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: 4.57). 09/2007; 22(8):2142-52. DOI: 10.1093/humrep/dem148
Source: PubMed


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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Available from: Kira C Taylor, Jan 07, 2014
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    • "Approximately 20% of premutation carriers will be diagnosed with FXPOI (Sherman, 2000). Even among those at younger ages who do not meet full criteria for FXPOI, women with a premutation on average experience menopause 5 years earlier than controls (Murray, 2000; Sullivan et al., 2011) and have more hot flashes (Smith et al., 2012); decreased levels of anti-Müllerian hormone (Spath et al., 2011); increased levels of follicle stimulating hormone (FSH; Murray, 2000; Hundscheid et al., 2001; Sullivan et al., 2005; Rohr et al., 2008; Welt, 2008; Spath et al., 2011); and irregular, shorter, or skipped menstrual cycles and subfertility (Allen et al., 2007; Welt, 2008). Hunter et al. (2010) also found an increased risk for depression/anxiety and thyroid problems for premutation women who had an indication of ovarian insufficiency, suggesting, as has been hypothesized in other studies (Mondul et al., 2005; Rodriguez-Revenga et al., 2008), that the increased risk for emotional challenges reported for premutation carriers may be linked to hormonal imbalances. "
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    ABSTRACT: Recently, research has indicated an increased risk for greater medical and emotional comorbidity and physical health symptoms among women with an FMR1 expansion. However, these studies have generally been limited in their ability to model multiple risk factors associated with these symptoms by small numbers (n = 112-146) of participants. This study used survey methodology to examine the health experiences of 458 adult women with the premutation with and without a history of a fragile X primary ovarian insufficiency (FXPOI) diagnosis. Results suggest similar findings to those reported in the literature with regard to the frequency of medical, emotional, and reproductive experiences of women with the premutation. In addition to expected reproductive differences, women with a diagnosis of FXPOI were also more likely to experience dizziness, nausea, and muscle weakness than women without a diagnosis of FXPOI. Women with and without FXPOI were more likely to have used reproductive assistance and were more likely to have experienced preeclampsia during at least one pregnancy than is reported in the general population. Having comorbid depression and anxiety was predictive of increased medical conditions and increased daily physical health symptoms.
    Frontiers in Genetics 09/2014; 5:300. DOI:10.3389/fgene.2014.00300
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    • "As in previous studies [11]–[17] our study also observed that in FMR1 premutation carriers there is a significant impairment in ovarian reserve biomarkers, such as high basal FSH levels and FSH/LH ratio [22], as well as a reduced response to COH protocol (Table 1). In addition, as in previous studies [18], [19] our study demonstrated a significant non-linear association between the number of CGG repeats and ovarian function with the mid-size range (80–120) having the worst prognosis. In the present study, women with 80–120 CGG repeats had significantly less oocyte retrieved compared to women with higher and lower repeats (Fig. 1). "
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    ABSTRACT: Aim To assess the role of mRNA accumulation in granulosa cells as the cause of low ovarian response among FMR1 premutation carriers undergoing pre-implantation genetic diagnosis (PGD). Design Case control study in an academic IVF unit. Twenty-one consecutive FMR1 premutation carriers and 15 control women were included. After oocyte retrieval the granulosa cells mRNA levels of FMR1 was measured using RT-PCR. Results In FMR1 premutation carriers, there was a significant non-linear association between the number of CGG repeats and the number of retrieved oocytes (p<0.0001) and a trend to granulosa cells FMR1 mRNA levels (p = 0.07). The lowest number of retrieved oocytes and the highest level of mRNA were seen in women with mid-size CGG repeats (80–120). A significant negative linear correlation was observed between the granulosa cells FMR1 mRNA levels and the number of retrieved oocytes (R2 linear = 0.231, P = 0.02). Conclusion We suggest that there is a no-linear association between the number of CGG repeats and ovarian function, resulting from an increased granulosa cells FMR1 mRNA accumulation in FMR1 carriers in the mid-range (80–120 repeats).
    PLoS ONE 08/2014; 9(8):e105121. DOI:10.1371/journal.pone.0105121 · 3.23 Impact Factor
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    • "Women with mid-range PM repeats (approximately 70 to 90 repeats) have the highest risk for POF. Carriers of both smaller and larger PM repeat lengths also have an increased risk of POF compared to the general population, but not to the same extent as mid-range repeat carriers [7,13,26-28]. Second, skewed XCI may play a role in modifying the risk or severity of FXPOI, as FMR1 is located on the X chromosome. "
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    ABSTRACT: Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP's function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI.
    Journal of Neurodevelopmental Disorders 08/2014; 6(1):26. DOI:10.1186/1866-1955-6-26 · 3.27 Impact Factor
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