1 Wessex Regional Genetics, Salisbury District Hospital, Salisbury, Wiltshire, SP2 8BJ and 2 Division of Endocrinology, Cobbold Laboratories, Middlesex Hospital, Mortimer Street, London, W1N 8AA, UK
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Abstract |
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Key words: fragile X/FSH/premature ovarian failure/premutation
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Introduction |
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It has been proposed (Conway et al., 1995) that alleles in the premutation range interfere in some way with FMR1 transcription in the fetal ovary, reducing the number of oocytes at birth. Attrition of the primordial follicle store leads to their depletion at a relatively earlier age and a compensatory rise in follicle stimulating hormone (FSH), presaging ovarian failure. We have examined families selected through fragile X probands to establish whether markers of an early menopause were present.
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Materials and methods |
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Since levels of hormones vary naturally with age (MacNaughton et al., 1992), regardless of FRAXA allele status, an adjustment for age was needed to ensure that only changes additive to natural fluctuations were considered. A double logarithm transformation of hormone levelx(y = lnlnx) was found to stabilize the variance within age better than a single logarithm transformation, but still not completely. We therefore obtained a predicted value (
) from the regression y = a + b(age) + c(age2), and a predicted variance (V) from the regression (y
)2 = A + B(age) + C(age2), to give the standardized variable (y
)/÷V, which was normalized through rank transformation (Blom, 1958
). Stepwise regression (SAS Institute Inc., Cary, NC, USA) was performed on the resulting variable which represented the FSH level x, with a stable mean and variance and a normal distribution within age.
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Results |
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Discussion |
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Women with premutations not only have an increased incidence of premature ovarian failure (Allingham-Hawkins et al., 1999) but our data suggest that those still menstruating have an occult raised serum FSH concentration, suggestive of a depleted ovarian reserve. These data support the hypothesis that premutation carriers as a group have an earlier age of menopause than their unaffected and full mutation carrier relatives (Partington et al., 1996), which manifests as premature ovarian failure in ~23% of premutation carriers, but in others will merely result in menopause at a younger age than they would otherwise have had.
It is rare for women to be fertile with a follicular phase FSH >20 IU/l (O'Herlihy et al., 1980), and therefore the results of this study have important implications for fertility. Female members of fragile X families require combined genetic and fertility counselling. From a practical point of view, women found to have raised FSH concentrations respond poorly to all modes of fertility treatment (Scott and Hofman, 1995). If, however, detected at an early stage (FSH <15 IU/l) conception may still be possible perhaps with the assistance of ovulation induction techniques. The Fragile X Society is aware of the risk of early ovarian failure and is advising women to consider starting their families earlier than they might otherwise have done.
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Acknowledgments |
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Notes |
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References |
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Blom, G. (1958) Statistical Elements and Transformed Beta Variables. Wiley, New York.
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Submitted on October 12, 1998; accepted on January 26, 1999.