OBJECTIVE: How does a gonadotrophin-releasing hormone (GnRH) agonist versus a GnRH antagonist protocol affect ovarian response when using an individualized fixed daily dose of follitropin delta for ovarian stimulation?
CONCLUSIONS: The BEYOND trial data demonstrate thatindividualized fixed-dose follitropin delta is effective when used in a GnRH agonist protocol, compared with a GnRH antagonist protocol, in women with anti-Müllerian hormone (AMH) ≤35 pmol/l and no increased risk of ovarian hyperstimulation syndrome (OHSS).
BACKGROUND: The efficacy and safety of an individualized fixed daily dose of follitropin delta (based on body weight and AMH) have been established in randomized controlled trials (RCTs) using a GnRH antagonist protocol. Preliminary study data indicate that individualized follitropin delta is also efficacious in a GnRH agonist protocol (RAINBOW trial, NCT03564509). There are no prospective comparative data using individualized follitropin delta for ovarian stimulation in a GnRH agonist versus a GnRH antagonist protocol.
METHODS: This is the first randomized, controlled, open-label, multi-centre trial exploring efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus a GnRH antagonist protocol in participants undergoing their first ovarian stimulation cycle for IVF/ICSI. A total of 437 participants were randomized centrally and stratified by centre and age. The primary endpoint was the number of oocytes retrieved. Secondary endpoints included ongoing pregnancy rates, adverse drug reactions (including OHSS), live births, and neonatal outcomes.
METHODS: Participants (18-40 years; AMH ≤35 pmol/l) were enrolled at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway, and Switzerland. The mean number of oocytes retrieved was compared between the GnRH agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. Analyses were based on all randomized subjects, using a multiple imputation method for randomized subjects withdrawing before the start of stimulation.
RESULTS: Of the 437 randomized subjects, 221 were randomized to the GnRH agonist, and 216 were randomized to the GnRH antagonist protocol. The participants had a mean age of 32.3 ± 4.3 years and a mean serum AMH of 16.6 ± 7.8 pmol/l. A total of 202 and 204 participants started ovarian stimulation with follitropin delta in the GnRH agonist and antagonist groups, respectively. The mean number of oocytes retrieved was statistically significantly higher in the agonist group (11.1 ± 5.9) versus the antagonist group (9.6 ± 5.5), with an estimated mean difference of 1.31 oocytes (95% CI: 0.22; 2.40, P = 0.0185). The difference in number of oocytes retrieved was influenced by the patients\' age and ovarian reserve, with a greater difference observed in patients aged <35 years and in patients with high ovarian reserve (AMH >15 pmol/l). Both the GnRH agonist and antagonist groups had a similar proportion of cycle cancellations (2.0% [4/202] versus 3.4% [7/204]) and fresh blastocyst transfer cancellations (13.4% [27/202] versus 14.7% [30/204]). The estimated ongoing pregnancy rate per started cycle was numerically higher in the GnRH agonist group (36.9% versus 29.1%; difference: 7.74% [95% CI: -1.49; 16.97, P = 0.1002]). The most commonly reported adverse events (≥1% in either group; headache, OHSS, nausea, pelvic pain, or discomfort and abdominal pain) were similar in both groups. The incidence of early moderate/severe OHSS was low (1.5% for the agonist group versus 2.5% for antagonist groups). Estimated live birth rates per started cycle were 35.8% and 28.7% in the GnRH agonist and antagonist groups, respectively (treatment difference 7.15%; 95% CI: -2.02; 16.31; P = 0.1265). The two treatment groups were comparable with respect to neonatal health data for singletons and twins and for incidence of congenital malformations (2.7% and 3.3% for the GnRH agonist versus antagonist groups, respectively).
CONCLUSIONS: All participants had AMH ≤35 pmol/l and were ≤40 years old. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH >35 pmol/l (i.e. those with an increased OHSS risk). The incidence of OHSS in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Outcomes of transfers with cryopreserved blastocysts were not followed up, therefore the cumulative live birth rates and neonatal outcomes after cryotransfer are unknown.
CONCLUSIONS: In women with AMH ≤35 pmol/l, an individualized fixed daily dose of follitropin delta resulted in a significantly higher number of oocytes retrieved when used in a GnRH agonist protocol compared with a GnRH antagonist protocol, with no additional safety signals observed and no additional risk of OHSS. Live birth rates following ovarian stimulation with individualized follitropin delta were not statistically different between the GnRH protocols; however, the trial was not powered to assess this endpoint. There were no safety concerns with respect to neonatal health after ovarian stimulation with follitropin delta in either protocol.
BACKGROUND: The trial was funded by Ferring Pharmaceuticals. EE, EP, and MS have no competing interests. AP has received research support from Ferring, and Gedeon Richter, and honoraria or consultation fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, Merck A/S. BC has received consulting fees from Ferring and Merck, and his department received fees from Ferring to cover the costs of patient enrolment. MBS has received support to attend meetings and/or travel from Ferring, and was a board member for FertiPROTEKT e.V. until 2023. JS has received honoraria or consultation fees from Ferring and Merck, and support for attending meetings and/or travel from Ferring, Merck, and GoodLife. TS has received support/travel expenses from Ferring for attending a congress meeting, and participated in an advisory board for Merck. YS has received grants/research support from Ferring and support to attend a professional society congress meeting from Merck. RL and PP are employees of Ferring Pharmaceuticals. PP is a BOD member of PharmaBiome and owns stocks of Takeda Pharmaceuticals.
BACKGROUND: ClinicalTrials.gov identifier NCT03809429; EudraCT Number 2017-002783-40.
UNASSIGNED: 7 April 2019.
UNASSIGNED: 2 May 2019.

Hyperprolactinemia has long been considered detrimental to fertility due to irregularity of ovulation. Whether mild hyperprolactinemia should be corrected before initiating an in-vitro fertilization/intracytoplasmic sperm injection cycle (IVF/ICSI) has not been determined; this study aimed to examine how different levels of prolactin affect IVF outcomes. A total of 3,009 patients with basal prolactin level <50 ng/mL undergoing IVF/ICSI cycles for tubal or male factors were recruited in this study. Patients diagnosed with anovulation owing to polycystic ovarian syndrome or hyperandrogenism were ruled out. Pregnancy outcomes were compared between patients with basal prolactin levels higher or lower than the median level of prolactin (16.05 ng/mL). Multifactor analyses were carried out among four subgroups depending on different prolactin levels. Repeated-measures analysis of variance was used to explore the relationship between the ascending trend of prolactin levels over ovarian stimulation and the corresponding cumulative pregnancy outcomes. There were significantly higher numbers of oocytes (9 vs. 8, P = 0.013) and embryos (6 vs. 5, P = 0.015) in patients with basal prolactin higher than 16.05 ng/mL. Basal prolactin higher than 30 ng/mL was positively related to cumulative clinical pregnancy, and a level higher than 40 ng/mL was a good indicator for the cumulative live birth rate. Throughout ovarian stimulation, the prognosis of pregnancy improved with increasing prolactin levels. Patients with better cumulated pregnancy outcomes had significantly higher prolactin levels as well as a profoundly increasing trend during the stimulating process than those who did not conceive. For patients who underwent the gonadotropin-releasing hormone agonist long protocol IVF/ICSI treatment, a slightly higher prolactin level during the controlled ovarian hyperstimulation protocol was a positive indicator for cumulated pregnancy/live birth rates.

OBJECTIVE: Are high-responder IVF patients protected from the deleterious effect of prematurely elevated serum progesterone level on the probability of pregnancy?
METHODS: In this retrospective cohort study, 2971 autologous fresh embryo transfer IVF cycles with gonadotrophin-releasing hormone agonist long protocol were analysed to investigate whether the detrimental effect of prematurely rising progesterone levels on clinical pregnancy rate (CPR) varies depending on the magnitude of ovarian response. Nine different evenly spaced intervals were constructed for serum progesterone level on the human chorionic gonadotrophin day (<0.5/0.5-0.9/1-1.4/1.5-1.9/2-2.4/2.5-2.9/3-3.4/3.5-3.9/>4 ng/ml). Then, IVF cycles in each of these intervals were further divided into low (≤3 oocytes), normal (4-15 oocytes) and high responders (≥16 oocytes).
RESULTS: The progressive rise of serum progesterone from the <0.5 to the >4 ng/ml interval caused a gradual and continuous decline in the CPR of all three types of ovarian response. The absolute difference in the CPR between the lowest and the highest progesterone groups was not related to the magnitude of ovarian response (-26.6%, -37.7% and -40.7% for the low, normal and high responders, respectively). On multivariate logistic regression analysis, the detrimental effect of progesterone started at 1.5-1.9 ng/ml, 3.0-3.4 ng/ml and 4.0-4.4 ng/ml intervals for the low, normal and high responders, respectively.
CONCLUSIONS: High responders are not exempt from the detrimental effects of prematurely rising serum progesterone levels but the threshold interval where the detrimental effect begins is higher in the high responders compared with the low and normal responders.

This study aims to investigate whether oral contraceptive pills (OCP) pretreatment impairs pregnancy outcomes in polycystic ovary syndrome (PCOS) women undergoing GnRH agonist protocol. A total of 1025 couples underwent their first cycle of in vitro fertilization. Patients were divided into GnRH agonist protocol group (LP group) and OCP dual suppression GnRH agonist protocol group (OC-LP group). Logistic regressions were performed to estimate the risk factors affecting live birth following fresh embryo transfer between groups. Frozen-thawed embryos from the first oocyte retrieval cycle were replaced into uterus for women did not get live birth. Cumulative live birth rates between groups were compared by Kaplan-Meier survival analysis. Serum luteinizing hormone level, endometrial thickness, and live birth rate were significantly reduced in the OC-LP group in fresh cycle. Thinner endometrium, higher progesterone, and poorer embryo quality were independent risk factors for failure in getting live birth following fresh embryo transfer. However, cumulative live birth rate, medium embryo transfer attempts required to achieve live birth were comparable between groups. OCP pretreatment in GnRH agonist protocol does not seem to impair the pregnancy outcome when calculated by cumulative live birth rate in PCOS women.

To compare the effect of the different protocols in patients receiving in vitro fertilization treatment due to poor ovarian response. Seventy-seven of the patients included in the study were treated with gonadotropin (450 IU) + GnRH antagonist (group 1), 84 of the patients were treated with gonadotropin (450 IU) + microdose GnRH analog (group 2), and 53 of the patients were treated with clomiphene citrate (100 mg/day) + gonadotropin (300 IU) + GnRH antagonist (Group 3). In assessing total gonadotropin dosage, patients in Group 3 detected significantly less gonadotropin as compared to the other two groups (p < .001). Group 1 were superior to the other two groups with respect to retrieved oocytes, meiosis II oocytes and number of embryos obtained at the end of the treatment. As for the evaluation of clinical pregnancy, although the highest pregnancy rate was in Group 3, this finding was not of statistical significance. Although increasing the dosage of gonadotropins for ovarian hyper stimulation treatment in patients with poor ovarian response is beneficial with respect to retrieved oocytes, meiosis II oocytes and number of embryos, the increased dosage does not provide a statistically significant increase in clinical pregnancy rates.

OBJECTIVE: To compare stimulation requirements and ICSI outcome when agonist treatment is started in the early follicular phase or in mid luteal phase of the cycle.
METHODS: 181 infertile patients were randomly assigned to: group A (N=66) and group B (N=115). GnRH-a (Triptorelin) subcutaneous daily injections started on day 20-22 of the previous cycle till pituitary suppression is achieved where gonadotropins stimulation commenced. In group A, agonist treatment was started on the first or second days of the cycle, in group B it was started on day 20-22 of the cycle. The agonist treatment was continued till the day of (hCG) administration.
RESULTS: The stimulation requirements were similar in the two groups. The days of t agonist treatment required to reach pituitary suppression were higher in group A: 12.5±6.4 than in group B, 11±4.5. Days of stimulation (10.4±1.7 and 10.3±1.6) and number of gonadotropin vials (40.1±8.7and 39.3±9.5) did not differ between both groups. The mean number of oocytes retrieved, mean number of embryos produced (11.7±7.4 and 13.3±9.3) (5.9±4.2and 6±5.2) were similar in both groups. The rates of fertilization and cleavage were similar in the two groups. Pregnancy rates were similar in both groups. The clinical pregnancy rates per cycle was 31.8% and 33%, while pregnancy rates per embryo transfer was 36.2 % and 36.5% in groups A and B respectively.
CONCLUSIONS: Starting pituitary suppression with GnRH agonist in the early follicular phase or mid luteal phase were comparable regarding stimulation requirements and final outcomes.

In this retrospective study the outcomes of two protocols of controlled ovarian hyperstimulation and natural cycle in poor ovarian responders defined according to the Bologna criteria were compared to elucidate which approach is more suitable for the treatment of these patients. We comparatively analyzed 142 cycles of GnRH antagonist (GnRH-ant) protocol, 53 cycles of GnRH agonist (GnRH-a) protocol, and 36 natural cycles. The mean number of oocytes (2.8±1.8) and embryos (1.6±1.2) per aspiration was significantly higher in GnRH-a protocol in comparison to GnRH-ant protocol and natural cycle, but the proportion of immature, fertilized oocytes, and embryos, including the quality of transferred embryos, was very similar in all treatments. The proportion of pregnancies per oocyte aspiration did not differ significantly between treatments (18.9% after GnRH-a, 10.6% after GnRH-ant, 5.6% after natural cycle), but the live birth rate per aspiration was significantly higher after GnRH-a protocol than after GnRH-ant protocol (15.1% vs. 4.2%; p=0.024).