The FMR1 gene as regulator of ovarian recruitment and ovarian reserve

The fragile X mental retardation 1 (FMR1) gene is primarily associated with neuro/psychiatric risks. Recent evidence suggests that the gene also exerts controlling functions on follicle recruitment and ovarian reserve (OR). We performed unrestricted Medline and PubMed searches of the medical literature independently under search terms, FMR1 gene, fragile X gene, and in association with premature ovarian aging, primary ovarian insufficiency, occult primary insufficiency, premature ovarian failure, premature menopause, ovarian reserve (OR), diminished ovarian reserve, follicle recruitment and ovarian aging. We also used web-based resources in regards to the FMR1 gene and reviewed additional citations from reviewed publications.Recently published data strongly suggest an independent function of the FMR1 gene on ovaries. This function appears distinct from the gene's neuro/psychiatric effects, associated with a different, and specific, triple nucleotide (CGG) repeat range and characterized by specific genotypes. Ovarian function in all races/ethnicities appears defined by a normal range of 26 to 34 CGG repeats (mean 30), including the reported distribution peak of 29 to 30 repeats in humans and maximal gene translation, reported at 30 repeats. Genotypes, defined by 2 normal count alleles (normal) demonstrate different OR aging patterns from women with 1 (heterozygous) or both alleles outside of range (homozygous). Heterozygous and homozygous genotypes recruit fewer follicles at younger ages, thus preserving OR into advanced age.These observations suggest a direct FMR1 effect on follicular recruitment and OR and, therefore, on women's fecundity. Target Audience: Obstetricians & Gynecologists, Family Physicians. Reproductive Endocrinologists, Geneticists Learning Objectives: After participating in this CME activity, readers should better able to: assess young women for risk of premature ovarian aging; obtain better patient histories to identify historical risks for premature ovarian aging; use FMR1 testing to determine risk for premature ovarian aging; develop a prospective screening schedule of ovarian reserve; and document premature decline in ovarian reserve, and refer the patient for special counseling and/or fertility preservation interventions.