The investigators' long-term goal is to elucidate the processes leading to trisomy, the most frequent chromosomal aberration seen among human births and clinically recognized spontaneous abortions and a major cause of severe mental retardation. Advancing maternal age is the primary risk factor for trisomy. The proposed project tests whether this association reflects accelerated physiologic aging, either in the ovary specifically or more generally. They hypothesize that trisomy arises as a function of the size of the oocyte pool (ovarian age), with risk increased in women with smaller oocyte pools and fewer developing follicles at any given chronologic age. Follicle counts are highest before birth and decrease as women age; similarly, after puberty, the numbers of follicles that develop during each menstrual cycle decrease as women age. While the total pool cannot be measured in vivo, recent advances in transvaginal sonography now allow counts of developing follicles. The project is designed to detect a difference in the numbers of developing follicles between women with and without trisomies. The sample will comprise 60 women with trisomy spontaneous abortions (cases) and two control groups: 80 women with chromosomally normal spontaneous abortions and 60 women with chromosomally normal livebirths.
The specific aims are as follow: 1. To test whether fewer ovarian follicles develop (indicating more advanced ovarian age) in cases than in controls of the same chronological age. 2. To test whether two more readily obtained indicators of ovarian age -- follicle stimulating hormone and inhibin indicate more advanced ovarian age in cases than in controls. 3. In the event that both follicle counts and hormonal indicators are related to trisomy, to contrast their utility in discriminating between cases and controls. 4. To explore whether associations are specific to aging in the ovary by testing whether one non-ovarian indicator of physiologic age X-aneuploidy in lymphocytes suggests advanced physiologic age in cases. The investigators state that confirmation of their hypothesis has implications both for the search for mechanisms of trisomy formation and for evaluating the clinical utility of indicators of physiologic age, whether ovarian or non-ovarian.
| Kline, Jennie K; Kinney, Ann M; Levin, Bruce et al. (2014) Intermediate CGG repeat length at the FMR1 locus is not associated with hormonal indicators of ovarian age. Menopause 21:740-8 |
| Kline, J; Kinney, A; Brown, S et al. (2012) Trisomic pregnancy and intermediate CGG repeat length at the FMR1 locus. Hum Reprod 27:2224-32 |
| Kline, J K; Kinney, A M; Levin, B et al. (2011) Trisomic pregnancy and elevated FSH: implications for the oocyte pool hypothesis. Hum Reprod 26:1537-50 |
| Kinney, A; Kline, J; Kelly, A et al. (2007) Smoking, alcohol and caffeine in relation to ovarian age during the reproductive years. Hum Reprod 22:1175-85 |
| Kinney, Ann; Kline, Jennie; Levin, Bruce (2006) Alcohol, caffeine and smoking in relation to age at menopause. Maturitas 54:27-38 |
| Kline, Jennie; Kinney, Ann; Levin, Bruce et al. (2006) X-chromosome inactivation and ovarian age during the reproductive years. Fertil Steril 85:1488-95 |
| Kline, J; Kinney, A; Kelly, A et al. (2005) Predictors of antral follicle count during the reproductive years. Hum Reprod 20:2179-89 |
| Warburton, D (2005) Biological aging and the etiology of aneuploidy. Cytogenet Genome Res 111:266-72 |
| Kline, J; Kinney, A; Reuss, M L et al. (2004) Trisomic pregnancy and the oocyte pool. Hum Reprod 19:1633-43 |
| Warburton, Dorothy; Dallaire, Louis; Thangavelu, Maya et al. (2004) Trisomy recurrence: a reconsideration based on North American data. Am J Hum Genet 75:376-85 |
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