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

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

Theoretical studies in tandem mirror physics

Recent developments in six areas of tandem-mirror theory are explored. Specifically, FLR terms (including electric-field drift) have been added to our 3-D paraxial MHD equilibrium code. Our low-frequency MHD stability analysis with FLR, which previously included only m/sub theta/ = 1 rigid perturbations, has been extended to incorporate moderate m/sub theta/, rotational drive, finite-beta effects on wall stabilization, and the well-digging effect of energetic electrons by using three computational techniques. In addition, we have examined the microstability of relativistic electrons with a loss-cone distribution, emphasizing the whistler and cyclotron-maser instabilities. We have also studied techniques for controlling radial transport, including the floating of segmented end plates and the tuning of transition-region coils, and have quantified the residual transport in a tandem mirror with axisymmetric throttle coils. Earlier work on the effect of ECRH on potentials in thermal-barrier cells has been extended. The transition between the weak- and strong-heating regimes has been examined using Fokker-Planck and Monte Carlo codes; an analytic model for the potentials relative to the end wall has been developed. Finally, our investigation of drift-frequency pumping of thermal-barrier ions has demonstrated that pumping is optimized when the magnetic fluctuation is perpendicular to both the unperturbed field and the thin fan, and that an adequate pumping rate is obtainable in future machines