Non-equivalence of anti-Müllerian hormone automated assays-clinical implications for use as a companion diagnostic for individualised gonadotrophin dosing.

STUDY QUESTION: Can anti-Müllerian hormone (AMH) automated immunoassays (Elecsys® and Access) be used interchangeably as a companion diagnostic for individualisation of follitropin delta dosing? SUMMARY ANSWER: The Access assay gives systematically higher AMH values than the Elecsys® assay which results in over 29% of women being misclassified to a different follitropin delta dose. WHAT IS KNOWN ALREADY: Follitropin delta is the first gonadotrophin to be licenced with a companion diagnostic, the Roche Elecsys® AMH Plus assay. Alternative automated AMH assays including the Beckman Coulter Access immunoassay are considered to provide similar results, but clarification of their suitability as an off-licence companion diagnostic for follitropin delta is required. STUDY DESIGN, SIZE, DURATION: We systematically searched the existing literature for studies that had measured AMH using both automated assays in the same cohort of women. Individual paired patient data were acquired from each author and combined with unpublished data. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified five eligible prospective published studies and one additional unpublished study. A 100% response from the authors was achieved. We collected paired AMH data on samples from 848 women. Passing-Bablok regression and Bland-Altman plots were used to compare the analytical performance of the two assays. The degree of misclassification to different treatment categories was estimated should the Access AMH be used as a companion diagnostic instead of the Elecsys AMH in determining the dosing of follitropin delta. MAIN RESULTS AND THE ROLE OF CHANCE: The Passing-Bablok regression shows a linear relationship (Access = -0.05 + 1.10 × Elecsys). The Access assay systematically gave higher values by an average of 10% compared with the Elecsys assay (slope = 1.10, 95% CI: 1.09 to 1.12). The average of the difference between the two assays was 2.7 pmol/l. The 95% limits of agreement were -11.7 to 6.3. Overall 253 (29.3%) women would have received an inappropriate follitropin delta dose if the Beckman Coulter Access assay was used. Specifically, a substantial proportion of women (ranging from 49% to 90% depending on the AMH category) would receive a lower dose of follitropin delta based on the Access AMH assay. Up to 10% (ranging from 2.5% to 10%) of women with high ovarian reserve would have been misclassified to a greater dose of follitropin delta based on the Access AMH assay. LIMITATIONS REASONS FOR CAUTION: We compared the values of the two principal automated assays, extrapolation of our findings to other automated AMH assays would require similar comprehensive examination. WIDER IMPLICATIONS OF THE FINDINGS: An international standard for the calibration of the automated AMH assays is warranted to facilitate efficient use of AMH as a companion diagnostic. The variable calibration of alternative automated AMH assays may adversely impact on the performance of the follitropin delta dosing algorithm. STUDY FUNDING/COMPETING INTEREST(S): No formal funding has been received for this study. SI is funded by a UK Medical Research Council skills development fellowship (MR/N015177/1). SMN has received speakers fees, travel to meetings and participated in advisory Boards for Beckman Coulter, IBSA, Ferring Pharmaecuticals, Finox, Merck Serono, Merck and Roche Diagnostics. SMN has received research support from Ansh laboratories, Beckman Coulter, Ferring Pharmaceuticals and Roche Diagnostics. TRIAL REGISTRATION NUMBER: N/A.

Serum antimüllerian hormone levels are independently related to miscarriage rates after in vitro fertilization-embryo transfer.

OBJECTIVE: To investigate whether serum antimüllerian hormone (AMH) levels are independently related to miscarriage rates after in vitro fertilization-embryo transfer (IVF-ET). DESIGN: Cohort study. SETTING: University-affiliated IVF-ET center. PATIENT(S): A total of 1,060 patients who attained a clinical pregnancy after IVF-ET. INTERVENTIONS(S): Centralized serum AMH measurements were performed within the 12 months before IVF-ET. Binary logistic regression was used to verify whether serum AMH levels were associated with the occurrence of a miscarriage independently from confounding factors, such as age and intensity of ovarian response to controlled ovarian stimulation assessed by the number of oocytes retrieved. MAIN OUTCOME MEASURE(S): Miscarriage rates. RESULT(S): In patients displaying reduced serum AMH levels, miscarriage rates were significantly increased independently from age and the number of oocytes retrieved. CONCLUSION(S): The present data indicate that serum AMH levels are independently associated with the occurrence of a miscarriage after IVF-ET.

Steroid hormone pretreatments in assisted reproductive technology.

Adequate availability and FSH sensitivity of ovarian antral follicles and coordination of their growth during controlled ovarian hyperstimulation (COH) rank among factors that may determine outcome, particularly in patients presenting ovarian function defects and so-called "poor responders." Growing evidence indicates that both factors are positively influenced by steroid hormone pretreatments. First, data from studies conducted in both animals and in women exposed to virilizing androgen doses indicate that androgen pretreatments may increase follicle responsiveness to FSH and/or the number of growing follicles in the ovary, thereby constituting an interesting perspective in the management of "poor responders." Second, overcoming pre-COH heterogeneities in antral follicle sizes, which are more pronounced in "poor responders," to achieve adequate coordination of multiple follicular growth during COH also is contributive. For this, suppression or attenuation of the premature FSH increase during the preceding late luteal phase using sex steroid pretreatments (oral contraceptives, synthetic progestogens, or estradiol), or additional strategies such as premenstrual GnRH antagonist administration has been shown to be effective. The present paper will critically review proposed mechanisms and clinical results of sex steroid hormone pretreatments in these two different indications as an effort to optimizing COH outcome.

New automated antimüllerian hormone assays are more reliable than the manual assay in patients with reduced antral follicle count.

OBJECTIVE: To compare the strength of the relationship between antral follicle count (AFC) and serum antimüllerian hormone (AMH) concentrations obtained with two automated and one manual AMH assays in three different AFC populations. DESIGN: Prospective cohort study. SETTING: University-affiliated IVF-ET center. PATIENT(S): Frozen-thawed serum samples of 211 assisted conception candidates, aged 24-43 years. INTERVENTION(S): Serum AMH was measured using one manual (AMH Gen II) and two fully automated (Access AMH and Elecsys AMH) assays. Antral follicle count was performed under strictly standardized conditions and sorted into three groups according to tercile values: low AFC (3-12 follicles; n = 73), intermediate AFC (13-20 follicles; n = 65), and high AFC (21-84 follicles; n = 73). MAIN OUTCOME MEASURE(S): Strength of correlation between AMH levels and AFC. RESULT(S): Overall, AMH levels were lower with Access AMH (-16%) and Elecsys AMH (-20%) than with AMH Gen II. Remarkably, the strength of correlations between AFC and circulating AMH levels was the same with the three assays (r = 0.83). Yet in the low AFC group, serum AMH levels obtained by Access AMH and Elecsys AMH showed a stronger correlation with AFC (r = 0.63 and r = 0.65, respectively) than the AMH Gen II (r = 0.52), a phenomenon that was not observed in the remaining AFC groups. CONCLUSION(S): As compared with conventional AMH Gen II assay results, [1] serum AMH concentrations were -16% and -20% lower with Access AMH and Elecsys AMH, respectively; and [2] automated assays were more strongly correlated to AFC in the subset of patients with reduced follicle count.