Study question When repeated cycles of OS for planned oocyte cryopreservation using a standard GnRH antagonist protocol are required, can OS protocol modifications improve oocyte yield? Summary answer Compared to repeating a standard GnRH antagonist protocol, switching to a long GnRH agonist protocol for POC results in a higher number of cryopreserved oocytes. What is known already The total number of cryopreserved oocytes is a key parameter of POC programs because of its association with livebirth. A substantial proportion of women embarking on POC will undergo repeated cycles of OS to reach their desired target number of vitrified oocytes. According to recent guidelines, the GnRH antagonist protocol with GnRH agonist triggering is considered the first choice protocol for POC, because of its safety profile and convenience. However, in women with normal ovarian reserve, the long GnRH agonist protocol results in a higher number of oocytes retrieved. Evidence regarding the optimal protocol for POC is limited. Study design, size, duration This is a single-centre, retrospective cohort study including 283 women who had a first cycle for POC using a standard GnRH antagonist protocol and who requested a second OS cycle to increase their total number of vitrified oocytes for later use. The choice of protocol for the second cycle was left at the discretion of the reproductive medicine specialist. All OS cycles took place between January 2009 and December 2019 in a tertiary referral hospital. Participants/materials, setting, methods After ovarian reserve testing, the first cycle OS was performed using rFSH or HPhMG in a GnRH antagonist protocol. For the second cycle, a GnRH antagonist protocol with or without antagonist pretreatment, or a long GnRH agonist protocol was prescribed. The primary outcome was the number of mature oocytes (MII) vitrified per cycle. Cycle characteristics were compared. Data were assessed by generalized estimating equation (GEE) regression analysis adjusting for covariates. Main results and the role of chance In total, 226 (79.9%) women had a GnRH antagonist protocol and 57 (20.1%) had a long GnRH agonist protocol in their second OS cycle for POC. Overall, mean age was 36.6±2.4 years. The median (CI) number of mature oocytes vitrified after the second OS cycle was significantly higher than that after the first cycle [8 (5–11) vs. 7 (4–10), p < 0.001]. According to GEE multivariate regression, adjusting for relevant confounders, switching from a GnRH antagonist protocol in the first cycle to a long GnRH agonist protocol in the second cycle was the only significant predictor of the number of vitrified oocytes after the subsequent cycle (coefficient 1.59, CI 0.29–2.89, p-value = 0.017). Age, AFC, initial dose and type of gonadotropins did not predict the number of vitrified oocytes. None of the women developed moderate or severe OHSS. Similarly, of 174 women who underwent their first OS cycle with a standard GnRH antagonist protocol, 133 women (76.4%) had the same protocol for their second cycle and 41 women (23.6%) an additional three-day course of GnRH antagonist pretreatment. According to GEE multivariate regression, this protocol modification did not result in more mature oocytes available for vitrification (coefficient –0.25, CI –1.86–1.36, p-value = 0.76). Limitations, reasons for caution These data should be interpreted with caution because of the retrospective design and limited sample. Although more oocytes were obtained with a long GnRH agonist protocol we have no data on livebirth in women returning to use their oocytes to support the choice for a specific OS protocol for POC. Wider implications of the findings: Although oocyte yield in the context of POC is an important parameter that may be modulated by the choice of OS protocol, the ultimate outcome measure of a successful POC program is livebirth after oocyte vitrification. Future research of oocyte parameters reflecting oocyte quality is paramount. Trial registration number Not applicable
Study question Does a 3-day pretreatment course with a GnRH antagonist in the early follicular phase increase the number of oocytes in a GnRH antagonist stimulation protocol? Summary answer The administration of 3 days of GnRH antagonist before starting ovarian stimulation in a GnRH antagonist protocol increases the number of COCs (Cumulus-Oocyte-Complexes). What is known already The GnRH antagonist protocol is characterized by higher gonadotropin and E2 serum levels at the start of ovarian stimulation (OS), compared with a long pituitary down regulation protocol. The unsuppressed FSH level at the start of a GnRH antagonist cycle allows the initial growth of follicles before addition of exogenous FSH, which may result in asynchrony of the follicular cohort. Menstrual administration of a GnRH antagonist can inhibit follicle growth and improve homogeneity of recruitable follicles. Previous studies showed a trend toward higher numbers of COCs and improved maturation and fertilization rates of retrieved oocytes. Study design, size, duration Retrospective single center crossover study, including consecutive women enrolled in an IVF program in a university hospital from January 2011 to December 2020. All women underwent one standard GnRH antagonist stimulation cycle (“standard cycle”) and one GnRH antagonist stimulation cycle preceded by early administration of GnRH antagonist for 3 days (“pretreatment cycle”). Women with basal progesterone levels >1.5ng/ml, and women undergoing oocyte freezing, oocyte donation or PGT were excluded. In total, 427 patients were included. Participants/materials, setting, methods Women were included when the pretreatment cycle occurred within a time interval of < 12 months following the start of stimulation in the standard cycle. The primary outcome was the total number of COCs. Main results and the role of chance The average female age was 35.1 ± 4.7 years. Indications for fertility treatment included unexplained infertility (34.3%), male-factor infertility (33.3%), age (16.9%), PCOS (8.2%) and endometriosis (2.6%). All cycles were divided into two groups: group 1 (standard, 427 cycles) and group 2 (pretreatment, 427 cycles). The mean duration of stimulation was similar in both groups (10.3 vs 10.3 days, p = 0.2). The starting dose of gonadotropin (196.8 vs 234.9IU, p < 0.001) and total amount of gonadotropin used (2000.7 vs 2415.2IU, p < 0.001) were higher in group 2. The total number of obtained COCs (6.2 vs 8.8 p < 0.001) and the number of mature oocytes (4.2 vs 6.4 p < 0.001) were significantly higher in group 2. The Generalized estimating equation (GEE) multivariate regression analysis showed that the pretreatment strategy had a significant positive effect on the number of COCs (coefficient 2.8, p value <0.001 after adjusting for the confounders age, indication of infertility, stimulation dose, type and total amount of gonatropins used). Limitations, reasons for caution Despite the large dataset, the presence of biases related to the retrospective study design cannot be excluded. Besides, the impact of GnRH pretreatment on pregnancy rate cannot be assessed because of the crossover design. Wider implications of the findings: A 3-day course of GnRH antagonist pretreatment increases the number of COCs obtained after OS. Furthermore, since the initiation of OS in a GnRH antagonist protocol relies on the occurrence of spontaneous menses, addition of three days of GnRH antagonist pretreatment may enhance scheduling flexibility without reducing efficacy. Trial registration number Not applicable
Study question Does late follicular phase stimulation yield similar outcomes compared with conventional early follicular phase stimulation in a GnRH antagonist protocol in oocyte donors? Summary answer Late follicular phase stimulation is not inferior in terms of number of oocytes compared to early follicular phase stimulation in a GnRH antagonist protocol. What is known already In patients undergoing fertility preservation for medical reasons, late follicular phase stimulation has been effectively used, resulting in similar numbers of total and mature oocytes obtained, oocyte maturation rate, mature oocyte yield, and fertilization rates compared to conventional early follicular phase ovarian stimulation. Because of LH suppression by endogenous progesterone in the luteal phase, there is less need for the use of a GnRH antagonist. Study design, size, duration This is an open label, phase 3, non-inferiority, randomized controlled trial using a two-arm design with 1:1 allocation ratio. The study included 71 oocyte donors between 18 and 36 years, with a regular menstrual cycle length and BMI 19-35 kg/m2, who underwent ovarian stimulation between November 2018 and May 2022. Patients were allocated to either early follicular start (Group A, n = 36), or to late follicular start (Group B, n = 35). Participants/materials, setting, methods In Group A, patients followed a fixed GnRH antagonist protocol with r-FSH 225IU daily. In Group B, r-FSH 225IU daily was initiated when a dominant follicle and late follicular hormonal values were observed, a GnRH antagonist was added if serum LH-levels were >10IU/L. The primary outcome was number of cumulus-oocyte-complexes (COCs). Secondary endpoints included number of mature oocytes, consumption of gonadotropins, duration of ovarian stimulation, days of GnRH antagonist used, and cost of the stimulation. Main results and the role of chance Using an intention-to-treat analysis, the total number of oocytes did not differ between Group A and Group B (17.7±10.0 vs 17.2±9.1, p = 0.82, difference 0.49 ,95% CI (-4.04 to 5.03)). In the per protocol analysis, after excluding 4 patients, there was no difference between Group A and Group B (18.2±9.7 vs 18.8±7.8, p = 0.62, difference -0.6, 95% CI (-4.9 to 3.7)).The number of mature oocytes did not differ between Group A and Group B (14.1±8.1 vs 12.7±8.5, p = 0.48). In none of the treatment arms OHSS was observed. The duration of stimulation was shorter in Group A than in Group B (10.0±1.6 vs 10.9±1.5 days, p = 0.01). The total amount of r-FSH used was lower in group A than in Group B (2240.7±313.9 IU vs 2453.9±330.1 IU p = 0.008). A GnRH antagonist was used for approximately 6 days in Group A, while in group B, only in one patient a GnRH antagonist was prescribed for 4 days (6.0±1.4 days vs 0.13±0.7 days p < 0.001). There was a significant difference in total medication cost per cycle between both protocols (1147.9±182.8 € in Group A, vs 979.9±129.0 € in group B, p < 0.001), i.e. a cost reduction of 15% for Group B as compared with Group A. Limitations, reasons for caution A limitation of the study is the lack of embryology data. Because of adaptations in the oocyte donation program in our center over the years, this study contains a mix of fresh and frozen donation cycles, leading to a very heterogenous group, making correct interpretation of the embryology data difficult. Wider implications of the findings Late follicular phase stimulation is as efficient as early follicular phase stimulation in terms of number of oocytes. It is patient-friendly, with reduced cost and reduced number of injections. Trial registration number NCT03767218
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