In this study, we evaluated how serum markers of ovarian reserve decline with age in a community-based, regularly cycling Caucasian population and compared these patterns to those identified from histologic data (7
). Of the markers considered, only AMH and AFC exhibited significant progressive declines with age, with AFC having a slightly better fit to the basic pattern observed histologically (); E2
and inhibin B did not and therefore the data do not provide support for them as markers of ovarian reserve.
Antimüullerian hormone levels therefore appear to be the best serum
marker of ovarian reserve (13
). Simple correlation coefficients between age and AMH have been reported previously. A recent study evaluating the relationship between AMH and age at menopause in 144 participants reported an accelerated rate of decline with age (16
). Reported correlations between age and AMH are dependent on the population studied (r
= −0.30 to −0.66) (17
). Perhaps the most similar patient group to ours is a subset analysis of 81 participants of the 162 subjects in their overall cohort; for that study, the reported correlation (r
) was −0.66, whereas we found an r
of −0.46. Unlike our results, they do not report quantitative loss across ages and judge whether that marker fit the histologic pattern of oocyte loss.
Among those markers following the pattern, R2
was used to compare the degree of relationship with age. Antral follicle count had a slightly better fit with the power model compared with AMH (R2
= 27.3% vs 22.7%, respectively). However, the R2
for nongrowing follicles with age using the power model was reported by Hansen et al. to be 0.83 (7
), much higher than ours. However, the population studied was from ages <1 month to 51 years. For comparison, we reanalyzed their data and restricted the ages to that of our study sample (25–45 years) and found a reduced R2
of approximately 0.30 using either the raw or log-transformed values of AMH, much more similar to our results. The R2
for our data for the log-transformed AMH levels was 0.38, and for AFC it was 0.37.
Inhibin B is a biologically plausible biomarker of ovarian reserve because its decline leads to a rise in FSH levels, and it is produced by small preantral and antral follicles (20
). Danforth et al. showed a statistically significant correlation of −0.54 between inhibin B and age (20
). Although their study included healthy volunteers and not infertile patients, it was small (n
= 25), and only included women between the ages of 39 and 52, not addressing correlation across the full reproductive age span. A larger study by Scheffer et al. composed of 162 participants from the general population, aged 25–46 years, showed that inhibin B was not significantly correlated with age (r
= −0.12 and NS) (23
). In our study, inhibin B levels did not show the expected gradual accelerated decline with age the other markers exhibited and thus was consistent with the work of Scheffer et al., suggesting poor correlation with age overall (r
= 0.11, P
Day 3 FSH and E2
levels have been utilized as a marker of ovarian reserve since the 1980s and was the first such marker (24
). Elevated day 3 FSH and E2
levels correlate well with those in late perimenopause and menopause, and milder elevations have been considered the hallmark for ovarian aging (27
). Earlier studies showed FSH levels to be significantly higher starting in the fifth decade of life (28
). Scheffer et al. showed that FSH (r
= 0.25, P
<.05) and day 3 E2
= 0.29, P
<.05) levels were significantly correlated with age (23
). We similarly found that FSH (r
= 0.37, P
<.001) and day 3 E2
= 0.22, P
<.001) levels were correlated with age, and found that the yearly rate of change was significant only at older ages (, ). Furthermore, the power model fit for day 3 E2
shows a relatively poor association with age (). This suggests that E2
alone is not an accurate marker of ovarian aging.
The panels in show that there is a considerable amount of variation with any surrogate marker of ovarian reserve that cannot be explained by age alone. Even with the best surrogate markers, AFC and AMH, more than 70% of the variation in women of reproductive age is left unexplained by age. This finding further illustrates that age is not the sole determinant of ovarian reserve. Several studies have shown that there is considerable variation in the natural age of onset of menopause (30
). Although the coefficients of variation for the surrogate markers are relatively low, they are similar to what has been observed histologically and therefore we consider them valid markers of ovarian reserve.
A major limitation of this study is that it used cross-sectional data, and so nonlinear longitudinal relationships are not recoverable. Another limitation is that the data set is limited to Caucasians. However, we made this decision to decrease potential ethnic variation. Currently, we are enrolling subjects of different ethnicities to address this shortcoming. Prospective longitudinal studies in the same women over time are planned to more accurately characterize the relationship of these noninvasive markers of ovarian reserve and aging. A strength of this study is the closer approximation to normative as the population was derived from the community and not an infertility clinic. However, determination of which ovarian reserve marker is more reliable is limited because of the absence of direct histologic specimens as an outcome for comparison. More studies are needed to compare these noninvasive tests with histologic assessments.
One must use caution when suggesting these markers are “true markers” of the number of follicles remaining in the ovary. It is noted that the number of growing antral follicles is correlated to the number of primordial follicles (34
). Most of these markers of ovarian reserve, other than FSH, are the direct product of growing antral follicles. If there is a disturbance in the number of growing follicles, measures of ovarian reserve may not be reliable (10
). For example, there is evidence that AMH levels may be temporally influenced by iatrogenic causes (35
). One study showed that AMH levels decrease for a short time after ovarian cystectomy (11
). Other studies suggest AMH levels decrease after uterine artery embolization or hysterectomy (36
This is the first study to characterize the relationship of the noninvasive serum markers of ovarian reserve with age in a large general (noninfertility) population. We found that the only markers that follow the pattern of oocyte loss observed histologically were AFC and AMH. Although AMH may be more cost-effective, AFC was a slightly more accurate noninvasive measure for ovarian aging.