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PurposeThe main purpose and research question of the study are to compare the efficacy of high-security closed versus open devices for human oocytes’ vitrification.MethodsA prospective randomized study was conducted. A total of 737 patients attending the Infertility and IVF Unit at S.Orsola University Hospital (Italy) between October 2015 and April 2020 were randomly assigned to two groups. A total of 368 patients were assigned to group 1 (High-Security Vitrification™ - HSV) and 369 to group 2 (Cryotop® open system). Oocyte survival, fertilization, cleavage, pregnancy, implantation, and miscarriage rate were compared between the two groups.ResultsNo statistically significant differences were observed on survival rate (70.3% vs. 73.3%), fertilization rate (70.8% vs. 74.9%), cleavage rate (90.6% vs. 90.3%), pregnancy/transfer ratio (32.0% vs. 31.8%), implantation rate (19.7% vs. 19.9%), nor miscarriage rates (22.1% vs. 21.5%) between the two groups. Women’s mean age in group 1 (36.18 ± 3.92) and group 2 (35.88 ± 3.88) was not significantly different (P = .297). A total of 4029 oocytes were vitrified (1980 and 2049 in groups 1 and 2 respectively). A total of 2564 were warmed (1469 and 1095 in groups 1 and 2 respectively). A total of 1386 morphologically eligible oocytes were inseminated by intracytoplasmic sperm injection (792 and 594 respectively, P = .304).ConclusionsThe present study shows that the replacement of the open vitrification system by a closed one has no impact on in vitro and in vivo survival, development, pregnancy and implantation rate. Furthermore, to ensure safety, especially during the current COVID-19 pandemic, the use of the closed device eliminates the potential samples’ contamination during vitrification and storage.

PurposeTo study the efficacy and efficiency of a “universal warming protocol” for vitrified human embryos, based on subsequent steps with 1 and 0.5 M concentration of extracellular cryoprotectant (ECCP).MethodTwo studies on patients undergoing fertility treatments via ICSI: a prospective randomized controlled trial (RCT) and a retrospective cohort study (CS). Setting: Private assisted reproductive (AR) center.RCT: duration 01/03/2017–01/10/2017; 315 embryos at blastocyst stage obtained from 169 patients. Each patient’s embryos were first randomized for vitrification with two different kits: Vitrification Kit (Kitazato, Japan) and Sage Vitrification Kit (Origio, Denmark). The embryos were randomly warmed with either Kitazato (K) or Sage (S) warming kits, specifically: group A (KK), group B (KS), group C (SK), and group D (SS). Primary outcome measure: survival rate (number of embryos surviving per number of embryos warmed). Secondary: implantation rate (number of embryos implanted per number of embryos transferred).CS: duration 01/01/2013–31/12/2015 embryos from patients’ own oocytes; 10/04/2015–31/07/2017 embryos from donors’ oocytes. A total of 1055 embryos vitrified at cleavage stage obtained from 631 warming cycles: 847 of these obtained from patients’ own oocytes, 208 egg-donation-derived embryos. Each patient’s embryos were vitrified and warmed in various combinations of three different vitrification/warming kits: Kitazato (K), Sage (S), or made in-house in our laboratory (H). Vitrification/warming kits from different manufacturers are routinely used in our AR center, and the warming procedures are randomly performed with any available kit on a “first-in-first-out” basis, irrespective of the kit used for vitrification. Group names: KK, KS, SK, SS, SH, HK, HS, HH (embryos from patients’ own oocytes); eKK, eKS, eSK, eSS (egg-donation-derived embryos).ResultsCryo-survival rates were comparable in all study groups.RCT. Group A 99.0% (96/97), group B 98.8% (83/84), group C 98.4% (61/62), and group D 98.6% (71/72).CS. Embryos from patients’ own oocytes: KK 96.4% (54/56), KS 100.0% (13/13), SK 98.8% (80/81), SS 97.2% (174/179), SH 97.6% (40/41), HK 95.2% (20/21), HS 99.5% (187/188), and HH 97.4% (261/268). Egg-donation-derived embryos: eKK 100.0% (91/91), eKS 98.4% (60/61), eSK 100.0% (26/26), and eSS 96.7 (29/30).Implantation was generally comparable in all study groups—exceptions were in CS: KS vs. SK (P = 0.049), SS (P = 0.012), HS (P = 0.010), HH (P = 0.025); and SH vs. SS (P = 0.042), HS (P = 0.035).ConclusionWorldwide, millions of embryos have been cryopreserved using different vitrification kits; these studies establish that it is possible to combine different kits for vitrification and warming using a universal warming protocol. This can optimize costs, simplify lab routines, and favor embryo exchange between IVF centers.RCT registration numberISRCTN12342851.

Purpose This study aimed to determine whether the new formulation of vitrification solutions containing a combination of hydroxypropyl cellulose (HPC) and trehalose does not affect outcomes in comparison with using conventional solutions made of serum substitute supplement (SSS) and sucrose. Methods Ovum donation cycles were retrospectively compared regarding the solution used for vitrification and warming of human oocytes. The analysis included 218 cycles ( N  = 2532 oocytes) in the study group (HPC + trehalose) and 214 cycles ( N  = 2353 oocytes) in the control group (SSS + sucrose). Results No statistical differences were found in ovarian stimulation parameters and baseline characteristics of donors and recipients. The survival rate was 91.3 % (95 % confidence interval (CI) = 89.8–92.9) in the HPC + trehalose group vs. 92.1 % (95 % CI = 90.4–93.7) in the SSS + sucrose group (NS). The implantation rate (42.8 %, 95 % CI = 37.7–47.9 vs. 41.2 %, 95 % CI = 36.0–46.4), clinical pregnancy rate (CPR) per transfer (60.7 %, 95 % CI = 53.9–67.5 vs. 56.4 %, 95 % CI = 49.3–63.5), and ongoing pregnancy rate (OPR) per transfer (48.5 %, 95 % CI = 41.5–55.5 vs. 46.3 %, 95 % CI = 39.2–53.4) were similar for patients who received either HPC + trehalose-vitrified oocytes or SSS + sucrose-vitrified oocytes. Statistical differences were found when analyzing blastocyst rate both per injected oocyte (30.2 %, 95 % CI = 28.3–32.1 vs. 24.1 %, 95 % CI = 22.3–25.9) and per fertilized oocyte (40.8 %, 95 %CI = 38.5–43.1 vs. 33.2 %, 95 % CI = 30.8–35.5) ( P  < 0.0001). Delivery rate was comparable between groups (37.2 %, 95 % CI = 30.8–46.6 vs. 36.9 %, 95 % CI = 30.4–43.4; NS). Conclusions Our data demonstrate that HPC and trehalose are suitable and safe substitutes for serum and sucrose. Therefore, the new commercial media can be used efficiently in the vitrification of human oocytes avoiding viral and endotoxin contamination risk.

Purpose The present study aims to investigate the effects of the combined therapy myo-inositol (MI) plus d -chiro-inositol (DCI) or d -chiro-inositol treatment in oocyte quality. Methods Polycystic ovary syndrome (PCOS) women undergoing IVF-ET were treated with myo-inositol combined with d -chiro-inositol in the physiological ratio (1.1 g myo-inositol plus 27.6 mg of d -chiro-inositol; INOFOLIC ® combi Lo.Li.pharma) or d -chiro-inositol alone (500 mg; Interquim, s.a., Barcelona, Spain) to evaluate the umber of morphological mature oocytes, total International Units (IU) of recombinant FSH administered and the number of grade 1 embryos. Results The data clearly showed that only the combined therapy was able to improve oocyte and embryo quality, as well as pregnancy rates, in PCOS women undergoing IVF-ET. Conclusion The present paper further supports the hypothesis that MI plays a crucial role in the ovary in PCOS women. In particular, due to the physiological role played by MI and DCI, the combined therapy should represent a better choice.

Purpose Time-lapse monitoring allows for a flexible embryo evaluation and potentially provides new dynamic markers of embryo competence. Before introducing time-lapse monitoring in a clinical setting, the safety of the instrument must be properly documented. Accordingly, the aim of this study was to evaluate the safety of a commercially available time-lapse incubator. Methods In a two center, randomized, controlled, clinical trial 676 oocytes from 59 patients in their 2nd or third treatment cycle, age <38 years and ≥8 oocytes retrieved were cultured in the time-lapse incubator or in a conventional incubator. The primary outcome was proportion of 4-cell embryos on day 2. Secondary outcomes were proportion of 7–8 cell embryos on day 3 and proportion of blastocysts on day 5. Implantation pregnancy rates were registered based on presence of fetal heart activity visualized by ultrasound 8 weeks after embryo transfer. Results No significant difference was found between the time-lapse incubator (TLI) and conventional incubator (COI) in proportion of 4-cell embryos on day 2 irrespective of whether data was analyzed according to ITT (RR TLI/COI : 0.81 (0.65; 1.02)) or PP (RR TLI/COI : 0.80 (0.63; 1.01)). Nor were any significant differences detected in the secondary endpoints; i.e. proportion of 7–8-cell embryos on day three ITT (RR TLI/COI : 0.96 (0.73; 1.26)); PP (RR TLI/COI : 0.95 (0.72; 1.26)) and proportion of blastocysts on day five ITT (RR TLI/COI : 1.09 (0.84; 1.41)); PP (RR TLI/COI : 1.09 (0.83: 1.41)). We found no differences in clinical pregnancy rate or implantation rate. Conclusion Culture in the time-lapse incubator supports embryonic development equally to a conventional incubator.

Polyunsaturated fatty acids (PUFAs) have beneficial effects on epileptic seizures and cardiac arrhythmia. We report that ω-3 and ω-6 all-cis-PUFAs affected the voltage dependence of the Shaker K channel by shifting the conductance versus voltage and the gating charge versus voltage curves in negative direction along the voltage axis. Uncharged methyl esters of the PUFAs did not affect the voltage dependence, whereas changes of pH and charge mutations on the channel surface affected the size of the shifts. This suggests an electrostatic effect on the channel's voltage sensors. Monounsaturated and saturated fatty acids, as well as trans-PUFAs did not affect the voltage dependence. This suggests that fatty acid tails with two or more cis double bonds are required to place the negative carboxylate charge of the PUFA in a position to affect the channel's voltage dependence. We propose that charged lipophilic compounds could play a role in regulating neuronal excitability by electrostatically affecting the channel's voltage sensor. We believe this provides a new approach for pharmacological treatment that is voltage sensor pharmacology.

In the mammalian ovary, progressive activation of primordial follicles from the dormant pool serves as the source of fertilizable ova. Menopause, or the end of female reproductive life, occurs when the primordial follicle pool is exhausted. However, the molecular mechanisms underlying follicle activation are poorly understood. We provide genetic evidence that in mice lacking PTEN (phosphatase and tensin homolog deleted on chromosome 10) in oocytes, a major negative regulator of phosphatidylinositol 3-kinase (PI3K), the entire primordial follicle pool becomes activated. Subsequently, all primordial follicles become depleted in early adulthood, causing premature ovarian failure (POF). Our results show that the mammalian oocyte serves as the headquarters of programming of follicle activation and that the oocyte PTEN-PI3K pathway governs follicle activation through control of initiation of oocyte growth.

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.

To evaluate the effect of atmospheric oxygen (O2) concentration on embryonic development, a controlled and randomized study using the sibling oocytes was carried out. A total of 147 patients were studied. Embryos were cultured in O2 concentration 20% versus 5% during the gamete, zygote, and first 3 days. The mean cell numbers of embryo (7.69 ± 1.91 vs 7.20 ± 1.82, P = .011) and rate of clinically useable embryos (81.62% vs 77.22%, P = .017) were significantly higher in 5% O2 than in 20% O2. There was no difference in the zygote developmental stage, day 2, day 4, and blastocyst stage. The quality of blastocyst (both inner cell mass and trophectoderm) showed no difference. Also, there was no increase in embryos fragmentation and uneven cells in 20% O2 culture condition. In conclusion, 20% O2 reduced the mean cell numbers of embryo and the number of clinically useable embryos on day 3. However, there was no subsequent negative impact on development of day 4 and blastocyst stage.

Oogenesis and folliculogenesis are dynamic processes that are regulated by endocrine, paracrine and autocrine signals. These signals are exchanged between the oocyte and the somatic cells of the follicle. Here we analyzed the role of AMP-activated protein kinase (AMPK), an important regulator of cellular energy homeostasis, by using transgenic mice deficient in α1AMPK specifically in the oocyte. We found a decrease of 27% in litter size was observed in ZP3-α1AMPK-/- (ZP3-KO) female mice. Following in vitro fertilization, where conditions are stressful for the oocyte and embryo, ZP3-KO oocytes were 68% less likely to pass the 2-cell stage. In vivo and in cumulus-oocyte complexes, several proteins involved in junctional communication, such as connexin37 and N-cadherin were down-regulated in the absence of α1AMPK. While the two signalling pathways (PKA and MAPK) involved in the junctional communication between the cumulus/granulosa cells and the oocyte were stimulated in control oocytes, ZP3-KO oocytes exhibited only low phosphorylation of MAPK or CREB proteins. In addition, MII oocytes deficient in α1AMPK had a 3-fold lower ATP concentration, an increase in abnormal mitochondria, and a decrease in cytochrome C and PGC1α levels, suggesting perturbed energy production by mitochondria. The absence of α1AMPK also induced a reduction in histone deacetylase activity, which was associated with an increase in histone H3 acetylation (K9/K14 residues). Together, the results of the present study suggest that absence of AMPK, modifies oocyte quality through energy processes and oocyte/somatic cell communication. The limited effect observed in vivo could be partly due to a favourable follicle microenvironment where nutrients, growth factors, and adequate cell interaction were present. Whereas in a challenging environment such as that of in vitro culture following IVF, the phenotype is revealed.