Administration Of GnRH Antagonist Research Articles

Administration of luteal GnRH antagonist in patients with high serum progesterone levels on the day of egg retrieval

Administration of luteal GnRH antagonist in patients with high serum progesterone levels on the day of egg retrieval

P-671 Comparing clomiphene citrate/ flexible GnRH antagonist vs ultrashort flare GnRH agonist protocols for controlled ovarian stimulation in poor ovarian reserve patients

Abstract Study question How do Clomiphene citrate (CC)/ flexible GnRH antagonist and ultrashort flare GnRH agonist protocols compare in poor ovarian reserve patients (POSEIDON groups 3 & 4)? Summary answer In poor ovarian reserve patients, irrespective of age, use of CC / flexible antagonist vs ultrashort flare protocol significantly reduces gonadotrophin consumption and stimulation duration. What is known already Poor responders constitute 47% of ART patients and up to 65% of these have diminished ovarian reserve. Despite the various treatment options available, lack of good quality evidence to enable recommendation of a particular protocol or adjuvant continues to pose a challenge to their effective management. The need for multiple stimulations for pooling up embryos also makes effective cost of treatment an added concern in them. Study design, size, duration An open label, multi centric, randomized controlled study was conducted over a period of 1 year recruiting 116 women having AMH <1.2ng/dl and antral follicle count (AFC) <5 who were further analysed in POSEIDON 3 and 4 subgroups. Patients were randomized to 1 of 2 groups for controlled ovarian stimulation. Those with severe endometriosis, adenomyosis, autoimmune or metabolic disorders, sustained hyperprolactinaemia, congenital uterine malformations and with male partners having severe oligoasthenoteratozoospermia were excluded. Participants/materials, setting, methods Group A (55 women) received CC 100mg from D1-D5 with 300 IU human menopausal gonadotrophin (hMG) in a flexible GnRH antagonist protocol. Group B (61 women) underwent ultrashort flare protocol. 1mg leuprolide was administered from D1-D4 and 300 IU hMG given D2 onwards followed by flexible GnRH antagonist administration. Dual trigger with triptorelin and recombinant hCG was administered 35-36 hours before oocyte retrieval. Embryos cultured till D5 were vitrified for transfer at a later stage. Main results and the role of chance The two groups were well matched for baseline characteristics like age, BMI, AMH, duration of infertility, D2 AFC, estradiol and FSH levels. The mean total gonadotrophin consumption (3387.29 + 1082.5 vs 4407 + 1224.2, p value <0.01) and the duration of stimulation (10.71 + 2.52 vs 11.95 + 2.43, p value <0.01) were significantly lower in group A vs group B. The primary outcomes of median number of oocytes retrieved (4 vs 4, p value- 0.71) , M2 rate (3 vs 3, p value-0.91), fertilisation rate were similar in the two groups. The secondary outcomes of oocyte retrieval rate (103.05 + 42.97 vs 97.14 + 42.96, p value- 0.63), FORT (0.81 +0.68 vs 0.96 + 0.48, p value- 0.37) FOI (0.91 + 0.55 vs 0.92+ 0.54, p value 0.92), top quality embryo rate (0.53 + 1.1 vs 0.41 + 0.84, p value 0.61), cycle cancellation rate (26.22% vs 29.09%), implantation rate (23.63% vs 24.59%) and clinical pregnancy rate (21.31% vs 20%) were also similar in group A vs B respectively. A subgroup analysis of POSEIDON 3 versus POSEIDON 4 patients revealed similar outcomes with both the protocols in the two groups. Limitations, reasons for caution Small sample size of the cases limits the current statistical power of the study. Wider implications of the findings CC /flexible GnRH antagonist protocol is an effective alternative to ultrashort flare protocol in patients with poor ovarian reserve irrespective of their age. The lower gonadotrophin dosage required and shorter duration of stimulation observed make it a viable option in patients who might need multiple stimulations for pooling up embryos. Trial registration number Not applicable

P-683 Live birth rate following medicated frozen-thawed embryo transfer with or without GnRH-antagonist (Cetrotide) pituitary suppression. A randomised, controlled pilot trial

Abstract Study question Does the administration of GnRH-antagonist (Cetrotide) in medicated frozen-thawed embryo transfer (FET) cycles improve live birth (LBR) or cycle cancellation rate? Summary answer Live birth and cycle cancellation were similar with or without Cetrotide. However, cancellation for threatened ovulation was statistically significantly lower when Cetrotide was administered. What is known already During medicated FET, embryo and endometrial development must be synchronized, with endometrial window of implantation dependent on duration of progesterone. Suppression of spontaneous ovulation is key to maintaining synchrony. There are insufficient data regarding the use of supplementary pituitary suppression in medicated FET. A recent Cochrane review identified one small RCT comparing live birth rate between medicated FET with or without GnRH-agonist pretreatment. The study suggested benefit to GnRH-agonist, but cycles were not monitored for ovulation. One RCT compared GnRH-antagonist with agonist showing better clinical pregnancy rate with GnRH-antagonist. No published RCT has compared medicated FET with versus without GnRH-antagonist. Study design, size, duration We conducted an open, two-arm, single-centre, randomised, controlled trial comparing medicated FET with or without Cetrotide. Target recruitment was 300. However, the study was stopped due to the Covid-19 pandemic. Recruitment occurred between 23rd January 2019 and 11th March 2020 and ended at 161 participants. Analysis was undertaken on an intention-to-treat basis, with live birth rate (LBR) as the primary outcome. Participants/materials, setting, methods Patients were given oestradiol 2mg orally TDS. Once the endometrium was ≥7mm, vaginal progesterone was commenced, with FET on the sixth day of progesterone. The Cetrotide group were given Cetrotide 0.25mg SC OD from days 1-7. Urine pregnancy test was done 11 days following FET, with oestradiol and progestogen continued to 10 weeks gestation. Cycles were cancelled for “threatened ovulation” if daily urinary LH-surge testing was positive or an ovarian follicle (≥12mm) was growing. Main results and the role of chance 161 patients were randomised (Cetrotide: 76, no Cetrotide: 85). Six were withdrawn after randomisation (three withdrew consent, two did not start, one natural pregnancy). 155 participants started treatment (Cetrotide: 73, no Cetrotide: 82) and 140 had embryo transfer (Cetrotide: 68, no Cetrotide: 72). The LBR was similar between groups (Cetrotide: 39% (30/76), no Cetrotide (29/85): 34%; OR 0.79, 95% CI 0.42 - 1.51), as were pregnancy rate (42% versus 38%; OR 0.87; 95% CI 0.47-1.63), clinical pregnancy rate (52% versus 49%; OR 0.83; 95% CI 0.44 – 1.56), biochemical pregnancy rate (20% versus 24%; OR 1.25; 95% CI 0.44 - 3.58) and miscarriage rate (7% versus 10%; OR 1.55; 95% CI 0.24 – 9.97). In the Cetrotide group, 7% of cycles were cancelled, compared to 12% in the no Cetrotide group (NS). However, cancellation due to threatened ovulation was statistically significantly lower in the Cetrotide group, with 0% of cycles cancelled compared to 5% in the no Cetrotide group (OR 1.05; 95% CI 1.001 – 1.105). Baseline characteristics (age at oocyte retrieval, age at FET, parity, subfertility diagnosis, number of oocytes retrieved, number of viable blastocysts, proportion of IVF/ICSI, endometrial thickness, number of embryos transferred, embryo quality) were similar between groups. Limitations, reasons for caution The study is limited by the fact it was unblinded, undertaken at a single site and was underpowered for live birth due to early trial cessation. Wider implications of the findings Results suggest no effect of Cetrotide on LBR in medicated FET. There was a significantly higher risk of cycle cancellation due to risk of ovulation in patients not taking Cetrotide. This is clinically significant and requires further study, as cancelled cycles increase costs and duration to birth. Trial registration number EudraCT Number: 2018-001915-63

Preventing Growth Stagnation and Premature LH Surge Are the Keys to Obtaining a Viable Embryo in Monofollicular IVF Cycles: A Retrospective Cohort Study.

How LH levels influenced the outcomes of monofollicular IVF cycles using different stimulation protocols was controversial. In this single-center, retrospective study, we analyzed 815 monofollicular IVF cycles between 2016−2022 using natural cycle (NC), medroxyprogesterone acetate (MPA) or clomiphene citrate (CC) in addition to human menopausal gonadotropin (hMG), with or without GnRH antagonist. A viable embryo was obtained in 35.7% of all cycles. Growth stagnation and premature LH surge are two markedly negative factors for obtaining viable embryos (odds ratios of 0.12 [0.08−0.65], p < 0.0001 and 0.33 [0.26,0.42], p < 0.0001, respectively). NC/hMG cycles are prone to premature LH surge (40.4%), yielding a significantly lower opportunity of obtaining embryos (24.7%, p = 0.029). The administration of GnRH antagonist on the background of MPA resulted in a significant decrease in LH levels (from 2.26 IU/L to −0.89 IU/L relative to baseline, p = 0.000214), leading to a higher risk of growth stagnation (18.6%, p = 0.007). We hypothesized that the abrupt decline of LH might increase the risk of apoptosis in granulosa cells. We proposed a “marginal effect” framework to emphasize that the change of LH was the key to its bioactivity, rather than the traditional “window” concept with fixed cutoff values of a threshold and a ceiling.

Determination of Half-lives of Circulating FSH and LH Glycoforms in Women During GnRH Receptor Blockade.

Both FSH and LH circulate as 2 glycoforms, differing in number of glycans: low-N-glycosylated glycoforms, FSHtri and LHdi, and fully N-glycosylated glycoforms, FSHtetra and LHtri. To determine the half-lives of endogenous circulating gonadotropin glycoforms in women during GnRH receptor blockade. Serum samples were collected in 8 healthy women before and up to 20 hours after administration of the NAL-GLU GnRH antagonist. Three women were in early follicular phase, 2 at mid-cycle phase, and 3 were postmenopausal. The half-life of each glycoform was estimated by monoexponential decay for FSH (n = 8) and LH (n = 5). Data were analyzed using paired t tests. Half-lives in the circulation of low-N-glycosylated glycoforms of both FSH and LH were shorter than those of the fully N-glycosylated glycoforms (mean; range, FSHtri 343; 116-686 minutes vs FSHtetra 757; 436-1038, minutes, P = 0.0003; LHdi 125, 84-198 minutes vs LHtri 164, 107-235 minutes, P = 0.004). The half-lives of low-and fully N-glycosylated forms of LH were shorter than the corresponding half-lives of FSH glycoforms, P = 0.0008. For both FSH and LH, low-N-glycosylated glycoforms disappeared from the circulation faster than the fully N-glycosylated. The half-lives of low and fully N-glycosylated forms of LH were shorter than the corresponding half-lives of FSH. The estimated values for half-life in the circulation of total FSH and total LH will depend on the relative amounts of the 2 glycoforms of each hormone and their individual disappearance rates in circulation.

P-608 A higher probability of ongoing pregnancy is present by using the fixed as compared to the flexible GnRH antagonist protocol

Abstract Study question Is the probability of ongoing pregnancy higher in the fixed as compared to the flexible gonadotrophin releasing hormone (GnRH) antagonist protocol? Summary answer A higher probability of ongoing pregnancy is present by using the fixed as compared to the flexible GnRH antagonist protocol. What is known already Although fixed GnRH antagonist initiation is a simpler protocol that requires less monitoring compared to the flexible one, the latter might avoid unnecessary antagonist use, by administering GnRH antagonist only when there is a real risk for premature luteinizing hormone (LH) rise. A meta-analysis of four randomised controlled trials (RCTs) published in 2005, comparing fixed versus flexible GnRH antagonist administration, showed a lower non-significant probability of clinical pregnancy in the flexible compared with the fixed protocol. Following that meta-analysis, four additional RCTs comparing the fixed versus the flexible GnRH antagonist protocol have been performed necessitating an update on this topic. Study design, size, duration A literature search was performed until 12/2021, in order to identify RCTs comparing the fixed versus the flexible GnRH antagonist protocol in patients undergoing ovarian stimulation for in-vitro fertilization (IVF) using gonadotrophins. The main outcome measure was achievement of ongoing pregnancy. Secondary outcome measures included duration of stimulation, incidence of premature LH rise, estradiol levels on the day of triggering final oocyte maturation and the number of cumulus-oocyte-complexes (COCs) retrieved. Participants/materials, setting, methods Seven RCTs comparing fixed versus flexible protocol, published between 2002 and 2021, were identified (1007 patients). A meta-analysis was performed using the fixed or random effects method depending on the presence of statistically significant heterogeneity. For dichotomous data, estimates were expressed as risk ratio (RR) with 95% confidence intervals (CIs). For continuous data, differences were pooled across resulting in a weighted mean difference (WMD) with 95% CI. Main results and the role of chance Ovarian stimulation was performed using recombinant gonadotrophins in all studies. In the fixed protocol initiation of GnRH antagonist was performed either on Day 6 (six studies) or on Day 5 (single study) of stimulation. In the flexible protocol antagonist was initiated using either ultrasound criteria (four studies) or by combination of ultrasound or hormonal criteria (three studies). No significant difference was present between the fixed and flexible groups in the duration of gonadotrophin stimulation (WMD:+0.23 days, 95% CI: -0.08 to + 0.53, random protocol) and in the incidence of premature LH rise (RR:0.86, 95% CI: 0.48-1.53, fixed protocol). Significantly lower estradiol levels were present on the day of triggering final oocyte maturation (WMD:-237.74, 95% CI: -463.87 to -11.61, random protocol) and significantly less COCs were retrieved (WMD:-1.83, 95% CI: -3.11 to -0.54, random protocol) in the fixed compared with the flexible protocol. A significantly higher probability of ongoing pregnancy was observed in the fixed as compared to the flexible protocol, both per intention to treat (RR:1.28, 95% CI: 1.02-1.61, I2:0%, fixed protocol, six studies, 898 patients) as well as per protocol analysis (RR:1.30, 95% CI: 1.04-1.62, I2:0%, fixed protocol, six studies, 757 patients). Limitations, reasons for caution In the current meta-analysis, the number of studies and patients included does not allow to perform subgroup analyses based on the time of fixed antagonist initiation or on the criteria used for flexible antagonist initiation. Wider implications of the findings Although in theory flexible antagonist initiation is an attractive protocol that leads to less antagonist administration, the current meta-analysis suggests that it is associated with a lower probability of ongoing pregnancy. Further RCTs examining the two antagonist protocols for additional outcomes, including live birth or cumulative live birth, are necessary. Trial registration number N/A

Novel protein markers of androgen activity in humans: proteomic study of plasma from young chemically castrated men.

Reliable biomarkers of androgen activity in humans are lacking. The aim of this study was, therefore, to identify new protein markers of biological androgen activity and test their predictive value in relation to low vs normal testosterone values and some androgen deficiency linked pathologies. Blood samples from 30 healthy GnRH antagonist treated males were collected at three time points: (1) before GnRH antagonist administration; (2) 3 weeks later, just before testosterone undecanoate injection, and (3) after additional 2 weeks. Subsequently, they were analyzed by mass spectrometry to identify potential protein biomarkers of testosterone activity. Levels of proteins most significantly associated with testosterone fluctuations were further tested in a cohort of 75 hypo- and eugonadal males suffering from infertility. Associations between levels of those markers and cardiometabolic parameters, bone mineral density as well as androgen receptor (AR) CAG repeat lengths, were explored. Using receiver operating characteristic analysis, 4-hydroxyphenylpyruvate dioxygenase (4HPPD), insulin-like growth factor-binding protein 6 (IGFBP6), and fructose-bisphosphate aldolase (ALDOB), as well as a Multi Marker Algorithm, based on levels of 4HPPD and IGFBP6, were shown to be best predictors of low (<8 nmol/l) vs normal (>12 nmol/l) testosterone. They were also more strongly associated with metabolic syndrome and diabetes than testosterone levels. Levels of ALDOB and 4HPPD also showed association with AR CAG repeat lengths. We identified potential new protein biomarkers of testosterone action. Further investigations to elucidate their clinical potential are warranted. The work was supported by ReproUnion2.0 (grant no. 20201846), which is funded by the Interreg V EU program.

Prevention of Premature Ovulation by Administration of Gonadotropin Releasing Hormone Antagonist the day After Ovulation Triggering in Diminished Ovarian Reserve Patients.

The aim of the present retrospective study was to investigate the effectiveness of single-dose gonadotropin releasing hormone (GnRH) antagonist administration, the day after human chorionic gonadotropin (hCG) triggering for final oocyte maturation, on the prevention of premature luteinization in patients with diminished ovarian reserve in in-vitro fertilization (IVF) cycles. The secondary objective of the study was to search the effect of this protocol on pregnancy outcomes. This is a retrospective study including 267 infertile patients who have single antral follicle seen with ultrasonography on the 2nd or 3rd day of the menstrual cycle before starting IVF treatment. We randomized patients into two groups. The case group comprised patients who had single-dose GnRH antagonist injection the day after hCG triggering formed, and the patients who had the standard treatment regime formed the control group. In both groups, the oocytes were collected 36 hours after hCG injection. The premature ovulation rate was significantly low in the case group compared with the control group (6.86 versus 20.6% per scheduled cycle) (p = 0.022). Also, the oocyte retrieval rate (93.14 versus 67.87% per scheduled cycle) (p = 0.013), the oocyte maturity rate (79.42 versus 47.87%) (p = 0.041), the fertilization rate (65.68 versus 34.54%) (p = 0.018), and the embryo transfer rate per scheduled cycle (44.11 versus 18.78%) (p = 0.003) were higher in the GnRH antagonist group than in the control group. The administration of GnRH antagonist the day after hCG trigger in IVF treatments of patients with diminished ovarian reserve enabled a significant decrease in the rate of premature ovulation but had no effect on live birth rate.

Effect of early GnRH antagonist administration on assisted reproductive technique outcomes in normal responders.

One of the main questions in assisted reproductive techniques is how to prevent premature LH surge using a variety of protocols depending on either pituitary down-regulation, in GnRH agonist protocols, or by receptors blockage, in GnRH protocols. It is possible to say that GnRH protocols are most popular nowadays. The study aimed to assess the effectiveness of early antagonist administration during days ≤6 and later antagonist administration on days >6 on assisted reproductive outcomes. Women admitted to the ART Department at the High Institute for Infertility Diagnosis and ART, Al-Nahrain University, Baghdad, Iraq were included in the study. Reproductive outcomes were evaluated in early ≤6 and late >6 antagonist administration in a total of 44 normal responders, as follows. Sandwich protocols in 14 patients that received antagonists in the first 3 days of the follicular phase and conventional flexible antagonist protocol in 30 patients. We compared the outcomes between the two groups. There were no differences between early antagonist administration ≤6 and late >6 days in the number of MII oocytes, 2PN, the number of transferred embryos, grades of the embryos, and pregnancy rates. However, there were statistically significant differences between the duration of stimulation and the total Gonadotropin dose required. There was no effect of antagonist administration on days ≤6 and >6 on controlled ovarian stimulation on assisted reproductive outcomes.

Oral Gonadotropin-Releasing Hormone Antagonist Relugolix Has the Same Effect as Gonadotropin-Releasing Hormone Agonist Injections in Terms of Preparation for Transcervical Resection Myomectomy.

For preparing the optimal condition in transcervical resection (TCR) surgery, gonadotropin-releasing hormone (GnRH) agonist has been utilized. Recently, an oral GnRH antagonist (relugolix) is available and acts directly on GnRH receptor, avoiding flare up and reducing blood E2 levels rapidly. We retrospectively compared the oral GnRH antagonist (n = 14) effect to that of subcutaneous GnRH agonist (n = 19) for the pretreatment of endometrium in TCR myomectomy. Endometrial thickening was determined by intraoperative videos. The color tone of the endometrium in the normal part was assessed by digital image processing. The median duration of the first GnRH agonist injection and the surgery was 67 days (21-136 days), which is significantly longer than that of the oral GnRH antagonist group, 18.5 days (7-157 days P < 0.01). Both the GnRH agonist and antagonist groups did not exhibit prominence in the endometrium. The GnRH antagonist group showed the same degree of whiteness in the normal endometrium as the GnRH agonist group. The oral GnRH antagonist administration could rapidly atrophy the endometrium and create an optimal surgical field for TCR in a short period.

Evaluation of GnRH antagonist pretreatment before ovarian stimulation in a GnRH antagonist protocol in normal ovulatory women undergoing IVF/ICSI: a randomized controlled trial

BackgroundSynchronization of follicles is key to improving ovulation stimulation with the gonadotropin-releasing hormone (GnRH) antagonist protocol. GnRH antagonist administration in the early follicular phase can quickly decrease gonadotrophin (Gn) levels and achieve downregulation before stimulation, which may improves synchronization. A previous small randomized controlled study (RCT) showed that pretreatment with a GnRH antagonist for 3 days before stimulation may increase oocyte retrieval but cannot increase the pregnancy rate. This study investigated whether the GnRH antagonist pretreatment protocol in ovulatory women can increase the synchronization of follicles and pregnancy outcomes compared with the conventional GnRH antagonist protocol.MethodsThis RCT included 136 normal ovulatory women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Both groups were treated with recombinant follicle-stimulating hormone (r-FSH) and a flexible GnRH antagonist protocol. The women were randomized into two equal groups with or without GnRH antagonist administration from day 2 of the menstrual cycle for 3 days before stimulation. Our primary outcome was the number of retrieved oocytes. Secondary outcomes included the pregnancy rate and live birth rate.ResultsBoth groups had similar baseline characteristics. The number of retrieved oocytes in the study group was comparable to that in the control group (9.5 [8.0–13.0] vs. 11.0 [7.0–14.8], P = 0.469). There was no significant difference in the follicle size. The fertilization rate, number of good-quality embryos, implantation rate, pregnancy rate, ongoing pregnancy rate, live birth rate per embryonic transfer cycle, and miscarriage rate were similar between the two groups.ConclusionThis large RCT analysed GnRH antagonist pretreatment with the GnRH antagonist protocol applied to normal ovulatory women undergoing IVF/ICSI. The number of retrieved oocytes and pregnancy outcomes did not significantly vary.Trial registrationChinese Clinical Trial Registry, ChiCTR1800019730. Registered 26 November 2018.

Early administration of gonadotropin-releasing hormone antagonist versus flexible antagonist ovarian stimulation protocol in poor responders: a randomized clinical trial

BackgroundDetermining the initiation day of antagonist administration is an important and challenging issue and different results have been reported in the previous studies. The present study was designed to compare the controlled ovarian hyperstimulation (COH) cycles outcomes of early-onset gonadotropin-releasing hormone antagonist (GnRH-ant) protocol with conventional flexible GnRH-ant protocol in patients with poor ovarian response (POR) diagnosis. This randomized clinical trial was performed on infertile women who were diagnosed as poor responders in in vitro fertilization/intra-cytoplasmic sperm injection (IVF/ICSI) cycles at Arash Women’s Hospital affiliated to Tehran University of Medical Sciences. POR was defined according to the Bologna criteria and the eligible women were randomly allocated into an experimental (early-onset GnRH-ant) and control (conventional flexible GnRH-ant) groups. The women in the experimental group received recombinant gonadotropins (150–225 IU) and GnRH-ant (0.25 mg) simultaneously on the second day of the cycle. In the control group, the starting and the dose of gonadotropins were similar but daily administration of GnRH-ant was initiated when the leading follicle diameter was ≥ 13 mm. The COH outcomes were compared between groups (n=58 in each group).ResultsThe analysis showed that the two groups did not have statistically significant differences in terms of the ovarian stimulation duration and the total dose of used gonadotropins. The total number of metaphase II (MII) oocytes in the experimental group was significantly higher than that of in control group (P = 0.04). Moreover, clinical and ongoing pregnancy rates per embryo transfer (ET) in the experimental group were significantly higher than those in the control group (P = 0.02 and P = 0.03, respectively); however, the implantation and miscarriage rates were similar between groups.ConclusionsThe early-onset GnRH-ant protocol can improve the number of retrieved and MII oocytes and probably the pregnancy outcomes after fresh embryo transfer in POR patients. However, larger randomized clinical trials are required to compare the pregnancy outcomes after this approach with other COH protocols with considering cost-effectiveness issue.Trial registrationIRCT20110731007165N9.The name of the registry: Ladan Kashani.The date of trial registration: 8.02.2020.

P–684 Impact of GnRH antagonist pretreatment on oocyte yield after ovarian stimulation: a retrospective analysis

Abstract 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 &amp;gt;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 &amp;lt; 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 &amp;lt; 0.001) and total amount of gonadotropin used (2000.7 vs 2415.2IU, p &amp;lt; 0.001) were higher in group 2. The total number of obtained COCs (6.2 vs 8.8 p &amp;lt; 0.001) and the number of mature oocytes (4.2 vs 6.4 p &amp;lt; 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 &amp;lt;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

P–594 Ovarian stimulation with luteinizing hormone supplementation: the impact of timing on ovarian response and ICSI outcomes

Abstract Study question Is there an impact of recombinant luteinizing-hormone (rLH) administration timing during controlled ovarian stimulation (COS) on ovarian response and intracytoplasmic sperm injection (ICSI) cycles outcomes? Summary answer rLH supplementation in patients with poor ovarian response (POR) improves laboratorial and clinical outcomes when started in the mid-follicular phase, in GnRH antagonist ICSI cycles. What is known already Meta-analyses demonstrated that the use of rLH combined with rFSH for COS may lead to more ongoing pregnancies than rFSH alone. However, there is limited evidence that the timing of rLH addition to rFSH may impact the ovarian response or the outcomes of ICSI, based on a limited casuistic, which demonstrated improved ovarian response, embryo quality and pregnancy rate with LH supplementation from GnRH antagonist administration day, in estimated POR patients. The objective of the present study was to further investigate this hypothesis in a larger population, and in subpopulations of patients stratified by age and response to COS. Study design, size, duration This historical cohort study included data obtained via chart review of 1278 ICSI cycles performed in 1278 patients between 2015 and 2018, in a private university-affiliated in vitro fertilization center. Post hoc power analysis was calculated, given α of 5%, sample size of 1278, and effect size for implantation rate. The achieved power was superior to 99%. Participants/materials, setting, methods Two groups were formed according to timing of LH administration: Group LH-start (n = 323), in which LH was started on day–1; and Group LH-mid (n = 955), in which LH was started with GnRH antagonist. Then, data were stratified according to female age (&amp;lt;35 years-old, n = 283, and ≥35 years-old, n = 995) and response to COS (poor response (POR): ≤4 retrieved oocytes, n = 423, and normal response: &amp;gt;5 retrieved oocytes, n = 855). Ovarian response and ICSI outcomes were compared among the groups. Main results and the role of chance In POR patients, significantly higher fertilization rate (68.3% ± 2.5 vs. 78.6% ± 3.7, p = 0.023), blastocyst development rate (22.5% ± 7.2 vs. 44.7% ± 6.2, p = 0.022) and implantation rate (17.6% ± 59.1 vs. 20.2% ± 43.2, p &amp;lt; 0.001) were observed in Group LH-mid, even though the amount of LH used in these patients was not significant different from that used in Group LH-mid from patients with normal response to COS (1062.35 IU ± 54.33 vs. 925.81 IU ± 414.41, p: 0.431, respectively). For the general group and in patients aged ≥ 35 years, higher blastocyst development rates were observed in Group LH-mid compared to Group LH-start (33.0% ± 31.9 vs. 40.8% ± 32.6, p = 0.012, and 28.8% ± 30.4 vs 38.5% ± 32.3, p = 0.006, respectively). In patients aged &amp;lt; 35 years and in those with normal response to COS, similar outcomes were obtained irrespective of timing of LH administration. Limitations, reasons for caution The limitations included the retrospective design and limited sample size in subpopulations. In addition, the reduced clinical outcomes related to POR patients may hamper the true estimation of the differences between the stimulation groups in terms of pregnancy and miscarriage rates. Wider implications of the findings: In POR patients, mid-follicular phase LH supplementation starting with 150 IU daily doses, may rescue the ongoing cycle by compensating an initial slow response, and balancing the deprivation of endogenous LH in GnRH antagonist cycles, with no need of expending more gonadotropin compared to patients with normal response to COS. Trial registration number Not applicable

P–616 Novel approaches for preventing ovarian hyperstimulation syndrome in breast cancer patients

Abstract Study question In this study we tried to assess the effectiveness of the use of aromatase inhibitors (AI) for the rapid relief of symptoms of hyperstimulation in patients with breast cancer. Summary answer AI showed great efficiency for OHSS prevention and are particulary useful in fertility preservation, when supraphysiologic estradiol levels cause a negative impact and delay treatment. What is known already To date the only unequivocally accepted method for fertility preservation is cryopreservation of embryos and unfertilized oocytes. However, controlled ovarian stimulation is associated with supraphysiological serum estradiol level. The majority of guidelines recommend to use aromatase inhibitors during ovarian stimulation (OS) in breast cancer patients with high estrogen receptor expression to protect them from the potential deleterious effects of elevated estrogen. Following oocyte retrieval the patients will be receiving chemotherapy, which is not desirable for hyperstimulated ovaries. The prolonged use of AI seems to be an interesting approach in such cases. Study design, size, duration This research was conducted at the V.I. Kulakov NMRC for OG&amp;P to demonstrate management tactics for OHSS prevention after OS in patients with breast cancer. It included 21 patients seeking cryopreservation of oocytes and embryos. The main outcomes included the results of dynamic steroidogeneses assessment, the size of the ovaries, main features of oogenesis and the onset of the menstrual blleding. All patients signed an informed consent form approved by Ethics Committee. Participants/materials, setting, methods The mean age of the participants was 26.7. The patients presented prior to gonadotoxic treatment for luminal A or B breast cancer, were randomly divided into two groups of 11 and 10 people and underwent conventional OS with letrozol (2.5 mg/day). Starting from the day of oocyte retrieval the AI dosage iIn the 1st group was increased to 0.75 mg/day; the 2nd group received GnRH antagonist (0.5 mg/day) instead of AI for 5 consecutive days. Main results and the role of chance The mean age, BMI and AMH were not different among groups. There was no statistically significant difference in the duration of stimulation and starting and total doses of gonadotropins. The mean number of retrieved oocytes was 15.3 for the 1st group and 16.1 for the 2nd group (p = 0.834). There was no significant difference in a number of mature oocytes between the groups (66.1% vs. 72.4% in the 2nd group, p = 0.059) or in how many of them formed into 2pn embryos after fertilization (80% vs. 73.9% in the 2nd group, p = 0.616). Steroid hormone levels were analyzed during OS and on days 2 and 5 after oocyte retrieval. The rapid decline in serum estradiol and progesterone levels manifested with ovary size reduction and the onset of menstrual bleeding, which were achieved on 3rd to 5th day of AI administration in the 1st group and on 5th to 7th day of GnRH antagonist administration in the 2nd group. Limitations, reasons for caution Further research is required to compare the mechanisms of luteolysis induced by aromatase inhibitors and GnRH antagonists to natural luteal regression. Wider implications of the findings: Our data has demonstrated a greater efficiency of AI compared to GnRH antagonists in reducing the risk of OHSS. These findings could be useful for future research and clinical use in patients without cancer but with a high risk of developing OHSS combined with segmentation of IVF treatment. Trial registration number none

Supplementation with human menopausal gonadotropin in the gonadotropin-releasing hormone antagonist cycles of women with high AMH: Pregnancy outcomes and serial hormone levels

ObjectiveTo evaluate the value of using both HMG and recombinant FSH (r-FSH) in the GnRH antagonist protocol for women with high AMH. Materials and methodsThis retrospective, single-center cohort study was conducted from January 2013 to December 2018. Of 277 GnRH antagonist IVF/ICSI cycles in women with anti-Mullerian hormone (AMH) ≥5 μg/L, 170 cycles receiving the combination of r-FSH and HMG (77 with HMG added at the beginning of the GnRH antagonist cycle and 93 with HMG added after GnRH antagonist administration) and 107 cycles receiving r-FSH alone were analyzed. The dynamic hormone profiles and embryonic and clinical outcomes of the patients were evaluated. ResultsWe observed significantly lower serum LH levels in the r-FSH + HMG groups during ovarian stimulation. The serum estradiol and progesterone levels were lower in the r-FSH + HMG groups on the trigger day. Nevertheless, there were no significant differences with respect to the number of oocytes retrieved, maturation, fertilization, blastocyst formation rate or ovarian hyperstimulation syndrome (OHSS). The implantation and live birth rates were increased in the r-FSH + HMG groups compared with the r-FSH alone group, with no statistical significance. ConclusionsHMG for LH supplementation in the GnRH antagonist protocol for patients with high AMH is not significantly superior to r-FSH alone in terms of ovarian response and pregnancy outcome. Nevertheless, HMG supplementation might be appropriate for women with an initially inadequate response to r-FSH or intracycle LH deficiency.

Fixed versus flexible antagonist protocol in women with predicted high ovarian response except PCOS: a randomized controlled trial

BackgroundNo previous study directly compares the fixed day-5 initiation versus the flexible initiation of GnRH antagonist administration in IVF/ICSI for those patients who are predicted as high ovarian responders without PCOS. To evaluate whether the number of oocytes retrieved is different by using the two GnRH antagonist protocols in Chinese women with predicted high ovarian response except PCOS.MethodsA randomized controlled trial of 201 infertile women with predicted high ovarian response except PCOS undergoing in vitro fertilization. Ovary stimulation was performed using recombinant FSH and GnRH antagonists. GnRH antagonist ganirelix (0.25 mg/d) was started either on day 5 of stimulation (fixed group) or when LH was > 10 IU/L, and/or a follicle with mean diameter > 12 mm was present, and/or serum E2 was > 600 pg/ml. Patient monitoring was initiated on day 3 of stimulation in flexible group.Result(s)No significant difference was observed between the fixed and flexible groups regarding the number of oocytes retrieved (16.72 ± 7.25 vs. 17.47 ± 5.88, P = 0.421), the Gonadotropin treatment duration (9.53 ± 1.07 vs. 9.67 ± 1.03, P = 0.346) and total Gonadotropin dose (1427.75 ± 210.6 vs. 1455.94 ± 243.44, P = 0.381). GnRH antagonist treatment duration in fixed protocol was statistically longer than the flexible protocol (6.57 ± 1.17 vs 6.04 ± 1.03, P = 0.001). There was no premature LH surge in either protocol.Conclusion(s)Fixed GnRH antagonist administration on day 5 of stimulation appear to achieve a comparable oocyte retrieved compared with flexible antagonist administration.Trial registrationNCT02635607 posted on December 16, 2015 in clinicaltrials.gov.

Coasting Versus GnRH Antagonist administration in Patients at High Risk of Ovarian Hyper stimulation Syndrome and its impact on the ICSI Outcome

Objectives: study the value of GnRH antagonist administration as an alternative protocol to coasting in preventingsevere OHSS in cases of long agonist ovarian stimulation protocol and its impact on embryos quality p P value = 0.001) and more oocytes number (8.2±3.1) versus(6.7±3.2; P value = 0.01) in Antagonist group as compared with coasting group. There were more number ofcoasting days than with antagonist administration days(2.9±1.4 versus 2.2±1.1; P value = 0.001).Conclusion: GnRH antagonist was superior to coasting inproducing higher numbers of mature oocytes, high quality embryos and reducing the number of days till the HCGinjection. There was no statistical significant difference inchemical pregnancy rate between two groups. No earlyor late OHSS developed in either group.

Patient burden and healthcare resource utilization of regimens for ovarian stimulation

Do women receiving corifollitropin alfa with a gonadotrophin-releasing hormone (GnRH) antagonist experience less emotional and/or physical exhaustion than women receiving standard of care gonadotrophin with daily administration of GnRH agonist or antagonist? The CoRifollitropin EvAluation in PracTicE (CREATE) study was a prospective observational study of fertility clinics in 17 countries in Europe and the Asia-Pacific region. Women undergoing IVF were categorized by treatment. Group A received single-dose corifollitropin alfa plus a GnRH antagonist; group B received usual care daily gonadotrophin regimens with a GnRH agonist or antagonist; and group B1i received daily GnRH agonist injections. For the primary analysis, two items from the Controlled Ovarian Stimulation Impact questionnaire were used to assess the level of emotional and physical exhaustion associated with ovarian stimulation. Secondary end-points included the impact of ovarian stimulation-related healthcare resource use. No statistical difference was found between the percentage of participants reporting emotional exhaustion in group A (11.6%) and B (13.1%) or the percentage reporting being 'often' or 'always' physically exhausted. More participants in group B1i (16.4%) reported being emotionally exhausted 'often' or 'always' during ovarian stimulation compared with group A (11.6%; P = 0.026). Patient questionnaire scores for psychological impact were higher in group A compared with group B, indicating less negative impact (72.7 versus 70.9; P = 0.004). Group A had fewer clinic visits, physician consultations, nurse contacts and transvaginal ultrasound scans (all P<0.001) than group B1. Treatment with corifollitropin alfa resulted in similar or numerically small differences in psychological impact and lower clinic service use compared with daily gonadotrophin regimens.

Treatment with an active vitamin D analogue blocks hypothalamic dysfunction-induced bone loss in mice

Estrogen deficiency can be caused by ovarian dysfunction in females. Mechanisms underlying osteoporosis in this condition have been characterized in animal models, such as ovariectomized mice and rats, although it remains unclear how hypothalamic dysfunction promotes osteoporosis. Here, we show that administration of a gonadotropin-releasing hormone antagonist (GnRHa) significantly decreases uterine weight, a manifestation of hypothalamic dysfunction, and promotes both cortical and trabecular bone loss in female mice in vivo. We also report that osteoclast number significantly increased in mice administered GnRHa, and that the transcription factor hypoxia inducible factor 1 alpha (HIF1α) accumulated in those osteoclasts. We previously reported that treatment of mice with the active vitamin D analogue ED71, also known as eldecalcitol, inhibited HIF1α accumulation in osteoclasts. We show here that in mice, co-administration of ED71 with GnRHa significantly rescued the reduced cortical and trabecular bone mass promoted by GnRHa administration alone. GnRHa-dependent HIF1α accumulation in osteoclasts was also blocked by co-administration of ED71. We conclude that hypothalamic dysfunction promotes HIF1α accumulation in osteoclasts and likely results in reduced bone mass. We conclude that treatment with ED71 could serve as a therapeutic option to counter osteoporotic conditions in humans.