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Objective: To determine the heritability of age at natural menopause from mother-daughter pairs., Design: Two-generation families were selected to study heritability of menopausal age., Setting: Subjects were drawn from a population-based study., Patient(s): One hundred sixty-four mother-daughter pairs with a natural menopausal age., Intervention(s): None., Main Outcome Measure(s): The heritability of age at natural menopause estimated by a random-effects model., Result(s): A heritability of 44% (95% confidence interval, 36%, 50%) was estimated., Conclusion(s): This study confirms that heritable components largely determine the natural age at menopause. Reasons for the differences between heritability estimates based on sibling pairs and parent-child comparisons are discussed.

Objective: Studies have shown that age at natural menopause is heritable. Mutations in the FSH-receptor have been identified in women with premature ovarian failure (POF) and the FSH-receptor gene may, therefore, be considered a candidate gene for (early) menopausal age. This study investigates whether there is linkage between genetic markers in the FSH-receptor region and (early) age at menopause using a sib-pair design., Design: Sib-pair based linkage analysis., Setting: Sister pairs and their first-degree family members from The Netherlands., Patient(s): The inclusion criteria for a family were natural menopause in upper or lower tail of the distribution of menopausal age in at least two sisters. A total of 126 families with at least one sib-pair were included in this study. Six polymorphic markers encompassing the FSH-receptor gene were genotyped., Intervention(s): None., Main Outcome Measure(s): Single point and multipoint logarithm of the odds (LOD) scores., Result(s): None of the markers showed evidence in favor of linkage with overall age at natural menopause or early age at natural menopause., Conclusion(s): Possibly, age at natural menopause in the more or less normal range is not part of the spectrum of phenotypes determined by mutations in the FSH-receptor gene. Alternatively, our results might be explained by genetic heterogeneity in the left tail of the distribution of menopausal age. This can limit the chance of finding a genetic locus, especially if this factor has a modest contribution to the phenotype.

Age at natural menopause may be used as parameter for evaluating the rate of ovarian aging. Environmental factors determine only a small part of the large variation in menopausal age. Studies have shown that genetic factors are likely to be involved in variation in menopausal age. To identify quantitative-trait loci for this trait, we performed a genomewide linkage study with age at natural menopause as a continuous quantitative phenotype in Dutch sister pairs, through use of a selective sampling scheme. A total of 165 families were ascertained using extreme selected sampling and were genotyped for 417 markers. Data were analyzed by Haseman-Elston regression and by an adjusted variance-components analysis. Subgroup analyses for early and late menopausal age were conducted by Haseman-Elston regression. In the adjusted variance-components analysis, 12 chromosomes had a LOD score of > or =1.0. Two chromosomal regions showed suggestive linkage: 9q21.3 (LOD score 2.6) and Xp21.3 (LOD score 3.1). Haseman-Elston regression showed rather similar locations of the peaks but yielded lower LOD scores. A permutation test to obtain empirical P values resulted in a significant peak on the X chromosome. To our knowledge, this is the first study to attempt to identify loci responsible for variability in menopausal age and in which several chromosomal regions were identified with suggestive and significant linkage. Although the finding of the region on the X chromosome comes as no surprise, because of its widespread involvement in premature ovarian failure, the definition of which particular gene is involved is of great interest. The region on chromosome 9 deserves further consideration. Both findings require independent confirmation.

Background: The aim of the study was to explore the extent to which accelerated ovarian ageing may lead to subfertility early in reproductive life and eventually cause early menopause., Methods: The population studied (n = 2393) never used oral contraceptives, hormone replacement therapy or an intrauterine device. Logistic regression analyses were performed using age at menopause as proxy for accelerated ovarian ageing. Measures of ovarian ageing and subfertility were menstrual cycle irregularity, ever consulted a physician for fertility problems, nulliparity, uniparity, miscarriage(s) and time interval >5 years between birth of first and second child., Results: For every 5 years later menopause, the probability of reporting menstrual cycle irregularity was reduced by 26% (OR = 0.74, 95% CI: 0.63-0.86); the probability of ever consulting a physician for fertility problems was reduced by 18% (OR = 0.82, 95% CI: 0.71-0.95); the probability of staying nulliparous was reduced by 22% (OR = 0.78, 95% CI: 0.64-0.96); the probability of being uniparous was reduced by 22% (OR = 0.78, 95% CI: 0.66-0.91); the probability of having a miscarriage was reduced by 11% (OR = 0.89, 95% CI: 0.79-1.01); the probability of a large time interval between birth of first two children was reduced by 27% (OR = 0.73, 95% CI: 0.61-0.89)., Conclusions: Fertility problems are frequently followed by early menopause. The findings support the view that both are an expression of accelerated ovarian ageing.

The delay in childbearing is an important societal change contributing to an increasing incidence of subfertility. The prevailing concept of female reproductive ageing assumes that the decline of both quantity and quality of the oocyte/follicle pool determines an age-dependent loss of female fertility. There is an apparent discrepancy between the ability to maintain a regular ovulatory cycle pattern and the several years earlier cessation of female fertility. This latter is largely explained by an age-related increase of meiotic non-disjunction leading to chromosomal aneuploidy and early pregnancy loss, such that most embryos from women > or =40 years old are chromosomally abnormal and rarely develop further. The final stage of reproductive ageing-the occurrence of menopause-shows a huge variation between women. Age at last birth in natural fertility populations, which marks the end of female fertility, shows an identically wide variation as age at menopause, but occurs on average 10 years earlier. Given the high heritability for age at menopause, the variation in both age of menopause and last birth are probably under genetic control by the same set of genes. Some of those genes must carry heritable variants which modulate the rate of ovarian ageing and give rise to the wide age variations for the various phases of reproductive ageing.