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Pang L.,Shandong University | Wei Z.,Guangxi Medical University | Li O.,Guangxi Medical University | Huang R.,Guangxi Medical University | And 7 more authors.
PLoS ONE | Year: 2013

Recurrent spontaneous abortion (RSA) is a health problem that affects approximately 1% to 5% reproductive age woman. Yet, in around half of these patients, the mechanism for RSA is unexplained. Recent studies have indicated that placental ischemia/hypoxia and endothelial dysfunction are important factors in miscarriage. Other studies have indicated that the level and expression of soluble FMS-like tyrosine kinase-1 (sFlt1) is increased under a hypoxic environment. However, decreased sFlt-1 in the maternal circulation during the first trimester has recently been proposed as a potential marker for identifying risk of pregnancy loss. In this prospective study clinical samples were obtained within a short time after the fetal death, protein expression and maternal serum levels of sFlt1 were assessed and compared to samples taken from those with normal pregnancies. Our results indicate that levels of VEGF and sFlt-1 are both increased in women during early pregnancy compared women that are not pregnant (p<0.05) indicating that VEGF and sFlt-1 are both associated with pregnancy. More importantly, we detected a significant (p<0.05) increase in sFlt1 and VEGF levels and expression in the RSA patients who suffered subsequent miscarriages compare to controls. These results demonstrate that there is likely a relationship between VEGF, sFlt-1 and RSA suggesting that the high levels and over expression of sFlt-1 and VEGF might be associated with the pathogenesis of RSA. © 2013 Pang et al. Source


Zhang N.,Shandong University | Zhang N.,Center for Reproductive Medicine | Hao C.-F.,Center for Reproductive Medicine | Zhuang L.-L.,Shandong University | And 11 more authors.
Reproductive BioMedicine Online | Year: 2013

This study assessed the true accuracy of follicular output rate (FORT) as a prognostic indicator of response to FSH and reproductive competence after IVF/intracytoplasmic sperm injection. A total of 1643 cycles, including 140 polycystic ovary syndrome (PCOS) patients who underwent ovarian stimulation, were studied. FORT was calculated as the ratio of preovulatory follicle count on the day of stimulation × 100/small antral follicle count (3-10 mm in diameter) at baseline. Low, medium and high FORT groups were defined according to tertile values. Among 1503 non-PCOS cycles, numbers of retrieved oocytes and of all embryos that could be transferred, as well as rates of good-quality embryos, embryo implantations and clinical pregnancies, progressively increased with FORT. In PCOS patients, FORT were significantly lower in patients who achieved clinical pregnancy compared with those who did not (0.56 ± 0.21 versus 0.66 ± 0.29, P = 0.031). Fertilization and good-quality embryo rates were significantly higher with medium FORT than low and high FORT (P = 0.001 and P = 0.047, respectively). Medium FORT in PCOS patients and high FORT in non-PCOS patients may predict better outcomes for IVF/ICSI. In the present study, we aimed to assess the true accuracy of the follicular output rate (FORT) as a prognostic indicator of the response to FSH and reproductive competence after IVF/intracytoplasmic sperm injection (ICSI). A total of 1643 IVF/ICSI cycles, including 140 polycystic ovary syndrome (PCOS) patients who underwent ovarian stimulation, were studied. FORT was calculated as the ratio of the preovulatory follicle count (PFC) on the day of human chorionic gonadotrophin stimulation × 100/small antral follicle count (AFC; 3-10 mm in diameter) at baseline. Low, medium and high FORT groups were defined according to the tertile values. Among 1503 non-PCOS cycles, the numbers of retrieved oocytes and of all embryos that could be transferred, as well as the rates of good-quality embryos, embryo implantations and clinical pregnancies, progressively increased from the lower to higher FORT groups. In PCOS patients, FORT was significantly lower in the patients who achieved clinical pregnancy compared with those who did not (0.56 ± 0.21 versus 0.66 ± 0.29, P < 0.05). Fertilization and good-quality embryo rates were significantly higher in the medium FORT group compared with the low and high FORT groups. The data from the present study suggest that medium FORT values in PCOS patients and high FORT values in non-PCOS patients may predict better outcomes for IVF/ICSI. © 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. Source


Wang P.,Shandong University | Wang P.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Wang P.,Key Laboratory for Reproductive Endocrinology of Ministry of Education | Wang P.,Shandong Provincial Key Laboratory of Reproductive Medicine | And 35 more authors.
Endocrinology | Year: 2014

Our previous genome-wide association study identified LH/choriogonadotropin receptor (LHCGR) as a susceptibility gene for polycystic ovary syndrome (PCOS). The objective of this study was to determine whether the genetic or epigenetic components associated with LHCGR participate in the pathogenesis of PCOS. The exons and flanking regions of LHCGR were sequenced from 192 women with PCOS, and no novel somatic mutations were identified. In addition, the methylation statuses of 6 cytosine-phosphate-guanine (CpG) sites in the promoter region of LHCGR were measured by pyrosequencing using peripheral blood cells from 85 women with PCOS and 88 control women. We identified 2 hypomethylated sites, CpG -174 (corrected P = .018) and -111 (corrected P = .006). Bisulfite sequencing then was performed to replicate these findings and detect additional CpG sites in the promoter. CpG +17 was significantly hypomethylated in women with PCOS (corrected P = .02). Methylation statuses were further evaluated using granulosa cells (GCs), and the region described was hypomethylated as a whole (P = .004) with 8 significantly hypomethylated sites (CpG -174, -148, -61, -43, -8, +10, +17, and +20). Transcription of LHCGR was elevated in women with PCOS compared with that in control women (P = .01). These findings were consistent with the decreased LHCGR methylation status associated with PCOS. The tendency of LHCGR to be hypomethylated across different tissues and its corresponding expression level suggest that hypomethylation of LHCGR is a potential mechanism underlying susceptibility to PCOS. Further studies are needed to evaluate whether a causal relationship exists between LHCGR methylation status and PCOS. Copyright © 2014 by the Endocrine Society. Source


Zhao H.,Shandong University | Zhao H.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Zhao H.,Shandong Provincial Key Laboratory of Reproductive Medicine | Xu X.,Shandong University | And 21 more authors.
Human Reproduction | Year: 2012

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder. A previous genome-wide association study (GWAS) identified five single nucleotide polymorphisms (SNPs) which were independently associated with PCOS in Han Chinese. To overcome population stratication, a family-based analysis was conducted to validate whether these five SNPs are associated with PCOS. METHODS: A total of 276 family trios (828 participants) having a proband with PCOS were included in the family-based study. The transmission disequilibrium test (TDT) was used to analyze the association between PCOS and five SNPs rs13429458, rs12478601, rs13405728, rs10818854 and rs2479106 in three susceptible loci 2p16.3, 2p21 and 9q33.3. RESULTS: A positive association was observed for the SNP rs13429458 (P 3.74 × 10 5). CONCLUSIONS: TDT confirms that SNP rs13429458, in the THADA gene, is significantly associated with risk of PCOS. This family-based analysis enhances our previous casecontrol GWAS and provides further support for the role of susceptibility loci in PCOS. © The Author 2011. Source


Cui L.,Shandong University | Cui L.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics | Cui L.,Key Laboratory for Reproductive Endocrinology | Cui L.,Shandong Provincial Key Laboratory of Reproductive Medicine | And 27 more authors.
Human Reproduction | Year: 2013

Study Question Are there any correlations between the phenotypes of polycystic ovary syndrome (PCOS) and the genotypes of the PCOS susceptibility single nucleotide polymorphisms (SNPs) in THADA, DENND1A and LHCGR? Summary Answer The PCOS susceptibility genes, THADA and DENND1A, carry risk alleles that are associated with endocrine and metabolic disturbances in patients with PCOS. What is Known AlreadyPCOS is a heterogeneous endocrinopathy characterized by oligo-anovulation, hyperandrogenism and polycystic ovaries. In a previous genome-wide association study, the SNP variants rs13429458, rs12478601, rs2479106, rs10818854 and rs13405728 in the THADA, DENND1A and LHCGR genes were identified as being independently associated with PCOS. The aim of this study was to identify any additional correlations between the phenotypes of PCOS and genotypes of the five SNPs described in the previous study. Study Design , Size, DurationIn the present cross-sectional study, a total of 1731 PCOS patients and 4964 controls were enrolled. Participants/Materials, Setting , Method SPatients were diagnosed according to Rotterdam criteria. Clinical information was collected from the patients and controls. Endocrine and metabolic parameters were evaluated for phenotype-genotype correlation analyses. Main Results and the Role of Chance Using a recessive model, the AA group for rs13429458 in THADA was associated with increased luteinizing hormone (LH) (P < 0.01) and testosterone (T) (P = 0.02) levels in subjects with PCOS; the LH/follicle-stimulating hormone ratio was also higher in the AA group (P < 0.01). Also using a recessive model, the CC genotype of rs12478601, also in THADA, was associated with increased levels of low-density lipoprotein (P = 0.02). Using a dominant model, the GG + AG group for rs2479106 in DENND1A was associated with elevated serum insulin levels 2 h after a glucose load in the patients with PCOS (P = 0.02). All of the comparisons were adjusted for age and BMI. Limitations , Reasons for Caution The relatively younger age of the participants may represent a considerable bias when evaluating metabolic alterations as a function of different genotypes, as significant metabolic disturbances may emerge later in life. Furthermore, the sample sizes of several sub-genotype groups were relatively small; to some extent this limited the statistical power of the analysis. Wider Implications of the FindingsThe PCOS susceptibility genes, THADA and DENND1A, carry risk alleles that are associated with endocrine and metabolic disturbances in PCOS patients of Han Chinese descent. The findings have shown genuine heterogeneity, stratified on the basis of both clinical findings and genotypes. Replication of these results is expected in other ethnic groups. Study Funding/Competing Interest (S)This research was supported by the National Basic Research Program of China (973 program) (2010CB945002, 2012CB944700), the National Natural Science Foundation of China (81000238, 81070461, 81000236, 30973170), the Graduate Independent Innovation Foundation of Shandong University (GIIFSDU) (21300070613242, 21300070613246), the Science Research Foundation item of no-earnings health vocation (201002013) and the National Key Technology Research and Development Program (2011BAI17B00). There are no competing interests. © 2012 The Author. Source

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