Gonadotropin-releasing Hormone Agonist Group Research Articles

Controlled ovarian stimulation for endometriosis patients with ultra-long GnRH-agonist or GnRH-antagonist protocols: A retrospective study by propensity score matching.

Although in vitro fertilization with embryo transfer is the most effective treatment for infertile patients with endometriosis, ovarian stimulation protocols are controversial. We recruited 639 patients with endometriosis from January 2016 to June 2020; 111 and 528 patients were treated with the gonadotropin-releasing hormone (GnRH) antagonist and ultra-long GnRH agonist protocols, respectively. Potential baseline differences between the regimens were adjusted by propensity score matching. Clinical and laboratory data, including the cumulative clinical pregnancy rate (CCPR) and cumulative live birth rate (CLBR), were compared. Ovulation induction required significantly longer use of gonadotropins in the GnRH agonist group. However, the GnRH agonist group had a lower starting dose of gonadotropin (all p < 0.05). Furthermore, significantly lower clinical pregnancy, implantation, and live birth rates were observed in the GnRH antagonist group receiving fresh assisted reproductive technology cycles (all p < 0.05); however, pregnancy outcomes using the subsequent freeze-thaw cycles for the same oocyte retrieval were not significantly different. CCPR and CLBR for the oocyte retrieval cycles of the antagonist and ultra-long agonist protocols were similar. The ultra-long agonist protocol resulted in more favorable implantation of fresh embryos and improved clinical outcomes of the fresh cycle. This novel strategy could be appropriate for endometriosis patients who are temporarily unsuitable for fresh embryo transfer. The GnRH antagonist protocol can be combined with the whole embryo freezing strategy to achieve CCPR and CLBR similar to the ultra-long agonist regimen, thus simultaneously avoiding the long pre-treatment duration of GnRH agonists during the ultra-long agonist protocol.

Androgen Deprivation Therapy and Risk of Cardiovascular Disease in Patients With Prostate Cancer Based on Existence of Cardiovascular Risk.

Controversy exists regarding the risk of cardiovascular disease (CVD) associated with androgen deprivation therapy (ADT) in patients with prostate cancer. We sought to evaluate the association between gonadotropin-releasing hormone (GnRH) agonists versus GnRH antagonist and the risk of CVD in patients with prostate cancer with or without prior CVD. Using administrative databases from Quebec, Canada, we identified first-time GnRH agonists and antagonist (degarelix) users between January 2012 and June 2016. Follow-up ended at the earliest of the following: first CVD event (myocardial infarction [MI], stroke, ischemic heart disease [IHD], arrhythmia, and heart failure [HF]); switch of GnRH group; death; or December 31, 2016. Inverse probability of treatment weighting (IPTW) based on the propensity score was used to control for potential confounding. IPTW-Cox proportional hazards model accounting for competing risks was used to evaluate the association of interest. Among 10,785 patients identified, 10,201 and 584 were on GnRH agonists and antagonist, respectively. Median age was 75 years (interquartile range, 69-81 years) for both groups. A total of 4,152 (40.7%) men in the GnRH agonists group and 281 (48.1%) men in the GnRH antagonist group had CVD in the 3-year period prior to ADT initiation. Risk of HF was decreased in the antagonist group compared with the GnRH agonist group among patients with prior CVD (hazard ratio [HR], 0.46; 95% CI, 0.26-0.79). Risk of IHD was decreased in the antagonist group in patients without prior CVD (HR, 0.26; 95% CI, 0.11-0.65). Use of antagonist was associated with an increased risk of arrhythmia among patients with no prior CVD (HR, 2.34; 95% CI, 1.63-3.36). Compared with GnRH agonists, the GnRH antagonist was found to be associated with a decreased risk of HF, specifically among patients with prior CVD. Among those with no prior CVD, the GnRH antagonist was associated with a decreased risk of IHD but an increased risk of arrhythmia.

Effect of gonadotropin-releasing hormone agonist monotherapy and combination therapy with growth hormone on final adult height in girls with central precocious puberty

This study aimed to compare clinical parameters, including final adult height (FAH), in girls with central precocious puberty treated with gonadotropin-releasing hormone agonists (GnRHa) with and without growth hormone (GH). This retrospective study reviewed data of 210 girls with precocious puberty who had reached FAH in a long-term trial of GnRHa treatment. The subjects were divided into the GnRHa treatment group (n = 188), and the combined GnRHa + GH treatment group (n = 22). Chronological age, bone age, height, height standard deviation score, predicted adult height (PAH), FAH, Tanner stage, and hormone levels were assessed during the treatment period. At the start of treatment, PAH was 156.35 ± 6.34 cm in the GnRHa monotherapy group and 150.41 ± 5.32 cm in the GnRHa + GH group (P < 0.001). At the end of treatment, PAH was 166.25 ± 5.26 cm in the GnRHa group and 164.07 ± 4.99 cm in the combined GnRHa + GH treatment group, which had increased compared to the start of treatment. The FAH in the GnRHa group and GnRHa + GH combination group were 161.07 ± 4.78 cm and 159.63 ± 3.8 6 cm, respectively, without significant difference. In addition, the height gain (FAH–PAH) was significantly higher in the GnRHa + GH group than the GnRHa group (9.22 ± 6.03 cm vs. 4.72 ± 5.01 cm, P < 0.001). In girls with central precocious puberty, the height gain in the FAH compared to PAH at the start of treatment was significantly higher with the GnRHa + GH combination treatment.

Comparison of pregnancy outcome after fresh embryo transfer between GnRH antagonist and GnRH agonist regimens in patients with thin endometrium.

To compare the pregnancy outcome after fresh embryo transfer between GnRH antagonist and GnRH agonist regimens in patients with thin endometrium. This retrospective study included all fresh embryo transfers following GnRH agonist or GnRH antagonist protocols in patients with thin endometrium from 2016 to 2021. The thin endometrium was defined as an endometrial thickness of 7.5 mm or less on the triggering day. Multivariant regression analysis was applied to assess the association of GnRH agonist or GnRH antagonist regimen with live birth following fresh embryo transfer in patients with thin endometrium. A total of 69 and 192 cases were, respectively, included in the GnRH antagonist or GnRH agonist group. The stimulation duration was significantly longer by the GnRH agonist protocol than the GnRH antagonist protocol (11.2 ± 2.1 vs. 9.1 ± 1.9 days, P = 0.002). The rates of clinical pregnancy or live birth were significantly lower in the GnRH antagonist group compared to the GnRH agonist group (26.1 vs. 47.9%, P = 0.027; 17.4 vs. 40.1%, P = 0.01, respectively). Multivariable regression analysis demonstrated that GnRH agonist regimen was related to higher live birth rate compared with GnRH agonist protocol [adjusted OR: 2.6, 95% confidence intervals (CI): 1.3-5.3]. No significant difference in miscarriage rate and the neonatal outcome was present between the two protocols. Our findings suggest that GnRH agonist protocol results in a higher rate of live birth after fresh embryo transfer than GnRH antagonist protocol in patients with thin endometrium.

Analysis of euploidy rates in preimplantation genetic testing for aneuploidy cycles with progestin-primed versus GnRH agonist/antagonist protocol

BackgroundProgestins can suppress endogenous luteinising hormone (LH) secretion from the pituitary gland and have shown similar efficacy in terms of collecting competent oocytes and embryos; however, some inconsistencies have been proposed regarding the quality of embryos collected with the use of progestins. This study aimed to evaluate euploidy rates and pregnancy outcomes in preimplantation genetic testing for aneuploidy (PGT-A) cycles using the progestin-primed ovarian stimulation (PPOS) protocol versus the gonadotropin-releasing hormone (GnRH) agonist/antagonist protocol.MethodsThis retrospective cohort study included 608 PGT-A cycles: 146 women in the PPOS group, 160 women in the GnRH agonist group, and 302 women in the GnRH antagonist group. This study was performed at the in vitro fertilisation (IVF) centre of Shanghai First Maternity and Infant Hospital between January 2019 and December 2021. Additionally, 267 corresponding first frozen embryo transfer (FET) cycles were analysed to assess pregnancy outcomes.ResultsThe euploid blastocyst rate per injected metaphase II(MII) oocytes (14.60% vs. 14.09% vs. 13.94%) was comparable among the three groups (p > 0.05). No significant differences were observed among the three groups regarding pregnancy outcomes, including biochemical pregnancy, clinical pregnancy, ongoing pregnancy, implantation, miscarriage, ectopic pregnancy, and live birth rates per transfer in the first FET cycles (p > 0.05).ConclusionsThe PPOS protocol had no negative effect on euploid blastocyst formation, and the pregnancy outcomes in FET cycles using the PPOS protocol were similar to those of the GnRH agonist and antagonist protocols.Trial registration This trial was retrospectively registered

Recombinant human chorionic gonadotropin and gonadotropin-releasing hormone agonist differently affect the profile of extracellular vesicle microRNAs in human follicular fluid.

To compare the expression profile of extracellular vesicle microRNAs (EV-miRNAs) derived from follicular fluid after a trigger with recombinant human chorionic gonadotropin (r-hCG) or with a gonadotropin-releasing hormone GnRH agonist (GnRH-a) for final oocyte maturation. A retrospective analysis of a prospective cohort. Women undergoing in vitro fertilization at a tertiary university-affiliated hospital were recruited between 2014 and 2016. EV-miRNAs were extracted from the follicular fluid of a single follicle, and their expression was assessed using TaqMan Open Array®. Genes regulated by EV-miRNAs were analyzed using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources, Kyoto-Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO). Eighty-two women were included in the r-hCG trigger group and 9 in the GnRH-a group. Of 754 EV-miRNAs screened, 135 were detected in at least 50% of the samples and expressed in both groups and were further analyzed. After adjusting for multiple testing, 41 EV-miRNAs whose expression levels significantly differed between the two trigger groups were identified. Bioinformatics analysis of the genes regulated by these EV-miRNAs showed distinct pathways between the two triggers, including TGF-beta signaling, cell cycle, and Wnt signaling pathways. Most of these pathways regulate cascades associated with apoptosis, embryo development, implantation, decidualization, and placental development. Trigger with GnRH-a or r-hCG leads to distinct EV-miRNAs expression profiles and to downstream biological effects in ovarian follicles. These findings may provide an insight for the increased apoptosis and the lower implantation rates following GnRH-a trigger vs. r-hCG in cases lacking intensive luteal phase support.

Comparison of Dydrogesterone and GnRH-a Effects After Laparoscopic Surgery in Patients with Stage III and IV Endometriosis.

To compare the spontaneous pregnancy rates between dydrogesterone and Gonadotropin-releasing hormone agonist (GnRH-a) treatments in patients with endometriosis stage III and IV after laparoscopy. The clinical data of patients with endometriosis stage III and IV administered laparoscopic surgery in our hospital from January 2018 to March 2020 were retrospectively analyzed. Totally 151 cases were divided into two groups according to postoperative medication, including the study (70 cases) and control (81 cases) groups treated with dydrogesterone and GnRH-a, respectively. The spontaneous pregnancy and subsequent pregnancy outcomes were assessed within 12 months. Totally 49 patients had spontaneous pregnancy. Among them, there were 31 cases in the dydrogesterone group (spontaneous pregnancy rate of 44.3%, 31/70), including 25 live birth cases (35.7%, 25/70), 4 miscarriage cases, and 2 ectopic pregnancy cases. The time to conception was 1-10 months (median value of 5 months). Totally 18 cases in the GnRH-a group had spontaneous pregnancy (22.2%, 18/81), including 16 live birth cases (19.8%, 16/81). 81) and 2 miscarriage cases; the time to conception was 3-11 months (median value of 6 months). There were significant differences in spontaneous pregnancy rate and cumulative spontaneous pregnancy rate between the two groups (P = 0.005 and 0.003, respectively). Dydrogesterone after laparoscopic surgery in patients with endometriosis stage III and IV improved the natural pregnancy rate.

Oncological and reproductive outcomes for gonadotropin-releasing hormone agonist combined with aromatase inhibitors or levonorgestrel-releasing intra-uterine system in women with endometrial cancer or atypical endometrial hyperplasia

ObjectiveTo evaluate the efficacy and safety of gonadotropin-releasing hormone agonist (GnRHa) combined with a levonorgestrel-releasing intrauterine device (LNG-IUD) or aromatase inhibitor (letrozole) in women with endometrial carcinoma or atypical endometrial...

Gonadotropin-releasing hormone agonist for the preservation of ovarian function in survivors of haematopoietic stem cell transplantation for haematological diseases

ObjectiveAdministration of GnRH agonist (GnRHa) prior to chemotherapy may decreases the risk of gonadal dysfunction in patients with tumors. However, relevant data in haematopoietic stem cell transplantation (HSCT) recipients has not yet been established. Hence, the present study was designed to evaluate the clinical efficacy of GnRHa cotreatment prior to myeloablative regimens on ovarian protection in female survivors of HSCT for haematological diseases.Patients and methodsEligible patients were divided into a GnRHa group and a control group. Medical records regarding age at HSCT; diagnosis/indication for HSCT; pre- and posttransplantation serum sex hormone levels; menstruation and perimenopausal symptoms after HSCT were collected and compared. The primary and secondary outcome was the incidence of premature ovarian insufficiency (POI) symptoms associated with hypoestrogenism.ResultsA total of 330 patients were enrolled in the study: 19 patients were lost to follow-up, and clinical information was obtained in 311 patients. There was no significant difference in the primary outcome of follow-up between the two groups (78.50% [84 of 107] for the GnRHa group versus 83.33% [170 of 204] for the control group). The adjusted relative risks (RR) and 95% confidence interval (CI) were 1.19 and 0.73–1.93 (P = 0.487). Among patients who received cotreatment with GnRHa, 62.62% (67 of 107) complained of perimenopausal symptoms, which was significantly lower than the 74.51% (152 of 204) in the control group (adjusted RR: 1.46, 95% CI: 1.04–2.06, P = 0.031).ConclusionGnRHa cotreatment may not decrease the POI rate in HSCT survivors. However, it may reduce perimenopausal symptoms in this population, suggesting a potential benefit of GnRHa in clinical practice and warrant further researches.

Effects of intracerebroventricular and intravenous administration of Kisspeptin-54 and Gonadotropin-releasing hormone agonist in rats with ovarian hyperstimulation

PurposeWe aim to determine the effect of local and systemic administration of kisspeptin-54 on ovarian hyperstimulation. MethodsImmature female rats were used. In order to generate the ovarian hyperstimulation model, 50 IU PMSG was administered for 4 consecutive days and a single dose of 25 IU hCG was administered to all groups except for the sham group. To synchronize the sham group, a single dose of 10 IU PMSG followed by 10 IU hCG (48 h later) was applied. Kisspeptin-54 and gonadotropin-releasing hormone (GnRH) agonists were administered 48 h after hCG injection. While intracerebroventricular injection is performed with stereotaxic surgery, Intravenous administration was from the tail vein. Ovarian weights were measured. FSH, LH, estrogen and progesterone hormones were detected in serum by ELISA. VEGFa, IL-1β, TNF-α, MCP-1 immunohistochemical staining was performed on the ovaries and hypothalamus and their optical densities were determined with Image J. Kiss1R mRNA expression was determined by qRT-PCR. ResultsOvarian weights increased significantly in the OHSS group and the systemic GnRH agonist group. The optical densities of VEGFa, IL-1β, TNF- α and MCP-1 immunoreactivity showed us that both local and systemic applied kisspeptin-54 attenuates the level of investigated inflammation parameters in the ovaries. Moreover, local administration of kisspeptin-54 has been shown to enhance the level of Kiss1R mRNA in both the ovaries and the hypothalamus. Conclusion(s)Local and systemic administration of Kisspeptin-54 as a post-treatment reduces inflammation parameters in the ovaries. These findings promote the potential use of kisspeptin-54 on OHSS.

Gonadotropin-releasing hormone agonist protects ovarian function in young patients with ovarian malignancy undergoing platinum-based chemotherapy: A prospective study.

We aimed to ascertain the effectiveness of gonadotropin-releasing hormone (GnRH) agonist co-therapy for the preservation of ovarian function in patients with ovarian malignancy who underwent unilateral salpingo-oophorectomy and platinum-based chemotherapy. We enrolled 158 patients with ovarian malignancy who underwent fertility preservation surgery and postoperative platinum-based chemotherapy between January 2018 and December 2020. Patients were divided into two groups based on the use of GnRH agonist (GnRHa) during chemotherapy. Two patients withdrew from the study. Laboratory tests (serum follicle-stimulating hormone [FSH], serum luteinizing hormone [LH], and serum anti-Müllerian hormone [AMH]) were performed pre-chemotherapy and one year post-chemotherapy. Data on menstruation resumption, perimenopausal symptoms (modified Kupperman Menopausal Index [KMI]), health-related quality of life (Medical Outcomes Study Short Form-36 [MOS SF-36]), and obstetric outcomes were collected. One year post-chemotherapy, the serum AMH level in the GnRHa group was higher than that in the control group (P<0.001), while the serum FSH and FSH/LH levels in the GnRHa group were lower than those in the control group (P<0.001). The mean period from last chemotherapy to menstrual resumption was 3.86 and 5.78 months in the GnRHa and control groups (P<0.001), respectively. The rate of menstrual resumption post-chemotherapy was 93.5% and 82.3% in the GnRHa and control groups (P<0.05), respectively. GnRHa co-administration during chemotherapy reduced the likelihood of low AMH levels post-chemotherapy and was significant in the multivariate analysis (P<0.05). The modified KMI scores and MOS SF-36 scores were better in the GnRHa group than in the control group (both P<0.001). GnRHa protects ovarian function during platinum-based adjuvant chemotherapy in young patients with ovarian malignancy. This study provides a therapeutic reference for gynecologists, especially for those in economically and medically underdeveloped areas. Chinese Clinical Trial Registry (chiCTR1800019114; October 26, 2018; http://www.chictr.org.cn/index.aspx).

Ovarian stimulation in IVF couples with severe male factor infertility: GnRH antagonist versus long GnRH agonist.

ObjectiveTo examine the efficacy of gonadotropin releasing hormone (GnRH) antagonist (GnRH-ant) protocol and the long GnRH agonist (GnRH-a) protocol during in vitro fertilization (IVF) therapy in patients with severe male infertile factors.MethodsA total of 983 women with severe male factor infertility undergoing IVF therapy from 2017 to 2020 at one center were retrospectively analyzed. Patients were divided into the GnRH-ant group (n=527) and the GnRH-a group (n=456) according to their ovarian stimulation protocols. Patient baseline characteristics, ovarian stimulation characteristics, and clinical pregnancy outcomes were compared between the groups. The live birth rate was considered the main pregnancy outcome.ResultsGnRH-a group had a higher live birth rate compared with the GnRH-ant group (41.0% versus 31.3%, p=0.002). Moreover, the implantation (32.8% vs. 28.1%, p=0.033), biochemical pregnancy (52.4% versus 44.8%, p=0.017), clinical pregnancy (49.3% versus 39.7%, p=0.002) and ongoing pregnancy rates (43.2% vs. 34.9%, p=0.008) were higher in GnRH-a group. For patients with one embryo transferred, the GnRH-a group demonstrated higher live birth (37.0% vs. 19.4%, p=0.010) and ongoing pregnancy rate (38.9% vs. 24.5%, p=0.046) than the GnRH-ant group. Among patients with two embryos transferred, the live birth rate was also higher in the GnRH-a group than in the GnRH-ant group, with no statistical difference. No significant differences were observed in the biochemical abortion rate, clinical miscarriage rate, early miscarriage rate, late miscarriage rate, heterotopic pregnancy rate, twin pregnancy rate, and birth sex ratio between the two groups.ConclusionFor individuals with severe male infertility undergoing IVF, the GnRH-a protocol is considered a more efficient and feasible strategy with a higher live birth rate compared to the GnRH-ant protocol, especially in single embryo transfer.

Administration of depot GnRH agonist prior to programmed frozen-thawed embryo transfer does not improve the live birth rate in ovulatory women: A large, multi-center retrospective study.

Despite that gonadotropin-releasing hormone (GnRH) agonist pretreatment has been widely used before programmed frozen-thawed transfer (FET), its impact on live birth rates in ovulatory women remains uncertain. In the present study, we aim to determine if GnRH agonists pretreatment before FET improves live birth rates in women undergoing in vitro fertilization with FET. Programmed FET cycles conducted in four infertility centers were retrospectively collected and reviewed for eligibility from January 2016 and December 2017. Patient’s demographics, ovarian stimulation parameters, and pregnancy outcomes were compared between those given GnRH agonist pretreatment versus no pretreatment in ovulatory women undergoing FET cycles. A total of 6397 programmed cycles were screened for eligibility, of which 5049 cycles were included in the study for analysis. Compared with the group of no GnRH agonist pretreatment (n = 4143), women in the GnRH agonist group (n = 906) were older (33.0 vs 34.0, P < .001), had a higher proportion of subjects with previous transfer attempts and had a higher number of embryos transferred. After controlling for confounders, the logistic regression results showed that GnRH agonist pretreatment did not increase the odds of both clinical pregnancy (OR 0.92, 95% CI [0.70–1.20]), ongoing pregnancy (OR 0.91, 95% CI [0.69–1.19]) and live birth rates (OR 0.84, 95% CI [0.64–1.10]). However, when restricted to women who had no previous transfer attempts, women in the GnRH pretreatment group had lower odds of achieving live birth (OR 0.49, 95% CI [0.30–0.79]). Sensitivity analysis performed in patients with male factor infertility causes showed GnRH agonist pretreated group had lower live birth rates compared to no GnRH agonist pretreatment group (OR = 0.65, 95% CI [0.43–0.97]). Our findings suggested that GnRH agonist pretreatment does not bring additional benefits in live birth rate improvements for ovulatory women undergoing FET cycles. Therefore, the pros of using GnRH agonist to reduce premature ovulation should be weighed against the cons of prolonged time to pregnancy, discomforts resulting from pituitary suppression, and increased medical costs associated with GnRH agonist use.

The efficacy of gonadotropin-releasing hormone agonist treatment before hysteroscopic myomectomy for large-sized submucosal leiomyoma.

To evaluate the efficacy and safety of a gonadotropin-releasing hormone (GnRH) agonist for treating large-sized submucosal leiomyoma before hysteroscopic myomectomy.The data were retrospectively collected from patients who underwent a hysteroscopic myomectomy for a submucosal leiomyoma >3.5 cm in size from January 2009 to December 2018. The patients were divided into the GnRH group and the control group according to whether they were pretreated before surgery.A total of 61 patients were included in the study, 31 in the GnRH agonist group and 30 in the control group. At diagnosis, the maximum leiomyoma diameter was similar between the 2 groups (4.67 ± 0.6 cm in the GnRH agonist group vs 3.82 ± 0.6 cm in the control group, P = .061). After pretreatment with the GnRH agonist, the maximum diameter was significantly smaller in the GnRH agonist group compared to the control group (3.82 ± 0.6 vs 4.33 ± 0.8 cm, respectively, P = .004). The leiomyoma volume in the GnRH agonist group decreased by 55.6%, from 41.68 ± 15.7 to 23.19 ± 10.4 cm3, which led to significant differences in leiomyoma volume between the 2 groups (23.19 ± 10.4 cm3 in the GnRH agonist group vs 33.22 ± 24.7 cm3 in the control group, P = .042). The GnRH agonist group showed a shorter operation time (37.7 vs 43.9 minutes, P = .040) and less uterine distention media was used (6800 vs 9373.3 mL, P = .037) compared to the control group. Postoperative complications such as estimated blood loss, remnant leiomyoma, and recurrence were similar between the 2 groups.Treatment with a GnRH agonist before hysteroscopic myomectomy for large submucosal leiomyoma might decrease the volume of the leiomyoma, reduce operation time, and the amount of uterine-distension media used without surgical complications.

Hippocampal volume changes in a pharmacological sex-hormone manipulation risk model for depression in women

Hormone transition phases may trigger depression in some women, yet the underlying mechanisms remain elusive. In a pharmacological sex-hormone manipulation model, we previously reported that estradiol reductions, induced with a gonadotropin-releasing hormone agonist (GnRHa), provoked subclinical depressive symptoms in healthy women, especially if neocortical serotonin transporter (SERT) binding also increased. Within this model, we here evaluated if GnRHa, compared to placebo, reduced hippocampal volume, in a manner that depended on the magnitude of the estradiol decrease and SERT binding, and if this decrease translated to the emergence of subclinical depressive symptoms.Sixty-three healthy, naturally cycling women were included in a randomized, double-blind, placebo-controlled GnRHa-intervention study. We quantified the change from baseline to follow-up (n = 60) in serum estradiol (ΔEstradiol), neocortical SERT binding ([11C] DASB positron emission tomography; ΔSERT), subclinical depressive symptoms (Hamilton depression rating scale; ΔHAMD-17), and hippocampal volume (magnetic resonance imaging data analyzed in Freesurfer 7.1, ΔHippocampus). Group differences in ΔHippocampus were evaluated in a t-test. Within the GnRHa group, associations between ΔEstradiol, ΔHippocampus, and ΔHAMD-17, in addition to ΔSERT-by-ΔEstradiol interaction effects on ΔHippocampus, were evaluated with linear regression models.Mean ΔHippocampus was not significantly different between the GnRHa and placebo group. Within the GnRHa group, hippocampal volume reductions were associated with the magnitude of estradiol decrease (p = 0.04, Cohen's f2 = 0.18), controlled for baseline SERT binding, but not subclinical depressive symptoms. There was no ΔSERT-by-ΔEstradiol interaction effects on ΔHippocampus.If replicated, our data highlight a possible association between estradiol fluctuations and hippocampal plasticity, adjusted for serotonergic contributions.

Letrozole Supplementation and the Increased Risk of Elevated Progesterone Levels on Trigger Day.

Although using letrozole (LE) during in vitro fertilisation and intracytoplasmic sperm injection (IVF/ICSI) has many advantages, it remains unclear whether LE induces an increase in progestogen during the late follicular phase. The objective of this study was to investigate whether progesterone levels increased under antagonist protocols supplemented with LE on the trigger day using a retrospective cohort study. The study included 1,133 women who underwent IVF/ICSI cycles from January 2018 to June 2020. After propensity score matching (PSM) for baseline characteristics, 266 patients with gonadotropin-releasing hormone-antagonist (GnRH-ant) were matched to 266 patients with letrozole + GnRH-ant (LE GnRH-ant) (PSM 1 cohort), and 283 patients with gonadotropin-releasing hormone-agonist (GnRH-a) were matched to 283 patients with LE GnRH-ant (PSM 2 cohort). In the PSM 1 cohort, patients in the LE GnRH-a group presented higher progesterone levels (1.22 ± 0.95 ng/mL vs 0.86 ± 0.60 ng/mL, P < 0.001), with a higher proportion of patients with progesterone level > 1.5 ng/mL (24.81% vs 7.52%, P < 0.001). In PSM 2 cohort, patients in the LE GnRH-a group presented higher progesterone levels on trigger day (1.23 ± 0.91 ng/mL vs 0.98 ± 0.61 ng/mL, P < 0.001), with a higher proportion of patients with progesterone level > 1.5 ng/mL (25.45% vs 12.70%, P < 0.001). In the PSM 1 cohort, progesterone levels on the trigger day increased by 0.05 ng/mL, with an increase in every retrieved oocyte in the LE GnRH-ant group (β 0.05 ng/mL [95% CI 0.04, 0.06], P < 0.001), whereas an increase of 0.02 ng/mL was observed in the GnRH-ant group (β 0.02 ng/mL [95% CI 0.01, 0.03], P < 0.001), with P for interaction being 0.0018. In the PSM 2 cohort, progesterone levels on the trigger day increased by 0.05 ng/mL with an increase in every retrieved oocyte in the LE GnRH-ant group (β 0.05 ng/mL [95% CI 0.04, 0.06], P < 0.001), whereas an increase of 0.02 ng/mL was observed in the GnRH-a group (β 0.02 ng/mL [95% CI 0.01, 0.03], P < 0.001), with P for interaction being 0.0002. LE supplementation on the antagonist protocols may increase progesterone levels in the late follicular stage.

GnRH Antagonist Protocol Enhances Coagulation During Controlled Ovarian Stimulation for IVF.

Changes in coagulation and fibrinolysis have been reported in women undergoing controlled ovarian hyperstimulation (COH) supporting a potential hypercoagulable condition related to this treatment. This study aimed at evaluating the changes in fibrin clot properties and thrombin generation induced by two different COH protocols: long with gonadotropin-releasing hormone agonist (GnRH-a) and GnRH antagonist (GnRH-ant). Primary outcomes included determination of plasma fibrin clot properties, including clot permeability (Ks) and efficiency of fibrinolysis using clot lysis time (CLT), along with thrombin generation (prothrombin fragments 1 + 2) and endogenous thrombin potential (ETP) and fibrinolysis inhibitor levels. One hundred twenty-nine infertile women were included in the final analysis. The GnRH-ant protocol resulted in increased ETP (+ 9.8%) and reduced Ks (- 2.4%). Conversely, COH with the GnRH-a protocol reduced thrombin generation by decreasing both ETP (- 6.6%) and F1 + 2 (- 30.8%) together with favorably altered fibrin clot properties represented by increased Ks (+ 21.7%) and reduced CLT (- 13.8%) as well as decreased PAI-1 levels (by 2.5 times). The GnRH-ant compared to the GnRH-a protocol increased PAI-1 levels (+ 77.3%), thrombin generation (9.3% higher ETP), and Ks (+ 13.7%). In the GnRH-a group, post-COH Ks was 14.3% higher (Ks ≥ 7.92 × 10-9 cm2) in women with positive vs. negative pregnancy outcomes. Our results show that the GnRH-ant protocol enhanced thrombin generation and slightly decreased fibrin clot density. COH with the GnRH-a reduced thrombin generation and improved fibrin clot features. This trial was registered (NCT04166825). Clinical Trial Registration Number: NCT04166825.

GnRH Antagonist Protocol Versus GnRH Agonist Long Protocol: A RetrospectiveCohortStudy on Clinical Outcomes and Maternal-Neonatal Safety.

ObjectiveTo evaluate the clinical outcomes and maternal-neonatal safety of gonadotropin releasing hormone antagonist (GnRH-ant) and gonadotropin releasing hormone agonist (GnRH-a) protocols.MethodsA total of 2505 women undergoing their first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) were retrospectively analyzed. Patients were divided into GnRH-ant group (n = 1514) and GnRH-a group (n = 991) according their stimulation protocol. Propensity Score Matching (PSM) was used for balancing the baseline of two groups. The pregnancy outcomes were analyzed in fresh transfer cycles, and the obstetric and perinatal outcomes were calculated in singleton live births of fresh cycles. The primary outcome was the live birth rate. The secondary outcome measures were maternal complications, preterm birth rate, low birthweight rate, multiple pregnancy rate, and moderate-severe OHSS rate.ResultsAfter 1:1 PSM, baseline characteristics of the GnRH-ant group and GnRH-a group were matched and assigned 991 cycles in each group. Before PSM, there were 700 fresh cycles including 237 singleton live births in the GnRH-ant group and 588 fresh cycles including 187 singleton live births in the GnRH-a group. After PSM, there were 471 fresh cycles including 166 singleton live births in the GnRH-ant group and 588 fresh cycles including 187 singleton live births in the GnRH-a group. No significant differences were observed in the live birth rate (44.6% vs 48.8%), maternal complications, preterm birth rate (9.0% vs 6.4%), and low birthweight rate (17.5% vs 24.1%) between two groups after PSM (P > 0.05). The moderate-severe OHSS rate (2.9% vs 6.0%, P = 0.002) and multiple pregnancy rate (24.5% vs 33.1%, P = 0.025) was significantly lower in the GnRH-ant group than that in the GnRH-a group after PSM.ConclusionGnRH-ant protocol was comparable with GnRH-a protocol in clinical outcomes, obstetric and perinatal outcomes, and with a lower risk of OHSS. For those who want to get an effective and safe outcome, and a shorter treatment period, GnRH-ant is a suitable choice.

P-240 Embryo division timings and morphikinetic top-quality embryo rates derived from GnRH-antagonist ICIS cycles triggered by either hCG, GnRH-agonist or Dual trigger

Abstract Study question To compare the division timings and morphikinetic top-quality embryo rates derived from GnRH-antagonist ICSI cycles triggered with either hCG, GnRH-agonist or Dual trigger. Summary answer GnRH-agonist trigger derived embryos had significantly shorter division timing durations and a higher top-quality cleavage embryo rates compared to the other trigger groups What is known already TMS allows embryo quality assessment by documenting timing of events and length of intervals in embryo development, providing a more objective scoring of the embryos for embryo selection. Developing an in-house model for embryo selection based on Known Implantation Data (KID) embryos enables detecting the top-quality embryos selected for transfer. It remains to be determined what factors influence oocyte maturation, embryo kinetics and the developmental potential and quality of the embryos obtained. We sought to evaluate if the rate of optimal timed top-quality embryos is influenced by the type of triggering in GnRH-antagonist ICSI cycles. Study design, size, duration Top quality embryo rates and outcome of embryos derived from GnRH- antagonist ICSI cycles triggered by hCG (Ovitrelle 250mcg), GnRH-agonist (Decapaptyl 0.2MG) and dual trigger (co- administration of GnRH-agonist and hCG) between July 2013 - December 2020 were compared. Top- quality embryos with the highest chance to implant were defined : tPNf &amp;lt;24.08, t2&amp;lt;26.6, S2&amp;lt;0.9 and t8&amp;lt;56 hours post insemination (hPi) for cleavage embryos and t2&amp;lt;26.6, S2&amp;lt;0.9, t8&amp;lt;56 and tSB&amp;lt;96.6 hPi for blastocysts. Participants/materials, setting, methods Optimal time durations: time to polar body extrusion (tPB2), time to pronucleus fading (tPNf), cleavage timings (t2-t8), synchrony of the second and third cycles (S2 and S3), duration of the second cycle (CC2) time to start blastulation (tSB) were set based on an in-house model including embryos with known implantation data. Multivariate logistic regression analysis age, type of gonadotrophins, number of oocytes aspirated and peak estradiol levels was performed. Pregnancy rates were calculated from transfers. Main results and the role of chance We analyzed 3,352 embryos derived from 1162 GnRH-antagonist ICSI cycles; 2,169 embryos in the hCG trigger group, 737 embryos in the GnRH-agonist group and 446 embryos in the Dual trigger group. The groups were similar in demographic characteristics apart for a higher maternal age with Dual trigger and higher gravidity with hCG. As for treatment parameters the groups were similar in dose of gonadotrophins, peak estradiol levels and endometrial thickness; however differed in number of oocytes aspirated - highest with GnRH-agonist (Decapeptyl 0.2mg) trigger and maturation rate - highest with hCG. Division timing durations (tPB2, tPNf, t2-t7) were significantly shorter in the GnRH-agonist group compared to the other groups. The highest top quality cleavage embryo rate was with GnRH-agonist trigger compared to hCG and Dual trigger (21.6% versus 12.7% and 20.2% respectively, p &amp;lt; 0.001). Pregnancy rates were similar between the groups. In the multivariate regression model assessing cell cycle divisions parameters and top quality cleavage rates; the type of trigger remained a significant factor after controlling for age, type of gonadotrophins, number of oocytes aspirated and peak estradiol levels. Limitations, reasons for caution The strengths are a single center study with embryos cultured under the same standardized laboratory conditions. GnRH-antagonist ICSI cycles were included to standardize the protocol and control for fertilization time. The retrospective nature of the study is a limitation. Wider implications of the findings Developing an in-house model an important additive tool for improving embryo selection for transfer. It enables the classification of embryo quality according to morphokinetic parameters. Finding treatment parameters that influence morphokinetic embryo quality may be of importance in IVF success rates. Trial registration number not applicable

P-324 Effectiveness of letrozole in symptomatic women with adenomyosis undergoing IVF: An overview of clinical features, sonographic characteristics, and reproductive outcome

Abstract Study question Is letrozole pre-treatment a cost-effective option in improving symptoms, sonographic features, and reproductive outcomes in women with adenomyosis, undergoing IVF treatment? Summary answer Only two months of low dose letrozole pre-treatment is as effective as GnRH-agonist in symptomatic adenomyosis while significantly reducing the cost of treatment. What is known already About 20%–25% of women undergoing IVF present with adenomyosis and many of them suffer from dysmenorrhea and menorrhagia. Adenomyosis is often underdiagnosed and neglected uterine pathology which has a major bearing on the quality of life and fertility. Since adenomyosis is an estrogen-dependent disorder, letrozole, an aromatase inhibitor (controls estrogen production) is reported to be effective in improving symptoms of adenomyosis similar to GnRH-agonist but its role as before treatment IVF is unclear. Although GnRH-agonist is an established and effective pre-treatment option, is expensive and comes with the concerns like menopausal symptoms, increased gonadotropin doses, and duration of stimulation. Study design, size, duration This longitudinal, randomized cohort study was conducted at a tertiary-care hospital during June-2019 and November-2021. 194 adenomyosis women with symptoms undergoing fresh-cycle IVF, were screened and 147 recruited. These women were resistant to OCPs/progestins for symptomatic relief. 72 patients were treated with letrozole and 75 with GnRH-agonist for 2 months, and changes in their sonographic features and symptoms were evaluated before and after treatment. Reproductive outcomes were also compared between the treatment groups after IVF. Participants/materials, setting, methods Adenomyosis was diagnosed on 2D-TVS according to MUSA criteria. Among them, 72 patients were treated with 2.5 mg letrozole (only thrice weekly instead of conventional 2.5mg/daily) and 75 women were treated with GnRH-agonist depot (3.6mg/month) for 2 months. Patients were evaluated before and after 2 months of treatment for improvements in dysmenorrhea (VAS score) and menorrhagia (PBAC score), and quantitative scoring of sonographic features. Reproductive outcomes were also compared after both treatment. Main results and the role of chance The majority of women had 3-4 sonographic criteria on TVS (median of 3), such as irregular or interrupted junctional zone (79.49%), asymmetrical thickening of the myometrium (71.15%), globular uterus (43.59%), and myometrial cyst (33.33%). Significant reductions in the sonographic severity scores for diffuse adenomyosis, adenomyoma, and asymmetry in myometrial thickness were observed following both the treatment (p &amp;lt; 0.05). The effects of both the treatments were comparable in terms of severity of sonographic features (p &amp;gt; 0.05). Significant decreases in dysmenorrhea (letrozole: pre-7.76±1.6, post-1.74±0.58; GnRH-agonist: pre-7.92±2.1, post-0) and menorrhagia (letrozole: pre-169±31, post-73±18; GnRH-agonist: pre-171±25, post-12±6) were observed after 2 months in both the treatment (p &amp;lt; 0.05). Since GnRH-agonist treated women experienced cessation of menstruation, the VAS and PBAC scores were not directly comparable between the groups after treatment. All fresh cycle IVF women were included to understand the effect of pre-treatment of these women. Following fresh cycle IVF, clinical pregnancy (23.61%, 25.33%), miscarriage rate (35.29%, 36.84%), and live birth rate (12.5%, 13.33%), respectively for letrozole and GnRH-agonist groups were comparable (p &amp;gt; 0.05). The cost of the treatment was 19 times less with letrozole pre-treatment when compared with GnRH-agonist, while a comparable reduction in symptoms and IVF outcome parameters were observed. Limitations, reasons for caution A possible limitation is the lack of a proper blinding due to different routes of administration of the therapies. In the absence of a standardized classification of severity, we have used the TVS based scoring proposed by Lazzeri et al (2018), which is not universally accepted or independently validated. Wider implications of the findings Low-dose letrozole pre-treatment for 2 months is an attractive option before IVF for symptoms relief and comparable reproductive outcome to that of GnRH-agonist but with lower cost and without over-suppression of pituitary. This protocol may also be extended to women in general who are suffering from symptomatic adenomyosis. Trial registration number CTRI/2019/01/016919 [04/01/2019]