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.

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.

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.

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.