Clinical Utility of Ovarian Reserve Testing
Age-related decline in oocyte quality and quantity undermines the success rate of IVF. There is a need for an ovarian reserve testing that can predict live birth. Anti-Müllerian hormone (AMH) and antral follicle count (AFC) are able to estimate ovarian response but not live birth with any degree of accuracy. AMH has the advantage of being a more objective measure as well as slightly superior in identifying any chance of pregnancy.
Within In Vitro Fertilization (IVF)
Historically, ovarian reserve testing was developed for women undergoing ART procedures in order to identify those that are likely to have a diminished or exaggerated ovarian response to hormonal stimulation. AMH and AFC predict ovarian response, such as the number of follicles, the number of oocytes retrieved, the number of embryos, and cancellation rate, with reasonable efficiency. Although both tests are comparable in terms of test accuracy for ovarian response and non-conception, AMH is considered by some to have an edge due to the subjective elements associated with AFC assessment.
AMH less than 0.5 ng/mL predicts poor ovarian response in IVF (defined as less than four oocytes). These women need careful counseling and protocols that optimize oocyte yield. Women with AMH levels greater than 1.0 ng/mL and <3.5 ng/mL is expected to have a normal response to ovarian stimulation with standard agonist or antagonist stimulation protocols. Levels of AMH greater than 3.5 ng/mL is associated with a risk of ovarian hyperstimulation syndrome (OHSS) and should prompt caution when planning stimulation protocols.
While ongoing live birth is the most clinically relevant indicator of success, most tests of ovarian reserve are poor predictors of this key outcome. An individual patient data (IPD) meta-analysis based on 1008 patients undergoing fertility treatment demonstrated a weak association of AMH with ongoing pregnancy. Although AMH is associated with live birth after assisted conception, its predictive accuracy is poor.
Results from a recent randomized trial indicate that in women undergoing IVF/intracytoplasmic sperm injection (ICSI), individualized FSH dosing based on ovarian reserve testing by AFC does not improve live birth rates or reduce costs as compared to a standard FSH dose. In women with predicted poor response, a personalized approach to ovarian stimulation based on AFC is unable to enhance live birth rates but does increase costs.
However, in women with a predicted hyper-response (based on AFC of greater than 15), a reduced dose of gonadotropins for ovarian stimulation results in comparable cumulative live birth rates in comparison with a standard dose but reduces the overall risk of ovarian hyperstimulation.
Use of Ovarian Biomarkers Beyond Assisted Reproduction
Beyond IVF, ovarian reserve testing has found limited utility in the management of women with fertility problems. They have not been found to be more useful than age alone in the prediction of pregnancy in women presenting with unexplained infertility or mild male infertility.
A number of studies suggest that AMH levels along with age are useful in predicting age at menopause with accuracy in women at advanced ages. However, in a recent individual participant data meta-analysis, the additional predictive value of AMH (compared to age alone) was minimal (age alone C-statistic 84%; age + AMH HR 0.66 95% CI 0.61–0.71, C-statistic 86%), although the accuracy of AMH as a predictive test increased with decreasing age of menopause.
With advances in cancer detection and therapy, younger women are surviving cancers. However, the major concern among survivors is the loss of ovarian function and fertility. With the availability of AMH, it has been possible to detect the iatrogenic loss in ovarian reserves by measuring this biomarker pre- and post-treatment with chemotherapy or radiotherapy. Further, AMH levels are useful in planning fertility-preserving options and counseling accordingly.
There is sufficient evidence to suggest that AMH be involved in the pathogenesis of PCOS, and levels correlate with the severity of the condition. A cutoff of AMH greater than 5.0 ng/mL has been shown to be highly diagnostic of PCOS (AUC 0.973, sensitivity 92%, specificity 97%), and it has been suggested that this should be incorporated as a diagnostic criterion.
Use in The General Population
Whether ovarian reserve testing should be offered to women without immediate fertility concerns is a contentious subject. In the last few decades, there has been an increase in the age of first planned pregnancy as women continue to delay childbearing in their pursuit of higher education and careers.
This has created a space for ovarian reserve testing to inform reproductive decisions such as cryopreservation of oocytes in order to preserve future fertility. Proponents of ovarian reserve testing suggest that many women might modify their plans for childbearing on the basis of their ovarian reserve testing results. However, the opponents of such ovarian reserve testing feel that it adds to anxiety and negative psychological impact that may have a bearing on their decisions on career and marital relationship.
There is no consensus on the routine ovarian reserve testing in the general population. From a methodological perspective, ovarian reserve testing, like AMH, is some distance away from fulfilling the criteria for an ideal screening testing. The positive predictive value is likely to be poor in an unselected population of younger women in whom the prevalence of diminished ovarian reserve is low. It is also unclear how often screening should be performed, what the potential physical and psychological impacts of screening might be, and what interventions are available for those who test positive.
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