Intra- and inter-cycle variability of anti-Müllerian hormone (AMH) levels in healthy women during non-consecutive menstrual cycles: the BICYCLE study

Objectives Determine variability of serum anti-Müllerian hormone (AMH) levels during ovulatory menstrual cycles between different women (inter-participant), between non-consecutive cycles (inter-cycle) and within a single cycle (intra-cycle) in healthy women. Methods Eligible participants were women aged 18–40 years with regular ovulatory menstrual cycles. Serum samples were collected every second day during two non-consecutive menstrual cycles. AMH levels were measured in triplicate using the Elecsys® AMH Plus immunoassay (Roche Diagnostics). AMH level variability was evaluated using mixed-effects periodic regression models based on Fourier series. The mesor was calculated to evaluate inter-participant and inter-cycle variability. Inter- and intra-cycle variability was evaluated using peak-to-peak amplitudes. Separation of biological and analytical coefficients of variation (CVs) was determined by analysing two remeasured AMH levels (with and without original AMH levels). Results A total of 47 women were included in the analysis (42 assessed over two cycles; five one cycle only). CV of unexplained biological variability was 9.61%; analytical variability was 3.46%. Inter-participant variability, given by time-series plots of AMH levels, was greater than inter-cycle variability. Between individual participants, both mesor and peak-to-peak amplitudes proved variable. In addition, for each participant, intra-cycle variability was higher than inter-cycle variability. Conclusions Inter-participant and intra-cycle variability of AMH levels were greater than inter-cycle variability. Unexplained biological variability was higher than analytical variability using the Elecsys AMH Plus immunoassay. Understanding variability in AMH levels may aid in understanding differences in availability of antral ovarian follicles during the menstrual cycle, which may be beneficial in designing gonadotropin dosage for assisted reproductive technology.

Clomiphene Citrate Priming Increases Sensitivity During Ovarian Stimulation in Poor Ovarian Responders Undergoing In Vitro Fertilization Treatment: A Retrospective Cohort Study

Background: Since ovarian stimulation was introduced as an assisted reproductive technology, poor ovarian response (POR) management has challenged clinicians. Guidance on optimally managing patients with poor response and/or low sensitivity to ovarian stimulation is still lacking. We aimed to investigate whether a clomiphene citrate (CC) priming protocol could increase ovarian sensitivity in poor ovarian responders. Methods: This single-center retrospective cohort study included 294 patients (374 ovarian stimulation cycles). Of these, 193 cycles were treated by a CC priming antagonist protocol (study group) and 181 by the classical flexible gonadotropin-releasing hormone antagonist protocol (control group). Stimulation data and laboratory and clinical outcomes were compared between the groups. Results: Total gonadotropin dosage and dosage per follicle were considerably lower, the follicle-to-oocyte index was significantly higher, and the gonadotropin duration was shorter in the study group. After adjusting for potential confounders, multivariate regression analysis showed that cumulative ongoing pregnancy remained comparable between the groups (adjusted odds ratio: 0.761, 95% confidence interval: 0.300-1.933, P = 0.566). Age, body mass index, gonadotropin dosage per follicle, and the follicle-to-oocyte index were directly associated with the reproductive outcomes. The result of the sensitivity analysis showed that patients stimulated by the CC priming antagonist protocol were administered less gonadotropin (1,739.09 ± 719.39 vs. 3,114.77 ± 1,171.23, P < 0.001) at a lower gonadotropin dosage per follicle (637.36 ± 373.05 vs. 1286.26 ± 976.66, P < 0.001) and for a shorter duration (6.58 ± 2.23 vs. 9.80 ± 1.90, P < 0.001). Conclusions: The CC priming antagonist protocol offered a convenient and patient-friendly way to increase ovarian sensitivity during ovarian stimulation in poor ovarian responders.

No effect of ovarian stimulation and oocyte yield on euploidy and live birth rates: an analysis of 12 298 trophectoderm biopsies

STUDY QUESTION Does ovarian stimulation affect embryo euploidy rates or live birth rates (LBRs) after transfer of euploid embryos? SUMMARY ANSWER Euploidy rates and LBRs after transfer of euploid embryos are not significantly influenced by gonadotropin dosage, duration of ovarian stimulation, estradiol level, follicle size at ovulation trigger or number of oocytes retrieved, regardless of a woman’s age. WHAT IS KNOWN ALREADY Aneuploidy rates increase steadily with age, reaching &gt;80% in women &gt;42 years old. The goal of ovarian stimulation is to overcome this high aneuploidy rate through the recruitment of several follicles, which increases the likelihood of obtaining a euploid embryo that results in a healthy conceptus. However, several studies have suggested that a high response to stimulation might be embryotoxic and/or increase aneuploidy rates by enhancing abnormal segregation of chromosomes during meiosis. Furthermore, a recent study demonstrated a remarkable difference in euploidy rates, ranging from 39.5 to 82.5%, among young oocyte donors in 42 fertility centres, potentially suggesting an iatrogenic etiology resulting from different stimulation methods. STUDY DESIGN, SIZE, DURATION This is a retrospective cohort study that included 2230 in vitro fertilisation (IVF) with preimplantation genetic testing for aneuploidy (PGT-A) cycles and 930 frozen-thawed single euploid embryo transfer (FET) cycles, performed in our centre between 2013 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 12 298 embryos were analysed for ploidy status. Women were divided into five age groups (&lt;35, 35–37, 38–40, 41–42 and &gt;42 years old). Outcomes were compared between different durations of stimulation (&lt;10, 10–12 and ≥13 days), total gonadotropin dosages (&lt;4000, 4000–6000 and &gt;6000 IU), numbers of oocytes retrieved (&lt;10, 10–19 and ≥20 oocytes), peak estradiol levels (&lt;2000, 2000–3000 and &gt;3000 pg/mL), and sizes of the largest follicle on the day of trigger (&lt;20 and ≥20 mm). MAIN RESULTS AND THE ROLE OF CHANCE Within the same age group, both euploidy rates and LBRs were comparable between cycles regardless of their differences in total gonadotropin dosage, duration of stimulation, number of oocytes harvested, size of the largest follicles or peak estradiol levels. In the youngest group, (&lt;35 years, n = 3469 embryos), euploidy rates were comparable between cycles with various total gonadotropin dosages (55.6% for &lt;4000 IU, 52.9% for 4000–6000 IU and 62.3% for &gt;6000 IU; P = 0.3), durations of stimulation (54.4% for &lt;10 days, 55.2% for 10–12 days and 60.9% for &gt;12 days; P = 0.2), number of oocytes harvested (59.4% for &lt;10 oocytes, 55.2% for 10–19 oocytes and 53.4% for ≥20 oocytes; P = 0.2), peak estradiol levels (55.7% for E2 &lt; 2000 pg/mL, 55.4% for E2 2000–3000 pg/mL and 54.8% for E2 &gt; 3000 pg/mL; P = 0.9) and sizes of the largest follicle (55.6% for follicles &lt;20 mm and 55.1% for follicles ≥20 mm; P = 0.8). Similarly, in the oldest group (&gt;42 years, n = 1157 embryos), euploidy rates ranged from 8.7% for gonadotropins &lt;4000 IU to 5.1% for gonadotropins &gt;6000 IU (P = 0.3), from 10.8% for &lt;10 days of stimulation to 8.5% for &gt;12 days of stimulation (P = 0.3), from 7.3% for &lt;10 oocytes to 7.4% for ≥20 oocytes (P = 0.4), from 8.8% for E2 &lt; 2000 pg/mL to 7.5% for E2 &gt; 3000 pg/mL (P = 0.8) and from 8.2% for the largest follicle &lt;20 mm to 8.9% for ≥20 mm (P = 0.7). LBRs after single FET were also comparable between these groups. LIMITATIONS, REASONS FOR CAUTION Although this large study (2230 IVF/PGT-A cycles, 12 298 embryos and 930 single FET cycles) demonstrates the safety of ovarian stimulation in terms of aneuploidy and implantation potential of euploid embryos, a multi-centre study may help to prove the generalisability of our single-centre data. WIDER IMPLICATIONS OF THE FINDINGS These findings reassure providers and patients that gonadotropin dosage, duration of ovarian stimulation, estradiol level, follicle size at ovulation trigger and number of oocytes retrieved, within certain ranges, do not appear to significantly influence euploidy rates or LBRs, regardless of the woman’s age. STUDY FUNDING/COMPETING INTEREST(S) No external funding was received and there are no competing interests to declare. TRIAL REGISTRATION NUMBER N/A

AMH as the primary marker for fertility

In women, the anti-Müllerian hormone (AMH) is secreted by the granulosa cells of growing follicles. Its measurement is strongly correlated with antral follicle count and represents a reliable marker of ovarian reserve. It also has the advantage of being highly reproducible since it has little variation within and between cycles. However, although it seems to be a good quantitative reflection of the ovarian reserve, it does not assess oocyte or embryo quality. This drawback precludes any good prediction of female fertility in the general population as well as in specific subgroups of patients. However, the AMH assay can become an indirect marker of the remaining female fertile years in some cases such as in those women who are at risk for premature ovarian failure or in those suffering from polycystic ovary syndrome. Its interest is no more to be proven in assisted reproductive technology where it is a valuable aid to the choice of the proposed techniques, ovarian stimulation protocols and gonadotropin dosage. AMH is finally very informative in monitoring cancer patients having received gonadotoxic drugs or having undergone mutilating ovarian surgeries. In conclusion, although it cannot be considered as a reliable predictor of pregnancy in women, AMH is now a useful tool in the management and treatment of female infertility.

Does the Modification of Starting Gonadotropin Dose During ICSI Cycle Have Any Significant Impact on Cycle Outcome?

<p><strong>OBJECTIVE:</strong> The aim of this study was to figure out the impact of gonadotropin dose alteration requirements due to high response or unresponsiveness on intracytoplasmic sperm injection cycle outcomes in a standard group of patients.</p><p><strong>STUDY DESIGN:</strong> One hundred cycles with same gonadotropin dosage along the stimulation were compared with 100 cycles in which gonadotropin dose alterations were needed due to high response or unresponsiveness. Groups were compared in terms of age, body mass index, serum follicle stimulating hormone and estradiol levels, antral follicle count, gonadotropin dosage, duration of stimulation, endometrial thickness at trigger day, number of total, mature and immature oocytes and finally the clinical pregnancy rates.</p><p><strong>RESULTS:</strong> There were significant differences between groups with regard to gonadotropin starting dose, total gonadotropin dose, duration of stimulation, estradiol level at trigger day, number of total oocytes and metaphase 1 oocyte number. Clinical pregnancy rates were similar between groups.</p><p><strong>CONCLUSION:</strong> Dose alteration requirement along intracytoplasmic sperm injection cycle result in high number of total and metaphase 1 oocyte yields, higher starting gonadotropin and total gonadotropin dose, duration of stimulation and estradiol level at trigger day, however clinical pregnancy rates were similar between groups.</p>