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Department of Obstetrics, Gynecology and Reproductive Medicine, Dexeus University Hospital, Department of Obstetrics and Gynecology, Coimbra Hospital and University Centre, Faculty of Medicine, University of Coimbra, Clinical Academic Center of Coimbra, Rua Augusta 17, Barcelona, Coimbra 08028, 3000-045, Spain, Portugal
Centre for Reproductive Medicine, UZ Brussel, Faculty of Medicine and Pharmacy, Department of Surgical and Clinical Science, Vrije Universiteit Brussel, Laarbeeklaan 101, Brussels 1090, Belgium
Department of Reproductive Medicine and Gynecological Endocrinology, University Hospital of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, Luebeck, Germany
Mother-Infant Department, Institute of Obstetrics and Gynecology, University of Modena and Reggio Emilia, Policlinico di Modena, Largo del Pozzo, Modena 41100, Italy
Centre for Reproductive Medicine, UZ Brussel, Faculty of Medicine and Pharmacy, Department of Surgical and Clinical Science, Vrije Universiteit Brussel, Laarbeeklaan 101, Brussels 1090, Belgium
Centre for Reproductive Medicine, UZ Brussel, Faculty of Medicine and Pharmacy, Department of Surgical and Clinical Science, Vrije Universiteit Brussel, Laarbeeklaan 101, Brussels 1090, Belgium
Department of Obstetrics, Gynecology and Reproductive Medicine, Dexeus University Hospital, Department of Clinical Medicine, Faculty of Health, Aarhus University, Barcelona, Aarhus 08028, 8000, Spain, Denmark
What is the performance of anti-Müllerian hormone (AMH) as measured by the Elecsys® AMH assay in predicting ovarian response in women treated with 150 µg corifollitropin alfa (CFA)?
Design
Multicentre, prospective study conducted between December 2015 and April 2018. Women were aged 18–43 years, had regular menstrual bleeding, a body mass index of 17–35 kg/m2 and weighed 60 kg or over. Exclusion criteria: previous oophorectomy, history of ovarian hyperstimulation syndrome, a previous IVF and intracytoplasmic sperm injection cycle producing over 30 follicles measuring 11 mm or wider, basal antral follicle count (AFC) over 20 or polycystic ovarian syndrome. All women were treated with 150 μg CFA followed by recombinant FSH (150–300 IU/day) in a fixed gonadotrophin releasing hormone antagonist protocol.
Results
Of the 219 patients enrolled, 22.8% had low ovarian response (three or fewer oocytes), 66.2% had normal response and 11% had high ovarian response (15 or more oocytes). The AMH and AFC presented an area under the curve of 0.883 (95% CI 0.830 to 0.936) and 0.879 (95% CI 0.826 to 0.930), respectively, for low ovarian response; and an AUC of 0.865 (95% CI 0.793 to 0.935) and 0.822 (95% CI 0.734 to 0.909) for high ovarian response. An AMH cut-off of 1.0 ng/ml provided a sensitivity of 92.0% and a specificity of 66.9% in the prediction of low ovarian response; a cut-off of 2.25 ng/ml predicted high ovarian response with a sensitivity of 54.2% and a specificity of 91.8%.
Conclusions
The automated Elecsys® AMH assay predicts ovarian response in a CFA antagonist protocol. The best predictors of ovarian response in CFA-treated patients were AMH and AFC.
Ovarian stimulation is a key part of the IVF and intracytoplasmic sperm injection (ICSI) procedure. The anticipated yield of oocytes varies according to patient age and ovarian reserve. Therefore, individualization of ovarian stimulation is of paramount importance, which makes ovarian reserve marker analysis essential for treatment and dose selection (
A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a “standard” dose of 150 IU/day in “standard” patients undergoing IVF/ICSI treatment.
Human Reproduction.2003; 18 (https://doi.org/10.1093/humrep/deg472): 2275-2282
). Therefore, a wide range of markers have been proposed as predictors of ovarian response. Antral follicle count (AFC) and anti-Müllerian hormone (AMH) are now recognized as the most accurate (
Does the time interval between antimüllerian hormone serum sampling and initiation of ovarian stimulation affect its predictive ability in in vitro fertilization – intracytoplasmic sperm injection cycles with a gonadotropin-releasing hormone antagonist? A retrospective single-center study.
Fertility and Sterility.2013; 100 (https://doi.org/10.1016/j.fertnstert.2013.03.031): 438-444
Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women.
Human Reproduction.2014; 29 (https://doi.org/10.1093/humrep/deu142): 1764-1772
Non-equivalence of anti-Müllerian hormone automated assays - Clinical implications for use as a companion diagnostic for individualised gonadotrophin dosing.
Human Reproduction.2017; 32 (https://doi.org/10.1093/humrep/dex219): 1710-1715
). Most studies have been used manual plate-based ELISAs and, although these reports provide valuable information, the reproducibility of the results among different laboratories has been controversial (
Within-laboratory and between-laboratory variability in the measurement of anti-müllerian hormone determined within an external quality assurance scheme.
). Comparisons between manual and automated assays, however, should be analysed with caution, taking into account the 20–30% higher values reported with manual assays (
The Elecsys® AMH assay is an electrochemiluminescence immunoassay for quantitative determination of serum AMH and was the first automated AMH assay to be approved by the US Food and Drug Administration. Its analytical performance, in terms of precision and increased sensitivity, has been reported in several trials (
Evaluation of the Elecsys® anti-Müllerian hormone assay for the prediction of hyper-response to controlled ovarian stimulation with a gonadotrophin-releasing hormone antagonist protocol.
European Journal of Obstetrics & Gynecology and Reproductive Biology,.2019; 236: 133-138
Jacobs, M. H., Reuter, L. M., Baker, V. L., Craig, L. B., Sakkas, D., Surrey, E., … Timm, B. (2019). A multicentre evaluation of the Elecsys® anti-Müllerian hormone immunoassay for prediction of antral follicle count. Reproductive BioMedicine Online, (pii), S1472-6483(19)30006-9.https://doi.org/10.1016/j.rbmo.2018.12.041
). Few studies have assessed the new automated Elecsys® AMH assay in predicting ovarian response to stimulation, and all were focused on patients receiving daily gonadotrophin injections with different daily doses. Corifollitropin alfa (CFA) is a fusion product of human FSH and the C-terminal peptide of the β-subunit of HCG, produced by recombinant DNA technology (
Advances in recombinant DNA technology: Corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency.
Human Reproduction Update.2009; 15 (https://doi.org/10.1093/humupd/dmn065): 309-321
). It has the same activity as FSH and recombinant FSH, with an increased serum half-life, which allows it to induce and sustain multi-follicular growth for 7 days after a single subcutaneous injection (
Advances in recombinant DNA technology: Corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency.
Human Reproduction Update.2009; 15 (https://doi.org/10.1093/humupd/dmn065): 309-321
A randomized dose-response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation.
Human Reproduction.2008; 23 (https://doi.org/http://dx.doi.org/10.1093/humrep/den288): 2484-2492
A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol.
Human Reproduction.2009; 24 (https://doi.org/10.1093/humrep/dep291): 3063-3072
Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation pr.
Fertility and Sterility.2015; 104 (https://doi.org/10.1016/j.fertnstert.2015.04.018): 94-103.e1
), have generalized its use among reproductive medicine physicians.
The scope of our study was to evaluate the predictive ability of AMH as measured using the Elecsys® AMH assay in women treated with CFA.
Materials and methods
A multicentre, prospective study of patients who underwent an IVF/ICSI cycle was conducted between December 2015 and April 2018. Patients were recruited in five centres (Dexeus University Hospital; Centre for Reproductive Medicine of the Universitair Ziekenhuis (UZ) Brussel, Belgium; IVI Madrid, Spain; Universitäres Kinderwunschzentrum Lübeck und Manhagen, Lübeck, Germany; Università degli Studi di Modena e Reggio Emilia, Italy).
Ethical approval
The study was conducted in accordance with the Declaration of Helsinki and with approval of the Institutional Review Board of the institutions involved in the study (Dates of final approval: Dexeus University Hospital, Barcelona, 23 January 2017; Centre for Reproductive Medicine of the Universitair Ziekenhuis (UZ) Brussel, 23 December 2015; IVI Madrid, 7 July 2016; Universitäres Kinderwunschzentrum Lübeck und Manhagen, 23 September 2016; Università degli Studi di Modena e Reggio Emilia, 8 November 2016). After detailed written and oral information regarding the study, all patients signed an informed consent sheet.
Patient selection criteria
The study included patients aged between 18 and 43 years old, with regular menstrual bleeding, a body mass index (BMI) of 17–35 kg/m2, weighing over 60 kg who planned to undergo ovarian stimulation with 150 μg CFA followed by recombinant FSH either for IVF or ICSI or in order to undergo fertility preservation for social or medical reasons. Patients were excluded if they had undergone a previous oophorectomy, had a history of ovarian hyperstimulation syndrome (OHSS), had undergone a previous ovarian stimulation cycle that resulted in more than 30 follicles measuring 11 mm or wider as determined by ultrasound examination, a basal AFC over 20, polycystic ovarian syndrome according to the Rotterdam criteria (
All women planned to be treated with 150 μg CFA followed by recombinant FSH in a fixed gonadotrophin releasing hormone (GnRH) antagonist protocol were enrolled. They received no pre-treatment with oral contraceptive pills. On day 2 or 3 of the menstrual cycle, a single subcutaneous injection of 150 µg CFA was administered (stimulation day 1). Starting on stimulation day 6, patients received a daily subcutaneous injection of 0.25 mg ganirelix up to and including the day of HCG administration to prevent premature LH surges. From stimulation day 8 onwards, treatment continued with a daily subcutaneous dose of recombinant FSH (150–300 IU/day) up to the day of HCG administration based on the patient’s ovarian reserve. Recombinant FSH dose was selected based on age, AFC, AMH and BMI as described in previous studies (
). No stepping up or down was allowed. In the case of monofollicular development and in the case of non-tubal factor infertility and adequate sperm quality, either rescue intrauterine insemination was considered or the cycle was cancelled. In case of no follicular development the treatment cycle was cancelled. Criteria for cycle cancellation or rescue intrauterine insemination were implemented on stimulation day 10. In both circumstances, the cycle was considered cancelled and the number of oocytes imputed was set to zero. These patients were included in the low response group. The allocated interventions are presented in Figure 1.
As soon as three follicles measuring 17 mm or wider were observed by ultrasound, recombinant 250 μg subcutaneous HCG was administered the same day or the day after to induce final oocyte maturation.
In case of excessive ovarian response (17 or more follicles measuring more than 11 mm on the day of final oocyte maturation) triggering with a GnRH agonist (triptorelin 0.2 mg) was used for safety reasons, followed by either freezing all embryos, or fresh embryo transfer with modified luteal phase support. About 34–36 h thereafter, oocyte retrieval followed by IVF/ICSI was carried out.
Blood sampling and sample analysis
At the routine blood sampling visit on the day of initiation of CFA, part of the blood sample collected for routine analysis was used to allow the measurement of AMH, oestradiol, FSH and LH.
Blood drawn in plain serum tubes for routine blood analysis during treatment underwent centrifugation within 1 h, and serum was separated and immediately stored at −80°C until analysis. All samples were analysed together at the end of the study in the central laboratory of UZ Brussel.
Elecsys® AMH assay (Roche Diagnostics GmbH, Germany) was used to analyse AMH, with a coefficient of variation for intermediate precision less than 3.0% and a detection range of 0.01 to 23 ng/ml (0.07–164 pmol/l).
Outcomes
The primary outcome was to evaluate the incidence of low and high ovarian response by serum AMH level. Secondary outcomes were to evaluate the ability of AFC, age and FSH to predict low and high ovarian response and to compare the ability of AMH, AFC, age and FSH as predictors of ovarian response. The cut-off for defining low ovarian response was three or fewer oocytes retrieved, in accordance with the Bologna criteria for ovarian response (
). Excessive ovarian response was defined as more than 15 oocytes retrieved, in accordance with earlier studies demonstrating an association between more than 15 oocytes retrieved and OHSS (
Sample size calculation was carried out on the assumption that up to five predictive factors will be selected in each logistic regression model. Therefore, assuming that for each predictive factor at least 10 events are required, a total of around 50 events are needed (
). A total sample size of 200 participants was planned, with an additional 20 participants (10%) to compensate for discontinued participants.
Continuous variables were expressed as mean and SD, and categorical variables as frequencies and percentages. Univariate logistic regression analysis was conducted to identify the best predictors for high (more than 15 oocytes) and low (fewer than three oocytes) ovarian responses. Categorical variables were compared using chi-squared test or Fisher’s exact test. Continuous variables were compared using the Student’s t-test or Wilcoxon Mann–Whitney Test. All tests were bilateral with a significance level set to 0.05. Receiver operating characteristic (ROC) curves were generated and the area under the ROC curves (AUC) was determined to assess the discriminative power of independent ovarian reserve markers (AMH, AFC, age and FSH) to predict low and high ovarian response. Subsequently, associated factors for prediction of high and low ovarian reserve were entered into logistic regression models. The performance of each model was evaluated using ROC curves and AUCs. The pROC package (Robin et al., 2011) in R Software (R Core Team, 2018) was used for statistical analyses.
Results
A total of 219 patients were enrolled in the study, of whom 22.8% (n = 50) had a low ovarian response, 66.2% (n = 145) had a normal response and 11% (n = 24) had a high ovarian response. Patients’ baseline characteristics and ovarian stimulation cycle characteristics according to the level of ovarian response are presented in Table 1.
Table 1Patient and cycle characteristics
Normal ovarian response (n=145)
High ovarian response (n=24)
Low ovarian response (n=50)
P-value (HOR versus others)
P-value (LOR versus others)
Age, years
36.08 ± 4.24
33.58 ± 4.62
37.54 ± 3.19
0.003
0.011
BMI, kg/m2
24.18 ± 4.49
25.27 ± 3.02
24.25 ± 3.99
0.120
0.360
Race, % (n)
White
80.0 (116)
91.7 (22)
84.0 (42)
Asian
4.8 (7)
0
2.0 (1)
0.507
0.599
Black or African American
2.8 (4)
4.2 (1)
6.0 (3)
Other
12.4 (18)
4.2 (1)
8.0 (4)
Smokers
21.4 (31)
29.2 (7)
20.0 (10)
0.363
0.709
Cause of infertility
Male
39.3 (57)
54.2 (13)
26.0 (13)
Idiopathic
33.1 (48)
33.3 (8)
28.0 (14)
Endometriosis
6.2 (9)
8.3 (2)
14.0 (7)
0.554
0.001
Tubal
6.9 (10)
4.2 (1)
10.0 (5)
Ovulatory disorders
2.8 (4)
0
18.0 (9)
Single mother
2.1 (3)
0
2.0 (1)
Information not available
9.7 (14)
0
2.0 (1)
Type of infertility
Primary
66.2 (96)
45.8 (11)
48.0 (24)
0.139
0.052
Secondary
33.8 (49)
54.2 (13)
52.0 (26)
Duration of infertility
34.61 ± 33.29
24.13 ± 15.18
51.00 ± 45.28
0.064
0.003
AMH, ng/ml
1.3 ± 0.72
2.47 ± 1.08
0.50 ± 0.38
<0.001
<0.001
AFC, n
9.47 ± 3.91
14.29 ± 8.35
4.76 ± 2.44
<0.001
<0.001
FSH, mIU/ml
8.52 ± 2.64
7.16 ± 1.97
10.14 ±3.72
0.026
0.040
LH, mIU/ml
6.43 ± 2.35
6.36 ± 2.32
6.72 ± 2.66
0.790
0.748
Oestradiol, pg/ml
42.04 ± 20.88
40.52 ± 17.87
48.33 ± 68.18
0.986
0.253
Progesterone, ng/ml
0.74 ± 3.31
0.30 ± 0.17
0.39 ± 0.21
0.249
0.586
Duration of stimulation, days
9.57 ± 2.16
9.88 ± 1.42
9.58 ± 2.95
0.502
0.729
Total gonadotrophin dose, IU
646.63 ± 413.5
617.05 ± 342.90
865.85 ± 664.78
0.778
0.103
Oocytes retrieved, n
8.21 ± 3.11
20.71 ± 4.14
1.46 ± 1.15
<0.001
<0.001
Mature oocytes retrieved, n
6.34 ± 3.28
14.13 ± 6.37
1.39 ± 0.86
<0.001
<0.001
Fertilized oocytes, n
4.08 ± 3.01
9.63 ± 5.63
0.71 ± 0.87
<0.001
<0.001
Quantitative variables are presented as mean ± SD and qualitative variables as or % (n).
AFC, antral follicle count; AMH, anti-Müllerian hormone; HOR, high ovarian response; LOR, low ovarian response.
The clinical performance of the different ovarian reserve markers in the prediction of low ovarian response was assessed by ROC curve analysis (Figure 2a). The best predictors of low ovarian response were AMH and AFC, with an AUC of 0.883 (95% CI 0.830 to 0.936) and an AUC of 0.879 (95% CI 0.826 to 0.930). A cut-off of 1.0 ng/ml provided a sensitivity of 92.0% and a specificity of 66.9% in the prediction of three or fewer oocytes retrieved, with a positive likelihood ratio (LR+) of 2.78 and a negative likelihood ratio (LR–) of 0.12. The addition of AFC, age and FSH to AMH in the prediction model slightly increased the AUC to 0.926 (95% CI 0.871 to 0.981), although the difference was not statistically significant compared with AMH or AFC alone (Figure 3).
Figure 2Receiver operating characteristics curve analysis for ovarian reserve markers as predictors of low (a) and high (b) ovarian response. AFC, antral follicle count; AMH, anti-Müllerian hormone; AUC, area under the curve; LR, likelihood ratio.
Figure 3Receiver operating characteristics curve analysis for predictors of low ovarian response. AFC, antral follicle count; AMH, anti-Müllerian hormone; AUC, area under the curve.
The ROC curve analysis also confirmed that AMH and AFC were the best predictors of high ovarian response, with an AUC of 0.865 (95% CI 0.793 to 0.935) and 0.822 (95% CI 0.734 to 0.909), respectively (Figure 2b). A cut-off of 2.25 ng/ml predicted more than 15 oocytes retrieved, with a sensitivity of 54.2% and a specificity of 91.8%, with a LR+ of 6.60 and a LR– of 0.50. Adding AFC, age and FSH to AMH slightly increased the AUC of the predictive model to 0.918 (95% CI 0.856 to 0.981), although the difference was not statistically significant compared with AMH or AFC alone (Figure 4). Of note, the oocyte retrieval process yielded more than 20 oocytes in only nine patients (4.1%).
Figure 4Receiver operating characteristics curve analysis for predictors of high ovarian response. AFC, antral follicle count; AMH, anti-Müllerian hormone; AUC, area under the curve.
In this prospective, multicentre study, the Elecsys® AMH assay demonstrated excellent clinical performance in identifying low and high ovarian response in women treated with CFA in an antagonist protocol. For a cut-off of 1.0 ng/ml, low ovarian response was predicted with a sensitivity of 92.0% and a specificity of 66.9%. Similarly, excellent predictive ability was demonstrated for high ovarian response. A cut-off of 2.25 ng/ml presented a sensitivity of 54.2% and a specificity of 91.8% in the prediction of high ovarian response. ROC curve analysis comparing different ovarian reserve markers also confirmed that AMH and AFC performed best as predictors of ovarian response for both low and high responders.
Anti-Müllerian hormone has proven its clinical utility in the prediction of ovarian response among different ovarian stimulation protocols (
The value of anti-Mllerian hormone measurement in the long GnRH agonist protocol: Association with ovarian response and gonadotrophin-dose adjustments.
Human Reproduction.2012; 27 (https://doi.org/10.1093/humrep/des101): 1829-1839
Evaluation of the Elecsys® anti-Müllerian hormone assay for the prediction of hyper-response to controlled ovarian stimulation with a gonadotrophin-releasing hormone antagonist protocol.
European Journal of Obstetrics & Gynecology and Reproductive Biology,.2019; 236: 133-138
Multicenter evaluation of the Access AMH antimüllerian hormone assay for the prediction of antral follicle count and poor ovarian response to controlled ovarian stimulation.
Fertility and Sterility.2018; 110 (https://doi.org/10.1016/j.fertnstert.2018.03.031): 506-513.e3
Does the time interval between antimüllerian hormone serum sampling and initiation of ovarian stimulation affect its predictive ability in in vitro fertilization – intracytoplasmic sperm injection cycles with a gonadotropin-releasing hormone antagonist? A retrospective single-center study.
Fertility and Sterility.2013; 100 (https://doi.org/10.1016/j.fertnstert.2013.03.031): 438-444
Within-laboratory and between-laboratory variability in the measurement of anti-müllerian hormone determined within an external quality assurance scheme.
). To the best of our knowledge, this is the first study to analyse the ability of the automated Elecsys® AMH assay to predict ovarian response in a CFA antagonist protocol. The AUC for the prediction of low ovarian response in this study was 0.883, which is in line with previous studies reporting AUCs between 0.836 and 0.929 with other assays (
Multicenter evaluation of the Access AMH antimüllerian hormone assay for the prediction of antral follicle count and poor ovarian response to controlled ovarian stimulation.
Fertility and Sterility.2018; 110 (https://doi.org/10.1016/j.fertnstert.2018.03.031): 506-513.e3
Jacobs, M. H., Reuter, L. M., Baker, V. L., Craig, L. B., Sakkas, D., Surrey, E., … Timm, B. (2019). A multicentre evaluation of the Elecsys® anti-Müllerian hormone immunoassay for prediction of antral follicle count. Reproductive BioMedicine Online, (pii), S1472-6483(19)30006-9.https://doi.org/10.1016/j.rbmo.2018.12.041
Does the time interval between antimüllerian hormone serum sampling and initiation of ovarian stimulation affect its predictive ability in in vitro fertilization – intracytoplasmic sperm injection cycles with a gonadotropin-releasing hormone antagonist? A retrospective single-center study.
Fertility and Sterility.2013; 100 (https://doi.org/10.1016/j.fertnstert.2013.03.031): 438-444
Evaluation of the Elecsys® anti-Müllerian hormone assay for the prediction of hyper-response to controlled ovarian stimulation with a gonadotrophin-releasing hormone antagonist protocol.
European Journal of Obstetrics & Gynecology and Reproductive Biology,.2019; 236: 133-138
Regarding AMH optimal cut-off levels for the prediction of the extremes of ovarian response, the cut-off of 1.0 ng/ml, identified as the value with maximal sensitivity and specificity for predicting low response, seems to be comparable with previous studies and close to the proposed cut-offs defined by the Bologna criteria (
Multicenter evaluation of the Access AMH antimüllerian hormone assay for the prediction of antral follicle count and poor ovarian response to controlled ovarian stimulation.
Fertility and Sterility.2018; 110 (https://doi.org/10.1016/j.fertnstert.2018.03.031): 506-513.e3
described a cut-off of 0.91 ng/ml and 1.03 ng/ml, respectively, as the most accurate to predict six or fewer oocytes retrieved.
For high responders, the cut-off of 2.25 ng/m was selected to optimize specificity. Taking into account that a GnRH antagonist protocol and GnRH agonist trigger were used, and that only women with a basal AFC of 20 or lower were included in the study, in accordance with the summary of product characteristics of CFA, the risk of OHSS is remarkably low. Therefore, a cut-off point with a higher specificity at the expense of a lower sensitivity was selected for high responders. The cut-off of 2.25 ng/ml is similar to the cut-offs of 2.24–3.52 ng/ml previously suggested using the manual assays (
As far as AFC is concerned, this biomarker also showed a good clinical performance in predicting low and high responders (AUC 0.879 and 0.822, respectively). Although AFC has some disadvantages, including inter-observer variability (
), the present study demonstrated that the predictive ability of AFC for low and high ovarian responses is comparable in women treated with CFA. Finally, in line with previous studies, age and FSH performed poorly in the prediction of both low and high ovarian responses (
A limitation of this study is that, although sample size was accurately calculated as per CFA administration instruction and in accordance with the summary of product characteristics, patients’ inclusion had to be restricted based on previous AFC values. Another limitation is that the dose of recombinant FSH administered from stimulation day 8 onwards was not fixed, varying between 150–300 IU/day. Although this dose was calculated based on patients’ age and ovarian reserve (
A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol.
Human Reproduction.2009; 24 (https://doi.org/10.1093/humrep/dep291): 3063-3072
Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation pr.
Fertility and Sterility.2015; 104 (https://doi.org/10.1016/j.fertnstert.2015.04.018): 94-103.e1
), no specific protocol criteria have been followed. This could, however, be seen as a strength because it allows the results to be generalized to the IVF population. Moreover this dose adjustment after stimulation day 8 is highly unlikely to have influenced the number of oocytes retrieved. In fact, considering that follicular recruitment occurs during the first days of ovarian stimulation, the number of growing follicles is not likely to be affected by these dose modifications. Furthermore, recent studies on the individualization of ovarian stimulation protocols have not demonstrated such a significant effect (
Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial.
Fertility and Sterility.2017; 107 (https://doi.org/10.1016/j.fertnstert.2016.10.033): 387-396.e4
Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).
Cochrane Database of Systematic Reviews.2018; 2 (CD012693.)
Finally, AMH was measured systematically on day 2–3 of the cycle, and this may limit the extrapolation of the results to samples obtained on other days of the cycle. Previous studies, however, have demonstrated limited inter- and intracycle variation in AMH levels (
Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women.
Human Reproduction.2014; 29 (https://doi.org/10.1093/humrep/deu142): 1764-1772
A major strength of our study is its prospective, multicentric design, optimizing the extrapolation of our results to the general IVF population. Furthermore, to our knowledge, this was the first study to evaluate the ability of the Elecsys® AMH assay to predict ovarian response in women treated with CFA. Therefore, our results provide clinical guidance for treatment and can be used in the prediction of low ovarian response in patients treated with CFA.
In the era of the OHSS-free clinic, closely related to the segmentation concept (
), it might seem that ovarian reserve markers are losing ground. Clinical practice, however, is still guided by validated recombinant FSH dose algorithms, such as the PIVET algorithm, adjusting for patient parameters such as age, AFC, BMI, AMH, day-2 FSH and history of smoking (
). In particular, this algorithm has also been validated for use with CFA, showing the critical role of age and AFC and the modulator role of AMH in defining recombinant FSH treatment dose (
). These findings highlight the importance of keeping an accurate evaluation of ovarian reserve markers in our daily practice.
In conclusion, considering the limitations discussed above, our results demonstrate that AMH and AFC are the best predictors of ovarian response in patients treated with CFA, identifying with high sensitivity and specificity patients who are likely to be poor responders. With AMH, a cut-off of 1.00 ng/ml identifies with high sensitivity and specificity patients who are likely to be poor responders. As for high responders, a cut-off of 2.25 ng/ml selects with high specificity those are at risk of high response. It is also of great interest that when the threshold of 20 AFC is set for the selection of patients treated with CFA, only 11% of patients will respond with more than 15 oocytes and 4.1% with more than 20 oocytes, thereby minimizing the risk for OHSS.
Acknowledgement
ARN conducted the literature search, contributed to data interpretation and wrote the manuscript; IR performed data collection and statistical analysis; BC, GG, GV, LM, DP, HT and MA contributed to the critical review of the manuscript; NPP designed the study, contributed to the writing and editing of the manuscript and provided critical review of the manuscript; all authors read and approved the final manuscript
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Broekmans F.
Hund M.
Evaluation of the Elecsys® anti-Müllerian hormone assay for the prediction of hyper-response to controlled ovarian stimulation with a gonadotrophin-releasing hormone antagonist protocol.
European Journal of Obstetrics & Gynecology and Reproductive Biology,.2019; 236: 133-138
The value of anti-Mllerian hormone measurement in the long GnRH agonist protocol: Association with ovarian response and gonadotrophin-dose adjustments.
Human Reproduction.2012; 27 (https://doi.org/10.1093/humrep/des101): 1829-1839
Multicenter evaluation of the Access AMH antimüllerian hormone assay for the prediction of antral follicle count and poor ovarian response to controlled ovarian stimulation.
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Professor Polyzos is the Clinical and Scientific Director of the Department of Reproductive Medicine of Dexeus University Hospital and a Professor of Reproductive Endocrinology in the University of Aarhus. He is the author of more than 150 publications, with special focus on reproductive endocrinology, ovarian reserve and poor ovarian response.
Key Message
The Elecsys® anti-Müllerian hormone (AMH) assay demonstrated an excellent clinical performance in identifying both low and high ovarian response. To the best of our knowledge, this is the first study to provide evidence on the ability of the automated Elecsys® AMH assay to predict ovarian response in a corifollitropin alfa antagonist protocol.
Article info
Publication history
Published online: April 30, 2020
Accepted:
March 30,
2020
Received in revised form:
March 21,
2020
Received:
October 26,
2019
Declaration: The authors report no financial or commercial conflicts of interest.
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