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1.
J Gynecol Obstet Hum Reprod ; 50(9): 102149, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33872814

RESUMO

OBJECTIVE: Women with septate uteri are at risk for subfertility, recurrent miscarriage, and preterm birth. It is not clear if hysteroscopic septum resection is beneficial to subsequent in vitro fertilization-intracytoplasmic sperm injection o (IVF/ICSI) outcomes in women with primary infertility. STUDY DESIGN: We analyzed all 278 women with uterine septum and primary infertility between January 2011 and January 2019. In this retrospective cohort study, the patients were divided into a surgery group and an expectant (non-surgery) group. RESULTS: Among them, 87 had a complete and 191 a partial septate uterus. The IVF-ET characteristics of the two groups showed no significant differences in the patients' age, body mass index, or basal follicle-stimulating hormone, luteinizing hormone, and estradiol levels (P>0.05). The miscarriage rate in those who underwent hysteroscopic septum resection, however, was significantly reduced (5.1% vs. 12.9%, P = 0.035). In contrast, the live birth rate between the two groups revealed no significant difference (51.4% vs. 43.6%, P = 0.1771), nor did the obstetric and neonatal outcomes (P>0.05). CONCLUSIONS: Hysteroscopic septum resection can be recommended prior to IVF/ICSI.

2.
Reprod Sci ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33721295

RESUMO

In this retrospective study, the effect of preimplantation genetic testing for aneuploidy (PGT-A) was evaluated in women younger than 38 years with a history of one prior miscarriage and embryonic chromosomal abnormalities were detected in previous products of conception (POCs). Abnormal karyotypes were detected in POCs at our center between January 2014 and December 2017. Of the women included in this analysis, 124 continued with conventional in vitro fertilization/intracytoplasmic sperm injection cycles (non-PGT-A group) and 93 chose PGT-A cycles (PGT-A group), and the pregnancy outcomes in both groups were compared. Although the clinical pregnancy rate per embryo transfer was significantly higher in the PGT-A group (67.23% vs. 51.85%, p-adj = 0.01), no between-group differences were found in the live birth rate or miscarriage rate (45.38% vs. 40.74%, p-adj = 0.59; 16.25% vs. 14.29%, p-adj = 0.15). Women in both groups had comparative cumulative live birth rates (PGT-A vs. non-PGT-A, 58.06% vs. 53.23%, p = 0.48). The main results of this study suggest that PGT-A is not associated with an increased likelihood of a live birth or a decreased rate of miscarriage among women younger than 38 years without recurrent pregnancy loss and with a history of POCs with embryonic chromosomal abnormalities.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33619544

RESUMO

CONTEXT: Accumulated literature has demonstrated the role of circadian clock in ovarian steroid hormone synthesis and attribute embryo implantation failure associated with arrhythmic circadian clock genes to insufficient ovarian-derived progesterone synthesis. Researches on expression of core circadian clock genes in the endometrium itself and possible roles in compromised endometrial receptivity and recurrent implantation failure (RIF) are limited. OBJECTIVE: We aimed to assess the core circadian clock gene profiling in human endometrium across the menstrual cycle and the possible gene interaction networks in the endometrial receptivity of window of implantation (WOI) as well as RIF. DESIGN: The study was initially an in silico study, with confirmatory lab-based data from primary human endometrial stromal cells (hESCs) as well as endometrial biopsies obtained from 60 women undergoing gynecological surgery. SETTING: Clinical research center. PATIENTS AND OTHER PARTICIPANTS: The study included 30 RIF women and 30 age-matched and body mass index-matched controls. RESULTS: Initial data mining and bioinformatics analysis of human endometrial microarray datasets across menstrual cycle and between RIF women versus controls demonstrated the varied expression of core circadian clock genes across menstrual cycle, including the key role of PER2 in WOI and RIF. A PER2-centered network was investigated in the regulation of endometrial receptivity. We also confirmed the evidently increased mRNA expression of SHTN1, RXFP1, KLF5, and STEAP4 in the endometrium of RIF women, displaying the same trend as PER2 did, without any changes in MT1E and FKBP5. Treatment of PER2 siRNA in hESCs verified the positive regulation of PER2 to SHTN1, KLF5, and STEAP4. CONCLUSION: Aberrant expression of endometrial PER2 might contribute to impaired endometrial receptivity and development of RIF via regulating SHTN1, KLF5, and STEAP4.

4.
Trends Endocrinol Metab ; 32(3): 170-189, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33478870

RESUMO

Following embryo implantation, extravillous trophoblasts (EVTs) invade the maternal decidua to a certain extent during early pregnancy, which is critical for normal placentation and successful pregnancy in humans. Although sharing a similar protein structure, the transforming growth factor-ß (TGF-ß) superfamily members exert divergent functions in regulating EVT invasion, which contributes to a relative balance of TGF-ß superfamily proteins in precisely modulating this process at the maternal-fetal interface during the first trimester of pregnancy. This review details recent advances in our understanding of the functions of TGF-ß superfamily members and their corresponding receptors, signaling pathways, and downstream molecular targets in regulating human EVT invasion from studies using various in vitro or ex vivo experimental models. Also, the relevance of these discoveries about TGF-ß superfamily members to adverse pregnancy outcomes is summarized. The application of 3D culture trophoblast organoids, single-cell sequencing, and microfluidic assays in EVT invasion studies will help better reveal the molecular mechanisms through which TGF-ß superfamily members regulate human EVT invasion, shedding light on the development of innovative strategies for predicting, diagnosing, treating, and preventing adverse human pregnancy outcomes related to EVT invasion dysfunction.

5.
Aging (Albany NY) ; 13(2): 2118-2134, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33318299

RESUMO

Advanced maternal-age is a major factor adversely affecting oocyte quality, consequently worsening pregnancy outcomes. Thus, developing strategies to reduce the developmental defects associated with advanced maternal-age would benefit older mothers. Multiple growth factors involved in female fertility have been extensively studied; however, the age-related impacts of various growth factors remain poorly studied. In the present study, we identified that levels of insulin-like growth factor 2 (IGF2) are significantly reduced in the serum and oocytes of aged mice. We found that adding IGF2 in culture medium promotes oocyte maturation and significantly increases the proportion of blastocysts: from 41% in the untreated control group to 64% (50 nM IGF2) in aged mice (p < 0.05). Additionally, IGF2 supplementation of the culture medium reduced reactive oxygen species production and the incidence of spindle/chromosome defects. IGF2 increases mitochondrial functional activity in oocytes from aged mice: we detected increased ATP levels, elevated fluorescence intensity of mitochondria, higher mitochondrial membrane potentials, and increased overall protein synthesis, as well as increased autophagy activity and decreased apoptosis. Collectively, our findings demonstrate that IGF2 supplementation in culture media improves oocyte developmental competence and reduces meiotic structure defects in oocytes from aged mice.

6.
Environ Int ; 146: 106231, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33171380

RESUMO

BACKGROUND: Whether exposure to airborne particulate matter less than 2.5 µm (PM2.5) could impact human fecundity is unclear. We aimed to evaluate the potential impact of PM2.5 exposure on time to pregnancy (TTP) and the prevalence of infertility in the general Chinese population. METHOD: We collected reproductive information, sociodemographic characteristics, and lifestyle data of 10,211 couples at risk of pregnancy from a large-scale community-based fertility survey in China. Then, we estimated each participant's 1-year, 3-year, and 5-year average PM2.5 exposure levels based on remote sensing information. After adjusting for demographic, lifestyle, and environmental co-variables, discrete-time Cox regression models were used to estimate the fecundability odds ratio (FOR) per 10 µg/m3 change of PM2.5. We also estimated the odds ratio (OR) of infertility per 10 µg/m3 change of PM2.5, using logistic regression models. FINDINGS: Among the 10,211 couples, 6,875 (67%) had conceived spontaneously, with a median TTP of 5 months (interquartile range: 2-10 months). The median PM2.5 exposure was 56.8 µg/m3, with a wide range of 9.2-93.5 µg/m3. In Cox regression models, each increase of 10 µg/m3 in the 1-year average PM2.5 exposure was associated with a significant decrease in fecundity by 11% (FOR: 0.89; 95% confidence interval [CI]: 0.86-0.92). In logistic regression models, it was also associated with an 20% increased likelihood of infertility (OR: 1.20; 95% CI: 1.13-1.27). CONCLUSION: PM2.5 exposure was associated with reduced human fecundity, presented by a longer TTP and higher odds of infertility, which might explain the increased infertility rates in areas with heavy PM2.5 pollution.

7.
Mol Ther ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33212300

RESUMO

Polycystic ovary syndrome (PCOS) is an endocrine-related disease and global cause of infertility that is associated with abnormal folliculogenesis. Inhibited granulosa cell (GC) proliferation is recognized as a key factor that underlies aberrant follicle maturation. Many epigenetic landscape modifications have been characterized in PCOS patients. However, the epigenetic regulation pathways in follicular dysplasia are not completely understood. In this study, we reported a novel mechanism of DNA hypomethylation induced by long non-coding RNAs (lncRNAs) and its function in cell cycle progression. We observed that lnc-MAP3K13-7:1 was highly expressed in GCs from patients with PCOS, with concomitant global DNA hypomethylation, decreased DNA methyltransferase 1 (DNMT1) expression, and increased cyclin-dependent kinase inhibitor 1A (CDKN1A, p21) expression. In KGN cells, lnc-MAP3K13-7:1 overexpression resulted in cell cycle arrest in the G0/G1 phase, as well as the molecular inhibition and genetic silencing of DNMT1. Mechanistically, lnc-MAP3K13-7:1 inhibited DNMT1 expression by acting as a protein-binding scaffold and inducing ubiquitin-mediated DNMT1 protein degradation. Moreover, DNMT1-dependent CDKN1A promoter hypomethylation increased CDKN1A transcription, resulting in attenuated GC growth. Our work uncovered a novel and essential mechanism through which lnc-MAP3K13-7:1-dependent DNMT1 inhibition regulates CDKN1A/p21 expression and inhibits GC proliferation.

8.
Endocrine ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33169290

RESUMO

PURPOSE: Anti-Müllerian hormone (AMH) is crucial for folliculogenesis. Prenatal exposure to AMH in mice produces a phenocopy of polycystic ovary syndrome (PCOS) in the adult female offspring. The aim of this study was to determine whether genetic variation in AMH gene contribute to PCOS in women of Chinese ancestry. METHODS: We conducted a case-control genetic study in 383 PCOS case and 433 control women of Chinese ancestry. The exons and the 5' flanking region of AMH were sanger sequenced. Bioinformatic prediction of variant deleteriousness was performed. RESULTS: Seven novel heterozygous variants along with 15 rare known variants in AMH were identified in women with PCOS but not in controls. The novel variants included one frameshift variant (c.125_129delACTTG), one synonymous variant (c.1095C>T), one variant (c.-14T>C) in the 5'-untranslated region (UTR), four variants(c.-775C>T, c.-682C>T, c.-333A>G, c.-137A>T) in 5' flanking sequence. Of all the AMH variants identified in women with PCOS, eight were predicted to be deleterious by bioinformatic analysis. The PCOS carriers of predicted-to-be-deleterious PCOS-specific AMH variants had increased total follicle numbers compared to PCOS noncarriers (p = 0.021). CONCLUSIONS: Our findings suggest the AMH plays a role in the development of PCOS. The exact mechanisms by which the predicted-to-be-deleterious novel and rare AMH variants described in our study affect AMH function requires further study.

9.
Prenat Diagn ; 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009680

RESUMO

OBJECTIVE: The objective of the study is to assess the clinical application of noninvasive prenatal testing (NIPT) for VTS pregnancies after the treatment of assisted reproductive technology (ART). METHOD: This was a retrospective study on VTS pregnancies through ART treatment. Participants underwent NIPT at 11 to 13 weeks gestation by sequencing. Resampling was recommended for both positive and testing failure cases. For NIPT positive results, participants were advised to have invasive testing. Clinical outcomes were obtained by telephone interview. RESULTS: In total of 579 cases, testing failure rates after first sampling and resampling were 7.6% and 1.4%, respectively. Twelve positive results were reported by NIPT. But only one true positive was confirmed, giving a PPV of 8%. A total of 576 cases completed the follow-up (including 533 NIPT negative, 12 positive, and 31 testing failure) and three cases lost follow-up. Among the 536 cases with NIPT negative results, 504 (94.0%) resulted in live-birth and 29 (5.4%) resulted in miscarriage or stillbirths. No false-negative result was reported. CONCLUSION: NIPT has the potential to be used in prenatal screening for VTS pregnancies. For the pregnant women who obtained positive and testing failure results, resampling after 15 weeks of gestation is recommended.

10.
Fertil Steril ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33041053

RESUMO

OBJECTIVE: To examine different expression profiles of plasma exosomal microRNA (miRNA) in polycystic ovary syndrome (PCOS) patients and controls, and their potential roles in PCOS pathogenesis. DESIGN: Experimental study. SETTING: Center for reproductive medicine. PATIENT(S): Seventy-five PCOS patients and 75 age-matched controls. INTERVENTION(S): Plasma exosomes miRNAs sequenced from 15 PCOS patients and 15 controls. MAIN OUTCOME MEASURE(S): Plasma exosomal miRNA expression and the correlation between PCOS phenotypes and miRNA expression. RESULT(S): The sequenced plasma exosomes miRNAs were further determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in a larger cohort, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Correlation analysis and receiver operating characteristic (ROC) curve analysis were used to determine the association between PCOS phenotypes and miRNA expression. The miRNA sequencing revealed 34 exosomal miRNAs were differentially expressed between PCOS patients and controls. Via qRT-PCR, five differentially expressed miRNAs (miR-126-3p, miR-146a-5p, miR-20b-5p, miR-106a-5p, and miR-18a-3p) were identified. The GO and KEGG analyses predicted their target functions included axon guidance, mitogen-activated protein kinase (MAPK) signaling, endocytosis, circadian rhythms, and cancer pathways. The expression of these miRNAs correlated with menstrual cycle, antral follicle count, hormone level, and combined yielded a ROC curve area of 0.781 in discriminating PCOS patients from the controls. CONCLUSION(S): Differential expression of plasma exosomal miRNAs may confer a risk of PCOS and may be helpful in distinguishing PCOS patients from controls. Certain miRNA expression may associated to the disease progression, which could help in an epigenetic understanding of the pathophysiology of PCOS.

11.
J Clin Endocrinol Metab ; 105(10)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32772095

RESUMO

CONTEXT: Premature ovarian insufficiency (POI) is characterized by cessation of menstruation before 40 years of age and elevated serum level of FSH (>25 IU/L). Recent studies have found a few causative genes responsible for POI enriched in meiotic recombination and DNA damage repair pathways. OBJECTIVE: To investigate the role of variations in homologous recombination genes played in POI pathogenesis. METHODS: The whole exome sequencing was performed in 50 POI patients with primary amenorrhea. Functional characterizations of the novel variants were carried out in budding yeast and human cell line. RESULTS: We identified 8 missense variants in 7 homologous recombination genes, including EXO1, RAD51, RMI1, MSH5, MSH2, MSH6, and MLH1. The mutation p.Thr52Ser in EXO1 impaired the meiotic process of budding yeast and p.Glu68Gly in RAD51-altered protein localization in human cells, both of them impaired the efficiency of homologous recombination repair for DNA double-stranded breaks in human cells. CONCLUSIONS: Our study first linked the variants of EXO1 and RAD51 with POI and further highlighted the role of DNA repair genes in ovarian dysgenesis.

12.
J Assist Reprod Genet ; 37(10): 2535-2544, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32772270

RESUMO

PURPOSE: To evaluate whether miR-148a-3p overexpression is associated with disrupted decidualization of recurrent implantation failure (RIF). METHODS: Endometrial miRNA and mRNA expression profiles during the implantation window derived from women with and without RIF were identified using microarray and RT-qPCR. Immortalized human endometrial stromal cells (HESCs) were cultured for proliferation and in vitro decidualization assays after enhancing miR-148a-3p expression or inhibiting putative target gene homeobox C8 (HOXC8) expression. RT-qPCR, western blot, and luciferase reporter assays were used to confirm the relationship between miR-148a-3p and HOXC8 gene. RESULTS: MiR-148a-3p was significantly upregulated in RIF endometrial tissues. Forced expression of miR-148a-3p notably attenuated HESC in vitro decidualization. Mechanistic studies revealed that miR-148a-3p directly bounds to the HOXC8 3' untranslated region (3'UTR) and suppressed HOXC8 expressions in both mRNA and protein levels. Further investigations demonstrated that inhibition of HOXC8 in HESCs induced similar effects on decidual process as those induced by miR-148a-3p overexpression. CONCLUSION: Taken together, our findings suggested that elevated miR-148a-3p might account for flawed decidualization in RIF by negatively regulating HOXC8, raising the possibility that miR-148a-3p might be a novel therapeutic target in RIF.

13.
Front Cell Dev Biol ; 8: 587, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850784

RESUMO

Background: 4-vinylcyclohexene diepoxide (VCD) has long been considered a hazardous occupational chemical that promotes ovarian failure. However, VCD is also used as a research compound to chemically induce animal models of premature ovarian insufficiency (POI), and in related work we unexpectedly found that VCD apparently exhibits both dose- and duration-dependent opposing, hormone-like effects on the maintenance of the primordial follicle pool, follicle development, and ovulation induction. Results: We conducted experiments with cultured murine ovaries and performed transplantation experiments using postnatal day (PD) 2 and PD12 mice and found that low-dose, short-term exposure to VCD (VCDlow) actually protects the primordial/primary follicle pool and improves the functional ovarian reserve (FOR) by disrupting follicular atresia. VCDlow inhibits follicular apoptosis and regulates the Pten-PI3K-Foxo3a pathway. Short-term VCD exposure in vivo (80 mg/kg, 5 days) significantly increases the number of superovulated metaphase II oocytes, preovulatory follicles, and corpus luteum in middle-aged mice with diminished ovarian reserve (DOR). We demonstrate that low-dose but not high-dose VCD promotes aromatase levels in granulosa cells (GCs), thereby enhancing the levels of estradiol secretion. Conclusion: Our study illustrates a previously unappreciated, hormone-like action for the occupational "ovotoxin" molecule VCD and strongly suggests that VCDlow should be explored for its potential utility for treating human ovarian follicular development disorders, including subfertility in perimenopausal women.

14.
Trials ; 21(1): 719, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807234

RESUMO

BACKGROUND: Recurrent implantation failure (RIF) brings great challenges to clinicians and causes deep frustration to patients. Previous data has suggested that prednisone may play a promising role in the establishment of pregnancy and help improve the pregnancy outcome in women with RIF. But there is insufficient evidence from randomized clinical trials that had adequate power to determine if prednisone can enhance live births as the primary outcome. METHODS/DESIGN: This trial is a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial (1:1 ratio of prednisone versus placebo). Infertile patients with RIF who intend to undergo frozen-thawed embryo transfer (FET) after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) or pre-implantation genetic testing for aneuploidy (PGT-A) will be enrolled and randomly assigned to two parallel groups. Participants will be given the treatment of prednisone or placebo from the start of endometrial preparation till the end of the first trimester of pregnancy if pregnant. The primary outcome is live birth rate. DISCUSSION: The results of this study will provide evidence for the effect of prednisone on pregnancy outcomes in patients with RIF. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800018783 . Registered on 9 October 2018.

15.
Diabetologia ; 63(10): 2150-2157, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32757153

RESUMO

AIMS/HYPOTHESIS: Assisted reproductive technology (ART) is the most widely used treatment for infertility and has resulted in millions of births worldwide. The safety of the offspring has been of the utmost concern. Previous studies suggested an increase in metabolic disorders in offspring later in life. The aim of the present study was to investigate metabolic changes at age 6-10 years in offspring conceived as a result of in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI). METHODS: A total of 380 children born from IVF/ICSI and a matched control group of 380 naturally conceived children, all aged 6-10 years, were recruited. Anthropometric measures, ultrasound and serum tests were performed for body mass, glucose metabolism and lipid profiles, and examination of vasculature structure. RESULTS: The children conceived by ART showed significantly higher fasting blood glucose and serum insulin levels and HOMA-IR (adjusted ß [95% CI]: fasting blood glucose 0.49 [0.42, 0.55]; loge-transformed insulin 0.28 [0.20, 0.35]; loge-transformed HOMA-IR 0.38 [0.30, 0.46]), as well as a lower HOMA-B and serum apolipoprotein A (ApoA) levels (adjusted ß [95% CI]: loge-transformed HOMA-B -0.19 [-0.27, -0.11]; ApoA -0.17 [-0.21, -0.13]), when compared with the control group. Furthermore, the ultrasound scan indicated elevated carotid intima-media thickness in children conceived by ART (ß 0.13 [95% CI 0.12, 0.13]). CONCLUSIONS/INTERPRETATION: Children conceived by IVF/ICSI have a less favourable glucose and cardiovascular metabolic profile in childhood when compared with naturally conceived children. The underlying mechanisms and potential long-term consequences need to be elucidated in future studies. Graphical abstract.

16.
Front Genet ; 11: 716, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719721

RESUMO

Adenomyosis is a prevalent, estrogen-dependent uterine disorder wherein endometrial cells are abnormally present in the myometrium and are surrounded by hyperplastic/hypertrophic smooth muscle. Its etiology is unclear, although endometrial cell invasion into the myometrium has been postulated. RNA methylation, particularly N6-methyladenosine (m6A), plays an important role in regulating various physiological processes and invasive disorders. The goal of this in silico and lab-based experimental study was to explore a possible role for m6A in adenomyosis. Gene expression profiles of both the endometrium and myometrium of women with adenomyosis (cases) and without disease (controls) were obtained from the publicly available Gene Expression Omnibus (GEO) database. In the endometrium, STRING database analysis revealed that METTL3 functions as a "hub" gene of m6A RNA methylation regulators, and the genes involved in m6A regulation, including METTL3, FTO, ZC3H13, and YTHDC1 expression, were significantly decreased in cases versus controls. Functional, co-expression, and correlational analyses of endometrium from cases versus controls revealed decreased total m6A levels, induced by METTL3, and the downstream elevated insulin-like growth factor-1(IGF1) and D-Dopachrome Tautomerase (DDT), with the latter two having known functions in epithelial proliferation and cell migration, which are important processes in the pathogenesis of adenomyosis in endometrium. m6A RNA methylation regulators, including RBM15/15B, ALKBH5, FTO, YTHDF1/2, KIAA1429, HNRNPC, METTL3, ZC3H13, and YTHDC2, were also differentially expressed in the myometrium from cases versus controls. We validated decreased total m6A levels and differential expression of m6A RNA methylation regulators in the myometrium of patients with adenomyosis using qRT-PCR, immunohistochemistry and tissues available from our biorepository. Possible target genes, including cadherin 3(CDH3), sodium channelß-subunit 4 (SCN4B), and placenta-specific protein 8 (PLAC8), which are involved in cell adhesion, muscle contraction and immune response in the myometrium of adenomyosis patients were also validated. Thus, through extensive public database mining and validation of select genes, this study, for the first time, implicates m6A and its methylation regulators in the pathogenesis of adenomyosis. Follow on functional studies are anticipated to elucidate mechanisms involving m6A and its regulators and down-stream effectors in the pathogenesis of this enigmatic reproductive disorder and potentially identify druggable targets to control its associated symptoms.

17.
Hum Reprod ; 35(7): 1711-1718, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32619219

RESUMO

STUDY QUESTION: Does the inheritance of polycystic ovary syndrome (PCOS) susceptibility single-nucleotide polymorphism affect the phenotype of offspring? SUMMARY ANSWER: Male offspring who inherit PCOS-related genetic variations from PCOS mothers were more susceptible to developing the metabolic abnormality in their later life. WHAT IS KNOWN ALREADY: Genetic factors are considered the major etiology of PCOS. Previous studies have highlighted that offspring of women with PCOS had an increased risk of the same disease or PCOS-like symptoms. STUDY DESIGN, SIZE, DURATION: The study involved 172 children born to women with PCOS and 529 children born to non-PCOS women. All offspring were conceived by assisted reproductive technologies. PARTICIPANTS/MATERIALS, SETTING, METHODS: The offspring ranged from 1 to 8 years old. Metabolic phenotype analyses were performed in offspring aged from 2 to 8 (N = 619). Sanger sequencing, TaqMan and Sequenom MassARRAY were used to sequence the samples. MAIN RESULTS AND THE ROLE OF CHANCE: In male offspring, the fasting insulin (FINS) (P = 0.037) homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.038) and the homeostasis model assessment of pancreatic beta-cell function (HOMA-ß) (P = 0.038) levels were higher in offspring of PCOS mothers compared to controls. In female offspring, PCOS offspring had a significantly higher anti-Müllerian hormone levels (P = 0.001) compared to those from control mothers. In male offspring of PCOS mothers, subjects with a T allele at rs2349415 in the gene FSHR had higher FINS (P = 0.023), HOMA-IR (P = 0.030) and HOMA-ß levels (P = 0.013) than those in the homozygous CC group. The same increased trend in FINS, HOMA-IR and HOMA-ß levels could be found in the CC and TC group in rs2268361 located in gene FSHR compared to the TT group (P = 0.029, P = 0.030, P = 0.046, respectively). As for rs10818854 in the DENND1A gene, the AA and AG group had a higher FINS (P = 0.037) and HOMA-ß (P = 0.008) levels than the homozygous CC group. LIMITATIONS, REASONS FOR CAUTION: Firstly, the offspring may be too young to see any phenotype changes. Secondly, this study only analyzed the differences of genotype frequency using the dominant model instead of all three models due to the limited sample size of the homozygous model. The results, therefore, should be replicated and performed in a larger sample size population. Thirdly, environmental impacts cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: The findings presented in this thesis add to our understanding the changes in offspring born to PCOS women and remind us to consider early intervention to avoid more severe effects. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China 2017YFC1001000 (to Z.-J.C.), the National Natural Science Foundation of China 81430029 (to Z.-J.C.), 81622021 and 31571548 (to H.Z.), the National Natural Science Foundation of Shandong Province JQ201816 (to H.Z.) and Shandong Provincial Key Research and Development Program 2017G006036 (to L.-L.C.) and 2018YFJH0504 (to Z.-J.C.). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

18.
Reprod Biomed Online ; 41(3): 395-401, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32600942

RESUMO

RESEARCH QUESTION: Is there a difference in live birth rate between a freeze-only strategy and fresh embryo transfer, and what is the effect of varying progesterone concentrations on the day of human chorionic gonadotrophin (HCG) administration? DESIGN: A secondary analysis of data from three randomized trials comparing the live birth rate after elective frozen versus fresh embryo transfer, which respectively enrolled 1508 women with polycystic ovary syndrome, 2157 ovulatory women who underwent cleavage-stage embryo transfer and 1650 ovulatory women who underwent single blastocyst transfer. Women were randomly assigned to the frozen or fresh embryo transfer group in the original trials. The primary outcome was live birth rate after the initial embryo transfer. RESULTS: The live birth rate after a freeze-only strategy was consistently higher than fresh embryo transfer at any progesterone concentration on the day of HCG administration. Nonetheless, the between-group difference in live birth rate after frozen versus fresh embryo transfer was greater in women with progesterone concentrations ≥1.14 ng/ml (52.7% versus 37.3%, odds ratio (OR) 1.88, 95% confidence interval (CI) 1.55-2.27, P = 7.89 â€¯×  10-11) than in women with progesterone concentrations <1.14 ng/ml (53.3% versus 48.1%, OR 1.23, 95% CI 1.08-1.41, P = 0.002). In women with progesterone concentration ≥1.14 ng/ml, frozen embryo transfer also resulted in higher rates of conception and clinical pregnancy than fresh embryo transfer. CONCLUSION: In women with normal or high ovarian response, a freeze-only strategy resulted in a higher live birth rate than fresh embryo transfer, irrespective of progesterone concentration. Moreover, women with progesterone concentration ≥1.14 ng/ml may benefit more from a freeze-only strategy.

19.
J Clin Endocrinol Metab ; 105(12)2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32506120

RESUMO

CONTEXT: Dysregulated immune hemostasis occurs in unexplained recurrent spontaneous abortion (URSA). Synthesized by cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE), hydrogen sulfide (H2S) promotes regulatory T-cell differentiation and regulates immune hemostasis; yet, its role in URSA is elusive. OBJECTIVE: To determine if H2S plays a role in early pregnancy and if dysregulated H2S signaling results in recurrent spontaneous abortion. DESIGN: First trimester placenta villi and decidua were collected from normal and URSA pregnancies. Protein expression was examined by immunohistochemistry and immunoblotting. Human trophoblast HTR8/SVneo and JEG3 cells were treated with H2S donors; HTR8/SVneo cells were transfected with CBS ribonucleic acid interference (RNAi) or complementary deoxyribonucleic acid. Cell migration and invasion were determined by transwell assays; trophoblast transcriptomes were determined by RNA sequencing (RNA-seq). Wild-type, CBS-deficient, and CBA/J × DBA/2 mice were treated with CBS and CSE inhibitors or H2S donors to determine the role of H2S in early pregnancy in vivo. RESULTS: CBS and CSE proteins showed cell-specific expressions, but only CBS decreased in the villous cytotrophoblast in URSA versus normal participants. H2S donors promoted migration and invasion and MMP-2 and VEGF expression in human placenta trophoblast cells that contain SV40 viral deoxyribonucleic acid sequences (HTR8/SVneo) and human placenta trophoblast cells (JEG3 cells), similar to forced CBS expression in HTR8/SVneo cells. The CBS-responsive transcriptomes in HTR8/SVneo cells contained differentially regulated genes (ie, interleukin-1 receptor and prostaglandin-endoperoxide synthase 2) that are associated with nuclear factor-κB-mediated inflammatory response. In vivo, dysregulated CBS/H2S signaling significantly increased embryonic resorption and decidual T-helper 1/T-helper 2 imbalance in mice, which was partially rescued by H2S donors. CONCLUSION: CBS/H2S signaling maintains early pregnancy, possibly via regulating maternal-fetal interface immune hemostasis, offering opportunities for H2S-based immunotherapies for URSA.

20.
Fertil Steril ; 113(6): 1093-1099, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32482244

RESUMO

As the first paper in this series of Views and Reviews on randomized controlled trials (RCTs), we aim to provide the basics of RCTs in infertility research. In this paper, we discuss the need and ethical considerations of large trials in infertility research and important aspects to guarantee the quality of a trial, including protocols, registrations and monitoring, issues of study design and analysis, and reporting standards. Because most of the treatment effects we would like to study represent relatively small signal-to-noise ratios, large RCTs are required to provide sufficient power to answer these questions. Trial protocols, registrations, and monitoring facilitate the transparency of conduct, analysis, and reporting of the trial. Issues of trial design and analysis, such as nonblinding and misuse of the denominators, are common in published trials in this area and could be further improved. Finally, following the current reporting standard facilitates complete and transparent reporting, critical appraisal, and interpretation.

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