Seven-hundred and ninety-five oocyte cryopreservation patients, comprising BRCA carriers with and without malignancy (n ¼ 57) and BRCA noncarriers (n ¼ 738). Intervention(s): Fertility preservation with oocyte cryopreservation. Main Outcome Measure(s): Antral follicle count (AFC), antim€ ullerian hormone (AMH) concentration, day-3 follicle-stimulating hormone (FSH) level, number of harvested oocytes, and number of mature/cryopreserved oocytes. Result(s): In the cancer cohort we compared BRCA-positive breast cancer (n ¼ 38) with BRCA-negative breast cancer (n ¼ 53) and with non-breast-cancer malignancies (n ¼ 85). In the cancer-free cohort we compared BRCA carriers (n ¼ 19) with women undergoing elective egg freezing (n ¼ 600). We also compared the BRCA1 (n ¼ 31) versus the BRCA2 carriers (n ¼ 18). The patients' mean ages were 32.4 AE 3.6 years and 35.5 AE 4.3 years in the BRCA carrier and noncarrier cohorts, respectively. BRCA status was associated with a higher day-3 FSH level in the cancer cohort, but we found no changes in the other outcomes compared with the BRCAnegative cancer groups. BRCA carriers without cancer exhibited a higher AFC and number of mature oocytes compared with the patients undergoing planned egg freezing. Overall (cancer and cancer-free cohorts), the BRCA carriers had an increased AFC (15.5 AE 4.6 vs. 12.6 AE 5.7) and number of mature/cryopreserved oocytes (14.0 AE 7.9 vs. 10.4 AE 6.9) compared with the BRCA noncarriers but had no differences in other outcomes. Conclusion(s): BRCA carriers with and without malignancy exhibit comparable ovarian reserve and responses to ovarian stimulation compared with women with BRCA-negative cancers and cancer-free controls. (Fertil Steril Ò 2019;111:363-71. Ó2018 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.

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 >80% in women >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 (<35, 35–37, 38–40, 41–42 and >42 years old). Outcomes were compared between different durations of stimulation (<10, 10–12 and ≥13 days), total gonadotropin dosages (<4000, 4000–6000 and >6000 IU), numbers of oocytes retrieved (<10, 10–19 and ≥20 oocytes), peak estradiol levels (<2000, 2000–3000 and >3000 pg/mL), and sizes of the largest follicle on the day of trigger (<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, (<35 years, n = 3469 embryos), euploidy rates were comparable between cycles with various total gonadotropin dosages (55.6% for <4000 IU, 52.9% for 4000–6000 IU and 62.3% for >6000 IU; P = 0.3), durations of stimulation (54.4% for <10 days, 55.2% for 10–12 days and 60.9% for >12 days; P = 0.2), number of oocytes harvested (59.4% for <10 oocytes, 55.2% for 10–19 oocytes and 53.4% for ≥20 oocytes; P = 0.2), peak estradiol levels (55.7% for E2 < 2000 pg/mL, 55.4% for E2 2000–3000 pg/mL and 54.8% for E2 > 3000 pg/mL; P = 0.9) and sizes of the largest follicle (55.6% for follicles <20 mm and 55.1% for follicles ≥20 mm; P = 0.8). Similarly, in the oldest group (>42 years, n = 1157 embryos), euploidy rates ranged from 8.7% for gonadotropins <4000 IU to 5.1% for gonadotropins >6000 IU (P = 0.3), from 10.8% for <10 days of stimulation to 8.5% for >12 days of stimulation (P = 0.3), from 7.3% for <10 oocytes to 7.4% for ≥20 oocytes (P = 0.4), from 8.8% for E2 < 2000 pg/mL to 7.5% for E2 > 3000 pg/mL (P = 0.8) and from 8.2% for the largest follicle <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

BackgroundThere is no consensus on the exact parameters that define the LH surge for natural cycle frozen-thawed embryo transfers (NC-FET). Accurately determining the LH surge would affect the timing, and subsequently the success rates, of embryo transfer. Therefore, the aim of this study was to delineate the optimal levels and relationship for luteinizing hormone (LH) and estradiol in an effort to optimally identify the LH surge in NC-FET.MethodsIt is a retrospective study that was performed in an academic medical center. Patients who underwent blastocyst NC-FET who either had preimplantation genetic screening (PGS) or were <35 years old but did not undergo PGS (non-PGS) were included in separate analyses. They were divided into two groups: Group A included patients whose LH surge was defined as the first attainment of LH ≥ 17 IU/L during the follicular phase with a ≥30% drop in estradiol levels the following day; group B encompassed patients whose LH level continued to rise and the surge was defined as the highest serum LH level occurring a day after LH ≥ 17 IU/L despite a ≥ 30% drop in estradiol levels. The main outcomes measures were implantation and live birth rates.ResultsFour hundred-seven non-PGS and 284 PGS NC-FET were included. Among non-PGS cycles, group A was associated with significantly higher implantation rates (48.7% vs. 38.1%) and live birth rates (52.9% vs. 40.1%) compared to group B. In contrast, group A and B had comparable live birth rates among PGS cycles.ConclusionsAmong non-PGS cycles, measuring LH and estradiol levels the day after an LH ≥ 17 IU/L and defining the surge as the first day of LH ≥ 17 IU/L in the context of a ≥ 30% drop in estradiol the following day was associated with better NC-FET outcomes than defining the surge as the day representing the highest serum LH level despite a ≥30% drop in estradiol levels.

In women who delay child bearing, elective oocyte cryopreservation in the mid 30s may be beneficial in terms of live birth rates and cost effectiveness. Prospective studies of women who have undergone oocyte cryopreservation and are now attempting conception are needed before official recommendations can be made regarding elective egg freezing.

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