Diminished ovarian reserve is not observed in infertility patients with high normal CGG repeats on the fragile X mental retardation 1 (FMR1) gene

STUDY QUESTION: Does an association exist between high normal numbers of CGG trinucleotide repeats on the fragile X mental retardation 1 (FMR1) gene and diminished ovarian reserve (DOR)? SUMMARY ANSWER: This large data set demonstrated that a high normal number of CGG repeats (35-54 repeats) on the FMR1 gene was not significantly correlated with DOR. WHAT IS KNOWN ALREADY: The FMR1 premutation (55-200 repeats) is a known cause of primary ovarian insufficiency. However, the relationship between high normal CGG repeat numbers (35-54 repeats) and ovarian reserve has yet to be conclusively demonstrated. STUDY DESIGN, SIZE, DURATION: This is a retrospective data analysis conducted between January 2012 and February 2014 that included 1287 women. Over 1140 women had complete data. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women, excluding oocyte donors, who presented to a large private practice specializing in reproductive endocrinology and infertility for treatment and who underwent both fragile X and ovarian reserve testing were included. All fragile X testing was performed using triplet repeat PCR, with confirmation of positives by Southern blot. CGG repeat numbers from both alleles were recorded, and the allele with the higher number of repeats was used for statistical calculations. We did not differentiate between patients with one or two high normal alleles. Women with >54 CGG repeats were excluded from the analysis. For our analysis, we considered both a 'high normal' number of CGG repeats (35-44) and an intermediate number of GCC repeats (45-54) as 'high normal'. Ovarian reserve testing was carried out on Cycle Day 2 or 3 and included measurements of FSH, anti-Mullerian hormone (AMH) and antral follicle count (AFC). A generalized linear regression model assuming gamma distribution and log link function that controlled for age was used to assess correlation between CGG repeat number and FSH, AMH and AFC. MAIN RESULTS AND THE ROLE OF CHANCE: As expected, there was a significant correlation between increasing age and increasing FSH and decreasing AFC and AMH for the patients in this study. For every 1-year increase in age, FSH increased by a factor of 1.04, AFC decreased by a factor of 0.93 and AMH decreased by a factor of 0.89. After controlling for age, there was no significant correlation between FMR1 CGG trinucleotide repeat number and FSH (P = 0.23), AFC (P = 0.14) or AMH (P = 0.53). Three subgroup analyses were also performed. We found a significant relationship between increasing CGG repeat number and decreasing AMH levels (P = 0.01) in women >44 years old. The second subgroup analysis included only Caucasian patients and found no significant correlation between CGG repeat number and DOR. In a subgroup analysis comparing women with at least one allele <26 repeats, at least one allele >35 and women with both alleles between 29 and 32, there were no significant associations regarding ovarian reserve in any of these groups. LIMITATIONS, REASONS FOR CAUTION: One limitation of this study is that it involved a heterogeneous population of infertile women with mixed diagnoses. Factors that could affect ovarian reserve, such as medical comorbidities, prior surgeries, family history and endometriosis, were not accounted for. Finally, there was a lack of racial diversity, with Caucasians representing 67.8% of the total population. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study are generalizable to an infertility population and are in line with several previously published studies. Women who are found to have high normal CGG repeat numbers can be counseled that this is not causative for DOR. Further studies are needed to investigate whether increasing CGG repeat numbers are associated with ovarian responsiveness to gonadotrophin stimulation or IVF outcome.