N.S. Macklon, M.D., Ph.D.; B.C.J.M. Fauser, M.D., Ph.D.

Disclosures

Semin Reprod Med. 2005;23(3):248-256. 

In This Article

Markers of Ovarian Reserve

The most widely used endocrine marker for ovarian reserve is the early follicular phase FSH level.[10] Early follicular (basal) FSH level has been shown to be an independent predictor of IVF outcome,[35,36] and is a stronger predictor of cycle cancellation due to poor response and the number of oocytes collected at pick-up. In contrast, age appears to be more closely related to the chance of implantation and ongoing pregnancy.[20,26,37] This was illustrated by the finding that women older than 40 years with normal basal FSH levels (< 15 U/L) may demonstrate lower cancellation rates, but the implantation rate per embryo and the ongoing pregnancy rates are lower than those observed in young women with elevated basal FSH levels.[38] Moreover, recent studies have indicated that young women with high FSH levels demonstrate lower numbers of growing follicles and a high probability of cycle cancellation, but can achieve good ongoing pregnancy rates if oocytes and embryos are obtained.[38] The combined and independent effects of increased basal FSH levels and age on IVF outcomes can be illustrated graphically[39] (Fig. 2).

The independent and combined affect of age and basal follicle-stimulating hormone (FSH) levels on delivery rate per cycle (%) derived from a theoretical model is illustrated. In young women, the success rate is greater than that in older women unless the basal FSH is highly elevated. Adapted from Toner JP. Modest follicle-stimulating hormone elevations in younger women: warn but don't disqualify. Fertil Steril 2004;8:1493-1495.

Discrepancies between the predictive value of FSH for ovarian response to ovarian stimulation and for ongoing pregnancy illustrate the limitations of tests of ovarian responsiveness as markers of ovarian reserve. Although response to stimulation reflects the quantity, pregnancy rate reflects both the quantity and quality of the oocytes.[40] The number of follicles or oocytes obtained after ovarian hyperstimulation is therefore merely a surrogate for ovarian reserve. This differentiation was emphasized by the conclusions of a recent meta-analysis, in which basal FSH levels showed a moderate predictive performance for poor response but a low predictive performance for nonpregnancy[41] (Fig. 3). A recent retrospective analysis showing that ongoing pregnancy rates of 28% may be achieved in regularly cycling women with basal FSH levels above 15 U/L suggests that quality can compensate for quantity of oocytes when the latter is diminished in younger women.[42] It is therefore suggested that young patients should not be excluded from IVF treatment purely on the basis of increased basal FSH levels. Caution is certainly required when interpreting basal FSH levels in a clinical context. Inconsistencies may arise from the wide interindividual variation that exists in follicular phase FSH concentrations in the normo-ovulatory cycle.[43] Moreover, cycle-to-cycle variations in basal FSH limit the reliability of a single measurement. When more than one measurement is made, it appears that the highest value is of most prognostic significance.[44,45]

Receiver operating characteristic curves of studies reporting on the performance of basal follicle-stimulating hormone (FSH) to predict poor ovarian response (A) and nonpregnancy (B). The curves indicate that although FSH is a moderate predictor for ovarian response, it is a poor predictor for nonpregnancy. Adapted from Bancsi LF, Broekmans FJ, Mol BW, Habbema JD, te Velde ER. Performance of basal follicle-stimulating hormone in the prediction of poor ovarian response and failure to become pregnant after in vitro fertilization: a meta-analysis. Fertil Steril 2003;79:1091-1100.

Receiver operating characteristic curves of studies reporting on the performance of basal follicle-stimulating hormone (FSH) to predict poor ovarian response (A) and nonpregnancy (B). The curves indicate that although FSH is a moderate predictor for ovarian response, it is a poor predictor for nonpregnancy. Adapted from Bancsi LF, Broekmans FJ, Mol BW, Habbema JD, te Velde ER. Performance of basal follicle-stimulating hormone in the prediction of poor ovarian response and failure to become pregnant after in vitro fertilization: a meta-analysis. Fertil Steril 2003;79:1091-1100.

Estradiol is frequently measured at the same time as basal FSH. When elevated on cycle day 3, it appears to predict poor response to ovarian stimulation for ART, even when basal FSH levels are normal.[46] It is suggested that elevated early follicular phase estradiol levels may indicate an inappropriately advanced stage of follicular development, consistent with ovarian aging. However, it may simply reflect the presence of functional ovarian cysts.[47]

Inhibin B is an alternative endocrine marker that has been postulated. It has been suggested that measuring inhibin B concentrations would provide a more direct assessment of ovarian reserve, given that (in contrast to FSH) it is directly produced by developing early antral follicles.[48,49] Inhibins are dimeric glycoproteins consisting of an α subunit linked through disulfide binding with either a βA (inhibin A) or βB (inhibin B) subunit. Interest in inhibin as a marker of ovarian aging has revived in recent years with the development of enzyme-linked immunosorbent assays capable of distinguishing between these two heterodimers.[50] It is now clear that elevated early follicular phase FSH concentrations are associated with a significant decrease in inhibin.[51] Initial studies reported an association between diminished ovarian response during IVF and decreased serum inhibin B levels.[52,53] However, later studies were unable to confirm these findings[48,54,55] and studies of the value of measuring inhibin B on cycle day 5 showed discordant results.[56,57] Recently, it was demonstrated in a multivariate analysis that addition of basal FSH and inhibin B levels to a logistic model including ultrasound characteristics can improve the performance of the model.[58]

The ultrasound parameter in question was the antral follicle count. The number of antral follicles in the early follicular phase assessed by ultrasound[59] has been found to decrease with advancing age and this is thought to represent ovarian aging. Recent data indicate that the number of antral follicles present on cycle day 3 provides a better single prognostic indicator for poor response during IVF than the patient's age or any other endocrine marker.[58,60] Ovarian volume, which partly reflects the number of ovarian follicles, has also been shown to decrease with age,[61] and several studies have suggested a role for this parameter as a marker of ovarian reserve.[62,63,64]

Several challenge tests have been designed that offer the theoretical benefit of measuring ovarian reserve in a dynamic, and perhaps more clinically representative way. The clomiphene citrate challenge test (CCCT) involves the administration of 100 mg clomiphene citrate on days 5 to 9, and the measurement of FSH levels on days 3 and 10. An abnormal test is defined as an abnormally high FSH on day 10.[65,66] It has been suggested that the CCCT may be better than basal FSH for predicting infertility treatment outcome because two levels of FSH are obtained, and the addition of clomiphene citrate may serve to reveal women who might not be detected by basal FSH screening alone.[67] In a recent meta-analysis, basal FSH and the CCCT were found to be of similar value in predicting a clinical pregnancy in women undergoing infertility treatment.[68] With either test a normal result was of little predictive value, but an abnormal result predicted poor outcome from infertility treatment. Given that the CCCT offers no clear advantage compared with a single basal FSH measurement, and is itself associated with potential adverse effects, basal FSH is preferred.

The exogenous FSH ovarian reserve test was designed to screen for good or poor response in IVF.[69] The change in estradiol levels in response to 300 U of FSH administered on cycle day 3 provides the dynamic component to this test and has recently been shown to demonstrate less intercycle variability than basal FSH levels.[70] However, the value of this parameter as an independent variable predictive of IVF outcome has not been evaluated fully. A test similar in concept is the GnRH agonist stimulation test, which evaluates the change in estradiol levels after 2 or 3 days in response to the flare effect of GnRH agonist administration.[71] The ability of this test to differentiate between normal and diminished ovarian reserve appears to be limited.[65]

The availability and application of so many tests of ovarian reserve serves to illustrate the lack of a single reliable technique ( Table 1 ). However, a recent addition to the list of promising candidates for predicting ovarian response is antimüllerian hormone (AMH), a member of the transforming growth factor-β superfamily. AMH is produced in the ovary by granulosa cells of growing preantral and small antral follicles. In a recent study in young normo-ovulatory women, serum concentrations of AMH decreased over time, whereas other markers associated with ovarian aging did not change[72] (Fig. 4). Given that AMH concentrations correlate well with antral follicle count and age, and less strongly with inhibin B and FSH levels, it might constitute a sensitive marker for ovarian aging.[72,73] Indeed, it has been shown that poor response in IVF is associated with decreased AMH levels.[74] Recently, prediction of poor response to ovarian stimulation based on inhibin B and basal FSH concentrations was improved after inclusion of AMH in a multivariate regression analysis.[75]

Serum levels of antimüllerian hormone, FSH, and follicle number in relation to age in 41 normo-ovulatory women. Serum levels at visit 1 and visit 2 in each woman are interconnected. Solid lines indicate the 95th (upper line), 50th (middle line), and 5th (lower line) percentiles. Reproduced with permission from De Vet A, Laven JS, de Jong FH, Themmen AP, Fauser BC. Anti-mullerian hormone serum hormone levels: a putative marker for ovarian aging. Fertil Steril 2002;2:357-362.

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