Anti-Müllerian hormone (AMH) is an important ovarian reserve marker for baseline assessment and therapeutic strategy in fertility treatments, which is considered reliable when measured on any day of the cycle. Recent data have pointed toward significant fluctuations of AMH and questioned whether a single measurement is reliable for clinical decision-making. The aim of this study was to evaluate whether the AMH does have significant variations during a natural cycle when a fully automated assay is used for the sample analysis. We performed a prospective study including healthy volunteers with regular cycles, from April to December 2017. Blood samples for AMH, FSH, LH, estradiol, and progesterone were obtained on day 2/3, day 10, day of LH surge, luteal phase and day 2/3 of subsequent menses. AMH analysis was performed with Elecsys® AMH automated assay. Trial was registered with clinical.trials.gov: NCT03106272. One hundred samples from 22 women with a mean age of 30.74 ± 0.11 years and a BMI of 23.23 ± 0.63 kg/m2 were analyzed. There was a substantial longitudinal fluctuation in AMH levels, indicated by the coefficient of variation (CV) intra-cycle of 0.2070 ± 0.143. A positive correlation between LH and AMH concentrations was found at the moment of LH rise (p < 0.0001). Absolute intra-individual inter-cyclic variability was 0.75 ng/mL (range: 0.03–2.81 ng/mL) and inter-cycle CV was 0.28 (Confidence interval: 0.16–0.39; p < 0.0001). According to our results, with the use of a fully automated assay in natural cycle, AMH shows significant intra- and inter-cycle variations, which are not caused by analytical variability. Future investigations, evaluating AMH dynamics and the best time for AMH assessment should be conducted.

A rise in serum progesterone in the late follicular phase is a well described adverse effect of ovarian stimulation for IVF/ICSI. Previous data suggest, that enhanced gonadotropin stimulation causes progesterone elevation and the incidence of premature progesterone elevation can be reduced by declining gonadotropin dosages. This randomized controlled trial (RCT) aimed to achieve a significant reduction of the progesterone level on the day of final oocyte maturation by a daily reduction of 12.5 IU rec-FSH from a follicle size of 14 mm in a GnRH-antagonist protocol. A total of 127 patients had been recruited (Control group (CG): 62 patients; Study group (SG): 65 patients). Due to drop out, data from 108 patients (CG: 55 patients; SG: 53 patients) were included into the analysis. Patients’ basic parameters, gonadotropin (Gn)-starting dose, total Gn-stimulation dosage, the number of retrieved and mature oocytes as well as in the hormonal parameters on the day of trigger (DoT) were not statistically significantly different. However, through stepwise Gn-reduction of 12.5 IU/day in the SG, there was a statistically highly significant difference in the Gn-stimulation dosage on the day of trigger (p &lt; 0.0001) and statistically significant associations for the DoT-P4-levels with the DoT-FSH-levels for both groups (CG: p = 0.001; SG: p = 0.0045). The herein described significant associations between DoT-P4-levels and DoT-FSH-levels confirm the theory that enhanced FSH stimulation is the primary source of progesterone elevation on the day of final oocyte maturation in stimulated IVF/ICSI cycles. Given the pathophysiologic mechanism of progesterone elevation during ovarian stimulation, the use of an increased FSH step-down dosage should be studied in future RCTs, despite the fact that a step-down approach of daily 12.5 IU rec-FSH did not achieve a significantly reduced progesterone level on the DoT.Clinical Trial Registration:clinicaltrials.gov, identifier NCT03356964.

In recent years there is increasing evidence that elevated progesterone levels during ovarian stimulation for IVF / ICSI have a negative impact on the ART-outcome. However, different progesterone assays were used in the previous studies and different assays might produce varying results. This retrospective study evaluated the reproducibility and reliability of different progesterone assays with a special focus on progesterone levels below 1.5 ng/ml, as this range is crucial for early detection of progesterone rise during ovarian stimulation for IVF. A total of 413 blood samples were categorized in different progesterone ranges and whether they were retrieved on the day of final oocyte maturation and the results were compared regarding their reproducibility and reliability. To compare the reproducibility between the different progesterone assays, the Intraclass Correlation Coefficient (ICC) was calculated and interpretation of the ICC results was done according to Cicchetti, ranging from poor to excellent. The correlation of the assays was excellent when all samples were compared including samples retrieved on day of final oocyte maturation, however in the ranges of progesterone levels 1.0 ng/ml to < 1.5 ng/ml, 0.8 ng/ml to < 1.0 ng/ml and < 0.8 ng/ml, the ICC varied between poor and excellent. The assays “gen III” and “Architect” showed an excellent reproducibility of progesterone results throughout all ranges of progesterone levels.This analysis demonstrates, that different progesterone assays have a limited reproducibility and that the results depend on the assay used and the range of progesterone level. This fact leads to two important conclusions. Firstly the limited reproducibility might lead to substantially different treatment decisions in ovarian stimulation treatment for IVF and secondly critical interpretation of thresholds, provided by meta-analysis, is crucial despite the risk that the so far gained clinical experience might become irrelevant and has to be adjusted to the results, obtained by each assay.

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