Abstract
Purpose
The purpose of this study is to investigate whether individual response of anti-Mullerian hormone (AMH) to gonadotropin-releasing hormone (GnRH) treatment is associated with difference in ovarian stimulation outcomes.
Methods
The retrospective study included 1058 non-polycystic ovary syndrome (PCOS) women undergoing long agonist protocol in a single in vitro fertilization unit from January 1, 2016, through December 31, 2016. Patients were grouped according to AMH changes from day 3 to the day of stimulation (group 1, change < 1 ng/ml, n = 714; group 2, decrease ≥ 1 ng/ml, n = 143; group 3, increase ≥ 1 ng/ml, n = 201). A generalized linear model including Poisson distribution and log link function was used to evaluate the association between AMH response and the number of oocytes retrieved.
Results
Group 2 was characterized by higher basal AMH level and increased AMH to AFC ratio in comparison with two other groups. However, the number of oocytes and ovarian sensitivity index in group 2 was significantly lower than group 3. Adjusted for age, BMI, ovarian reserve markers, and stimulation parameters, the population marginal means (95% confidence interval) of oocyte number in groups 1 through 3 were 9.51 (9.17, 9.86), 8.04 (7.54, 8.58), and 10.65 (10.15, 11.18), respectively. For patients from group 2 and group 3, basal AMH is no longer significantly associated with oocyte yield.
Conclusions
AMH change in response to GnRH agonist varies among individuals; for those undergoing significant changes in AMH following GnRH agonist treatment, basal AMH may not be a reliable marker for ovarian response in long agonist protocol.
Electronic supplementary material
The online version of this article (10.1007/s10815-017-1095-z) contains supplementary material, which is available to authorized users.
Keywords: Controlled ovarian hyperstimulation, Anti-Mullerian hormone, GnRH agonist, Pituitary downregulation, Long agonist protocol
Introduction
Anti-Mullerian hormone (AMH) is widely used as an ovarian reserve marker in reproductive medicine and demonstrates great value among a wide variety of ovarian response predictors [1]. In in vitro fertilization (IVF), it can be used as a predictor for ovarian response and may aid in the individualization of gonadotropin dosing and protocol planning [2]. Unlike other well-established markers, such as FSH, inhibin B, and AFC, fluctuation of AMH across the menstrual cycle is relatively small, and measurement of AMH is not restricted to a specific day or phase of the menstrual cycle [3].
Despite its outstanding performance as ovarian reserve marker, AMH concentration is currently known to be affected by endocrine environment which influences follicular activation and development. Pregnancy, gonadotropin-releasing hormone (GnRH) analogues, and combined hormonal contraceptives are now all known to reduce AMH concentrations [3]. An increase in AMH level following pituitary downregulation with daily-dosed GnRH agonist was observed by Jayaprakasan et al. [4]. Similarly, Su et al. reported an increase in AMH above pretreatment levels at 14 and 30 days after pituitary downregulation with a GnRH agonist depot of 3.75 mg (which is the same dose as the triptorelin depot used in this study) [5]. Changes in AMH may suggest a direct effect of GnRH agonist on granulosa cell expression of AMH or an indirect effect on the development and/or dynamics of the follicle pool. Jayaprakasan et al. proposed that the increase in AMH levels following pituitary downregulation with GnRH agonist may be associated with enhanced ovarian response and improved pregnancy rates in conventional ovarian stimulation [4]. However, evidence to support their hypothesis is still lacking. Given GnRH agonist treatments are employed in a variety of reproductive medicine scenarios ranging from management of endometriosis to ovarian preservation and long ART protocols using GnRH agonists remain the most popular ovarian stimulation protocols for IVF treatment, the clinical relevance of AMH changes during GnRH agonist treatment may have wide implications.
The purpose of the present study was to investigate whether the change in AMH levels following pituitary downregulation with GnRH agonist affects the performance of subsequent ovarian stimulation in a long agonist stimulation protocol. We hypothesized that AMH dynamic would be independently associated with oocyte yield, if the size of selectable follicle pool was affected during GnRH agonist treatment.
Materials and methods
Study subjects
The retrospective analysis was performed on patients who underwent IVF/ICSI treatment and fresh embryo transfer in the affiliated Chenggong Hospital of Xiamen University in the period between January 2016 and December 2016. Institutional Review Board approval for this retrospective study was obtained from the Ethical Committee of the Medical College Xiamen University. Informed consent was not necessary, because the research was based on non-identifiable records as approved by the ethics committee.
Data from women who had their AMH measured both on cycle day 3 and on the first day of stimulation were reviewed. The inclusion criteria were: women on long agonist protocol, regular menstrual cycles ranging from 25 to 35 days; body mass index (BMI) < 28 kg/m2; normal basal serum follicle-stimulating hormone (FSH) (<12 IU/L) and estradiol (E2) (< 75 pg/mL) levels determined on day 3 of the cycle previous to ovarian stimulation. Exclusion criteria were polycystic ovary syndrome (PCOS) diagnosis according to Rotterdam Consensus [6], history of surgical treatment on ovary (e.g., correction of ovarian endometriosis), abnormal findings on thyroid function test or elevated prolactin level, and current medication for chronic diseases (1 patient with arthritis and 4 patients with chronic kidney disease).
All patients underwent a modified long agonist protocol for ovarian stimulation as previously described [7]. Pituitary downregulation was obtained with triptorelin depot (Diphereline 3.75; Ipsen Pharma, France) in the early follicular phase and confirmed after 28 days (no ovarian cysts > 8 mm; E2 < 50 pg/L). Two or three ampoules (150–225 IU) recombinant FSH (Gonal-F; Merck-Serono, Switzerland) or domestic urinary HMG (HMG; Livzen, China) were administrated per day during the gonadotropin stimulation. The initial and ongoing dosage was adjusted according to the patient’s age, AFC, BMI, and follicular growth response. An intramuscular injection of human chorionic gonadotropin (4000–6000 IU, hCG; Livzen, China) or a subcutaneous injection of recombinant human chorionic gonadotropin (250 μg, Ovidrel, Merck-Serono, Switzerland) was given for final triggering. Oocyte retrieval under transvaginal ultrasound guidance was scheduled 34 to 36 h after hCG administration.
AMH measurements
AMH measurements were carried out within 30 min following blood collection using automated Elecsys® AMH assay on the Cobas e601 electrochemiluminescence immunoassay platform (Roche Diagnostics, IN, USA). The lowest level of detection was 0.01 ng/ml. The testing system was adjusted for quality control standard (PC AMH, Roche) for every 2 days. The max intra-assay and inter-assay imprecision coefficients of variation at 1 ng/ml during the period of study was 4.18 and 6.53%, respectively.
Statistical analysis
Patients were grouped according to AMH changes from day 3 to the day of stimulation (group 1, change < 1 ng/ml, n = 714; group 2, decrease ≥ 1 ng/ml, n = 143; group 3, increase ≥ 1 ng/ml, n = 201). All continuous variables were presented as median (interquartile range). The Kruskal–Wallis test with 2 × 2 post hoc pairwise comparisons was used for between-subgroups comparison, and pairwise Wilcoxon test was used for the comparison between pre- and post-GnRH agonist treatment. Non-parametric Spearman’s test was used for bivariate correlations. To perform multivariate analyses, we analyzed our data with generalized linear model (GLM) including Poisson distribution and log link function. Multivariate analyses were performed to evaluate the association between AMH changes and the number of oocytes retrieved, with adjustment for important covariates. Covariates were selected based on their clinical importance. Age, basal FSH, basal AMH, and AFC were included due to their importance in predicting oocyte yield. Parameters which potentially affect oocyte yield, including starting dose (< 150, 150, and 225 IU), BMI, addition of HMG [8], and the type of hCG (urinary or recombinant) [9] were also adjusted. All calculations were performed with SPSS (version 19; IBM).
Results
The present study included 1058 patients. The median of age was 30 (27, 33) years. The median of the basal AMH in the overall population was 3.27 (2.19, 4.68) ng/ml and AMH on the day of stimulation was 3.40 (2.31, 4.82) ng/ml. The difference between basal AMH levels and AMH levels on the day of stimulation was significant (P < 0.001). For those who had a positive change in AMH, the medians of absolute and percentage change were 7 (0.34, 1.29) ng/ml and 27.17 (11.74, 48.91)%, respectively. For those who had a negative change in AMH, the medians of absolute and percentage change were 0.64 (0.29, 1.19) ng/ml and 17.97 (8.75, 28.69)%, respectively. Distribution of percentage change in AMH levels is presented in Fig. 1.
Fig. 1.
Frequency distribution of percentage change in AMH levels
When patients were categorized according to the aforementioned criteria, patients’ demographics and stimulation outcomes are shown in Table 1. Patients in group 1 had higher basal FSH and lower basal AFC and AMH than the two other groups, whereas group 2 was characterized by significantly higher basal AMH and basal LH than group 1 and group 3. And a suggestive trend of elevated testosterone (P = 0.09) was also observed in group 2. However, the AFC was comparable between group 2 and group 3. AMH to AFC ratio was significantly increased in group 2 but comparable between group 1 and group 3.
Table 1.
Patients’ demographics and stimulation outcomes according to AMH changes following GnRH treatment
| AMH change < 1 ng/ml | AMH decrease ≥ 1 ng/ml | AMH increase ≥ 1 ng/ml | P | |
|---|---|---|---|---|
| N | 714 | 143 | 201 | |
| Female’s age, year | 30 (28, 33) a | 30 (27, 32) ab | 29 (27, 32) b | 0.026 |
| BMI, kg/m2 | 20.9 (19.3, 22.7) | 20.4 (19.1, 22.3) | 20.7 (19.2, 22.15) | 0.073 |
| Basal FSH, mIU/ml | 6.68 (5.82, 7.8925) a | 6.35 (5.37, 7.37) b | 6.35 (5.525, 7.48) b | 0.002 |
| Basal LH, mIU/ml | 4.12 (3.23, 5.27) a | 4.81 (3.9, 6.57) b | 4.33 (3.38, 5.54) a | < 0.001 |
| Basal E 2, pg/ml | 42 (31, 57) | 44 (31, 57) | 43 (31.63, 58.4) | 0.824 |
| Basal T, ng/ml | 0.41 (0.3, 0.52) | 0.43 (0.32, 0.57) | 0.39 (0.31, 0.51) | 0.09 |
| AFC | 9 (7, 11) a | 10 (8, 13) b | 10 (8, 13) b | < 0.001 |
| Basal AMH, ng/ml | 2.87 (1.9775, 4.0425) a | 5.65 (4.32, 7.47) b | 3.39 (2.27, 4.72) c | < 0.001 |
| AMH to AFC ratio | 0.33 (0.25, 0.45) a | 0.56 (0.44, 0.71) b | 0.34 (0.25, 0.45) a | < 0.001 |
| AMH on the day of stimulation (ng/ml) | 2.94 (2.03, 4.16) a | 3.77 (2.51, 5.68) b | 5 (4.01, 6.71) c | < 0.001 |
| Absolute change in AMH, ng/ml | 0.07 (− 0.33, 0.46) a | − 1.58 (− 2.18, − 1.23) b | 1.62 (1.27, 2.17) c | < 0.001 |
| Percentage change in AMH, % | 1.81 (− 9.84, 17.46) a | − 31.83 (− 40.04, − 23.27) b | 53.05 (36.36, 74.69) c | < 0.001 |
| FSH on the day of stimulation, mIU/ml | 2.21 (1.55, 3.08) | 2.12 (1.6, 2.75) | 2.3 (1.675, 3.28) | 0.188 |
| LH on the day of stimulation, mIU/ml | 0.86 (0.63, 1.13) | 0.81 (0.62, 1.11) | 0.91 (0.665, 1.20) | 0.163 |
| E 2 on the day of stimulation, pg/ml | 21 (15, 29) | 20 (14, 29) | 21 (14, 27.5) | 0.668 |
| Total gonadotropin dose, IU | 2475 (2213, 2925) a | 2325 (1800, 2700) b | 2250 (1800, 2663) b | < 0.001 |
| Starting gonadotropin dose, IU | 225 (150, 225) a | 187.5 (150, 225) b | 150 (150, 225) b | < 0.001 |
| Duration of stimulation, day | 12 (11, 13) | 12 (11, 13) | 12 (10, 13) | 0.05 |
| Daily dose of stimulation, IU | 225 (187.5, 225) a | 198.21 (163.15, 225) b | 187.54 (151.06, 225) b | < 0.001 |
| E 2 on the day of triggering, pg/ml | 3053 (1744.25, 4733.75) a | 3605 (1927.75, 5056.25) ab | 3886 (2346, 5191) b | 0.001 |
| Progesterone on the day of triggering, ng/ml | 0.985 (0.68, 1.37) | 1.01 (0.72, 1.54) | 0.96 (0.74, 1.44) | 0.299 |
| Endometrial thickness on the day of triggering, mm | 10.9 (9.2, 12.88) | 11.05 (9.68, 12.85) | 10.9 (9, 12.6) | 0.443 |
| Oocytes retrieved | 9 (6, 13) a | 10 (6, 15) a | 12 (8, 15) b | < 0.001 |
| Ovarian sensitivity index | 3.575 (2.22, 5.75) a | 4.29 (2.67, 6.67) b | 5.33 (3.31, 7.69) c | < 0.001 |
| Mature oocyte rate, % | 91.67 (80, 100) | 90.91 (80, 100) | 90.91 (83.33, 100) | 0.837 |
| Fertilization rate, % | 83.33 (66.67, 100) | 85.71 (70, 100) | 84.62 (71.43, 94.74) | 0.977 |
| Number of cleavage | 6 (3, 9) a | 6 (4, 10) a | 8 (5, 11) b | < 0.001 |
| Cleavage rate, % | 90.91 (77.78, 100) | 87.5 (77.78, 100) | 88.89 (80, 100) | 0.21 |
| Good embryo proportion, % | 50 (33.33, 75) | 57.14 (35.71, 75) | 55.56 (36.61, 75) | 0.322 |
Ovarian sensitivity index = (No. of oocytes retrieved ÷ total gonadotropin dose) × 1000
AMH anti-Mullerian hormone, AFC antral follicle count
a,b,cGroups not sharing common letter are significantly different at P < 0.05
When exploring the correlation between basal endocrine parameters (Supplemental Table 1), group-specific significant correlations were found. Negative correlations between AMH to AFC ratio and FSH were found in group 1 and group 3, but not in group 2. Significant correlation between testosterone and LH was only observed in group 3 while significant correlation between estrogen and FSH was only found in group 1.
Following pituitary downregulation, there were no significant differences in FSH, LH, and E2 on the day of stimulation. However, the AMH level following pituitary downregulation in group 2 was significantly lower than group 3. Patients in group 3 required lower doses of gonadotropin for stimulation and had a higher degree of ovarian response evaluated by oocyte yield, ovarian sensitivity index (OSI), and estrogen levels on the day of triggering (Table 1). No difference in laboratory parameters was found among groups, except that group 3 had a higher number of embryos.
A total of 766 patients had their embryos transferred in fresh cycle (535 in group 1, 98 in group 2, and 133 in group 3) and 488 pregnancies were achieved (343 in group 1, 57 in group 2, and 88 in group 3). Clinical pregnancy rates were 64.1, 58.2, and 66.2% in groups 1 through 3, respectively, and no significant difference among groups was detected (P = 0.43).
Generalized linear model adjusted for aforementioned covariates showed that AMH changes following pituitary downregulation were significantly associated with oocyte yield (P < 0.0001). Coefficients of covariates were presented in Supplemental Table 2. The adjusted population marginal means (95% confidence interval) of oocyte number in groups 1 through 3 were 9.51 (9.17, 9.86), 8.04 (7.54, 8.58), and 10.65 (10.15, 11.18), respectively.
In multivariate models adjusted for several covariates (age, starting dose, addition of HMG, BMI, AFC, basal FSH), AMH level measured either before or after GnRH agonist treatment was a significant predictor for oocyte yield (Supplemental Table 3). However, for those undergoing significant changes in AMH, only AMH level measured following pituitary downregulation was significantly associated with oocyte yield (Table 2).
Table 2.
Association between basal AMH level or AMH level following pituitary downregulation and oocyte yield in patients undergoing AMH changes following pituitary downregulation, derived from a multivariate generalized linear model adjusted for age, starting dose, BMI, basal FSH, AFC, and addition of HMG
| Covariates | Model I | Model II | ||
|---|---|---|---|---|
| Coefficient (95% confidence interval) | P | Coefficient (95% confidence interval) | P | |
| Basal AMH | 0.004 (− 0.011–0.018) | 0.623 | N/A | N/A |
| AMH following pituitary downregulation | N/A | N/A | 0.032 (0.016–0.049) | < 0.001 |
| Starting dose | ||||
| 225 IU vs less than 150 IU | 0.159 (0.023–0.295) | 0.022 | 0.204 (0.066–0.341) | 0.004 |
| 150 IU vs less than 150 IU | 0.172 (0.051–0.294) | 0.005 | 0.184 (0.063–0.305) | 0.003 |
| Age | − 0.018 (− 0.026–0.01) | < 0.001 | − 0.018 (− 0.026–0.009) | < 0.001 |
| BMI | − 0.03 (− 0.042–0.018) | < 0.001 | − 0.03 (− 0.042–0.019) | < 0.001 |
| Basal FSH | − 0.032 (− 0.048–0.017) | < 0.001 | − 0.029 (− 0.044–0.014) | < 0.001 |
| AFC | 0.012 (0.002–0.022) | 0.014 | 0.005 (− 0.005–0.015) | 0.294 |
| Addition of HMG | − 0.28 (− 0.359–0.201) | < 0.001 | − 0.272 (− 0.351–0.192) | < 0.001 |
| Intercept | 3.701 (3.324–4.078) | < 0.001 | 3.576 (3.195–3.957) | < 0.001 |
AMH anti-Mullerian hormone, AFC antral follicle count
Discussion
Variation in AMH levels has been observed under several clinical conditions, such as pituitary downregulation with GnRH agonist [4, 5] and exogenous sex steroids used for contraception [10]. The clinical relevance of these observations, however, appears to be less known. In the present study, we associated the changes in AMH levels following pituitary downregulation with ovarian response to controlled ovarian stimulation and showed that women who had undergone an increase in AMH levels had higher oocyte yield than those who had a decrease in AMH levels, even though the basal ovarian reserved markers were higher in the latter. Multivariate analyses suggested that AMH increase following pituitary downregulation positively related to the number of oocytes retrieved independent of age, BMI, basal AMH, and stimulation parameters. The results implied that basal AMH may not be a reliable predictor for ovarian response in a certain population.
The positive association between AMH elevation and oocyte yield supported the hypothesis proposed by Jayaprakasan et al., which suggested that AMH increase correlates to an enhanced ovarian response during conventional controlled ovarian stimulation and higher pregnancy rates when pretreatment with GnRH agonists is experienced [4]. Increase in serum AMH level is supposed to reflect either the enhanced secretion of AMH by early growing follicles or the increased size of selectable follicle cohort [4]. Increased oocyte yield, however, is more likely to be associated with the size of selectable follicle cohort. In cyclic mice, immunochemistry assay revealed that AMH expression of individual follicle initially increased and then decreased gradually during GnRH agonist treatment up to 7 days [11], but the late pre-antral follicle count increased significantly following 8-day downregulation with pharmacological dose (25 μg/day) of GnRH agonist injection [12]. These data may partially support the positive effect of GnRH agonist on the size of selectable follicle rather than per-follicle expression. However, rodent model also demonstrated very different effects from human observation, such as a decrease in AFC following GnRH treatment [12]. The underlining mechanism linking the AMH elevation and increased oocyte yield is yet to be elucidated.
Regarding the changes in AMH levels, Jayaprakasan et al. reported an approximately 32% increase in AMH levels following 14-day GnRH agonist treatment [4]. Su et al. found that serum AMH decreased 7 days after GnRH agonist administration and increased above pretreatment levels 14 and 30 days after GnRH agonist by 13 and 32% [5]. A decline in AMH levels, however, was observed in early maturing girls following 3–12 months GnRH agonist treatment [13]. Difference may be due to target population or treatment duration. The dual effect of GnRH agonist on AMH observed in rodent may also explain the observation of Su et al. that the change in AMH transferred from decrease to increase after GnRH agonist treatment [5]. The initial decrease may be due to suppression of per-follicle expression [11] and the following increase may reflect the changes in size of selectable follicle [12]. These data may imply that the timing of AMH measurement is associated with the direction of observed change in AMH levels following GnRH agonist treatment. If the transfer from decrease to increase in AMH occurred around the observation time point, it may lead to a potential confusion. However, individual variation may also contribute to this issue. Difference in individual AMH response to GnRH agonist was noted in the work of Jayaprakasan et al. but the authors did not discuss this issue further. In the present study, we investigated the AMH changes 28 days after GnRH agonist administration in a larger population and found a remarkable variation of AMH response among patients. Our data suggested that GnRH agonist may have either positive or negative impact on AMH levels. However, when the patients who had a decrease in AMH level were excluded, the degree of AMH elevation (~ 27%) approximated previously reported population [4, 5].
The patients who had undergone a decrease in AMH levels following GnRH agonist treatments may represent a specific population, as patients in group 2 were characterized by elevated AMH to AFC ratios in comparison with those with minor changes or significant increase in AMH level. Serum AMH to AFC ratio could be used as a surrogate marker of per-follicle AMH production [14–16]. High pre-follicle AMH production suggests an intrinsic AMH dysregulation and correlates to PCOS phenotypes [15]. Although the patients in group 2 lack typical phenotypes for PCOS diagnosis, the elevated AMH/AFC may suggest a distinct follicular dynamic and hormone interaction in follicular pool. Under this condition, high basal AMH resulted from excessive production may not reliably reflect the size of selectable follicles.
In group 2, increased basal LH levels and a suggestive trend of basal testosterone elevation were also observed along with elevated AMH/AFC ratio. Although serum AMH levels are rather independent of gonadotropin, interactions between AMH, gonadotropins, and ovarian hormones have been elucidated [17]. A stimulating effect of LH on AMH production is observed in PCOS patients [18] and AMH in turn may also increase GnRH-dependent LH secretion [19]. Additionally, synthesis of testosterone in theca cells is also under LH stimulus. Testosterone is another important ovarian hormone which is positively associated with AMH in women of the reproductive age [20]. It is proposed that intrinsic androgen excess may render granulosa cells hypersensitive to FSH and consequently resulted in excessive AMH production [17]. The hormone interactions resulting in the excess production of AMH would be impaired during GnRH agonist treatment while the gonadotropin-independent part of AMH production was not affected. The difference in AMH response following pituitary downregulation could be explained by the different pattern of hormone interaction. It is partially supported by our observation that correlation coefficients between basal reproductive hormones were different between study groups (Supplemental Table 1). For instance, AMH to AFC ratios negatively correlated to basal FSH in both groups 1 and 3 but were irrelevant to basal FSH in group 2, leading to speculation on an altered interaction between AMH production and FSH sensitivity in individual follicles in group 2.
Su et al. concluded that AMH would not be a reliable marker of ovarian reserve following depot Lupron administration in mid-luteal phase, as it is significantly affected by the treatment [5]. However, the opposite may be true in predicting ovarian response in long agonist protocol. As demonstrated in our study, AMH levels following depot GnRH agonist treatment in the early follicular phase rather than basal AMH levels were significantly associated with oocyte yield in patients undergoing AMH changes. In long agonist protocol for IVF treatment, AMH were measured on either days 2–3 of the menstrual cycle [21–24] or just before the stimulation [25,26]. The change in AMH following pituitary downregulation may contribute to inconsistency between studies. A potential clinical implication is that the efficacy and safety of individualized gonadotropin dosing for IVF treatment based on AMH may be affected by timing of AMH measurement and individual response to GnRH agonist. According to our results, adjusting starting dose for ovarian stimulation based on AMH following pituitary downregulation may yield advantages of adjustment based on basal AMH in patients undergoing long agonist protocols. However, our data also showed that the majority of patients only underwent small changes in AMH and a significant change in AMH is likely to occur in patients with high basal AMH levels. Therefore, the effect of AMH change following pituitary downregulation may bias toward certain populations.
Our study was limited by a retrospective design and biased to young patients with normal ovarian reserve. Non-standardized ovarian stimulation regiments may also mask the true difference in ovarian response. Although the differences in stimulation parameters were adjusted in multivariate analyses, it could still be argued that the real-life stimulation regiment is not completely independent of patients’ characteristics. Our conclusion should be taken with caution also because the basal AMH levels in our study were only based on a single test. Intra-individual variation in AMH may contribute to the confounding.
In conclusion, our study demonstrated that changes in AMH levels following pituitary downregulation may affect the outcomes of subsequent ovarian stimulation. Variation in AMH response to GnRH agonist administration may reflect the hormone interactions affecting AMH production. Although ovarian reserve is accounted for 55~75% of the variance in AMH levels, the rest of determinants of AMH levels are less known [27]. Our study may contribute to a better understanding of AMH in ovarian stimulation protocol.
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Acknowledgements
The authors would like to thank all the staff, nurses, and physicians at the Reproductive Medicine Center for their support in generating this manuscript. This work was supported by the National Natural Science Foundation of China [grant number 81302454], the Science and Technology Project funding in Xiamen City [grant number 3502Z20144039], and the Natural Science Foundation of Fujian Province [grant numbers 2016D025 and 2015D016].
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Footnotes
Electronic supplementary material
The online version of this article (10.1007/s10815-017-1095-z) contains supplementary material, which is available to authorized users.
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