Steve Young, MD, PhD - Division of Reproductive Endocrinology and Infertility
Premature ovarian insufficiency (POI) represents a continuum of dysfunction related to early aging of the ovaries. POI can culminate in premature ovarian failure (POF), defined as follicle stimulating hormone (FSH) levels over 40 IU/L and at least 4 months of amenorrhea before the age of 40. A trinucleotide (CGG) repeat level between 55-199 in the FMR1 gene occurs in 5-6% of women with POF, with a greater risk of POF if she has a family history of early menopause. We are funded by NICHD to determine the prevalence of CGG FMR1 repeats in the 55-199 range in women with one particular infertility condition along the POI continuum, termed Diminished Ovarian Reserve (DOR). These women have elevated FSH (>10 IU/L) but still have regular menses. In normal individuals, the number of CGG repeats is typically less than 40. The “intermediate zone”, whether defined as 40-54 or 44-54 repeats, has not been associated with any phenotype. Our preliminary results (n=61) indicate that 15% of DOR women had 35-44 CGG repeats, which is very similar to the only published report on this topic (17% of alleles from occult POI women had 35-44 repeats, total n=27). Comparison data on the frequency of high normal/intermediate triplet repeats in the general female population (cohort sizes ranged from 32 to 370 women) report 3-6% of women had 35-44 CGG repeats. These comparison data are inadequate as they did not assess for infertility or a family history of mental retardation. This study will compare the CGG repeat length in a cohort of DOR cases (n=85 enrolled from another study plus n=?? new cases) with 2 comparison cohorts (n=800 women with proven fertility and normal ovarian aging defined by natural menopause over age 45; n=135 women who are infertile due to an anatomical reason such as tubal occlusion). DNA samples from the first comparison group have already been collected through the SWAN Study; this grant will fund the sample acquisition fee and the FMR1 PCR tests. The second comparison group and the additional cases will be recruited through this grant. The specific aims are to assess if there is a greater frequency of DOR women with 35-44, 45-54 and >55 CGG repeats in the FMR1 gene than the 2 comparison groups, to estimate the optimal threshold of CGG repeats for an elevated risk of DOR, and to characterize the CGG repeat distribution and potential modifiers in these phenotypically distinct cohorts. These specific aims are distinct from the current funded research, which does not involve a comparison arm. These comparisons cohorts will provide valuable information with which to distinguish if DOR is a new phenotype associated with high normal/intermediate CGG repeat levels and will provide data with which to disentangle the potential separate mechanistic influences on infertility and ovarian aging. This application is in direct response to the NIH Research Plan on Fragile X Syndrome and Associated Disorders Objectives 1.4 and 3.1. The results of this study will have important reproductive decision-making and genetic counseling implications for women with POI, as these findings are anticipated to challenge the current reference range used clinically in adult females for FMR1 DNA screening.