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Nirmatrelvir (PF-07321332;NMV) the antiviral component of PAXLOVID PACK is a potent and selective inhibitor of the SARSCoV- 2 main protease (Mpro), which plays a critical role in viral replication. PAXLOVID PACK, comprised of nirmatrelvir and ritonavir (used as a pharmacokinetic enhancer), is an oral therapy currently in development as a therapeutic option for those infected with SARS-CoV-2 to prevent progression to severe disease, hospitalization, and death. It is also being tested for its potential benefit in the post-exposure prophylactic setting. Given that males and females of reproductive age are included in the intended patient population, we assessed the potential effects of NMV up to the limit dose of 1000 mg/kg/day in ICH guideline embryo-fetal development studies in rats and rabbits, and a fertility and early embryonic development study in rats. There were no effects on male and female fertility or early embryonic development in rats, and no severe manifestations of developmental toxicity in rats or rabbits. The lack of adverse findings reported here in nonclinical species is consistent with the intended therapeutic target of NMV (a virus specific protein not present in mammalian cells), the favorable off-target selectivity profile, and lack of genetic toxicity. All procedures performed on the animals in these studies were in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and Use Committee or through an ethical review process.
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Investigation of the effect COVID-19 mediated with autoantibodies has on reproductive outcomes is important. This study aimed to evaluate the profile of antiphospholipid antibodies (aPL) and their association with the outcomes of assisted reproductive technology (ART) programs in patients with a history of COVID-19. The study included 240 patients: 105 of them did not have a history of COVID-19 (group 1) and 135 of them had a history of COVID-19 (group 2) with a mild course (subgroup 2a, n = 85) or moderate course (subgroup 2b, n = 50). With the help of ELISA, serum antibodies (M, G) to cardiolipin, beta2-glycoprotein-I, annexin V (AnV), phosphatidylethanolamine (PE), phosphatidylserine, and phosphatidylserine/prothrombin complex were determined. The evaluated parameters were the indices of oogenesis, embryogenesis, ART intervention outcomes. In group 2, growing levels of anti-AnV and anti-PE IgG were observed more often (in 28 (20.7%) and 8 (5.9%) patients) than in group 1 (in 10 (9.5%) and 1 (0.95%);p = 0.02 and p = 0.045, respectively). In subgroup 2b we registered a higher level of anti-PE IgG and a higher incidence of early miscarriages (in 6 (12%) patients) than in group 1 (in 3 (2.9%)) (p = 0.024). Weak inverse correlations were found between the level of anti-PE IgG and the number of oocytes and zygotes. The results of this study suggest a negative impact of aPL-mediated COVID-19 on the outcomes of ART programs and the course of early pregnancy. Copyright © 2022 Pirogov Russian National Research Medical University. All rights reserved.
ABSTRACT
Objective: To investigate the outcomes of assisted reproductive technology (ART) programs in patients with a history of COVID-19 of various severity. Material(s) and Method(s): This prospective study enrolled 240 infertile patients. They were divided into group 1 comprising patients without a history of COVID-19 (n=105) and group 2 (n=135) including patients who less than 12 months before the ART cycle had mild (subgroup 2a, n=85) or moderate (subgroup 2b, n=50) COVID-19. The level of specific antibodies to SARS-CoV-2, parameters of oogenesis, early embryogenesis, and clinical outcomes of HRT were evaluated. Result(s): The parameters of oogenesis and embryogenesis, pregnancy and delivery rates did not differ between groups 1 and 2. A weak negative correlation was detected between the level of IgG-antibodies to SARS-CoV-2 and the number of obtained oocytes and embryos. Patients with an interval between COVID-19 and ART cycle <=6 months had a significantly higher relative number of poor-quality blastocysts than women with >6 months interval. Patients who experienced moderate COVID-19 had a high early miscarriage rate of (12%). Conclusion(s): COVID-19 can adversely affect reproductive outcomes, lead to a decrease in the number of oocytes and embryos obtained in ART cycles and their quality, and increase the risk of early miscarriage. More research is needed to investigate the mechanisms underlying the adverse effects of COVID-19 and the post-COVID syndrome. Copyright © A group of authors, 2022.
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Study question: Does a history of SARS-CoV-2 vaccination (CoronaVac) in males influence male fertility, gamete and embryo development, and in vitro fertilization (IVF) outcomes? Summary answer: CoronaVac vaccination in males may not have an adverse effect on patient's performance or the gamete and embryonic development potential during ART treatments. What is known already: Vaccines against COVID-19 have been approved for emergency use in several countries and regions, while concerns about the potential negative effect of vaccines on fertility contributed to vaccine hesitancy. It is urgent to explore the effect of CoronaVac on human fertility to help to overcome vaccine hesitancy about possible fertility impairment. Study design, size, duration: A retrospective cohort study enrolled couples undergoing IVF cycles between June and August 2021 at Reproductive Medicine Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. According to the history of SARS-CoV-2 vaccination in males, the participants were divided into the vaccination group and the non-vaccination group. Participants/materials, setting, methods: A self-controlled study of semen analyses for males before and after CoronaVac vaccination was conducted. Baseline characteristics were matched using propensity score matching. Participants were categorized into the unexposed group (non-vaccination) and exposed group (vaccination), and the population was 271 for each. Semen parameters and IVF outcomes were the main outcomes. Main results and the role of chance: Generally, no statistically significant differences were exhibited between the matched cohorts regarding embryo developmental parameters, including fertilization rate, cleavage rate, high-quality embryo rate, blastocyst formation rate, and available blastocyst rate, as well as clinical outcomes, such as implantation rate, biochemical pregnancy rate, and clinical pregnancy rate. Moreover, males after vaccination seemed to have fluctuated semen parameters including increased semen volume, lower motility, and decreased normal forms of sperms, while the motile sperm counts were similar. In addition, all semen parameters were above the lower reference limits. Limitations, reasons for caution: It was a single-center retrospective cohort study with a small sample size, and the men enrolled were suffering from infertility, which limited the generalizability of the conclusions. In addition, the endpoint of the current is a confirmation of clinical pregnancy, a study with a longer period of follow-up was urgent. Wider implications of the findings: Our findings suggested that CoronaVac vaccinations in males may not have adverse effects on patient's performance or the gamete and embryonic development potential during ART treatments. Larger studies among a wider population with longer followup in the future are required to support and validate our observations.
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The period of conception, pregnancy and the first 1000 days of life are crucial for a person's lifelong health. The recent rises in obesity before conception, through pregnancy and during childhood are increasing the risk of a non-communicable disease epidemic in the near future. Preventive measures targeted at the community level and implemented by local authorities may be the most effective way of creating healthy environments that improve lifelong health.
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Since melatonin was discovered by humans in 1958. It is believed to be related to vertebrate reproduction, especially seasonal reproduction. It is in a large measure attributed to the fact that melatonin is secreted by the pineal gland and exhibits a unique circadian rhythm. The diurnal variation of melatonin levels in the blood of vertebrates is accessed not just for reproductive rhythms, but for seasonal cycles of metabolic activities, immune functions, and behavioral expression. With the widespread application of modern technology, the effect of seasons on reproductive performance has been weakened, but it is because of the rhythmic secret ion characteristics of melatonin that animal reproduction and even human reproduction have greater controllability. In the past 60 years, a large number of studies reveal the effect of melatonin on animal reproduction. Nowadays, faced with the impact of African swine fever and novel coronavirus outbreaks on animal husbandry in China, how to improve female animal reproduction economically and effectively is the key to animal husbandry reproduction. This article mainly discusses about the researches of melatonin on female reproduction in terms of follicular development, hormone levels of organism, and embryonic development. The purpose of this article is to provide an effective basis for new research in this field, especially those with relevance to animal re- production and reproductive medicine, and for animal reproduction and production.
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The reproductive system can be infected by a variety of double-stranded RNA viruses, which disrupt ovary function and pregnancy. However, whether viral infection directly affects early embryonic development remains unknown. Here we show that Poly(I:C), which mimics a double-stranded RNA virus, significantly impaired mouse early embryonic development in vitro, and up-regulated TLR3 and IFNα at the two cells embryo stage. Further studies indicated that Poly(I:C)-treatment caused DNA damage and abnormal spindle morphology at the first cleavage. Moreover, CDX2 and SOX2 expression was decreased while blastocyst cell apoptosis was increased. Altogether, Poly(I:C) decreased the rate of successful in vitro fertilization via DNA damage and abnormal spindle morphology at the first cleavage and inhibited early embryonic development by inducing immune response and promoting blastocyst cell apoptosis. This study provides an implication for exploring the causes of reproductive disorders in mammals and humans caused by infection of double-stranded RNA virus.
Subject(s)
Embryonic Development , RNA, Double-Stranded , Animals , Blastocyst , DNA Damage , Female , Fertilization in Vitro , Humans , Mammals/genetics , Mice , PregnancyABSTRACT
OBJECTIVE: The ZyMot sperm separation device has proven favorable for use in elevated DNA fragmentation index (DFI) male factor patients, as an alternative to density gradient (DG) washing or surgically attained testicular sperm. In 2020, without fully understanding the infectivity and transmission potential of SARS-CoV2 in semen, a more liberal application of a timed ZyMot microfluidic swim-up was applied to our IVF patients to dilute out and minimize potential pathogens. This study aimed to evaluate whether the use of ZyMot sperm improved normal embryo development. MATERIALS AND METHODS: Retrospective analysis of PGT-A/ICSI cycles (N= 3219) between 2016-2020 was conducted to assessed fertilization rates (FR), blastocyst development/utilization rates (BUR) and genetic outcomes. Sperm preparations were performed per standard operating or manufacturer advised (i.e., ZyMot) procedures. Cumulus oocyte complexes were harvested 36h post-hCG, stripped and ICSI performed 3-5hr later. Zygotes were assessed at 16-18hr post-ICSI, and embryos cultured under humidified tri-gas incubation for up to 7 days. Blastocyst (BL) development as evaluated, and expanded BL or greater were biopsied on Days 5, 6 or 7. All BL were vitrified and genetics determinations for euploidy, aneuploidy and mosaicism were contrast. Applying Chi-squared analysis, we compared potential differences (p<0.05) between oocytes inseminated by DG wash (n=23,549), ZyMot wash (n=7,331) or testicular sperm (n=815). RESULTS: No difference in FR (76%), D5 BL formation (52-56%) or BUR (52-53%) was detected between DG and ZyMot washed sperm, respectively. Meanwhile, testicular sperm had a lower FR (70%;p<0.05), fewer BL forming on D5 (48%;p<0.05) and a lower overall BUR (41%;p<0.05). In addition, fewer testicular-derived BL were euploid (39%;p<0.05) with more aneuploidy (54%;p<0.05) than DG wash (50%, 39%;respectively) or ZyMot swim-up (45%, 37%;respectively) derived-embryos. No difference in potentially viable BL (Euploidy+Mosiac outcome) was observed between DG or ZyMot wash groups (63-64%). CONCLUSIONS: Application of the ZyMot device in the general IVF population offered no benefit to embryo development outcomes compared to standard sperm wash procedures. Our data does support that microfluidic separation of sperm using ZyMot for male factor patients with elevated DFI is a more favorable and cost-effective approach to surgically attaining testicular sperm when ejaculated sperm is possible. However, when insufficient motile and or morphologically normal sperm are available in an ejaculate further analysis is needed to elucidate the benefit of testicular biopsy treatment, as our assessments in this study may be biased by including men with non-obstructive azoospermia. IMPACT STATEMENT: The timed selection of morphologically normal, highly progressive sperm by ICSI, PVP-swim-out likely mimics the potential benefits the ZyMot device may offer infertile men with elevated sperm DNA fragmentation generating similar blastocyst development and euploidy outcomes.
ABSTRACT
To investigate the effects of tannins (TA) on porcine oocyte in vitro maturation (IVM), different concentrations of TA (0, 1, 10 and 100 µg/mL) were supplemented with a maturation medium and the COCs and subsequent embryonic development were examined. The results showed that 10 µg/mL TA significantly improved the cumulus expansion index (CEI), cumulus-expansion-related genes (PTGS1, PTGS2, PTX-3, TNFAIP6 and HAS2) expression and blastocyst formation rates after parthenogenetic activation (PA), in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT) compared to the control groups, but not oocyte nuclear maturation. Nevertheless, 10 µg/mL TA dramatically enhanced the mRNA expression of oocyte-development-related genes (BMP15, GDF9, CDC2 and CYCLIN B1), GSH, ATP, SOD1, PGC1α, BMP15, GDF9 and CDC2 levels and reduced intracellular ROS level in porcine oocytes. These results indicated that porcine oocyte cytoplasmic maturation was improved by 10 µg/mL TA treatment during IVM. In contrast, a high concentration of TA (100 µg/mL) significantly decreased the CEI and PTGS1, PTGS2, PTX-3 and HAS2 mRNA expressions in cumulus cells, and reduced oocyte nuclear maturation and the total cell numbers/blastocyst. In general, these data showed that 10 µg/mL TA supplementation has beneficial effects on oocyte cytoplasmic maturation and subsequent embryonic development in pigs.
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PURPOSE: We aimed to assess whether home collection and increased time to semen processing are associated with altered sperm parameters, fertilization rates (FR), day 5 usable quality blastocyst development rates (D5-UQBR), or pregnancy rates (PR) in patients undergoing IVF/ICSI. METHODS: This was a retrospective cohort study of patients undergoing IVF/ICSI before the coronavirus disease 2019 (COVID-19) pandemic ("clinic" collection, n = 119) and after COVID-19 ("home" collection, n = 125) at an academic fertility practice. Home collection occurred within 2 h of semen processing. Patient sperm parameters, FR (#2PN/MII), D5-UQBR (# transferable and freezable quality blastocysts/# 2PN), and PR in fresh transfer cycles were compared between clinic and home groups with t-tests. The association between time to processing on outcomes was assessed with regression modeling, controlling for potential confounders. RESULTS: Mean male age was 37.9 years in the clinic group and 37.2 years in the home group (p = 0.380). On average, men were abstinent for 3.0 days (SD 1.7) in the clinic group and 4.1 days (SD 5.4) in the home group (p = 0.028). Mean time to semen processing was 35.7 min (SD 9.4) in the clinic group and 82.6 min (SD 33.8) in the home group (p < 0.001). There was no association between collection location and increased time to processing on sperm motility, total motile count, FR, D5-UQBR, or PR. CONCLUSIONS: Our data suggest that increased time to processing up to 2 h with home semen collection does not negatively impact sperm parameters or early IVF/ICSI outcomes.