BackgroundAnomalous levels of gonadotropin-releasing hormone (GnRH) secretion result in a variety of reproductive phenotypes associated with infertility or subfertility. The normosmic isolated hypogonadotropic hypogonadism (nIHH) is due to a failure of either GnRH pulsatile secretion in hypothalamus or its reception in pituitary. The spectrum of nIHH-associated alterations continues to expand, especially when additional ethnic populations are investigated. The aim of this study was to uncover genetic causes for nIHH in patients of Russian origin.MethodsFor two nIHH patients referred to infertility clinic, both exons and promoter sequences of 6 GnRH signaling genes were sequenced.ResultsPatient 1 was a compound heterozygote for mutations in GnRH and its receptor encoding genes, while in Patient 2 GnRHR mutations were found in homozygous state. In both patients, the coding frame of GnRHR gene harbored missense-mutation Arg139His previously described as founder mutation in Polish and Brazilan patients. IVF/ET treatments were successful, with phenotypically healthy offsprings delivered.ConclusionPolish founder mutation Arg139His in GnRHR was found in two nIHH patients originating from Western region of Russia. Common variant of GnRH-encoding gene, Trp16Ser, could possibly contribute to reproductive phenotypes in patients with heterozygous mutations of other GnRH signaling pathway genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-016-0183-8) contains supplementary material, which is available to authorized users.
Introduction The endometrial microbiota has been linked to several gynecological disorders, including infertility. It has been shown that the microbial profile of endometrium could have a role in fertilization and pregnancy outcomes. In this study we aim to assess the microbial community of endometrial tissue (ET) and endometrial fluid (EF) samples in women receiving in vitro fertilization (IVF) treatment. We also search for possible associations between chronic endometritis (CE) and endometrial microbiota. Material and methods This was a cohort study involving 25 women aged between 28 and 42 years with both primary and secondary infertility and with at least one IVF failure. The ET and EF sample collection was carried out between September 2016 and November 2018. Each of the participants provided two types of samples—tissue and fluid samples (50 samples in total). A 16S rRNA sequencing was performed on both of the sample types for microbial profile evaluation. CE was diagnosed based on a CD138 immunohistochemistry where CE diagnosis was confirmed in the presence of one or more plasma cells. Microbial profiles of women with and without CE were compared in both sample types separately. Results We report no differences in the microbial composition and alpha diversity (pObserved = 0.07, pShannon = 0.65, pInverse Simpson = 0.59) between the EF and ET samples of IVF patients. We show that the abundance of the genus Lactobacillus influences the variation in microbial beta diversity between and fluid samples (r2 = 0.34; false discovery rate [FDR] <9.9 × 10−5). We report that 32% (8/25) of the participants had differences in Lactobacillus dominance in the paired samples and these samples also present a different microbial diversity (pShannon = 0.06, FDRweighted UniFrac = 0.01). These results suggest that the microbial differences between ET and fluid samples are driven by the abundance of genus Lactobacillus. The microbiome of CE and without CE (ie non‐CE) women in our sample set of IVF patients was similar. Conclusions Our findings show that genus Lactobacillus dominance is an important factor influencing the microbial composition of ET and fluid samples.
Study question To investigate the therapeutic efficacy of follitropin alpha biosimilar therapy in nonselected patients undergoing IVF. Summary answer This large retrospective study demonstrated similar therapeutic efficacy for follitropin alpha biosimilar therapy in women who underwent ovarian stimulation (OS) using different protocols. What is known already Based on data from the last meta-analyses (Budani et al., 2020), follitropin alpha biosimilars showed similar efficacy and safety in randomized controlled trials aimed at proving the therapeutic equivalence in terms of oocytes retrieved in women undergoing OS. In most cases, normogonadotrophic patients were enrolled in such studies without any endocrine or ovarian disturbances. The absence of real-world data can be compensated by additional post-marketing studies aimed at investigating the efficacy of biosimilars in different OS protocols using antagonists and agonists of GnRH and OS with mixed gonadotropins. Study design, size, duration A retrospective, observational, anonymized cohort study conducted at 35 IVF clinics in Russia, named “FOLLITROPIN”, compared the efficacy of OS in 2020. The OS protocols analysed where follitropin alpha biosimilar (Primapur®) was applied for at least 5 days. All of the analysed subjects underwent OS using GnRH antagonist/agonist protocols, with no restrictions on the OS protocol or food supplements/vitamins. No inclusion or exclusion criteria were applied. Overall, 5484 OS protocols were analysed. Participants/materials, setting, methods The efficacy of 5484 OS protocols was calculated, and two subgroups were extracted: (1) mixed gonadotropin OS protocols (N = 2625) vs monotherapy with Primapur® (N = 2859); (2) GnRH antagonist OS (N = 2183) vs GnRH agonist (N = 676) using only Primapur®. Demographic and clinical characteristics: (1) Age 34.9±4.8 vs 32.9±4.7 (p < 0.001), BMI 23.9±4.7 vs 23.6±4.5 (p < 0.001), IVF attempt 1.4±0.7 vs 1.3±0.6 (p < 0.001); (2) Age 32.9±4.6 vs 33.1±4.9 (p = 0.449), BMI 23.7±4.6 vs 23.1±4.5 (p = 0.019), and IVF attempt 1.2±0.5 vs 1.4±0.9 (p < 0.001). Main results and the role of chance The total efficacy of OS with Primapur®: oocytes retrieved: 9.5±7.2, MII: 6.8±6.6, 2PN: 6.1±5.8, clinical pregnancy per ET (PR) 6 weeks after ET: 38.4%. Subgroup 1 analysis: oocytes retrieved: 8.6±6.8 vs 10.3±7.4 (p < 0.001), MII: 6.7±6.2 vs 7.7±6.9 (p < 0.001), 2PN: 5.8±5.2 vs 7.2±6.2 (p < 0.001). There were statistically significant differences between oocyte yields in mixed vs monotherapy protocols due to subgroup differences, including age, BMI and IVF attempts. No statistically significant differences were found for PR in subgroup 1: 39.3% [95% CI: 36.9–41.7%] vs 37.6% [95% CI: 35.3–39.8%] (p = 0.314). The major accompanying gonadotropin in the mixed protocol was menotropin (75% for mixed OS protocols). Subgroup 2 analysis: oocytes retrieved: 10.5±7.5 vs 9.6±7.0 (p = 0.032), MII: 7.6±6.9 vs 6.7±5.7 (p < 0.001), 2PN: 7.3±6.3 vs 5.7±5.0 (p < 0.001). There were statistically significant differences between oocyte yields in GnRH antagonist vs GnRH agonist monotherapy due to subgroup differences, including BMI and IVF attempts. No statistically significant differences were found for PR in subgroup 2: 37.9% [95% CI: 35.5–40.5%] vs 35.9% [95% CI: 30.8–41.1%] (p = 0.482). All medicines were well tolerated at the injection site, and no serious adverse reactions were reported. This large retrospective cohort study in a nonselected population demonstrated similar clinical efficacy for follitropin alpha biosimilar therapy. Limitations, reasons for caution The real-world patient data analysed in this study were representative, showing the ability of follitropin biosimilars to develop both folliculogenesis and clinical pregnancy in a nonselected population. Additional comparative studies are needed to confirm the efficacy of the biosimilars in patients with classified types of infertility causes, including unexplained infertility. Wider implications of the findings: In this study, we demonstrated the therapeutic efficacy of biosimilars in terms of oocyte yield and clinical pregnancy development in women undergoing different OS protocols. Further large-scale studies with known hormonal levels before and during OS, as well as the micro- and macronutrient status of both parents, are needed. Trial registration number None
Рассмотрены молекулярные процессы, происходящие в ооците и клетках гранулезы человеческого фолликула во время овуляции. Описаны закономерности возобновления мейоза в ооците, расширение и выход комплекса ооцит-кумулюс из фолликула, лютеинизация клеток гранулезы. Уточнен механизм овуляции на уровне группы нейронов кисспептин-нейрокинин-В-динорфин, находящихся в дугообразном ядре гипоталамуса.
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