Article

Examination of reproductive aging milestones among women who carry the FMRI premutation

Department of Gynecology and Obstetrics, Emory University, Atlanta, Georgia, United States
Human Reproduction (Impact Factor: 4.59). 09/2007; 22(8):2142-52. DOI: 10.1093/humrep/dem148
Source: PubMed

ABSTRACT The fragile X premutation is characterized by a large CGG repeat track (55-199 repeats) in the 5' UTR of the FMR1 gene. This X-linked mutation leads to an increased risk for premature ovarian failure; interestingly, the association of repeat size with risk is non-linear. We hypothesize that the premutation-associated ovarian insufficiency is due to a diminished oocyte pool and examined reproductive aging milestones by repeat size group to determine if the same non-linear association is observed.
We analyzed cross-sectional reproductive history questionnaire data from 948 women with a wide range of repeat sizes.
We have confirmed the non-linear relationship among premutation carriers for ovarian insufficiency. The mid-range repeat size group (80-100 repeats), not the highest group, had an increased risk for: altered cycle traits (shortened cycle length, irregular cycles and skipped cycles), subfertility and dizygotic twinning. Smoking, a modifiable risk, decreased the reproductive lifespan of women with the premutation by about 1 year, similar to its effect on non-carriers. As expected, premutation carriers were found to be at an increased risk for osteoporosis.
Possible molecular mechanisms to explain the non-linear repeat size risk for ovarian insufficiency are discussed.

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    • "CGG repeats in the intermediate range, 45 –55 repeats, however, may become unstable during transmission and have the ability to expand to a premutation (55 –200 repeats), which can further expand to a full mutation (.200 repeats) causing the fragile X syndrome in the subsequent generation (Nolin et al., 2003; Kronquist et al., 2008). CGG repeats in the premutation range have been associated with primary ovarian insufficiency (POI, i.e. menopause before the age of 40 years, also known as POF, premature ovarian failure), referred to as fragile X-associated POI (Allingham-Hawkins et al., 1999; Sherman, 2000; Allen et al., 2007). The prevalence of POI in women carrying the FMR1 premutation is estimated to be between 13 and 26% (Sherman, 2000; Sullivan et al., 2005). "
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    ABSTRACT: STUDY QUESTION: Is there an association between the number of CGG repeats in the FMR1 gene in the normal and intermediate range and age at natural menopause? SUMMARY ANSWER: The number of CGG repeats in the normal and intermediate range in the FMR1 gene was not associated with age at natural menopause. WHAT IS KNOWN ALREADY: Excessive triple CGG repeats in the FMR1 gene have been widely associated with primary ovarian insufficiency. Recently, the number of CGG repeats in the normal and intermediate range (up to 55 repeats) was found to be associated with serum levels of anti-Müllerian hormone and follicle-stimulating hormone, as markers for ovarian ageing. This suggests that repeats in the normal and intermediate range could be involved in the rate of exhaustion of the ovarian primordial follicle pool and ultimately the timing of menopause. STUDY DESIGN, SIZE: Cross-sectional study in a population-based sample of 3611 Caucasian women with natural menopause. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FMR1 CGG repeat number was determined by PCR amplification in 3611 women with a known age at natural menopause. A possible relation between CGG repeats in the normal and intermediate range (up to 55 repeats) and menopausal age were analysed in various ways, including linear regression analysis and analysis of variance. MAIN RESULTS AND THE ROLE OF CHANCE: The number of CGG repeats in the normal and intermediate range in the FMR1 gene was not associated with age at natural menopause. The mean age at menopause was 50.30 (±4.2) years for women with <45 repeats and 50.64 (±3.4) years for women with intermediate-sized repeats (P = 0.37). Linear regression analysis of the number of CGG repeats showed no association with menopausal age (β = 0.019, P = 0.16). LIMITATIONS, REASONS FOR CAUTION: In our cohort, age at menopause was self-reported and determined retrospectively. WIDER IMPLICATIONS OF THE FINDINGS: Earlier observations suggesting that the number of CGG repeats in the normal and intermediate range is associated with the individual variation of the ovarian ageing process could not be confirmed in the current, large sample size study. A relation between the number of CGG repeats in the normal and intermediate range and age at natural menopause appeared to be absent. This finding questions the role of CGG repeat sizes in the ovarian ageing process. STUDY FUNDING/COMPETING INTEREST(S): N.C.O.-M., Y.T.S. and H.K.P.A. have nothing to declare. M.V. is financially supported by a grant from the Dutch Organisation for Scientific Research (NWO). F.J.B. is a member of the external advisory board for Merck Serono, The Netherlands, and does consultancy work for MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. TRIAL REGISTRATION NUMBER: Not applicable.
    Human Reproduction 11/2012; 28(2). DOI:10.1093/humrep/des392 · 4.59 Impact Factor
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    • "Similarly, Ennis, Ward, and Murray (2006) found a nonlinear association between repeat length and age at menopause, with women who had midsize repeats at greatest risk of early menopause . Sherman and colleagues also reported a curvilinear association of repeat length and reproductive aging in premutation carrier women (Allen et al., 2007; Sullivan et al., 2005). This curvilinear pattern may clarify why some studies that used linear analytic methods concluded that there was not an association between maternal CGG repeat length and measures of maternal well-being (e.g., Bailey, Raspa, Olmstead, & Holiday, 2008; Hessl et al., 2005). "
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    ABSTRACT: Objective: The premutation of the FMR1 gene (defined as between 55 and 200 CGG repeats) is estimated to affect 1 in 149 females and 1 in 643 males, and some people who carry the FMR1 premutation display signs of impairment. Method: This study focuses on 82 premutation carrier mothers (M age = 51.4 years; SD = 7.7) of adolescent and adult children with fragile X syndrome (FXS). A Gene × Environment interaction approach examined the ways in which the experience of negative life events interacts with genetic vulnerability to predict depressive symptoms, anxiety, and daily cortisol levels. Results: The associations of life events with all 3 dependent measures were associated with CGG repeat length but in a curvilinear manner. Mothers with midsize CGG repeats who experienced above-average numbers of negative life events in the previous year had more depressive symptoms and anxiety and had a blunted cortisol awakening response, as compared with those with higher or lower repeat lengths. However, mothers with midsize CGG repeats who experienced below-average numbers of negative life events in the previous year had the lowest levels of depressive symptoms and anxiety, and they exhibited the typical cortisol response to awakening, meeting the criteria for differential susceptibility. Conclusions: This research extends our understanding of the phenotypic effects of the expansion of the FMR1 gene, and it adds to the growing literature on the curvilinear relationship between CGG repeat length and mental and physical health. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
    Health Psychology 12/2011; 31(5):612-22. DOI:10.1037/a0026528 · 3.95 Impact Factor
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    • "A normal allele with , 45 CGG repeats is stably inherited, but an intermediate allele (45 –54 CGG repeats) may show instability upon transmission (Kronquist et al., 2008). Within the premutation range, a high risk for FXPOI has been suggested for 80 – 100 repeats (Sullivan et al., 2005; Ennis et al., 2006; Allen et al., 2007; Tejada et al., 2008). Women with a normal repeat length or a full mutation are not at risk for POI (Allingham-Hawkins et al., 1999; Murray et al., 1999). "
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    ABSTRACT: Carriers of a premutation (CGG repeat length 55-200) in the fragile X mental retardation (FMR1) gene are at risk for primary ovarian insufficiency (FXPOI). The anti-Müllerian hormone (AMH) level acts as a useful marker of ovarian follicle reserve and, thus, may serve to predict when this ovarian reserve becomes too low to sustain ovarian function. We investigated the intra-individual variation of AMH levels over time for premutation carriers compared with non-carriers. We determined AMH levels in blood samples from 240 women ascertained through fragile X families, of which 127 were premutation carriers and 113 were non-carriers. Linear mixed models were used to assess the effect of age and premutation status on AMH levels and to determine a modeled AMH value. The stability over time of the deviation of observed AMH levels from modeled levels, referred to as standardized AMH values, was assessed through correlation coefficients of 41 longitudinal samples. At all ages, premutation carriers exhibited lower AMH levels. For all women, AMH was found to decrease by 10% per year. The added effect of having a premutation decreased AMH levels by 54%. The deviation of an individual's AMH level from the modeled value showed a reasonable intra-individual correlation. The Pearson correlation coefficient of two samples taken at different ages was 0.36 (P = 0.05) for non-carriers and 0.69 (P = 0.01) for carriers. We developed a unique standardized AMH value, taking FMR1 premutation status and the subject's age into account, which appears to be stable over time and may serve as a predictor for FXPOI after further longitudinal assessment.
    Human Reproduction 05/2011; 26(8):2185-91. DOI:10.1093/humrep/der146 · 4.59 Impact Factor
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