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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.

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