Effect Of Gonadotropin-releasing Hormone Agonist Research Articles

Effectiveness of gonadotropin-releasing hormone agonists for ovarian function suppression in premenopausal patients with hormone receptor-positive breast cancer: a retrospective single-center real-world study

PurposeThis study evaluated the effectiveness of ovarian function suppression (OFS) of various gonadotropin-releasing hormone agonists (GnRHa) combined with aromatase inhibitors (AI) in premenopausal patients with hormone receptor-positive (HR-positive) breast cancer. Potential risk factors associated with insufficient OFS were analyzed.Patients and methodsPremenopausal HR-positive breast cancer patients who had received AI with GnRHa were studied retrospectively. Patients were divided into different groups according to monthly or trimonthly GnRHa schedules they received, and the effectiveness of OFS was compared between groups. Insufficient OFS was defined as at least one instance of estradiol ≥ 30 pg/ml. Patient data was gathered from medical records for this comparison.ResultsOf the 264 patients enrolled in this study, 117 were administered 3.6 mg of goserelin monthly (goserelin 1 M group), 63 received 3.75 mg of leuprorelin monthly (leuprorelin 1 M group) and 84 were given 11.25 mg of leuprorelin every three months (leuprorelin 3 M group). Overall, 7.20% experienced insufficient OFS. The incidence rates in the three GnRHa depot groups were 7.69%, 6.35%, and 7.14%, respectively, without a significant statistical difference (P = 0.900). Notably, younger patients exhibited a higher likelihood of insufficient OFS [OR = 0.900, 95%CI (0.824–0.982), P = 0.018].ConclusionInsufficient OFS remains a concern during GnRHa and AI treatment. The effectiveness of the three GnRHa depots commonly used in China seems comparable. Younger patients face a heightened risk of insufficient OFS.

Fibroid pseudocapsule: a modern view of the problem. A literature review

Uterine fibroids are a benign polyetiological, hormone-sensitive, monoclonal tumor originating from the smooth muscle cells of the myometrium. They differ in size, location, growth rate, parenchyma-stroma ratio, morphohistogenesis, and clinical manifestations. Despite the frequent occurrence of this disease, its pathogenesis is poorly understood. In particular, the role of the fibroid pseudocapsule is a topic of interest. The appropriateness of retaining the pseudocapsule during myomectomy and the association of its retention with the risk of disease recurrence also remain controversial. This article is a literature review of data ranging from 2013 to 2023, available in the PubMed and Scopus databases. The main aspects of domestic and international clinical guidelines are also presented. This review covers epidemiological features and clinical aspects of uterine fibroids, as well as intraoperative and morphological characteristics of the fibroid pseudocapsule. Current data on the role of the MED12 gene, PGP 9.5, SP, VIP, VEGFR, IGF-2, endoglin, and oxytocin in the pathogenesis of uterine fibroids are also presented. Literature on the effect of gonadotropin-releasing hormone agonists on the morphology and functions of the pseudocapsule is submitted in the text. Despite the possible regenerative properties of the fibroid pseudocapsule, there is still a lack of systematic studies in the literature regarding the molecular and biochemical characteristics of the pseudocapsule, which makes it necessary to further investigate this morphological structure.

Effect of GnRH agonist trigger with or without low-dose hCG on reproductive outcomes for PCOS women with freeze-all strategy: a propensity score matching study.

This study aimed to compare the effect of gonadotropin-releasing hormone agonist (GnRHa) trigger alone versus dual trigger comprising GnRHa and low-dose human chorionic gonadotropin (hCG) on reproductive outcomes in patients with polycystic ovary syndrome (PCOS) who received the freeze-all strategy. A total of 615 cycles were included in this retrospective cohort study. Propensity score matching (PSM) was performed to control potential confounding factors between GnRHa-trigger group (0.2mg GnRHa) and dual-trigger group (0.2mg GnRHa plus 1000/2000IU hCG) in a 1:1 ratio. Multivariate logistic regression was applied to estimate the association between trigger methods and reproductive outcomes. After PSM, patients with dual trigger (n = 176) had more oocytes retrieved, mature oocytes, and 2PN embryos compared to that with GnRHa trigger alone. However, the oocytes maturation rate, normal fertilization rate, and frozen embryos between the two groups were not statistically different. The incidence of ovarian hyperstimulation syndrome (OHSS) (14.8% vs. 2.8%, P < 0.001) and moderate/severe OHSS (11.4% vs. 1.7%, P < 0.001) were significantly higher in dual-trigger group than in GnRHa-alone group. Logistic regression analysis showed the adjusted odds ratio of dual trigger was 5.971 (95% confidence interval 2.201-16.198, P < 0.001) for OHSS. The pregnancy and single neonatal outcomes were comparable between the two groups (P > 0.05). For PCOS women with freeze-all strategy, GnRHa trigger alone decreased the risk of OHSS without damaging oocyte maturation and achieved satisfactory pregnancy outcomes.

The effects of gonadotropin-releasing hormone agonist on final adult height among girls with early and fast puberty.

This study aimed to explore the impact of gonadotropin-releasing hormone agonists (GnRHa) on final adult height (FAH) in girls with early and fast puberty. A retrospective study was conducted by reviewing data from the medical records of the Pediatric Endocrinology Clinics between January 1, 2010, and December 31, 2020, at MacKay Children's Hospital. The treatment group included 109 patients who received 3.75 mg monthly for at least 1 year, whereas the control group consisted of 95 girls who received no treatment. The treatment group was significantly older at the time of inclusion(chronological age (CA1), treatment vs. control, 8.7 vs. 8.4 years, p < 0.001), had a more advanced bone age (BA) (BA1, 11.5 vs. 10.8 years, p < 0.001), BA1-CA1 (2.7 vs. 2.2 years, p < 0.001), and shorter predicted adult height (PAH1) (153.3 vs. 157.1 cm, p = 0.005) that was significantly lower than their target height (Tht)(PAH1-Tht, -3.9 vs. -1.3 cm, p = 0.039). The FAHs of the GnRHa and the control group were similar (157.0 vs. 156.7 cm, p = 0.357) and were not significantly different from their Tht (FAH vs. Tht in the GnRHa group, 157.0 vs. 157.0 cm; control group, 156.7 vs. 157.0 cm). In the subgroup analysis, FAH was significantly higher after GnRHa treatment in those with PAH1 less than 153 cm and Tht (154.0 vs. 152.0 cm, p = 0.041), and those whose CA1 was between 8 and 9 years (158.0 vs. 155.4 cm, p = 0.004). We defined satisfactory FAH outcome as FAH-PAH1≥5 cm and significant factors were GnRHa therapy, PAH1 shorter than their Tht, age younger than 9 years, and faster growth velocity during the first year. GnRHa is effective in restoring the Tht in some early and fast pubertal girls, especially in those with poorly PAH (PAH lower than 153 cm and shorter than their target height). A younger age at initiation of treatment and a faster growth velocity during treatment are associated with a better height gain.

Indices of cellular and humoral immunity in a patient with a history of central precocious puberty in anamnesis

The etiology of precocious puberty includes organic anomalies, genetic mutations, but the primary cause remains unclear in the vast majority of cases. Gonadotropin-releasing hormone (GRH) agonists are used as a treatment of gonadotropin-dependent precocious puberty. Blocking the secretion of gonadotropin-releasing hormone, these drugs stop the premature development of sexual features, prevent premature closure of ossification zones, thereby increasing the child’s expected adult height. The interest in the effects of this group of drugs beyond the hypothalamic-pituitary-gonadal axis has been recently increased. A series of clinical cases have been reported on the development of autoimmune diseases, e.g., autoimmune thyroiditis, Graves disease and type 1 diabetes. The article presents a clinical observation of a patient with central form of premature development who exhibited satisfactory response to treatment with a GRH agonist drug. Further follow-up did not show any reproductive dysfunction. Upon immunological examination, a disturbance was revealed only in the cellular component of immunity. An increased metabolic activity of neutrophils was found, thus, probably, indicating a nonspecific inflammatory process. The levels of immunoglobulins A, M, G matched the reference values. Thus, the therapy with a drug from the group of GRH agonists was effective and safe in terms of influencing the patient’s immune system. The role of hormonal disorders and effects of GRH agonists on the development of immunopathological conditions require further research.

RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids.

Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized by accumulation of abundant extracellular matrix (ECM) and sex steroid-dependent growth. Women with symptomatic UFs have reduced quality of life and decreased labor productivity. Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs. They are gain-of-function mutations and are more frequently observed in Black women and commonly observed even in small UFs. MED12 mutation-positive UFs (MED12-UFs) often develop multiple rather than solitary and have distinct gene expression profiles, DNA methylomes, transcriptomes, and proteomes. Gene expressions related to ECM organization and collagen-rich ECM components are upregulated, and impaired Mediator kinase activity and dysregulation of Wnt/β-catenin signaling are identified in MED12-UFs. Clinically, the UF shrinking effect of gonadotropin-releasing hormone agonists and ulipristal acetate is dependent on the MED12 mutation status. Understanding of characteristics of MED12-UFs and functions of MED12 mutations for UF tumorigenesis may elucidate the pathophysiology of UFs, leading to the development of new therapeutic options in women with symptomatic UFs.

Effects of GnRH Agonist and Dienogest in Combination on HE4 and CA125 Levels in Patients with Adenomyosis and Adenomyoma: A Prospective Cohort Study

Effects of GnRH Agonist and Dienogest in Combination on HE4 and CA125 Levels in Patients with Adenomyosis and Adenomyoma: A Prospective Cohort Study

The effect of gonadotrophin-releasing hormone agonist versus human chorionic gonadotrophin trigger on pregnancy and neonatal outcomes in Letrozole-HMG IUI cycles

BackgroundGnRHa and hCG are both used for oocyte maturation and ovulation triggering. However, GnRHa have a shorter half-life than hCG, which leads to luteal phase deficiency. Letrozole (LE) has been found to improve the luteal function. Thus, the choice of triggering strategy can be different in intrauterine insemination (IUI) cycles using LE and human menopausal gonadotropin (HMG). The aim of this study was to compare the pregnancy and neonatal outcomes of patients triggered with GnRHa versus hCG versus dual trigger in LE-IUI cycles.MethodsThis retrospective cohort study included 6,075 LE-HMG IUI cycles between January 2010 and May 2021 at a tertiary-care academic medical center in China. All cycles were divided into three groups according to different trigger strategies as hCG trigger group, GnRHa trigger group and dual trigger group. The primary outcome was clinical pregnancy rate. Logistic regression analysis was performed to explore other risk factors for clinical pregnancy rate.ResultsNo significant difference was observed in clinical pregnancy rate between hCG, GnRHa and dual trigger cycles in LE-HMG IUI cycles (P = 0.964). The miscarriage rate was significantly lower in the GnRHa trigger group, and higher in the dual trigger group, compared with the hCG group (P = 0.045). Logistic analysis confirmed that triggering strategy was associated with miscarriage (aOR:0.427, 95%CI: 0.183–0.996, P = 0.049; aOR:0.298, 95%CI: 0.128–0.693, P = 0.005). No significant differences were observed regarding neonatal outcomes between the three groups.ConclusionsOur findings suggested that both GnRHa and dual trigger can be used to trigger ovulation in LE-HMG IUI cycles, but dual trigger must be used with caution.

The Cardiovascular Risks Associated with Aromatase Inhibitors, Tamoxifen, and GnRH Agonists in Women with Breast Cancer.

Cardiovascular disease accounts for up to 10% of all-cause mortality in women with a diagnosis of breast cancer, and the causes for this are multifaceted. Many women at risk of or with a diagnosis of breast cancer are on endocrine-modulating therapies. It is therefore important to understand the effect of hormone therapies on cardiovascular outcomes in breast cancer patients to mitigate against any adverse effects and to identify those most at risk so that they can be proactively managed. Here we discuss the pathophysiology of these agents, their effect on the cardiovascular system, and the latest evidence on their cardiovascular risks association. Tamoxifen appears to be cardioprotective during treatment but not over the longer term, while the effect of AIs on cardiovascular outcomes remains controversial. Heart failure outcomes remain understudied, and the cardiovascular effects of gonadotrophin-releasing hormone agonists (GNRHa) in women need further research, especially since data from men with prostate cancer have indicated an increased risk of cardiac events in GNRHa users. There remains a need for a greater understanding of the effects of hormone therapies on cardiovascular outcomes in breast cancer patients. Further areas of research in this area include developing evidence to better define the optimal preventive and screening methods for cardiovascular effects and the risk factors for patients on hormonal therapies.

Long-acting recombinant human follicle-stimulating hormone (SAFA-FSH) enhances spermatogenesis.

Administration of follicle-stimulating hormone (FSH) has been recommended to stimulate spermatogenesis in infertile men with hypogonadotropic hypogonadism, whose sperm counts do not respond to human chorionic gonadotropin alone. However, FSH has a short serum half-life requiring frequent administration to maintain its therapeutic efficacy. To improve its pharmacokinetic properties, we developed a unique albumin-binder technology, termed "anti-serum albumin Fab-associated" (SAFA) technology. We tested the feasibility of applying SAFA technology to create long-acting FSH as a therapeutic candidate for patients with hypogonadotropic hypogonadism. SAFA-FSH was produced using a Chinese hamster ovary expression system. To confirm the biological function, the production of cyclic AMP and phosphorylation of ERK and CREB were measured in TM4-FSHR cells. The effect of gonadotropin-releasing hormone agonists on spermatogenesis in a hypogonadal rat model was investigated. In in vitro experiments, SAFA-FSH treatment increased the production of cyclic AMP and increased the phosphorylation of ERK and CREB in a dose-dependent manner. In animal experiments, sperm production was not restored by human chorionic gonadotropin treatment alone, but was restored after additional recombinant FSH treatment thrice per week or once every 5 days. Sperm production was restored even after additional SAFA-FSH treatment at intervals of once every 5 or 10 days. Long-acting FSH with bioactivity was successfully created using SAFA technology. These data support further development of SAFA-FSH in a clinical setting, potentially representing an important advancement in the treatment of patients with hypogonadotropic hypogonadism.

Height benefit of GnRH agonists after age 8 in a Portuguese cohort of central precocious puberty.

Idiopathic central precocious puberty (iCPP) is common in paediatric endocrinology. Gonadotropin-releasing hormone agonists (GnRHa) are safe, but the effect on final height and the ideal timing for treatment remains controversial. This study aims to assess the effectiveness of GnRHa on growth outcomes in girls with iCPP treated before and after the age of 8 years old. This retrospective longitudinal study evaluated data from Portuguese girls with iCPP who completed treatment between 2010 and 2021. Auxological and clinical characteristics were compared according to age at treatment onset. A cohort of 134 girls with iCPP, was divided into early treatment (ET) (<8 years, n = 48) and later treatment (LT) groups (≥8 years, n = 86). In both groups, most children presented with Tanner II and III. Tanner IV was more frequent in LT group (p = .003).At the end of treatment, predicted adult height increased in both groups (ET p = .032; LT p = .04) and bone age significantly slowed down in all participants (p = .008, p = .034). The height gain was greater in the ET group, but without significant differences (p = .065). Treatment with GnRHa improved final height in all girls with iCPP, even when initiated after 8 years. To achieve better outcomes, treatment should be provided promptly after diagnosis.

Gonadotropin-Releasing Hormone Agonists during Gonadal Chemotherapy for the Effect on Pregnancy Outcome and Ovarian Function in Premenopausal Patients with Breast Cancer: A Systematic Review and Meta-Analysis.

The aim of this study was to evaluate the effects of gonadotropin-releasing hormone agonists (GnRHas) on pregnancy outcomes, premature ovarian failure (POF), menstrual recovery, disease-free survival (DFS), and adverse events in premenopausal breast cancer patients during gonadal chemotherapy. We systematically searched PubMed, Cochrane Library, and Embase databases. The trials were eligible if they included premenopausal breast cancer patients treated with chemotherapy alone or with concurrent GnRHa and reported ovarian function recovery data. Heterogeneity for the eligible data was assessed, and a pooled risk ratio (RR) with 95% confidence interval (CI) was calculated. A meta-analysis was conducted using a fixed-effect model. Fifteen randomized controlled trials were included in this analysis. The results indicated that GnRHa combined with chemotherapy significantly increased pregnancy rates compared with chemotherapy alone (RR = 1.76; 95% CI: 1.16-2.67) and decreased rates of POF (RR = 0.42; 95% CI: 0.35-0.51). For secondary endpoints, the GnRHa group improved menstrual recovery rates (RR = 1.20; 95% CI: 1.11-1.30) and decreased the rate of amenorrhea 1-2 years after chemotherapy (RR = 0.50; 95% CI: 0.40-0.63). Furthermore, the 5-year DFS and overall survival (OS) rates were significantly improved in the GnRHa group. For premenopausal breast cancer patients receiving gonadal toxic chemotherapy, adjuvant chemotherapy with GnRHa can better protect the ovarian function of patients, reduce the rate of POF and amenorrhea, and improve the pregnancy rate, menstrual recovery rate, DFS rate, and OS rate of patients.

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.

Endometrial Mesenchymal Stem Cells and Their Role in the Origin and Treatment of Endometriosis

Background: To identify endometrial mesenchymal stem cells (eMSCs) in retrograde menstruation, in various endometriosis lesions, in normal control tissues, and to investigate the association between eMSCs and endometriosis. We also plan to evaluate the effect of gonadotropin-releasing hormone agonists (GnRH-a) on eMSCs. Methods: Patients diagnosed with endometriosis were included if they had experienced surgery during the time frame 1 January 2015 to 31 December 2019 in West China Second Hospital, Sichuan University. Immunofluorescence was performed to identify eMSCs in those tissues with cell surface markers PDGFR-β/CD146. The percents of eMSCs in various tissues were calculated, and compared using analysis of variance. A two-sided pvalue less than 0.05 showed significant difference. Results: This study included 508 patients. eMSCs were identified in retrograde menstruation and numerous pathologic specimen but were not detected in normal control tissues. There was no significant difference in the percent of eMSCs between the GnRH-a treatment group and the control group (p &gt; 0.05). Conclusions: Our study demonstrated that eMSCs played a critical role in the development and recurrence of endometriosis and that GnRH-a did not affect eMSCs. Gynecologists should regard endometriosis as a chronic disease requiring lifetime management, especially for patients with chronic pelvic pain.

Ovarian functions and polycystic ovary syndrome in adult women with type 1 diabetes mellitus in a Turkish population.

The effect of gonadotropin-releasing hormone agonist (GnRHa) stimulation has not been studied in adult women with type 1 diabetes mellitus (DM). We investigated the baseline and stimulated hormone levels after GnRHa and the frequency and relationship between polycystic ovary syndrome (PCOS) and type 1 DM in adult women with type 1 DM. We included 55 adult women (age, 17-35years) with type 1 DM and 15 healthy women (age, 20-29years). Hormones including total testosterone, androstenedione, dehydroepiandrosterone sulphate (DHEAS), follicle-stimulating hormone (FSH), luteinising hormone (LH), estradiol, prolactin, and thyroid-stimulating hormone were measured in the early follicular phase of the menstrual cycle. All participants underwent GnRHa stimulation test, and FSH, LH, estradiol and 17-OHP response levels were measured every 6h for 24h. PCOS was diagnosed according to ESHRE/ASRM (Rotterdam) criteria. Between patients with type 1 DM and healthy controls, no significant differences were noted in mean age and body mass index (BMI) as well as baseline and stimulated hormone levels after buserelin stimulation, except for baseline serum 17-OHP levels, which was higher in patients with type 1 DM. Polycystic ovary morphology (PCOM) was detected in 14 (25%) patients, clinical hyperandrogenism in 16 (29%), hyperandrogenemia in 25 (45%), anovulatory cycle in 72%, and PCOS in 20 (36%). All parameters representing androgen excess disorders, except 17-OHP level, of both groups were similar, and frequencies of PCOS and anovulatory cycle in adult women with type 1 DM were 36% and 72%, respectively.

Effects of gonadotropin-releasing hormone agonist pretreatment on frozen embryo transfer outcomes in artificial cycles: a meta-analysis.

Gonadotropin-releasing hormone agonist (GnRHa) before artificial cycle (AC) is expected to improve pregnancy outcomes in frozen-thawed embryo transfer (FET). Many studies have explored the impact of GnRHa pretreatment of AC in FET, but the results were inconsistent. This meta-analysis was performed to systematically evaluate the effect of GnRHa pretreatment on AC in FET. The last search was January 31, 2022. Randomized controlled trials and cohort studies aiming to assess the effect of GnRHa as the pretreatment of AC for endometrial preparation in FET were included. GnRHa was used before AC in the treatment group. In the control group, no pretreatment was used before AC. The eligible studies included at least one of the following outcomes: implantation, clinical pregnancy, and live birth. We calculated the odds ratio (OR) or mean difference (MD) and 95% confidence interval (CI) for each study and used a random-effects or fixed model to estimate the results. 27 articles (10 RCTs and 17 non-RCTs) and 14152 patients were included. AC + GnRHa improved the implantation rate (OR = 1.31, 95% CI 1.03-1.66, I2 = 79%), clinical pregnancy rate (OR = 1.27, 95% CI 1.10-1.45, I2 = 53%), and live birth rate (OR = 1.16, 95% CI 1.05-1.29, I2 = 39%). We also found that AC + GnRHa increased the implantation rate (OR = 1.35, 95% CI 1.07-1.69, I2 = 53%) and clinical pregnancy rate (OR = 1.50, 95% CI 1.12-2.01, I2 = 50%) in repeated implantation failure. In addition, AC + GnRHa was positively associated with preterm birth (OR = 1.5, 95% CI 1.15-1.94, I2 = 0%). GnRHa pretreatment in FET can improve implantation, clinical pregnancy, and live birth rates, especially in patients with repeated implantation failure. GnRHa pretreatment seems to improve FET outcomes, though with a higher preterm birth rate.

MED12 mutations in uterine leiomyomas: prediction of volume reduction by gonadotropin-releasing hormone agonists

Gonadotropin-releasing hormone agonists are used to treat premenopausal uterine leiomyomas; however, leiomyoma volume reduction is not always achieved. The reduction rate after this treatment varies for each leiomyoma, even in the same patient. Therefore, an effective method for predicting uterine leiomyoma volume reduction is required to reduce the adverse hypoestrogenic effects and drug-related economic burden related to gonadotropin-releasing hormone agonists. This study aimed to determine the predictive use of MED12 mutations for evaluating the effect of gonadotropin-releasing hormone agonist treatment concerning reducing uterine leiomyoma volume and to predict the MED12 mutation status based on the findings of magnetic resonance imaging performed before treatment. MED12 exon 2 mutation and erythropoietin expression in uterine leiomyomas were evaluated concerning volume reduction, as measured using magnetic resonance imaging. We developed a system for classifying leiomyomas according to T2-weighted magnetic resonance imaging signals to noninvasively predict the presence or absence of MED12 mutations in leiomyomas. Leiomyoma samples (>5 cm) were obtained from 168 patients during surgery (hysterectomy or myomectomy) between 2005 and 2021 at Yokohama City University Hospital. To analyze the rate of leiomyoma volume reduction, 41 patients had been preoperatively administered the gonadotropin-releasing hormone agonist (leuprorelin acetate 3.75 mg, monthly subcutaneous injection) for 3 months; magnetic resonance imaging was performed before and after treatment without contrast material. Patients with MED12 exon 2 mutations had smaller volume reduction after treatment with the gonadotropin-releasing hormone agonist (P<.001, Mann-Whitney U test) and displayed lower signal intensity on T2-weighted images than those with leiomyomas expressing wild-type MED12 exon 2. The newly proposed magnetic resonance imaging-based classification system showed that MED12 exon 2 mutations were more frequent in the low-signal group than in the high-signal group, with nearly equal proportions of mutated and wild-type MED12 exon 2 leiomyomas noted in the intermediate group. The low-signal group had significantly lower erythropoietin expression levels than the high-signal group (P<.001, Kruskal-Wallis test with the Dunn posthoc analysis). MED12 mutation status can be a candidate marker for predicting the effect of gonadotropin-releasing hormone agonists on uterine leiomyoma reduction. Magnetic resonance imaging findings can be used to determine MED12 mutation status as a noninvasive strategy to select patients who will most likely benefit from gonadotropin-releasing hormone agonist treatment.

Estradiol (E2) levels in premenopausal women with hormone receptor-positive (HR+) breast cancer (BC) on ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHa).

524 Background: OFS is an important treatment component for premenopausal women with early and advanced HR+ BC and optimal efficacy may depend on complete E2 suppression with GnRHa, especially when combined with aromatase inhibitors (AI). However, standard assays lack sensitivity and accuracy at very low E2 concentrations, rendering detection of breakthrough ovarian function challenging. More informative data regarding endocrine effects of GnRHa are needed, particularly in young women who derive the most benefit from OFS yet more frequently had breakthrough E2 levels in the SOFT trial substudy, SOFT-EST. Methods: Using a prospective cohort study of women with BC diagnosed at age ≤ 40 years, we identified participants with stage I-IV HR+ BC on OFS treatment with leuprolide, goserelin or triptorelin and blood collected 1 year after diagnosis. Clinical data were obtained through surveys and medical records. Plasma estrogens were measured by liquid chromatography-tandem mass spectrometry, with a limit of detection of 0.2 pg/mL compared to 10 pg/mL with standard assays. We assessed the proportion of women on OFS with E2 &gt; 2.72 pg/mL (10 pmol/L) and &gt; 10 pg/mL. Patient characteristics, estrone (E1) and FSH levels, and disease-free (DFS) and overall survival (OS) were compared between those with and without elevated E2 using Fischer’s exact, Wilcoxon rank sum and log rank tests, respectively. Results: Of 84 patients who met inclusion criteria, 72 (86%) had stage I-III and 12 (14%) had stage IV BC; 25 were on OFS plus AI and 59 were on OFS plus tamoxifen (TAM). Median E2 was 3.1 pg/mL (range 0.2-30.9). 46 patients (55%) had E2 &gt; 2.72 pg/mL, including 8 on AI and 38 on TAM; 4 (5%) had E2 &gt; 10 pg/mL, including 1 on AI and 3 on TAM. Factors associated with E2 &gt; 2.72 pg/mL were no prior chemotherapy, TAM and high E1 ( P ≤.05), but not age, BMI or GnRHa schedule (Table). After a median follow-up of 7 years, DFS events were seen in 6 patients with E2 &gt; 2.72 pg/mL and 5 without ( P =.232); OS events were seen in 7 patients with E2 &gt; 2.72 pg/mL and 5 without ( P =.608). Conclusions: More than half of young women with ER+ BC had E2 &gt; 2.72 pg/mL on OFS, 91% of whom would not have been detected by standard assays. This may be an area amenable to intervention to improve outcomes in young women. However, larger studies are needed to elucidate the optimal E2 target on OFS and clinical implications of incomplete E2 suppression on ultrasensitive assays. [Table: see text]

Effect of GnRH agonist alone or combined with different low-dose hCG on cumulative live birth rate for high responders in GnRH antagonist cycles: a retrospective study

BackgroundThere is insufficient evidence regarding the impact of dual trigger on oocyte maturity and reproductive outcomes in high responders. Thus, we aimed to explore the effect of gonadotropin-releasing hormone agonist (GnRHa) trigger alone or combined with different low-dose human chorionic gonadotropin (hCG) regimens on rates of oocyte maturation and cumulative live birth in high responders who underwent a freeze-all strategy in GnRH antagonist cycles.MethodsA total of 1343 cycles were divided into three groups according to different trigger protocols: group A received GnRHa 0.2 mg (n = 577), group B received GnRHa 0.2 mg and hCG 1000 IU (n = 403), and group C received GnRHa 0.2 mg and hCG 2000 IU (n = 363).ResultsThere were no significant differences in age, body mass index, and rates of oocyte maturation, fertilization, available embryo, and top-quality embryo among the groups. However, the incidence of moderate to severe ovarian hyperstimulation syndrome (OHSS) was significantly different among the three groups (0% in group A, 1.49% in group B, and 1.38% in group C). For the first frozen embryo transfer (FET) cycle, there were no significant differences in the number of transferred embryos and rates of implantation, clinical pregnancy, live birth, and early miscarriage among the three groups. Additionally, the cumulative ongoing pregnancy rate and cumulative live birth rate were not significantly different among the three groups. Similarly, there were no significant differences in gestational age, birth weight, birth height, and the proportion of low birth weight among subgroups stratified by singleton or twin.ConclusionsGnRHa trigger combined with low-dose hCG (1000 IU or 2000 IU) did not improve oocyte maturity and embryo quality and was still associated with an increased risk of moderate to severe OHSS. Therefore, for high responders treated with the freeze-all strategy, the single GnRHa trigger is recommended for final oocyte maturation, which can prevent the occurrence of moderate to severe OHSS and obtain satisfactory pregnancy and neonatal outcomes in subsequent FET cycles.

GnRH agonist treatment regulates IL-6 and IL-11 expression in endometrial stromal cells for patients with HRT regiment in frozen embryo transfer cycles

To evaluate the effect of gonadotropin-releasing hormone agonist (GnRHa) pretreatment time on clinical outcomes of patients who underwent endometrial preparation in HRT cycles and the molecular mechanism in frozen-thawed embryo transfer (FET) cycles, we retrospectively chose 1143 cycles and separated four groups. Endometrial tissues were collected from 44 patients who were cancelled on the day of embryo transfer (there were 10 patients refused to collect endometrium) and were tested for endometrial receptivity marker mRNA and miR-124-3p expression. Furthermore, endometrial stromal cells (ESCs) were transfected to investigate the molecular mechanism. The clinical pregnancy rate and live birth rate were significantly high in group B. The endometrial expression of the IL-6 and IL-11 mRNAs was significantly increased in groups with GnRHa pretreatment compared with group A without the GnRHa pretreatment. Similar results were obtained for the endometrial receptivity markers LIF and integrin αvβ3. The groups treated with GnRHa exhibited a progressive and significant time-dependent decrease in the IL-6 and IL-11 mRNA. In contrast, the levels of LIF and integrin αvβ3 expression remained unaltered among group B-D. In addition, transfection of ESCs with miR-124-3p mimics significantly reduced levels of the IL-6 and IL-11 mRNAs and proteins. The luciferase report assay demonstrated that IL-6 and IL-11 is a target gene of miR-124-3p. The results showed that ultra-long GnRHa administration can improve outcomes, especially after 3 cycles of GnRHa pretreatment, and endometrial receptivity through IL-6 and IL-11 expression levels of ESC regulated by the miR-124-3p for patients with HRT, who underwent FET cycles.