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Objective: The purpose of this study was to investigate the association of microRNA polymorphisms (miR-25T>C, miR-32C>A, miR-125C>T, and miR-222G>T) with primary ovarian insufficiency (POI) in Korean women., Methods: We conducted a case-control study of Korean women: 142 participants with POI and 266 controls with at least 1 live birth and no history of pregnancy loss., Results: The haplotype-based multifactor dimensionality reduction analysis revealed that the T-C-T-G (miR-25/-32/-125/-222), T-A-C-G (miR-25/-32/-125/-222), C-T-G (miR-32/-125/-222), A-C-G (miR-32/-125/-222), T-G (miR-122/-222), C-T (miR-32/-125), and C-C (miR-25/-32) inferred haplotypes were significantly less frequent in POI (P < 0.05), which suggested potential protective effects. Participants with POI had significantly increased luteinizing hormone levels (P < 0.05), but hormonal levels, including luteinizing hormone, were not significantly different between POI women and control women with miR-32/-125/-222., Conclusions: After considering multiple comparisons, we concluded that miR-25T>C, miR-32C>A, miR-125C>T, and miR-222G>T had no relation with POI.

Premature ovarian failure during chemotherapy is a serious problem for young women with cancer. To preserve the fertility of these patients, approaches to prevent chemotherapy-induced ovarian failure are needed. In a previous study, we reported that melatonin treatment prevents the depletion of the dormant follicle pool via repression of the simultaneous activation of dormant primordial follicles by cisplatin. However, melatonin's protective effect was only partial and thus insufficient. In this study, we found that the hormone ghrelin enhances the protective effect of melatonin against cisplatin-induced ovarian failure in mouse model. Co-administration of melatonin and ghrelin more effectively prevented cisplatin-induced follicle disruption. Simultaneous treatment with melatonin and ghrelin almost restored the number of primordial follicles and the corpus luteum in cisplatin-treated ovaries, compared with single administration. We found melatonin and ghrelin receptors on the cell membrane of premature oocytes of primordial follicles. In addition, melatonin and ghrelin co-administration inhibited the cisplatin-induced phosphorylation of PTEN and FOXO3a that induces cytoplasmic translocation of FOXO3a. Inhibition of FOXO3a phosphorylation by melatonin and ghrelin increased the binding affinity of FOXO3a for the p27 Kip1 promoter in primordial follicles. Co-administration of melatonin and ghrelin in cisplatin-treated ovaries restored the expression of p27 Kip1 , which is critical for retention of the dormant status of primordial follicles. In conclusion, these findings suggest that melatonin and ghrelin co-administration is suitable for use as a fertoprotective adjuvant therapy during cisplatin chemotherapy in young female cancer patients., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

MicroRNAs post-transcriptionally regulate gene expression in animals and plants. The aim of this study was to identify new target genes for microRNA polymorphisms (miR-146aC>G and miR-196a2T>C) in primary ovarian insufficiency (POI). We cloned and transfected miR-146aC>G and miR-196a2T>C into human granulosa cells and used microarrays and qPCR-arrays to examine the changes in the messenger RNA expression profile. We show miR-146aC>G and miR-196a2T>C change the mRNA expression patterns in granulosa cell. In each case, mRNAs were up or down-regulated after treatments with miR-146a C or G and miR-196a2 T or C. We found that miR-146a led to a significantly altered regulation of the mRNA levels of FOXO3, FOXL2 and CCND2 compared to controls. We also found that the polymorphisms of miR-146a led to a significantly altered regulation of CCND2 and FOXO3. Our results suggest that miR-146aC>G and miR-196a2T>C can regulate the levels of many of their target transcripts. In addition, specific target genes of miR-146aC>G polymorphisms may be involved in granulosa cell regulation.

MicroRNAs (miRNAs) post-transcriptionally regulate gene expression in animals and plants. The aim of this study was to investigate whether polymorphisms in miR-938 are associated with the risk of primary ovarian insufficiency (POI) and POI-related target gene regulation. We identified the miR-938 G>A polymorphisms within the seed sequence of mature miRNA and aligned the seed sequence with the 3' untranslated region (UTR) of the gonadotropin-releasing hormone receptor ( GnRHR ) mRNA, a miR-938 target gene. We found that the binding of miR-938 to the 3'-UTR of GnRHR mRNA was significantly different between normal and variant alleles. Our data suggests that the dysregulation of miR-938 G>A influences the binding to GnRHR and that miR-938 G>A polymorphisms might contribute to regulation of POI-related target genes., Competing Interests: The authors declare no conflict of interest.

Objective: The aim of our study was to investigate whether breast cancer-related microRNA polymorphisms are associated with primary ovarian insufficiency (POI) risk., Methods: Four breast cancer-related microRNA polymorphisms (miR-27aA > G [rs895819], miR-135bC > T [rs74141216], miR-423C > A [rs6505162], and miR-608G > C [rs4919510]) were genotyped in 136 women with idiopathic POI and 224 controls of Korean ethnicity using polymerase chain reaction-restriction fragment length polymorphism analysis. Differences in genotype frequencies between cases and controls were compared. Odds ratios and 95% CIs were determined as measures of the strength of association between genotype and POI., Results: Two haplotypes (G-C-A-G and A-T-C-C) of miR-27a/miR-135b/miR-423/miR-608 were associated with increased POI risk. The haplotypes G-A-G of miR-27a/miR-423/miR-608 and A-T-C of miR-27a/miR-135b/miR-608 were associated with higher POI risk, whereas the G-T haplotype of miR-27a/miR-135b was associated with decreased POI risk. The association between POI risk and the G-A-G haplotype of miR-27a/miR-423/miR-608 remained significant after false discovery rate correction for multiple comparisons. The combined genotypes AA/CT/CC/CC, AG/CC/CA/GC, GG/CC/CC/CC, and GG/CC/CA/GG of miR-27a/miR-135b/miR-423/miR-608 were also associated with higher POI risk. Increased POI risk was observed in combined genotypes GG/CC/GG of miR-27a/miR-135b/miR-608; AA/CC/GC, AG/CA/GC, GG/CC/GG, GG/CC/CC, and GG/CA/GG of miR-27a/miR-423/miR-608; and GG/GG of miR-27a/miR-608; however, these associations were not significant after false discovery rate correction. None of the four microRNA polymorphisms alone was associated with POI risk., Conclusions: Our data suggest that breast cancer-related microRNA polymorphisms, including miR-27aA > G, miR-423C > A, and miR-608G > C, are associated with increased POI risk via interactions between miR-27aG, miR-423A, and miR-608G variants. However, our results should be interpreted cautiously because of our small sample size and the low statistical power of our study design.

Objective: The aim of this study was to investigate whether two polymorphisms in the promoter region of inhibin alpha (INHA) are associated with risk of idiopathic primary ovarian insufficiency (POI) in Korean women, which is a controversial topic., Study Design: We genotyped the INHA polymorphisms c.-16C>T (rs35118453) and c.-124A>G (rs11893842) of 136 POI patients and 225 controls in Korean women by polymerase chain reaction and restriction fragment length polymorphism analysis. We then compared differences in genotype and allele frequencies (AF) of the polymorphisms between the two groups to determine odds ratios (OR) and 95% confidence intervals (CI) as measures of the strength of association between genotype and POI., Results: There were no significant differences in genotype or AF of the polymorphisms between the POI patients and controls. Haplotype analysis revealed that the T-G haplotype of the two variant alleles was more frequent in POI patients than in the controls (OR=1.630, 95% CI=1.081-2.457). Combination genotype analysis showed that the CT+TT/GG genotype frequency was higher in POI patients than in the controls (OR=2.414, 95% CI=1.190-4.895)., Conclusions: We provide evidence to suggest that when the two variant alleles are combined, the c.-16C>T and c.-124A>G polymorphisms are associated with increased POI risk in Korean women. We postulate that interactions between the INHA polymorphisms may affect POI risk., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim of the study was to investigate whether the -604T>C, 1192G>A, and 1719A>T polymorphisms in the kinase insert domain-containing receptor (KDR) gene confer risk for premature ovarian failure (POF) in Korean women., Methods: DNA samples from 133 POF patients and 230 controls were genotyped for the three KDR single nucleotide polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis., Results: The POF patients had significantly increased frequencies of the KDR -604TC and -604TC + CC genotypes (odds ratio [OR], 1.975; 95% CI, 1.219-3.201 and OR, 1.948; 95% CI, 1.221-3.109, respectively) and of the -604TC + CC/1192GG combined genotype (OR, 2.271; 95% CI, 1.359-3.795) and a decreased frequency of the 1192GA genotype (OR, 0.457; 95% CI, 0.231-0.905) compared with the controls. The genotype frequency of the 1719A>T polymorphism was not significantly different between the two groups. The frequencies of the KDR -604C/1192G/1719T, -604C/1192G, and -604C/1719T haplotypes (OR, 3.319; 95% CI, 1.564-7.041; OR, 2.083; 95% CI, 1.351-3.212; and OR, 1.979; 95% CI, 1.073-3.649, respectively) were significantly higher among POF patients than controls, whereas the -604T/1719T haplotype frequency (OR, 0.657; 95% CI, 0.472-0.915) was lower among POF patients., Conclusions: Carriers of the KDR -604C variant allele (-604TC and -604TC + CC genotypes; -604TC + CC/1192GG combined genotype; -604C/1192G/1719T haplotype, -604C/1192G haplotype, -604C/1719T haplotype) are consistently more prevalent among POF patients than among controls, suggesting that the KDR -604C allele may increase the risk of POF development in Korean women.

Objective: To identify whether epistasis between TG and HSD17B4 and whether polymorphisms in HSD17B4 are associated with premature ovarian failure (POF)., Design: Case-control genetic association study., Setting: Research laboratory of a university., Patient(s): Female patients with POF (98) and controls (218) of Korean ethnicity participated in this study., Intervention(s): None., Main Outcome Measure(s): Genotype distribution, haplotype (HT) inference, and gene-gene interaction., Result(s): Distribution of one haplotype (A-G-A-A-G-G) on the HSD17B4 gene was significantly different between the POF group and the control group in a dominant model. In addition, the combined effect of the single nucleotide polymorphisms (SNPs) HSD17B4 rs28943592 and TG rs2076740 was significantly associated with POF (odds ratio = 7.74, 95% confidence interval = 1.67-35.94), although a significant association was not observed in the single SNP model., Conclusion(s): A haplotype in the HSD17B4 gene was identified that was significantly associated with resistance to POF. In addition, epistasis between two missense SNPs (rs28943592, rs2076740) located in HSD17B4 and TG was significantly associated with susceptibility to POF., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To study the association of vascular endothelial growth factor (VEGF) polymorphisms (-2578C>A, -1154G>A, -634G>C, and 936C>T) with premature ovarian failure (POF) in Korean patients., Study Design: Prospective case-control study. One hundred and thirty five patients with POF and confirmed serum follicle-stimulating hormone levels of >40IU/L before the age of 40 years and 120 healthy controls with at least one live birth, regular menstrual cycles, and karyotype 46, XX., Results: POF patients exhibited significantly different frequencies of the VEGF -1154GA genotype (odds ratio [OR], 2.002; 95% confidence interval [CI], 1.116-3.592; P=0.019), and -2578CA+AA/-1154GA+AA combination genotype (OR, 1.805; 95% CI, 1.013-3.217; P=0.044) compared to the control group. The frequency of the -2578A/-1154A haplotype (OR, 1.647; 95% CI, 1.017-2.677; P=0.041) was significantly higher in the POF group than in the control group., Conclusion: The VEGF -1154G>A mutation, -2578CA+AA/-1154GA+AA combination genotype, and -2578A/-1154A haplotype are significantly associated with POF in Korean women., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Follicle-stimulating hormone secreted from the pituitary gland plays a key role in human reproduction and regulates estrogen production by acting on the regulatory region of CYP19A1. We observed a significant association between premature ovarian failure and the combined genetic effect of single nucleotide polymorphism (SNP) rs4646 (CA+AA) in the 3' untranslated region of CYP19A1 and the missense FSHR SNP rs6166 (AG+GG) genotype (odds ratio 5.42, 95% confidence interval 1.96-14.98), and we identified a significant association between premature ovarian failure and the combined genetic effect of the FSHR missense SNP rs6166 (AA) and the rs4646-rs10046 haplotype (C-T)+(C-C) (odds ratio 5.47, 95% confidence interval 2.03-14.75), suggesting that two biochemical pathways may be involved in the regulation of folliculogenesis., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)