FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/193532 |
Resumo: | Background: Fragile-X-Mental-Retardation-1- (FMR1)-gene is supposed to be a key gene for ovarian reserve and folliculogenesis. It contains in its 5’-UTR a triplet-base-repeat (CGG), that varies between 26 and 34 in general population. CGG-repeat-lengths with 55–200 repeats (pre-mutation = PM) show instable heredity with a tendency to increase and are associated with premature-ovarian-insufficiency or failure (POI/POF) in about 20%. FMR1-mRNA-expression in leucocytes and granulosa cells (GCs) increases with CGG-repeat-length in PM-carriers, but variable FMR1-expression profiles were also described in women with POI without PM-FMR1 repeat-length. Additionally, associations between low numbers of retrieved oocytes and elevated FMR1-expression levels have been shown in GCs of females with mid-range PM-CGG-repeats without POI. Effects of FMR1-repeat-lengths-deviations (n < 26 or n > 34) below the PM range (n < 55) on ovarian reserve and response to ovarian stimulation remain controversial. Methods: We enrolled 229 women undergoing controlled ovarian hyperstimulation for IVF/ICSI-treatment and devided them in three ovarian-response-subgroups: Poor responder (POR) after Bologna Criteria, polycystic ovary syndrome (PCO) after Rotterdam Criteria, or normal responder (NOR, control group). Subjects were subdivided into six genotypes according to their be-allelic CGG-repeat length. FMR1-CGG-repeat-length was determined using ALF-express-DNA-sequencer or ABI 3100/3130 × 1-sequencer. mRNA was extracted from GCs after follicular aspiration and quantitative FMR1-expression was determined using specific TaqMan-Assay and applying the ΔΔCT method. Kruskall-Wallis-Test or ANOVA were used for simple comparison between ovarian reserve (NOR, POR or PCO) and CGG-subgroups or cohort demographic data. All statistical analysis were performed with SPSS and statistical significance was set at p ≤ 0.05. Results: A statistically significant increase in FMR1-mRNA-expression-levels was detected in GCs of PORs with heterozygous normal/low-CGG-repeat-length compared with other genotypes (p = 0.044). Conclusion: Female ovarian response may be negatively affected by low CGG-alleles during stimulation. In addition, due to a low-allele-effect, folliculogenesis may be impaired already prior to stimulation leading to diminished ovarian reserve and poor ovarian response. A better understanding of FMR1 expression-regulation in GCs may help to elucidate pathomechanisms of folliculogenesis disorders and to develop risk-adjusted treatments for IVF/ICSI-therapy. Herewith FMR1-genotyping potentially provides a better estimatation of treatment outcome and allows the optimal adaptation of stimulation protocols in future. |
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Rehnitz, JuliaAlcoba, Diego DuarteBrum, Ilma SimoniDietrich, Jens ErikYouness, BertheHinderhofer, KatrinMessmer, BirgittaFreis, AlexanderStrowitzki, ThomasGermeyer, Ariane2019-04-26T02:38:15Z20181477-7827http://hdl.handle.net/10183/193532001074897Background: Fragile-X-Mental-Retardation-1- (FMR1)-gene is supposed to be a key gene for ovarian reserve and folliculogenesis. It contains in its 5’-UTR a triplet-base-repeat (CGG), that varies between 26 and 34 in general population. CGG-repeat-lengths with 55–200 repeats (pre-mutation = PM) show instable heredity with a tendency to increase and are associated with premature-ovarian-insufficiency or failure (POI/POF) in about 20%. FMR1-mRNA-expression in leucocytes and granulosa cells (GCs) increases with CGG-repeat-length in PM-carriers, but variable FMR1-expression profiles were also described in women with POI without PM-FMR1 repeat-length. Additionally, associations between low numbers of retrieved oocytes and elevated FMR1-expression levels have been shown in GCs of females with mid-range PM-CGG-repeats without POI. Effects of FMR1-repeat-lengths-deviations (n < 26 or n > 34) below the PM range (n < 55) on ovarian reserve and response to ovarian stimulation remain controversial. Methods: We enrolled 229 women undergoing controlled ovarian hyperstimulation for IVF/ICSI-treatment and devided them in three ovarian-response-subgroups: Poor responder (POR) after Bologna Criteria, polycystic ovary syndrome (PCO) after Rotterdam Criteria, or normal responder (NOR, control group). Subjects were subdivided into six genotypes according to their be-allelic CGG-repeat length. FMR1-CGG-repeat-length was determined using ALF-express-DNA-sequencer or ABI 3100/3130 × 1-sequencer. mRNA was extracted from GCs after follicular aspiration and quantitative FMR1-expression was determined using specific TaqMan-Assay and applying the ΔΔCT method. Kruskall-Wallis-Test or ANOVA were used for simple comparison between ovarian reserve (NOR, POR or PCO) and CGG-subgroups or cohort demographic data. All statistical analysis were performed with SPSS and statistical significance was set at p ≤ 0.05. Results: A statistically significant increase in FMR1-mRNA-expression-levels was detected in GCs of PORs with heterozygous normal/low-CGG-repeat-length compared with other genotypes (p = 0.044). Conclusion: Female ovarian response may be negatively affected by low CGG-alleles during stimulation. In addition, due to a low-allele-effect, folliculogenesis may be impaired already prior to stimulation leading to diminished ovarian reserve and poor ovarian response. A better understanding of FMR1 expression-regulation in GCs may help to elucidate pathomechanisms of folliculogenesis disorders and to develop risk-adjusted treatments for IVF/ICSI-therapy. Herewith FMR1-genotyping potentially provides a better estimatation of treatment outcome and allows the optimal adaptation of stimulation protocols in future.application/pdfengReproductive biology and endocrinology. London. Vol. 16 (2018), 65, [9 p.]Insuficiência ovariana primáriaCélulas da granulosaHormônio folículo estimulanteFMR1 expressionGranulosa cellsFMR1 CGG repeat lengthFMR1 genotypeFMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserveEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001074897.pdf.txt001074897.pdf.txtExtracted Texttext/plain47817http://www.lume.ufrgs.br/bitstream/10183/193532/2/001074897.pdf.txt294db414ee2a9fe48c3e83d367614625MD52ORIGINAL001074897.pdfTexto completo (inglês)application/pdf626737http://www.lume.ufrgs.br/bitstream/10183/193532/1/001074897.pdf76116507ee465c6b3872dbd1d322da27MD5110183/1935322019-04-27 02:37:29.367297oai:www.lume.ufrgs.br:10183/193532Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2019-04-27T05:37:29Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve |
title |
FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve |
spellingShingle |
FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve Rehnitz, Julia Insuficiência ovariana primária Células da granulosa Hormônio folículo estimulante FMR1 expression Granulosa cells FMR1 CGG repeat length FMR1 genotype |
title_short |
FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve |
title_full |
FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve |
title_fullStr |
FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve |
title_full_unstemmed |
FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve |
title_sort |
FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve |
author |
Rehnitz, Julia |
author_facet |
Rehnitz, Julia Alcoba, Diego Duarte Brum, Ilma Simoni Dietrich, Jens Erik Youness, Berthe Hinderhofer, Katrin Messmer, Birgitta Freis, Alexander Strowitzki, Thomas Germeyer, Ariane |
author_role |
author |
author2 |
Alcoba, Diego Duarte Brum, Ilma Simoni Dietrich, Jens Erik Youness, Berthe Hinderhofer, Katrin Messmer, Birgitta Freis, Alexander Strowitzki, Thomas Germeyer, Ariane |
author2_role |
author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Rehnitz, Julia Alcoba, Diego Duarte Brum, Ilma Simoni Dietrich, Jens Erik Youness, Berthe Hinderhofer, Katrin Messmer, Birgitta Freis, Alexander Strowitzki, Thomas Germeyer, Ariane |
dc.subject.por.fl_str_mv |
Insuficiência ovariana primária Células da granulosa Hormônio folículo estimulante |
topic |
Insuficiência ovariana primária Células da granulosa Hormônio folículo estimulante FMR1 expression Granulosa cells FMR1 CGG repeat length FMR1 genotype |
dc.subject.eng.fl_str_mv |
FMR1 expression Granulosa cells FMR1 CGG repeat length FMR1 genotype |
description |
Background: Fragile-X-Mental-Retardation-1- (FMR1)-gene is supposed to be a key gene for ovarian reserve and folliculogenesis. It contains in its 5’-UTR a triplet-base-repeat (CGG), that varies between 26 and 34 in general population. CGG-repeat-lengths with 55–200 repeats (pre-mutation = PM) show instable heredity with a tendency to increase and are associated with premature-ovarian-insufficiency or failure (POI/POF) in about 20%. FMR1-mRNA-expression in leucocytes and granulosa cells (GCs) increases with CGG-repeat-length in PM-carriers, but variable FMR1-expression profiles were also described in women with POI without PM-FMR1 repeat-length. Additionally, associations between low numbers of retrieved oocytes and elevated FMR1-expression levels have been shown in GCs of females with mid-range PM-CGG-repeats without POI. Effects of FMR1-repeat-lengths-deviations (n < 26 or n > 34) below the PM range (n < 55) on ovarian reserve and response to ovarian stimulation remain controversial. Methods: We enrolled 229 women undergoing controlled ovarian hyperstimulation for IVF/ICSI-treatment and devided them in three ovarian-response-subgroups: Poor responder (POR) after Bologna Criteria, polycystic ovary syndrome (PCO) after Rotterdam Criteria, or normal responder (NOR, control group). Subjects were subdivided into six genotypes according to their be-allelic CGG-repeat length. FMR1-CGG-repeat-length was determined using ALF-express-DNA-sequencer or ABI 3100/3130 × 1-sequencer. mRNA was extracted from GCs after follicular aspiration and quantitative FMR1-expression was determined using specific TaqMan-Assay and applying the ΔΔCT method. Kruskall-Wallis-Test or ANOVA were used for simple comparison between ovarian reserve (NOR, POR or PCO) and CGG-subgroups or cohort demographic data. All statistical analysis were performed with SPSS and statistical significance was set at p ≤ 0.05. Results: A statistically significant increase in FMR1-mRNA-expression-levels was detected in GCs of PORs with heterozygous normal/low-CGG-repeat-length compared with other genotypes (p = 0.044). Conclusion: Female ovarian response may be negatively affected by low CGG-alleles during stimulation. In addition, due to a low-allele-effect, folliculogenesis may be impaired already prior to stimulation leading to diminished ovarian reserve and poor ovarian response. A better understanding of FMR1 expression-regulation in GCs may help to elucidate pathomechanisms of folliculogenesis disorders and to develop risk-adjusted treatments for IVF/ICSI-therapy. Herewith FMR1-genotyping potentially provides a better estimatation of treatment outcome and allows the optimal adaptation of stimulation protocols in future. |
publishDate |
2018 |
dc.date.issued.fl_str_mv |
2018 |
dc.date.accessioned.fl_str_mv |
2019-04-26T02:38:15Z |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10183/193532 |
dc.identifier.issn.pt_BR.fl_str_mv |
1477-7827 |
dc.identifier.nrb.pt_BR.fl_str_mv |
001074897 |
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1477-7827 001074897 |
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http://hdl.handle.net/10183/193532 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
Reproductive biology and endocrinology. London. Vol. 16 (2018), 65, [9 p.] |
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info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
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