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 20–25 % of carriers will develop premature ovarian failure (POF), or cessation of menses prior to age 40 compared to 1 % of the general population (Sherman 2000; Wittenberger et al. 2007). FXPOI can manifest in a spectrum of symptoms related to early onset ovarian changes and may present distinct challenges according to stage of life (Allen et al. 2007; Rohr et al. 2008; Sullivan et al. 2005; Welt et al. 2004; Wheeler et al. 2014). Early concerns focus on family planning and decreased fertility, while later concerns shift to medical conditions associated with early estrogen deficiency, such as osteoporosis , cardiovascular health and the associated treatments (i.e., hormone replacement therapy options). "
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    ABSTRACT: Women who carry an FMR1 (i.e., fragile X) premutation have specific health risks over their lifetime. However, little is known about their experience understanding these risks and navigating their health needs. The aim of this study was to use qualitative analysis to uncover both barriers and facilitators to personal healthcare using a framework of the Health Belief Model. Five focus groups were conducted with a total of 20 women who carry the FMR1 premutation using a semi-structured discussion guide. All sessions were transcribed verbatim and independently coded by two researchers. The coders used a deductive - inductive approach to determine the prominent themes related to the participants' experiences seeking healthcare for premutation-related conditions. Salient barriers to personal healthcare included difficult clinical translation of research findings, lack of knowledge among healthcare providers and among the women themselves, different priorities, and shortage of premutation-specific support and targeted educational materials. Facilitators included family members, national and community support organizations, research studies, compassionate physicians, and other premutation carriers. Addressing barriers to personal healthcare through up-to-date educational materials can help diminish misperceptions regarding health risks. Targeted educational materials will aid in information sharing and awareness for women who carry the FMR1 premutation and their physicians.
    Full-text · Article · Jul 2015 · Journal of Genetic Counseling
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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.
    Full-text · Article · Sep 2014 · Frontiers in Genetics
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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).
    Full-text · Article · Aug 2014 · PLoS ONE
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