Use of antimüllerian hormone: the risks of interpreting ovarian reserve markers in isolation

Abstract

In this issue's special contribution by Drs. Toner and Seifer (1Toner J.P. Seifer D.B. Why we may abandon basal FSH testing: a sea change in determining ovarian reserve using AMH.Fertil Steril. 2013; 99: 1825-1830Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar), the authors advocate for antimüllerian hormone (AMH) as the ideal singular assay for assessing ovarian reserve. Indeed, the consistency of AMH measurements throughout the menstrual cycle and AMH's usefulness in predicting both low and high response to ovarian stimulation make it a helpful metric in clinical practice. The authors also provide personal perspectives on the evolution of ovarian reserve testing, culminating with a set of guidelines for using AMH as the principal method for assessing ovarian reserve, informing pretreatment counseling, and for selecting and managing infertility treatments. It is of interest to note that although the authors admit that there are instances in which FSH and/or antral follicle count (AFC) may further predict treatment response, they nevertheless propose fairly rigid guidelines for AMH's predictive attributes.Like the authors, we find AMH assessment to be a useful addition to the infertility workup. In September 2010 we incorporated the second-generation AMH assay into our practice, adding it to AFC and day-3 FSH as measures of ovarian reserve. Although the creation of guidelines associated with laboratory test cutoff points can be useful in simplifying and streamlining clinical practice, we found that the general guidelines regarding AMH put forth by Drs. Toner and Seifer did not resonate with our own observations of stimulation response in patients with low AMH values. Citing several published works, Drs. Toner and Seifer suggest that an AMH level of <0.5 ng/mL “predicts difficulty in getting more than 3 follicles to grow” (2Muttukrishna S. Mcgarrigle H. Wakim R. Khadum I. Ranieri D.M. Serhal P. Antral follicle count, anti-mullerian hormone and inhibin B: predictors of ovarian response in assisted reproductive technology?.BJOG. 2005; 112: 1384-1390Crossref PubMed Scopus (242) Google Scholar, 3Fiçicioglu C. Kutlu T. Baglam E. Bakacak Z. Early follicular antimüllerian hormone as an indicator of ovarian reserve.Fertil Steril. 2006; 85: 592-596Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 4Peñarrubia J. Fábregues F. Manau D. Creus M. Casals G. Casamitjana R. et al.Basal and stimulation day 5 anti-Mullerian hormone serum concentrations as predictors of ovarian response and pregnancy in assisted reproductive technology cycles stimulated with gonadotropin-releasing hormone agonist–gonadotropin treatment.Hum Reprod. 2005; 20: 915-922Crossref PubMed Scopus (176) Google Scholar). Although low AMH is indeed correlated with fewer oocytes retrieved after ovarian stimulation, our initial impression was that this correlation at the lower range of the assay is not as dire as presented by the authors.Since 2010 we have initiated IVF cycles on 1,052 patients whose AMH values ranged from the lower detectable limit of the assay (0.16 ng/mL) to the upper bound for poor response proposed by Drs. Toner and Seifer (≤0.5 ng/mL). In this cohort (mean age 39.3 years, mean AMH 0.33 ng/mL), 73.9% of patients underwent oocyte retrieval, with a mean number of 6.2 oocytes harvested and a clinical pregnancy rate of 25.7% per retrieval. We additionally initiated IVF cycles in 224 patients whose AMH levels were undetectable; in this cohort (average age 40.2 years) 61.2% of cycles were carried through to oocyte retrieval, with an average of 3.9 oocytes harvested and a clinical pregnancy rate of 19.0% per retrieval.Drs. Toner and Seifer's second general guideline states that AMH <1.0 ng/mL signals a limited egg supply at any age. Although this can be debated as a semantic point, we caution against labeling a patient as having diminished ovarian reserve on the basis of a single AMH value. More data are needed before we can definitively counsel young patients regarding the window of opportunity to conceive, or for that matter, when that window will close. Moreover, counter to prevailing consensus, we have occasionally observed intraindividual AMH variability, with differences of up to 1.0 ng/mL measured within several months.In light of our experience, we believe that patients should not be dissuaded from pursuing IVF solely because of a low AMH value, and we propose that AMH of <0.16 ng/mL should be the more conservative value at which patients are carefully counseled regarding potential difficulty in recruiting more than three follicles. Even so, patients with undetectable AMH levels and seemingly negligible ovarian reserve can still achieve pregnancies and should not be denied the chance by clinicians or by insurance providers, especially when the assessment is made using a single laboratory value. As the authors, to their credit, acknowledge when discussing “caveats,” AFC and day-3 FSH can provide useful information at the lower limits of the AMH assay. Certainly a 37-year-old patient with an undetectable AMH level but an FSH level of 7 mIU/mL and an AFC of six follicles should be counseled differently than a 40-year-old patient with an FSH level of 14 mIU/mL and an AFC of two follicles. Moreover, it should be acknowledged that no single or combination of ovarian reserve markers can absolutely predict the probability of achieving a pregnancy. Indeed, rather than abandoning other ovarian reserve markers (e.g., AFC, FSH) in favor of AMH, as the authors' title suggests, we believe that AMH should be considered an important adjunct to existing ovarian reserve markers. Finally, we strongly caution against the use of strict AMH cutoffs for counseling patients regarding the possibility of success or for denying access to treatment. In this issue's special contribution by Drs. Toner and Seifer (1Toner J.P. Seifer D.B. Why we may abandon basal FSH testing: a sea change in determining ovarian reserve using AMH.Fertil Steril. 2013; 99: 1825-1830Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar), the authors advocate for antimüllerian hormone (AMH) as the ideal singular assay for assessing ovarian reserve. Indeed, the consistency of AMH measurements throughout the menstrual cycle and AMH's usefulness in predicting both low and high response to ovarian stimulation make it a helpful metric in clinical practice. The authors also provide personal perspectives on the evolution of ovarian reserve testing, culminating with a set of guidelines for using AMH as the principal method for assessing ovarian reserve, informing pretreatment counseling, and for selecting and managing infertility treatments. It is of interest to note that although the authors admit that there are instances in which FSH and/or antral follicle count (AFC) may further predict treatment response, they nevertheless propose fairly rigid guidelines for AMH's predictive attributes. Like the authors, we find AMH assessment to be a useful addition to the infertility workup. In September 2010 we incorporated the second-generation AMH assay into our practice, adding it to AFC and day-3 FSH as measures of ovarian reserve. Although the creation of guidelines associated with laboratory test cutoff points can be useful in simplifying and streamlining clinical practice, we found that the general guidelines regarding AMH put forth by Drs. Toner and Seifer did not resonate with our own observations of stimulation response in patients with low AMH values. Citing several published works, Drs. Toner and Seifer suggest that an AMH level of <0.5 ng/mL “predicts difficulty in getting more than 3 follicles to grow” (2Muttukrishna S. Mcgarrigle H. Wakim R. Khadum I. Ranieri D.M. Serhal P. Antral follicle count, anti-mullerian hormone and inhibin B: predictors of ovarian response in assisted reproductive technology?.BJOG. 2005; 112: 1384-1390Crossref PubMed Scopus (242) Google Scholar, 3Fiçicioglu C. Kutlu T. Baglam E. Bakacak Z. Early follicular antimüllerian hormone as an indicator of ovarian reserve.Fertil Steril. 2006; 85: 592-596Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 4Peñarrubia J. Fábregues F. Manau D. Creus M. Casals G. Casamitjana R. et al.Basal and stimulation day 5 anti-Mullerian hormone serum concentrations as predictors of ovarian response and pregnancy in assisted reproductive technology cycles stimulated with gonadotropin-releasing hormone agonist–gonadotropin treatment.Hum Reprod. 2005; 20: 915-922Crossref PubMed Scopus (176) Google Scholar). Although low AMH is indeed correlated with fewer oocytes retrieved after ovarian stimulation, our initial impression was that this correlation at the lower range of the assay is not as dire as presented by the authors. Since 2010 we have initiated IVF cycles on 1,052 patients whose AMH values ranged from the lower detectable limit of the assay (0.16 ng/mL) to the upper bound for poor response proposed by Drs. Toner and Seifer (≤0.5 ng/mL). In this cohort (mean age 39.3 years, mean AMH 0.33 ng/mL), 73.9% of patients underwent oocyte retrieval, with a mean number of 6.2 oocytes harvested and a clinical pregnancy rate of 25.7% per retrieval. We additionally initiated IVF cycles in 224 patients whose AMH levels were undetectable; in this cohort (average age 40.2 years) 61.2% of cycles were carried through to oocyte retrieval, with an average of 3.9 oocytes harvested and a clinical pregnancy rate of 19.0% per retrieval. Drs. Toner and Seifer's second general guideline states that AMH <1.0 ng/mL signals a limited egg supply at any age. Although this can be debated as a semantic point, we caution against labeling a patient as having diminished ovarian reserve on the basis of a single AMH value. More data are needed before we can definitively counsel young patients regarding the window of opportunity to conceive, or for that matter, when that window will close. Moreover, counter to prevailing consensus, we have occasionally observed intraindividual AMH variability, with differences of up to 1.0 ng/mL measured within several months. In light of our experience, we believe that patients should not be dissuaded from pursuing IVF solely because of a low AMH value, and we propose that AMH of <0.16 ng/mL should be the more conservative value at which patients are carefully counseled regarding potential difficulty in recruiting more than three follicles. Even so, patients with undetectable AMH levels and seemingly negligible ovarian reserve can still achieve pregnancies and should not be denied the chance by clinicians or by insurance providers, especially when the assessment is made using a single laboratory value. As the authors, to their credit, acknowledge when discussing “caveats,” AFC and day-3 FSH can provide useful information at the lower limits of the AMH assay. Certainly a 37-year-old patient with an undetectable AMH level but an FSH level of 7 mIU/mL and an AFC of six follicles should be counseled differently than a 40-year-old patient with an FSH level of 14 mIU/mL and an AFC of two follicles. Moreover, it should be acknowledged that no single or combination of ovarian reserve markers can absolutely predict the probability of achieving a pregnancy. Indeed, rather than abandoning other ovarian reserve markers (e.g., AFC, FSH) in favor of AMH, as the authors' title suggests, we believe that AMH should be considered an important adjunct to existing ovarian reserve markers. Finally, we strongly caution against the use of strict AMH cutoffs for counseling patients regarding the possibility of success or for denying access to treatment. Why we may abandon basal follicle-stimulating hormone testing: a sea change in determining ovarian reserve using antimüllerian hormoneFertility and SterilityVol. 99Issue 7PreviewAntimüllerian hormone is the most informative serum marker of ovarian reserve currently available and should be considered an important part of any contemporary reproductive medicine practice. It is both more convenient and informative than basal FSH and can be assessed at any point in the cycle. It is the most useful serum method of determining ovarian reserve, which guides pretreatment counseling, choice of infertility treatment, and avoidance of ovarian hyperstimulation. The future role of basal FSH testing is in doubt. Full-Text PDF But isn't antimüllerian hormone still better than follicle-stimulating hormone?Fertility and SterilityVol. 99Issue 7PreviewWe sincerely appreciate Drs. Rosenwaks' and Reichman's commentary on our opinion piece (1). We are especially grateful for the explicit reporting of their program's IVF outcomes in cases of low antimüllerian hormone (AMH) levels, which is the largest experience yet reported. (Perhaps our admittedly provocative title spurred their useful and pertinent report of these results.) Finding that 6.2 eggs were retrieved from 1,052 patients with AMH <0.5 ng/mL, resulting in a 25.7% clinical pregnancy rate per retrieval, is reassuring. Full-Text PDF