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Open Access 01-12-2018 | Research

FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve

Authors: Julia Rehnitz, Diego D. Alcoba, Ilma S. Brum, Jens E. Dietrich, Berthe Youness, Katrin Hinderhofer, Birgitta Messmer, Alexander Freis, Thomas Strowitzki, Ariane Germeyer

Published in: Reproductive Biology and Endocrinology | Issue 1/2018

Abstract

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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Title: FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve
Authors: Julia Rehnitz
Diego D. Alcoba
Ilma S. Brum
Jens E. Dietrich
Berthe Youness
Katrin Hinderhofer
Birgitta Messmer
Alexander Freis
Thomas Strowitzki
Ariane Germeyer
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Reproductive Biology and Endocrinology / Issue 1/2018
Electronic ISSN: 1477-7827
DOI: https://doi.org/10.1186/s12958-018-0383-5

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve

Abstract

Background

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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