1 Research Institute for Endocrinology, Reproduction and Metabolism, Department of Obstetrics and Gynaecology and 2 Research Institute for Endocrinology, Reproduction and Metabolism, Department of Clinical Endocrinology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands
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Abstract |
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Key words: Down's syndrome/FSH/inhibin B/ovarian ageing
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Introduction |
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The aim of the current study was to clarify whether the elevated basal FSH concentrations in women with a history of a Down's syndrome pregnancy were due to a diminished ovarian reserve or to an increased secretory drive, controlling for other causes of elevated FSH concentrations. We addressed this issue by measurement of basal inhibin B and estradiol concentrations in relation to Down's syndrome pregnancies, since basal state concentrations of these hormones were reported to be associated with depletion of the primordial follicle pool (Khalifa et al., 1992; Klein et al., 1996
; Buyalos et al., 1997
; Danforth et al., 1998; Nasseri et al. 1999
; Seifer et al., 1999
).
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Materials and methods |
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After centrifugation, samples were stored in aliquots at 80°C for a maximum of 12 months. For each analysis, a fresh aliquot was used. FSH concentrations were measured with a MEIA (micro particle enzyme immunoassay; Abbott Laboratories, Abbott Park, IL, USA), calibrated against the second International Reference Preparation for FSH (78/549). The intra- and interassay coefficients of variation were 3.77.6 and 05.9% respectively. Estradiol concentrations were measured with a competitive immunoassay (Amerlite, Kodak Clinical Diagnostics, Amersham, UK), with an intra- and interassay coefficient of variation of 13 and 11% for estradiol concentrations <500 pmol/l respectively. Inhibin concentrations were determined immunometrically by a commercially available assay (Serotec Ltd, Oxford, UK), using an immunopurified preparation of human follicular fluid to establish the standard curve. The interassay variability for the inhibin B assay was 17% at 25 ng/l, 14% at 55 ng/l and 9% at 120 ng/l; the lower limit of detection was 15 ng/l.
Data were analysed using SPSS Base 7.5 for Windows (SPSS Inc., Chicago, IL, USA). Basic characteristics were compared between Down's syndrome mothers and controls by Student's t-tests or 2 tests as appropriate. Mean concentrations of FSH, estradiol and inhibin B were compared between the two groups using a Student's t-test. Since basal FSH values did not have a Gaussian distribution, these data were log10-transformed before analysis. Estradiol and inhibin B concentrations were distributed in a Gaussian way and therefore no log10 transformation was used on these values. The Pearson's correlation coefficient was calculated for the correlation between basal FSH and inhibin B concentrations and between basal FSH and estradiol concentrations. Statistical significance was set at P < 0.05.
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Results |
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Discussion |
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Two mechanisms may underlie the relation between inhibin B concentrations and oocyte quality. In the first place, impaired oocyte quality leading to aneuploid conceptions may occur together with a decrease in the number of available follicles with quantitatively less granulosa cells, resulting in a decrease of hormonal feedback. This is in line with several studies reporting a relation between the size of the antral follicle cohort and oocyte quality, for example patients with a decreased number of recruitable follicles during IVF (`poor responders') were also shown to have a reduced fecundity per oocyte retrieved (Muasher et al., 1988; Roest et al., 1996
). In the second place, the granulosa cells per se may function suboptimally and secrete less inhibin B into the follicles with qualitatively compromised oocytes. Indeed, Vitt et al. and Hayashi et al. recently reported that the oocyte directly influences granulosa cell differentiation by production of GDF-9, a growth factor also postulated to influence inhibin B concentrations (Hayashi et al. 1999
; Vitt et al., 2000
). In case of a decreased oocyte quality, impaired GDF-9 production may indirectly cause decreased inhibin B concentrations. Thus, the findings of our study are in-vivo support that a diminished oocyte quality might be directly associated with a decrease in its surrounding granulosa cell functioning.
The fact that we observed no significant correlation between basal FSH concentrations and inhibin B concentrations in the control group is likely to be caused by the smaller range of FSH concentrations in the control group. We hypothesize that a significant correlation between basal FSH concentrations and inhibin B concentrations would also be observed in the control group, had this group included more women with elevated basal FSH concentrations. Alternatively, increased basal FSH concentrations in the control group may also have been caused by an increased secretory drive for FSH and not by a diminished ovarian reserve.
Considering basal estradiol concentrations, we found no significant correlation with FSH concentrations, which is possibly due to the timing of blood sampling. Since estradiol concentrations rise predominantly in late follicular phase of the menstrual cycle, the early follicular phase of the menstrual cycle is likely to be too early to detect a relation between FSH and estradiol concentrations. Alternatively, the fact that other hormones than estradiol influence FSH concentrations as well may obscure the relation between basal FSH and estradiol concentrations on cycle day 3.
The difference in basal FSH concentrations between Down's syndrome mothers and controls was not large, and there was considerable overlap in FSH and inhibin B concentrations between Down's syndrome mothers and controls. In our opinion, this means that basal FSH values are not a specific parameter for advanced ovarian ageing in relation to an increased risk for a Down's syndrome pregnancy. Other mechanisms than elevated basal FSH values may play a role as well in the origination of Down's syndrome (Eichenlaub-Ritter, 1996). Also, there may be other possible causes of elevated FSH concentrations then reduced ovarian reserve (Lambalk and De Koning, 1998
). These causes theoretically include altered FSH activity or resistance to FSH (Anobile et al., 1998
; Dahl et al., 1988
) possibly caused by altered FSH receptor genotype (Perez Mayorga et al., 2000
).
In conclusion, our findings provide further evidence for the theory that accelerated ovarian ageing may lead to an increased aneuploidy rate in oocytes. Further research of the ovarian ageing process could therefore provide more insight in the origination of chromosomal abnormalities during pregnancy.
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Acknowledgements |
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Notes |
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References |
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Submitted on April 25, 2001; accepted on September 10, 2001.