There is an assumption that ovarian reserve may reflect not only decreased quantity, but also decreased fecundity. This study tested the hypothesis that ovarian reserve, as measured by AFC, in infertile women was different from that in a community-based population. In this analysis we found a significantly lower median AFC in women who are infertile. Furthermore, we showed within the community-based group, AFC is significantly lower in women who had experienced difficulties conceiving.
AFC is considered one of the most reliable non-invasive methods for determining ovarian reserve. This conclusion is based on AFC correlating well with the number of non-growing follicles noted in histological sections and following a parallel pattern of decline with age to that observed histologically[20
]. In addition, AFC has been correlated with the occurrence of the menopausal transition, response to ovarian stimulation and possibly pregnancy outcomes [23
]. In our study, we show that AFC is lower in women who are infertile over a wide range of ages.
Since menopause ensues when oocyte depletion is almost complete (postulated to be with approximately 1000 remaining oocytes), lowered AFC would be expected to predict an earlier menopause[28
]. And, consistent with teVelde’s model of reproductive aging, lowered reproductive potential would be associated with both lowered AFC and earlier menopause[4
]. Kok et al.(2003) studied a large study population (n= 2393) that had never used birth control and found the age at onset of menopause was significantly associated with reproductive potential[11
]: for every 5 year increase in the age of onset of menopause, there was a decrease in the probability of consulting with a fertility specialist (OR=0.82; 95%CI 0.71,95), of being nulliparous (OR=0.78; 95%CI 0.64,96) and of requiring more than 5 years to achieve a second livebirth (OR=0.73; 95%CI 0.61,0.89).
While it has been demonstrated that the earlier age at onset of menopause is associated with diminished reproductive potential, clinical usefulness is limited unless we have a prospective marker for menopause. This has led to considerable interest over the last decade in identifying non-invasive (indirect) markers of ovarian age that may predict both menopause and the likelihood for successful pregnancy. Few studies, however, have evaluated whether ovarian reserve tests predict spontaneous pregnancy. Earlier studies in subfertile women suggested high FSH, as a marker of low ovarian reserve, was associated with a decline in pregnancy rate in subfertile patients and longer time to spontaneous pregnancy regardless of age [29
] More recently, Haadsma et al (2008) addressed this question in an ovulatory, subfertile population, and found an inverted U-shape best described the relationship between pregnancy likelihood and both AFC and FSH. However, excluding those with low FSH and/or high AFC eliminated any significance of ovarian reserve testing for predicting conception. Additionally, as above, this was a cohort of subfertile patients who were only allowed to continue with expectant management if their chances for conception were thought to be> 30%. (31) Thus only those considered to have the best fertility prognosis continued expectant management for a prolonged period. To identify if poor ovarian reserve was predictive of spontaneous pregnancy, they performed a sub- analysis of those women with an FSH>10 and found no association. In our study, rather than modeling within a group already known to be subfertile, we compared women with unexplained infertility to women in the community. We observed a significant decrease in AFC in the infertile women, up to age 40. FSH differences between the groups were variable which may be expected since FSH is considered a late marker of ovarian aging and varies from month-to-month [31
The association of age with diminishing reproductive capacity is well known. The etiology is often attributed solely to aneuploidy[35
]. The mechanisms that are thought to promote meiotic nondisjunction are multifactorial and are thought to accumulate over time. Therefore they are considered most dependent upon chronological age. However, it has also been proposed that aneuploidy can independently be attributed to falling oocyte number resulting from poorer quality oocytes remaining in the ovary after euploid oocytes have been selected for ovulation[2
]. This would imply aneuploidy is negatively associated with the quantity of oocytes remaining in the ovary. This hypothesis is supported by studies that have shown decreased AFC in women with spontaneous abortions following IVF compared with those with live births, and increased FSH among those with miscarriages and aneuploid conceptions[14
]. Interestingly, this finding has been observed when decreased follicular reserves resulted from both genetic and iatrogenic (ovarian surgery) causes, and was independent of age [12
]. However, as discussed above, this conclusion has not been supported by all studies[10
]. These inconsistencies may be explained by differences in study populations and study design. In addition many of these studies lack sufficient power to assure no difference. It is also possible that loss of oocyte developmental competence results from different
mechanisms when associated with advanced ovarian aging or iatrogenic loss rather than expected chronologic aging.
The major limitation of our study is its cross-sectional nature, as we cannot establish that lower AFC actually results in infertility. In addition, while lower AFCs are seen among infertile women at the time of presentation, it is uncertain whether this results from a smaller initial oocyte pool or an accelerated rate of loss. If an increased rate of loss is responsible, it is necessary to know the timing of onset of this loss to improve predictive ability for women. Longitudinal studies of AFC in both fertile and infertile women will be necessary to determine the predictive value of AFC for future fertility. Threshold values that predict a very low likelihood of spontaneous conception may be identified and thus the nonspecific term “diminished ovarian reserve,” currently overused in the infertility literature, could gain clinical relevance among the general population.
Although age is considered to be the most predictive variable for pregnancy success, there is considerable variation in the onset of reproductive compromise for any individual woman. We are not yet able to predict who will have difficulty conceiving. In this study, we show AFC is decreased in women who are infertile and those with subfertility. Thus AFC appears to have an independent association with reproductive potential and may account for at least part of the considerable variation that exists between women for any given age. Decreased AFC may, in fact, be a marker of both oocyte quantity and quality. If our results are replicated in longitudinal studies, age-specific AFC percentile may represent a powerful tool helping women assess their future fertility potential.