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Research question While growth hormone (GH) is hypothesized to potentially enhance embryo quality, results of current basic and clinical researches remain inconclusive. This study assesses the effect of GH supplementation on embryo quality and explores the relationship between baseline insulin-like growth factor-1 (IGF-1) levels and the efficacy of GH supplementation among Chinese patients undergoing in vitro fertilization (IVF). Design A randomized controlled Open-label trial was performed with 128 women experiencing poor embryonic development in IVF. Participants were allocated to the GH group (GH + Gonadotropin-Releasing Hormone [GnRH] antagonist protocol) and the Control group (GnRH antagonist protocol). The primary outcome was the number of high-quality embryos on Day 3. Results Patients in the GH group required significantly lower total doses of gonadotropin (2213 ± 667 IU vs. 2573 ± 630 IU, p  = 0.0058) and shorter duration of controlled ovarian stimulation (10.1 ± 1.60 days vs. 10.6 ± 1.30 days, p  = 0.0488). While there was no statistically significant overall increase in the number of high-quality embryos, subgroup analysis indicated that patients with lower baseline IGF-1 levels, especially those below the lowest quartile, might show a higher rate of high-quality embryos with GH supplementation ( p  = 0.0488). Additionally, the fresh embryo transfer clinical pregnancy rate was numerically higher in the GH supplementation group (46.2%) compared to the control group (38.5%), although not statistically significant. Conclusions This study suggests that GH co-treatment may enhance ovarian responsiveness in IVF patients with poor embryo quality, thereby reducing the dosage and duration of Gonadotropin (Gn) administration. Among individuals with lower IGF-1 levels, adding GH may improve the rate of high-quality embryos, highlighting the potential benefits of personalized treatment strategies in IVF. Clinical trial registration ClinicalTrials.gov ID: NCT03966339 (Registration time: 2019-05-24).

Purpose We aimed to analyse the in vitro fertilization-embryo transfer (IVF-ET) outcomes of the patients with sleep disturbances who were administered melatonin. Methods A total of 60 patients with sleep disturbances were divided into two groups. The study group (group A, n  = 30) had underwent the IVF-ET with melatonin administration and the control group (group B, n  = 30) without melatonin. Sleeping status after melatonin administration and the IVF outcomes were compared between the two groups. Results Sleeping status change was not significant ( p  > 0.05). The mean number of the retrieved oocytes, the mean MII oocyte counts, the G1 embryo ratio were significantly higher in the melatonin administered group (group A) than that the non-administered group (group B); p  = 0.0001; p  = 0.0001; p  < 0.05 respectively. Conclusion IVF patients with sleep disorders may benefit from melatonin administration in improving the oocyte and the embryo quality, but the sleeping problem itself may not be fixed.

Background The success of in vitro fertilization techniques is defined by multiple factors including embryo culture conditions, related to the composition of the culture medium. In view of the lack of solid scientific data and in view of the current general belief that sequential media are superior to single media, the aim of this randomized study was to compare the embryo quality in two types of culture media. Methods In this study, the embryo quality on day 3 was measured as primary outcome. In total, 147 patients younger than 36 years treated with IVF/ICSI during the first or second cycle were included in this study. Embryos were randomly cultured in a sequential (group A) or a single medium (group B) to compare the embryo quality on day 1, day 2 and day 3. The embryo quality was compared in both groups using a Chi-square test with a significance level of 0.05. Results At day 1, the percentage of embryos with a cytoplasmic halo was higher in group B (46%) than in group A (32%). At day 2, number of blastomeres, degree of fragmentation and the percentage of unequally sized blastomeres were higher in group B than in group A. At day 3, a higher percentage of embryos had a higher number of blastomeres and unequally sized blastomeres in group B. The number of good quality embryos (GQE) was comparable in both groups. The embryo utilization rate was higher in group B (56%) compared to group A (49%). Conclusions Although, no significant difference in the number of GQE was found in both media, the utilization rate was significantly higher when the embryos were cultured in the single medium compared to the sequential medium. The results of this study have a possible positive effect on the cumulative cryo-augmented pregnancy rate. Trial registration number NCT01094314

Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2 −/− embryos. Nevertheless, acetaldehyde-catabolism-competent mothers ( Aldh2 +/− ) can support the development of double-mutant ( Aldh2 −/− Fancd2 −/− ) mice. However, these embryos are unusually sensitive to ethanol exposure in utero , and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh2 −/− Fancd2 −/− mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients. Aldehyde toxicity in Fanconi anaemia Individuals with Fanconi anaemia exhibit developmental defects, stem-cell failure and a strong predisposition to leukaemia. Cells derived from patients with Fanconi anaemia are susceptible to DNA damage caused by DNA crosslinking agents such as cisplatin and mitomycin C. These are cancer chemotherapeutics, so cells are not normally exposed to them, prompting the question: what is the natural source of DNA damage repaired by this pathway? Experiments with mice deficient in Fancd2 (one of several Fanconi anaemia genes) and Aldh2 (which encodes an enzyme that detoxifies aldehydes) suggest that acetaldehyde is an endogenous source of DNA damage in Fanconi anaemia, contributing to cancer predisposition and haematopoeitic failure. Intriguingly, these mouse models also suggest a possible mechanism for the damaging effects of fetal alcohol exposure during pregnancy.

Gastruloids are a powerful in vitro model of early human development. However, although elongated and composed of all three germ layers, human gastruloids do not morphologically resemble post-implantation human embryos. Here we show that an early pulse of retinoic acid (RA), together with later Matrigel, robustly induces human gastruloids with posterior embryo-like morphological structures, including a neural tube flanked by segmented somites and diverse cell types, including neural crest, neural progenitors, renal progenitors and myocytes. Through in silico staging based on single-cell RNA sequencing, we find that human RA-gastruloids progress further than other human or mouse embryo models, aligning to E9.5 mouse and CS11 cynomolgus monkey embryos. We leverage chemical and genetic perturbations of RA-gastruloids to confirm that WNT and BMP signalling regulate somite formation and neural tube length in the human context, while transcription factors TBX6 and PAX3 underpin presomitic mesoderm and neural crest, respectively. Looking forward, RA-gastruloids are a robust, scalable model for decoding early human embryogenesis. Hamazaki, Yang et al. report that an early pulse of retinoic acid robustly induces human gastruloids with a neural tube, segmented somites and more advanced cell types than conventional gastruloids.

We compared two methods of zona pellucida drilling. 213 embryos were biopsied with acid Tyrode. Each biopsy took 3 minutes and the entire procedure ~29 minutes. 5% of blastomeres lysed, 49% of embryos became blastocyst and 36% of patients became pregnant. 229 embryos were biopsied with laser. Each biopsy took 30 seconds and the entire procedure ~7 minutes. 2.5% of blastomeres lysed, 50.6% of embryos became blastocyst and 47% of patients became pregnant. We can conclude that laser can be used for embryo biopsy. Reduction of embryo exposure and of removed blastomeres is associated with increased blastocysts available for transfer and a better clinical outcome.

Objective To compare early vs. mid-follicular exposure to LH in patients with poor ovarian responsiveness undergoing in vitro fertilization (IVF). Design Prospective, randomized, controlled trial. Setting University Hospital, University-affiliated private Clinic. Patients Five hundred-thirty women with poor ovarian responsiveness during the first IVF cycle, undergoing their second IVF attempt. Interventions In a GnRH-analogue long protocol, ovarian stimulation with recombinant FSH (300 IU/day) plus randomly assigned addition of recombinant LH (150 IU/day) from day 1 (early LH exposure; n  = 264) or from day 7 (late LH exposure; n  = 266). Main outcome measure(s) Primary outcome was the number of oocytes retrieved. Secondary outcomes were: cancellation rate, total gonadotropin dose, duration of ovarian stimulation, number of embryos available for transfer, pregnancy rate per started cycle, per OPU and per embryo transfer, implantation rate, delivered/ongoing pregnancy rate. Results Apart from the totally administered LH dose, that was significantly higher in the group receiving it from day 1, all parameters related to IVF outcome were non significantly different in the two groups. Conclusions Adding LH to FSH from day 1 or from day 7 of ovarian stimulation in a GnRH-agonist long protocol exerts comparable effects on IVF outcome in poor responders.

Numerous small molecules (termed inducers), many of which are electrophiles, upregulate cytoprotective responses and inhibit pro-inflammatory pathways by activating nuclear factor-erythroid 2 p45-related factor 2 (NRF2). Key to NRF2 activation is the ability to chemically modifying critical sensor cysteines in the main negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), of which C151, C273 and C288 are best characterized. This study aimed to establish the requirement for these cysteine sensor(s) for the biological activities of the most potent NRF2 activators known to date, the cyclic cyanoenones, some of which are in clinical trials. It was found that C151 in KEAP1 is the main cysteine sensor for this class of inducers, irrespective of molecular size or shape. Furthermore, in primary macrophage cells expressing C151S mutant KEAP1, at low concentrations, the tricyclic cyanoenone TBE-31 is inactive as an activator of NRF2 as well as an inhibitor of lipopolysaccharide-stimulated gene expression of the pro-inflammatory cytokines IL6 and IL1β. However, at high inducer concentrations, NRF2 activation proceeds in the absence of C151, albeit at a lower magnitude. Our findings highlight the intrinsic flexibility of KEAP1 and emphasize the critical importance of establishing the precise dose of NRF2 activators for maintaining on-target selectivity.

Somatic cell nuclear transfer (SCNT) cloning is the sole reproductive engineering technology that endows the somatic cell genome with totipotency. Since the first report on the birth of a cloned sheep from adult somatic cells in 1997, many technical improvements in SCNT have been made by using different epigenetic approaches, including enhancement of the levels of histone acetylation in the chromatin of the reconstructed embryos. Although it will take a considerable time before we fully understand the nature of genomic programming and totipotency, we may expect that somatic cell cloning technology will soon become broadly applicable to practical purposes, including medicine, pharmaceutical manufacturing and agriculture. Here we review recent progress in somatic cell cloning, with a special emphasis on epigenetic studies using the laboratory mouse as a model.

Previous studies have discussed the importance of an optimal range of metabolic activity during preimplantation development. To avoid factors than can trigger an undesirable trajectory, it is important to learn how nutrients and metabolites interact to help launching the correct developmental program of the embryo, and how much the in vitro culture system can impair this process. Here, using the bovine model, we describe a factorial experimental design used to investigate the biochemical and molecular signature of embryos in response to different combinations of morphological features—i.e. speed of development—and external stimuli during in vitro culture—i.e. different oxygen tensions and glucose supplementation. Our analyses demonstrate that the embryos present heterogeneous metabolic responses depending on early morphological phenotypes and the composition of their surroundings. However, despite the contribution of each single stimulus for the embryo phenotype, oxygen tension is determinant for such differences. The lower oxygen environment boosts the metabolism of embryos with faster kinetics, in particular those cultured in lower glucose concentrations.