Browsing by Subject "menopause"

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  • Tsuiko, O.; Noukas, M.; Zilina, O.; Hensen, K.; Tapanainen, J. S.; Magi, R.; Kals, M.; Kivistik, P. A.; Haller-Kikkatalo, K.; Salumets, A.; Kurg, A. (2016)
    Can spontaneous premature ovarian failure (POF) patients derived from population-based biobanks reveal the association between copy number variations (CNVs) and POF? CNVs can hamper the functional capacity of ovaries by disrupting key genes and pathways essential for proper ovarian function. POF is defined as the cessation of ovarian function before the age of 40 years. POF is a major reason for female infertility, although its cause remains largely unknown. The current retrospective CNV study included 301 spontaneous POF patients and 3188 control individuals registered between 2003 and 2014 at Estonian Genome Center at the University of Tartu (EGCUT) biobank. DNA samples from 301 spontaneous POF patients were genotyped by Illumina HumanCoreExome (258 samples) and HumanOmniExpress (43 samples) BeadChip arrays. Genotype and phenotype information was drawn from the EGCUT for the 3188 control population samples, previously genotyped with HumanCNV370 and HumanOmniExpress BeadChip arrays. All identified CNVs were subjected to functional enrichment studies for highlighting the POF pathogenesis. Real-time quantitative PCR was used to validate a subset of CNVs. Whole-exome sequencing was performed on six patients carrying hemizygous deletions that encompass genes essential for meiosis or folliculogenesis. Eleven novel microdeletions and microduplications that encompass genes relevant to POF were identified. For example, FMN2 (1q43) and SGOL2 (2q33.1) are essential for meiotic progression, while TBP (6q27), SCARB1 (12q24.31), BNC1 (15q25) and ARFGAP3 (22q13.2) are involved in follicular growth and oocyte maturation. The importance of recently discovered hemizygous microdeletions of meiotic genes SYCE1 (10q26.3) and CPEB1 (15q25.2) in POF patients was also corroborated. This is a descriptive analysis and no functional studies were performed. Anamnestic data obtained from population-based biobank lacked clinical, biological (hormone levels) or ultrasonographical data, and spontaneous POF was predicted retrospectively by excluding known extraovarian causes for premature menopause. The present study, with high number of spontaneous POF cases, provides novel data on associations between the genomic aberrations and premature menopause of ovarian cause and demonstrates that population-based biobanks are powerful source of biological samples and clinical data to reveal novel genetic lesions associated with human reproductive health and disease, including POF. This study was supported by the Estonian Ministry of Education and Research (IUT20-43, IUT20-60, IUT34-16, SF0180027s10 and 9205), Enterprise Estonia (EU30020 and EU48695), Eureka's EUROSTARS programme (NOTED, EU41564), grants from European Union's FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, SARM, |EU324509) and Horizon 2020 innovation programme (WIDENLIFE, 692065), Academy of Finland and the Sigrid Juselius Foundation.
  • Olivieri, Fabiola; Ahtiainen, Maarit; Lazzarini, Raffaella; Pollanen, Eija; Capri, Miriam; Lorenzi, Maria; Fulgenzi, Gianluca; Albertini, Maria C.; Salvioli, Stefano; Alen, Markku J.; Kujala, Urho M.; Borghetti, Giulia; Babini, Lucia; Kaprio, Jaakko; Sipila, Sarianna; Franceschi, Claudio; Kovanen, Vuokko; Procopio, Antonio D. (2014)
    MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case-control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54-62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142-3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR-223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes' IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women.
  • Gavrilyuk, Oxana; Braaten, Tonje; Weiderpass, Elisabete; Licaj, Idlir; Lund, Eiliv (2018)
    IntroductionLifetime number of years of menstruation (LNYM) reflects a woman's cumulative exposure to endogenous estrogen and can be used as a measure of the combined effect of reproductive factors related to endometrial cancer (EC) risk. Material and methodsWe aimed to study the association between LNYM and EC risk among postmenopausal women and calculate the population attributable fraction of EC for different LNYM categories. Our study sample consisted of 117589 women from the Norwegian Women and Cancer (NOWAC) Study. All women were aged 30-70years at enrollment and completed a baseline questionnaire between 1991 and 2006. Women were followed up for EC to December 2014 through linkages to national registries. We used Cox proportional hazards models to estimate hazard ratios with 95% confidence intervals (95% CIs), adjusted for potential confounders. ResultsIn all, 720 women developed EC. We found a statistically significant, positive dose-response relationship between LNYM and EC, with a 9.1% higher risk for each additional year of LNYM (P for trend ConclusionsOur study supports that increasing LNYM is an important and independent predictor of EC risk.