportunities, threats) analysis, the different aspects of this strategy are evaluated. Current evidence suggests that PGT-A 2.0 should not at present have an indiscriminate application, but it might be indicated in cases in which the risk of aneuploidy is increased.

Polycystic ovary syndrome throughout a woman's life.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged women and the main cause of infertility due to anovulation. However, this syndrome spans the lives of women affecting them from in-utero life until death, leading to several health risks that can impair quality of life and increase morbidity and mortality rates. Fetal programming may represent the beginning of the condition characterized by hyperandrogenism and insulin resistance which leads to a series of medical consequences in adolescence, adulthood, and old age. Menstrual and fertility problems evolve into metabolic complications as age advances. An early and precise diagnosis is important for an adequate management of PCOS, especially at the extreme ends of the reproductive lifespan. However, many different phenotypes are included under the same condition, being important to look at these different phenotypes separately, as they may require different treatments and have different consequences. In this way, PCOS exhibits a great metabolic complexity and its diagnosis needs to be revised once again and adapted to recent data obtained by new technologies. According to the current medical literature, lifestyle therapy constitutes the first step in the management, especially when excess body weight is associated. Pharmacotherapy is frequently used to treat the most predominant manifestations in each age group, such as irregular menses and hirsutism in adolescence, fertility problems in adulthood, and metabolic problems and risk of cancer in old age. Close surveillance is mandatory in each stage of life to avoid health risks which may also affect the offspring, since fetal and post-natal complications seem to be increased in PCOS women.

Strategies to manage refractory endometrium: state of the art in 2016.

The endometrium is one of a number of factors involved in achieving optimal outcomes after assisted reproductive treatment. Owing to its "passive" growth following adequate ovarian stimulation, it has received virtually no attention. Only when either endometrial thickness or ultrasonographic pattern seem inadequate have different strategies been assessed to try to improve it, especially in those cases where it seems difficult or impossible to make it grow. The objective of this review is to summarize the different strategies that have been investigated in patients with inadequate endometrium, to attempt to provide solid evidence of therapies that may be beneficial and to move away from empirism. A review of the existing literature was performed by searching MEDLINE, EMBASE, Cochrane library and Web of Science for publications in English related to refractory endometrium. Most current treatments are based on anecdotal cases and not on solid data, although worldwide many doctors and patients use them. In conclusion, this review found that it is not easy to provide a pragmatic, evidence-based approach to help physicians and patients confused by the available data on how to improve a poor endometrium. Honest balanced information provided to our patients is the best that we can do.

Spanish consensus on premature menopause.

INTRODUCTION: While we recognise that the term premature menopause is more accepted by most non-specialist health care providers and by the general population, 'primary ovarian insufficiency' (POI) is currently considered the most apposite term to explain the loss of ovarian function, because it better explains the variability of the clinical picture, does not specify definitive failure, and highlights the specific ovarian source. Its pathogenesis involves a congenital reduction in the number of primordial follicles, poor follicle recruitment, or accelerated follicular apoptosis. However, its cause is unknown in most cases. AIM: This guide analyses the factors associated with the diagnosis and treatment of POI and provides recommendations on the most appropriate diagnostic and therapeutic measures for women under 40 years of age who experience POI. METHODOLOGY: A panel of experts from various Spanish scientific societies related to POI (Spanish Menopause Society, Spanish Fertility Society, and Spanish Contraception Society) met to reach a consensus on these issues. RESULTS: Hormonal therapy (HT) is considered the treatment of choice to alleviate the symptoms of hypoestrogenism and to prevent long-term consequences. We suggest that HT should be continued until at least age 51, the average age at natural menopause. The best treatment to achieve pregnancy is oocyte/embryo donation. If a patient is to undergo treatment that will reduce her fertility, she should be informed of this issue and the available techniques to preserve ovarian function, mainly vitrification of oocytes.

Cumulative live birth rate after two single frozen embryo transfers (eSFET) versus a double frozen embryo transfer (DFET) with cleavage stage embryos: a retrospective cohort study.

PURPOSE: According to the latest ART report for Europe, about 13% of pregnancies after frozen embryo transfer are multiple. Our objective was to analyse the impact on the multiple pregnancy rate of two eSFET (elective single frozen embryo transfers) versus a DFET (double frozen embryo transfer) in women aged under 38 years, who had not achieved pregnancy in their fresh transfer and who had at least two vitrified embryos of A/B quality. METHODS: This study was conducted from January 2010 to June 2013 at a public hospital. The couples were divided into three groups. Group DFET: the first cryotransfer of two embryos (105 women); cSFET group: the only cryotransfer of a single vitrified embryo (60 women); eSFET group, individually vitrified embryos: 20 patients included in a clinical trial of single-embryo fresh and frozen transfer and 21 patients who chose to receive eSFET. RESULTS: The clinical pregnancy rate was 38.1% in the DET group and the cumulative clinical pregnancy rate was 43.3% in the eSFET group. There were no significant differences between the DFET and eSFET groups (30.0 vs 34.1%) in cumulative live birth delivery rate. The rate of multiple pregnancies varied significantly between the DFET and eSFET groups (32.5 vs 0%, p < 0.05). CONCLUSIONS: For good-prognosis women aged under 38 years, taking embryo quality as a criterion for inclusion, an eSFET policy can be applied, achieving acceptable cumulative clinical pregnancy and live birth rates and reducing multiple pregnancy rates.

Randomised clinical trial comparing elective single-embryo transfer followed by single-embryo cryotransfer versus double embryo transfer.

OBJECTIVE: To analyze the impact of the eSET followed by single-embryo cryotransfer versus double embryo transfer in older women (<38 years) without taking into account embryo quality. STUDY DESIGN: This is a prospective randomised clinical trial performed on 194 couples attempting a first IVF cycle in a Public Hospital in Spain. The women in Group 1 received eSET plus a single-embryo cryotransfer, and those in Group 2 received a double embryo transfer (DET). RESULTS: In the intention-to-treat analysis, the cumulative live birth delivery rate in the eSET group was similar to the results obtained for the DET group (45.2% vs. 41.8%; p = 0.60). The rate of multiple gestation was significantly lower in the eSET group than in the DET group (0% vs. 26.4%; p < 0.05). The findings obtained in the per-protocol analysis were similar to those obtained in the intention-to-treat analysis. The per-protocol analysis revealed no significant differences in the rate of implantation (29.8% in eSET vs. 29.7% in DET; p = 0.98), in cumulative pregnancy rates per transfer (49.1% in eSET vs. 46.9% in DET; p = 0.80) or in the cumulative live birth delivery rate (38.6% in eSET vs. 42.2% in DET; p = 0.69). In the cycles with eSET, there were no twin pregnancies (0% in eSET vs. 27.6 in DET; p < 0.05). CONCLUSIONS: For women aged under 38 years with good prognosis, without taking embryo quality as a criterion for inclusion, an eSET policy can be applied, achieving acceptable cumulative clinical pregnancy rates and birth rates.

Pelvic abscess after oocyte retrieval in women with endometriosis: A case series.

BACKGROUND: Pelvic inflammatory disease with progression to pelvic abscess is a rare complication after oocyte retrieval during in vitro fertilization cycles. However, in patients with endometriosis the risk appears to be increased. Many authors agree on the need for antibiotic prophylaxis during the oocyte retrieval in these patients, but there is no consensus regarding the best antibiotic. CASE: We discuss 3 clinical cases of tubo-ovarian abscess in women with endometriosis after oocyte retrieval despite antibiotic prophylaxis between 2004 and 2011 at our center, and discuss our experience in the context of earlier reports. CONCLUSION: It is unclear whether antibiotic prophylaxis is necessary in these women, and which antibiotic is best. Only douching with povidone-iodine appears to decrease the rate of pelvic infection.

Coverage and current practice patterns regarding assisted reproduction techniques.

Access to assisted reproduction techniques (ARTs) is highly variable worldwide. The aim of this paper is to analyse the association between systems for ART coverage, patterns of clinical practice, and outcomes for these procedures. We performed a retrospective analysis of ART activity records in the USA and Europe, and concluded that the availability of ART services, and the activity in this respect, is higher in public than in private coverage systems. Effectiveness decreases with greater coverage, but this occurs in parallel with lower numbers of embryos transferred and with multiple birth rates. Healthcare policy on assisted reproduction should take into account the necessary balance between the effectiveness of the treatment provided and its associated risks, the latter mainly concerning multiple pregnancies.

Multilocus analysis of estrogen-related genes in Spanish postmenopausal women suggests an interactive role of ESR1, ESR2 and NRIP1 genes in the pathogenesis of osteoporosis.

Osteoporosis is a common disease with multiple environmental and genetic risk factors involved. Using a marker-by-marker approach, the role of different estrogen-related genes has been analyzed in different populations, but most of these studies ignore the complex multigenic nature of human osteoporosis. Looking for markers related to osteoporosis, we have analyzed five single nucleotide polymorphisms located in genes related to the estrogen pathway, Follicle Stimulating Hormone Receptor (FSHR) gene, the CYP19 aromatase (CYP19A1) gene, the Estrogen Receptor alpha (ESR1) gene, the Estrogen Receptor beta (ESR2) gene and the Nuclear Receptor Interacting Protein 1 (NRIP1) gene in 265 unrelated postmenopausal women. We have obtained nominal P values for the NRIP1 Gly75Gly and ESR2 *39A>G markers (P=0.013 and P=0.02 respectively), but no gene seems to be associated after multiple test corrections. Reanalysis of this study using 437 postmenopausal women confirmed our results and only detect marginal effects for ESR2 marker (P=0.045). By contrast, multilocus analysis predicted epistatic interactions between ESR1, ESR2 and NRIP1 loci and its involvement in postmenopausal osteoporosis (P=0.003). We detected two digenic genotypes involving ESR2-NRIP1 and ESR2-ESR1 genes strongly associated with osteoporosis (P=0.007). Replication of multilocus studies using 437 patients confirmed the detected interactions (P<0.01). We proposed a non-additive non-multiplicative oligogenic model including ESR2 AG genotype modulated by NRIP1 A+ or ESR1 TT genotypes involved in osteoporosis. Our results reaffirm the polygenic nature and the genetic complexity of osteoporosis trait adding a new candidate gene (NRIP1) for association studies of bone-related traits.

Apoptosis in human granulosa cells after induction of ovulation in women participating in an intracytoplasmic sperm injection program.

OBJECTIVES: To investigate whether analysis of granulosa cell apoptosis can be useful in assessing follicular and oocyte maturation and the regulation of granulosa cell apoptosis by follicular fluid steroids in preovulatory follicles of stimulated women. STUDY DESIGN: Apoptosis in aspirated granulosa cells (n=64) was measured using the Annexin V-affinity assay by flow cytometry. Follicular fluid steroids were determined by ELISA and RIA. Statistics were evaluated using the Levenne test, Student t-test and simple linear regression analysis. RESULTS: No significant differences in the number and percentage of apoptotic granulosa cells per follicle were observed according to the maturity and fertilizability of the oocytes by intracytoplasmic sperm injection within these follicles. No correlations were found between levels of steroid hormones in follicular fluid and the number and proportion of granulosa cells undergoing apoptosis. CONCLUSIONS: The percentage of apoptosis in granulosa cells is not related to oocyte maturity and fertilizability by ICSI or to follicular quality in stimulated cycles of normal women. However, the possibility cannot be discarded that this parameter may be of importance at other phases of follicular development or in natural cycles when no treatment that influences follicular physiology is being applied.

Expression of transcription factors in endometrium during natural cycles.

PURPOSE: The sex steroid control of the endometrial cycle is mediated by transcription factors, four of which are the estrogen and progesterone receptors, c-jun and c-fos, all expressed by the endometrium. The aim of this study was to analyze the distribution of the transcription factors in the different endometrial compartments during natural cycles. METHODS: We studied 53 reproductively-normal women, of whom 26 were in the proliferative phase and 27 in the secretory phase. An endometrial biopsy was performed and serum values of LH, FSH, estradiol, and progesterone were determined. We studied the expression of transcription factors using monoclonal antibodies. RESULTS: A correlation between estrogen receptor and c-jun and c-fos expression was observed in stroma and epithelia, and progesterone receptor expression correlated with c-jun expression in epithelia. C-jun and c-fos presented greater expression in the proliferative phase than in the secretory phase, in the stroma and in both epithelia. No relation was found between estradiol serum levels and any transcription factor, but progesterone serum levels correlated significantly with most such factors. CONCLUSION: The two proto-oncogenes could play a decisive role in regulating the endometrial cycle; they could mediate the effects induced by sex steroid, and could be related to other transcription factors.