GnRH Receptor Research Articles

Female-specific pituitary gonadotrope dysregulation in mice with chronic focal epilepsy

Gonadotropin hormone release from the anterior pituitary is critical to regulating reproductive endocrine function. Clinical evidence has documented that people with epilepsy display altered levels of gonadotropin hormones, both acutely following seizures and chronically. Despite this relationship, pituitary function remains a largely understudied avenue in preclinical epilepsy research. Recently, we showed that females in the intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy displayed changes in pituitary expression of gonadotropin hormone and gonadotropin-releasing hormone (GnRH) receptor genes. Circulating gonadotropin hormone levels, however, have yet to be measured in an animal model of epilepsy. Here, we evaluated the circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), GnRH receptor (Gnrhr) gene expression, and sensitivity to exogenous GnRH in IHKA males and females. Although no changes in overall dynamics of pulsatile patterns of LH release were found in IHKA mice of either sex, estrus vs. diestrus changes in basal and mean LH levels were larger in IHKA females with prolonged, disrupted estrous cycles. In addition, IHKA females displayed increased pituitary sensitivity to GnRH and higher Gnrhr expression. The hypersensitivity to GnRH was observed on diestrus, but not estrus. Chronic seizure severity was not found to be correlated with LH parameters, and FSH levels were unchanged in IHKA mice. These results indicate that although there are changes in pituitary gene expression and sensitivity to GnRH in IHKA females, there may also be compensatory mechanisms that aid in maintaining gonadotropin release in the state of chronic epilepsy in this model.

Conventional and new proposals of GnRH therapy for ovarian, breast, and prostatic cancers.

For many years, luteinizing hormone-releasing hormone or gonadotropin-releasing hormone (GnRH) analogs have been used to treat androgen or estrogen-dependent tumors. However, emerging evidence shows that the GnRH receptor (GnRH-R) is overexpressed in several cancer cells, including ovarian, endometrial, and prostate cancer cells, suggesting that GnRH analogs could exert direct antitumoral actions in tumoral tissues that express GnRH-R. Another recent approach based on this knowledge was the use of GnRH peptides for developing specific targeted therapies, improving the delivery and accumulation of drugs in tumoral cells, and decreasing most side effects of current treatments. In this review, we discuss the conventional uses of GnRH analogs, together with the recent advances in GnRH-based drug delivery for ovarian, breast, and prostatic cancer cells.

Circulating miRNAs in Women with Polycystic Ovary Syndrome: A Longitudinal Cohort Study.

Women with polycystic ovary syndrome (PCOS) often change their metabolic profile over time to decrease levels of androgens while often gaining a propensity for the development of the metabolic syndrome. Recent discoveries indicate that microRNAs (miRNAs) play a role in the development of PCOS and constitute potential biomarkers for PCOS. We aimed to identify miRNAs associated with the development of an impaired metabolic profile in women with PCOS, in a follow-up study, compared with women without PCOS. Clinical measurements of PCOS status and metabolic disease were obtained twice 6 years apart in a cohort of 46 women with PCOS and nine controls. All participants were evaluated for degree of metabolic disease (hypertension, dyslipidemia, central obesity, and impaired glucose tolerance). MiRNA levels were measured using Taqman® Array cards of 96 pre-selected miRNAs associated with PCOS and/or metabolic disease. Women with PCOS decreased their levels of androgens during follow-up. Twenty-six of the miRNAs were significantly changed in circulation in women with PCOS during the follow-up, and twenty-four of them had decreased, while levels did not change in the control group. Four miRNAs were significantly different at baseline between healthy controls and women with PCOS; miR-103-3p, miR-139-5p, miR-28-3p, and miR-376a-3p, which were decreased in PCOS. After follow-up, miR-28-3p, miR-139-5p, and miR-376a-3p increased in PCOS women to the levels observed in healthy controls. Of these, miR-139-5p correlated with total testosterone levels (rho = 0.50, padj = 0.013), while miR-376-3p correlated significantly with the waist-hip ratio at follow-up (rho = 0.43, padj = 0.01). Predicted targets of miR-103-3p, miR-139-5p, miR-28-3p, and miR-376a-3p were enriched in pathways associated with Insulin/IGF signaling, interleukin signaling, the GNRH receptor pathways, and other signaling pathways. MiRNAs altered during follow-up in PCOS patients were enriched in pathways related to immune regulation, gonadotropin-releasing hormone signaling, tyrosine kinase signaling, and WNT signaling. These studies indicate that miRNAs associated with PCOS and androgen metabolism overall decrease during a 6-year follow-up, reflecting the phenotypic change in PCOS individuals towards a less hyperandrogenic profile.

Characteristics of submucosal leiomyomas that could cause severe hemorrhage with relugolix: an observational study

BackgroundRelugolix, an oral gonadotrophin-releasing hormone receptor antagonist, was launched in Japan in 2019. Although there have been several studies on relugolix for leiomyomas, few have focused on submucosal leiomyomas. Submucosal leiomyomas cause bleeding more frequently than leiomyomas in other locations. There is only one case report described a patient treated for a submucosal leiomyoma with relugolix who developed severe hemorrhage. However, it remains unclear which characteristics of submucosal leiomyomas can lead to severe hemorrhage. Thus, the aim of this study was to investigate the characteristics of submucosal leiomyomas that would cause severe hemorrhage when treated with relugolix.MethodsWe retrospectively reviewed records of patients who underwent treatment for submucosal leiomyoma with relugolix (40 mg once daily for up to 6 months) in our institute between December 2019 and September 2021. We evaluated the clinical course and characteristics of submucosal leiomyoma in patients who developed severe hemorrhage.ResultsA total of 17 patients were treated for submucosal leiomyoma with relugolix. Two patients developed severe hemorrhage and required emergent surgery and blood transfusions. Only those two of the 17 patients had a submucosal leiomyoma of the International Federation of Gynecology and Obstetrics (FIGO) type 0, which has a stalk. In the remaining 15 patients who had FIGO type 1 or 2 leiomyoma, hemorrhage did not occur.ConclusionsOur study suggests that the use of relugolix for FIGO type 0 leiomyomas may be associated with a risk of hemorrhage. However, relugolix may be a safe and effective treatment option for patients with FIGO type 1 or 2 leiomyomas.

Use of oral GnRH antagonists combined therapy in the management of symptomatic uterine fibroids.

Uterine fibroids have an impact on women's lives due to their high prevalence, physical symptoms, their consequences on patients' emotional and psychological well-being and loss of work productivity. The choice of therapeutical approaches varies depending on several factors, and therefore should be applied individually. Currently, there is an unmet need for good, reliable, uterine-sparing options. The oral GnRH antagonists (Elagolix, Relugolix, Linzagolix) represent a new alternative for the medical management of hormone-dependent gynaecological diseases such as uterine fibroids or endometriosis. They rapidly bind to the GnRH receptor, block endogenous GnRH activity and directly suppress LH and FSH production, avoiding unwanted flare-up effects. Some GnRH antagonists are marketed in combination with hormone replacement therapy add-back to counteract hypo-oestrogenic side effects. According to the registration trials, once-daily GhRH antagonist combination therapy results in a significant reduction in menstrual bleeding, as compared with placebo, and preserves bone mineral density, for up to 104 weeks. Further studies in the long term are needed to evaluate the whole impact of medical treatment of uterine fibroids on the management of this common women's disease.

GnRh agonists as precipitating components of psychiatric pathology. A case report.

IntroductionGnRh agonists are drugs used in various gynecological pathologies, among which is endometriosis. They act by stimulating GnRh receptors in the pituitary gland. This sustained and continuous stimulation of GnRh, will initially generate an increase in the release of luteinizing hormones and follicle-stimulating hormones, subsequently losing sensitivity to the receptors, internalizing them, and thus suppressing the release of these hormones, which would entail an ovarian suppression, thereby inhibiting the release of estrogens and progesterone. Psychiatric adverse effects have been described. Gonzalez-Rodriguez et al (Front Psychiatry 2020; 11:479), described this association with changes in mood, and the presence of a series of cases where the link between GnRh agonist and the possibility of presenting psychotic symptoms is observed. Wieck (Curr Top Behav Neurosci 2011;8:173-87), Frokjaer (J Neurosci Res 2020;98(7):1283-1292), Brzezinski-Sinai et al (Front Psychiatry 2020;11:693) reported that this association could be related with the relationship of the hypothalamic-pituitary-gonadal axis, hormonal fluctuation and its relationship with the dopaminergic regulation, a genetic component that would increase the predisposition to trigger psychiatric pathology in patients with greater sensitivity to hormonal fluctuations, and the loss of neuroprotection generated by the decrease of estrogens in the central nervous system. All of this in the context of multiple environmental and genetic factors that participate together in the appearance of the disease.ObjectivesTo describe the importance of detecting the risk factors that can precipitate a psychotic episode, including the use of certain drugs, such as GnRh agonists.MethodsWe describe a case of a 45 year old patient with endometriosis with multiple organ involvement who went to the emergency room due to behavioral changes in the context of a brief psychotic disorder with “ad-integrum” recovery.ResultsA retrospective analysis of the case is conducted, observing an association between the introduction of GnRh agonists and the presentation of a first psychotic episode.ConclusionsThe importance of this case lies in the limited evidence of this association in the literature, and the implication of these drugs in the triggering of psychiatric pathology, being an aspect to be considered by psychiatrists in their patient’s follow-up.Disclosure of InterestNone Declared

Ganirelix and the prevention of premature luteinizing hormone surges

Ganirelix is a gonadotropin-releasing hormone (GnRH) antagonist with high antagonistic activity that blocks the GnRH receptor by competitive binding. A daily dose of 0.25 mg of ganirelix was sel5ected after a phase II study because it was the minimal, effective daily dose to prevent premature luteinizing hormone surges and this dose yielded the highest ongoing pregnancy rate per started cycle. After subcutaneous administration, ganirelix is rapidly absorbed, reaching peak levels within 1-2 hours (tmax), and has a high absolute bioavailability (>90%). Prospective, comparative studies have demonstrated the advantages of GnRH antagonists over long GnRH agonist treatment in assisted reproduction, including the immediate reversibility of drug effects, a requirement for less follicle-stimulating hormone, a shortened duration of stimulation, a reduced incidence of ovarian hyperstimulation syndrome, and reduced patient burden. Combined analyses concluded that in the general invitro fertilization population, there is a trend for a slightly lower ongoing pregnancy rate and a lower risk of ovarian hyperstimulation syndrome that is largely eliminated when considering triggering with GnRH agonist instead of human chorionic gonadotropin. Regardless of all the research, it is still not fully elucidated why the long GnRH agonist protocol has a trend for higher pregnancy rates after fresh transfer of the same number of good-quality embryos.

A multi-center, prospective, observational study of patients with prostate cancer being treated with relugolix: OPTYX.

TPS398 Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists are the foundation of advanced prostate cancer (aPC) treatment. Relugolix is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 HERO trial, relugolix maintained suppression of testosterone to castration levels in 96.7% of men from Day 29 to 48 weeks, with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). The goal of this current study (OPTYX) is to generate real-world evidence about the safety and effectiveness of relugolix in patients with prostate cancer during routine clinical care. Methods: This prospective observational cohort study (registry) is enrolling patients who have planned initiation with relugolix within 1 month prior to the time of study enrollment. The study is designed to prospectively understand the actual experience of patients with prostate cancer treated with relugolix through data collection on patients selected for treatment, treatment patterns, adherence, patient reported quality of life (QoL) and safety data. Additionally, a better understanding of the trajectory of patients with prostate cancer following cessation of relugolix therapy will be gained by observing the clinical course of the disease, health outcomes, and health-related quality-of-life (HRQoL) in these patients. Inclusion criteria include patients > 18 years old with prostate cancer and planned total treatment with relugolix of at least 4 months. Estimated enrollment is 1000 patients, and patients will be followed for up to 5 years. In addition to assessing routine clinical care and disease progression, patient reported outcomes will be assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) for HRQoL and Simplified Medication Adherence Questionnaire (SMAQ) for adherence at 3 and 6 months then every 6 months. Clinical trial information: NCT05467176 .

Real-world combination therapy patterns in patients receiving leuprolide or relugolix for androgen deprivation therapy in 2021 (The REAL-ADT COMBO Study): Analysis from a US EMR database.

74 Background: Relugolix, an oral gonadotropin releasing hormone (GnRH) receptor antagonist, was FDA approved for the treatment of adults with advanced prostate cancer (PC) in December 2020 and became commercially available in January 2021. Data from a subgroup of patients from the Phase 3 HERO study showed patients combining relugolix with enzalutamide or docetaxel had similar efficacy and safety as other cohorts in the study. However, due to limited data, some guidelines do not recommend relugolix in combination with other therapies. We evaluated real world utilization of leuprolide and relugolix in combination with other PC medications. Methods: An observational retrospective analysis was conducted using Electronic Medical Record (EMR) data. PPS Analytics data from 89 urology practices with patients represented across all 50 states in the US were analyzed. Patients with at least one record of androgen deprivation therapy (ADT) in 2021 were included. Patients whose date of ADT initiation could not be determined were excluded from this analysis. This analysis focused on the occurrence of patients with ADT as well as in combination with other PC medications. Data are reported for all patients treated with leuprolide or relugolix and stratified by new and continuing ADT use. Combination PC medications were reported for these two ADT groups. Results: In 2021, 51,735 patients were treated with ADT; 45,599 (88.1%) were treated with leuprolide and 3,096 (6.0%) patients had at least 1 prescription for relugolix. Combination PC medications (ComboPCRx) were proportionately higher in relugolix patients than in leuprolide patients (698 [22.5%] vs 8,897 [19.5%] respectively; p < 0.0001). ComboPCRx in users new to ADT was more frequent for relugolix users (342/2,169 [15.8%]) than for leuprolide users (1934/17,737 [10.9%]). In both groups, novel anti-androgens were the most frequent type of ComboPCRx. Conclusions: In this real-world EMR analysis, relugolix use in combination with other PC medication was frequently observed, for both new to ADT and continuing ADT patients. The percentage of combination therapy with PC medications was higher for relugolix users than it was for leuprolide users. These results provide insight into the real-world use of relugolix in combination with other PC medications. Further analyses are needed to make informed treatment decisions. [Table: see text]

NRG-GU011: A phase II double-blinded, placebo-controlled trial of prostate oligometastatic radiotherapy with or without androgen deprivation therapy in oligometastatic prostate cancer (NRG PROMETHEAN).

TPS283 Background: There is no clear standard of care for biochemically recurrent prostate cancer (PCa) with positron emission tomography (PET)-detected oligometastases and normal conventional imaging (CIM). Phase II trials show that stereotactic ablative body radiotherapy (SABR) to oligometastases may delay cancer progression and initiation of androgen deprivation therapy (ADT) and its untoward effects. ADT with radiation prolongs survival in locally advanced PCa and in CIM metastatic PCa. However, there is a knowledge gap about timing and benefit vs toxicity of ADT with SABR in early oligometastatic PCa. NRG GU011 (PROMETHEAN) is a randomized phase II trial of SABR with or without relugolix for early PET-detected recurrent oligometastatic PCa. This study aims to evaluate the impact of relugolix, a novel oral gonadotropin-releasing hormone receptor antagonist, when combined with SABR to oligometastases. Relugolix allows for rapid testosterone recovery and is associated with fewer cardiovascular events when compared to leuprolide and is hypothesized to have low late ADT toxicity. GU011 will provide patients and their physicians data on the relative risks and benefits of early or delayed ADT in this setting. Methods: NRG-GU011 NCT# 05053152 is a randomized phase II double-blinded, placebo-controlled trial with randomization to SABR + 6 months placebo vs SABR + 6 months relugolix. Eligible patients have biochemical recurrence after prior curative intent radiation or surgery for localized PCa, PSA < 10 ng/mL, negative CIM and 1-5 PET-evident metastases (≥1 extrapelvic). SABR is delivered in 1-5 fractions to BED >100 Gy1.5, followed by placebo or relugolix 120mg daily for 6 months. Patients will then be followed with imaging at time of biochemical recurrence. The planned sample size of 260 patients (130 per arm) will provide 85% power to detect a hazard ratio of 0.65 for radiographic progression-free survival (rPFS), based on a one-sided test at alpha 0.10. Planned enrollment is predicted at 8 patients per month with an estimated study completion date of late 2026. The primary endpoint is CIM rPFS. Secondary endpoints include PET-based rPFS, sexual and hormonal quality of life (QoL) assessed by EPIC-26, other QoL measures from EQ5D-5L, EORTC QLQ-30 and PROMIS Fatigue, and between-group comparisons of time to salvage therapy, castration-resistance, local progression (SABR-targeted lesion), biochemical progression, distant metastases, prostate cancer-specific mortality, metastasis-free survival, and overall survival. We also aim to determine adverse event rates for both treatment arms and evaluate genomic and blood markers of treatment response. This study opened in December 2021. Clinical trial information: NCT05053152 .

Discovery of microglia gonadotropin‑releasing hormone receptor and its potential role in polycystic ovarian syndrome.

Hypothalamic inflammation is a pathophysiological basis of polycystic ovarian syndrome (PCOS), while overactivated and/or excess M1 polarized microglia are considered to be the main reason for the occurrence of hypothalamic inflammation. Therefore, invitro and invivo experiments were performed to assess the relationships between microglia‑mediated inflammatory reactions and endocrine functions in the PCOS hypothalamus. The expression of gonadotropin‑releasing hormone (GnRH) receptor (GnRHR) was demonstrated in hypothalamic microglia, and it was found that low concentration, GnRH agonist, leuprolide acetate accelerated the expression of M2 polarization marker CD206, while high concentration leuprolide acetate increased the expression of M1 polarization marker CD86 invitro. Furthermore, aerobic exercise not only reduced the levels of serum testosterone, luteinizing hormone and GnRH and the amount of overactivated microglia, but also increased the number of M2 microglia in the hypothalamus of letrozole‑induced PCOS rats. In combination, these results not only demonstrated the expression of GnRHR in hypothalamic microglia, but also demonstrated that GnRH can induce microglial polarization, while aerobic exercise may improve the microglia‑mediated inflammatory reaction by reducing the expression of GnRHR in the hypothalamic microglia of PCOS rats.

Anticancer and Biological Effects of Some Natural Compounds and Theoretical Investigation of them Against RdRP of SARS-COV-2: In Silico and In Vitro Studies.

In this study, Skullcapflavone I and Skullcapflavone II molecules showed good inhibitory activities against α-glucosidase and sorbitol dehydrogenase enzymes with IC50 values of 102.66 ± 8.43 and 95.04 ± 11.52nM for α-glucosidase and 38.42 ± 3.82 and 28.81 ± 3.26µM for sorbitol dehydrogenase. The chemical activities of Skullcapflavone I and Skullcapflavone II against α-glucosidase and sorbitol dehydrogenase were assessed by conducting the molecular docking study. The anticancer activities of the compounds were examined against SW-626, SK-OV-3, OVCAR3, and Caov-3 cell lines. The chemical activities of Skullcapflavone I and Skullcapflavone II against some of the expressed surface receptor proteins (estrogen receptor, EGFR, androgen receptor, and GnRH receptor) in the mentioned cell lines were investigated using in silico calculations. Moreover, the activity of the compounds against RNA polymerase of SARS-COVE-2 was also assessed using the molecular modeling study. These compounds created strong contacts with the enzymes and receptors. The considerable binding affinity of the compounds to the enzymes and proteins showed their ability as inhibitors. Furthermore, even at modest dosages, these substances markedly reduced the viability of ovarian cancer cells. Additionally, the viability of ovarian cancer cells was significantly decreased by a 300 μM dosage of all compounds. Antiovarian cancer results of Skullcapflavone I on SK-OV-3, SW-626, OVCAR3, and Caov-3 were 63.14, 1.55, 19.42, and 52.04µM, respectively. Also, cytotoxicity results of Skullcapflavone II on SK-OV-3, SW-626, OVCAR3, and Caov-3 were 5.18, 21.44, 33.87, and 72.66µM, respectively.

Profile of Linzagolix in the Management of Endometriosis, Including Design, Development and Potential Place in Therapy: A Narrative Review.

Estrogens play a critical role in the pathogenesis of endometriosis and it is logical to assume that lowering estradiol levels with oral gonadotropin-releasing hormone (GnRH) antagonists may prove effective, especially in women who fail to respond to progestogens. Indeed, due to progesterone resistance, oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis, but are ineffective in 33% of women. Oral GnRH antagonists have therefore been evaluated for management of premenopausal women with endometriosis-associated pelvic pain. The first publication on these drugs reported the efficacy of elagolix. The present paper is a narrative review of linzagolix, which is an orally administered GnRH receptor antagonist with low pharmacokinetic/pharmacodynamic variability. It binds to and blocks the GnRH receptor in the pituitary gland, resulting in a dose-dependent drop in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production. This reduction in LH and FSH levels in turn leads to a dose-dependent decline in estrogen. Phase 2 and 3 trials are reviewed and discussed here. There is a place for GnRH antagonists in the management of symptomatic endometriosis, and linzagolix with or without add-back therapy (ABT) is one option that can be used at low doses, avoiding the need for ABT, which is contraindicated in some patients.

Targeted silencing of the MCL-1 gene using multi-layered dendrimer-based nanoconstructs achieves efficient tumor regression in xenografted mice models

The setback in the practical clinical use of RNA interference (RNAi)-based cancer treatment stems from the lack of targeted small interfering RNA (siRNA) delivery. Here, we show that luteinizing hormone-releasing hormone(LHRH) analog-tethered multi-layered polyamidoamine (PAMAM) nanoconstructs silence the anti-apoptotic MCL-1 gene in LHRH receptor overexpressing human breast (MCF-7) and prostate cancer (LNCaP) cells with 70.91 % and 74.10 % efficiency, respectively. These results were confirmed by RT-PCR. The Acridine orange/Ethidium bromide (AO/EB) dual staining revealed that the silencing of MCL-1 induced apoptosis in both the cell lines. In vivo tumor regression studies performed using MCF-7 and LNCaP xenografted severe combined immunodeficiency(SCID) mice demonstrated highly improved tumor regression in groups treated with targeted nanoconstructs complexed with MCL-1 siRNA (T + siMCL-1) compared to the other treatment groups. The quantitative RT-PCR results of tumor tissues demonstrated significant MCL-1 gene silencing, i.e., 73.76 % and 92.63 % in breast and prostate tumors, respectively, after T + siMCL-1 treatment. Reduction in MCL-1 protein expression as assessed by immunohistochemistry further confirmed these results. Furthermore, the caspase 3/7 assay demonstrated apoptosis in the MCL-1 silenced tissues. The study strongly suggests that targeted delivery of siRNAs using multi-layered dendrimer nanostructures could be an effective therapy for LHRH overexpressing cancers.

Association between Leukemia Inhibitory Factor Gene Polymorphism and Clinical Outcomes among Young Women with Poor Ovarian Response to Assisted Reproductive Technology.

Does the presence of single-nucleotide polymorphisms (SNPs) in the leukemia inhibitory factor (LIF) gene affect ovarian response in infertile young women? This was a case-control study recruiting 1744 infertile women between January 2014 to December 2015. The 1084 eligible patients were stratified into four groups using the POSEIDON criteria. The gonadotropin-releasing hormone receptor (GnRHR), follicle-stimulating hormone receptor (FSHR), anti-Müllerian hormone (AMH), and LIF SNP genotypes were compared among the groups. The distributions of LIF and FSHR among younger and older patients were compared. Clinical outcomes were also compared. The four groups of poor responders had different distributions of SNP in LIF. The prevalence of LIF genotypes among young poor ovarian responders differed from those of normal responders. Genetic model analyses in infertile young women revealed that the TG or GG genotype in the LIF resulted in fewer oocytes retrieved and fewer mature oocytes relative to the TT genotypes. In older women, the FSHR SNP genotype contributed to fewer numbers of mature oocytes. LIF and FSHR SNP genotypes were associated with a statistically significant reduction in ovarian response to controlled ovarian hyperstimulation in younger and older women with an adequate ovarian reserve, respectively.

Relugolix: A Review in Advanced Prostate Cancer.

Relugolix (Orgovyx®), an orally active nonpeptide gonadotropin-releasing hormone (GnRH) receptor antagonist that provides rapid testosterone suppression, is indicated in the USA for the treatment of advanced prostate cancer and in the EU for advanced hormone-sensitive prostate cancer. In the pivotal phase III HERO trial in men with advanced prostate cancer, once-daily oral relugolix (with a loading dose on day 1) led to a sustained castration rate over 48weeks of treatment of > 90%, a rate that was non-inferior to that provided by intramuscular leuprolide depot every 3months (with an exploratory analysis further indicating the superiority of relugolix over leuprolide). Relugolix was generally well tolerated, having an adverse event profile that is consistent with testosterone suppression. Furthermore, there is evidence that relugolix may be associated with a lower risk of major adverse cardiac events compared with leuprolide. With the ability to provide the rapid testosterone suppression (with no initial surge in testosterone upon treatment initiation) combined with the benefits of oral administration and potentially improved cardiac safety, relugolix presents a valuable treatment option for men with advanced prostate cancer where androgen deprivation therapy is indicated.

Synthetic microfiber exposure negatively affects reproductive parameters in male medaka (Oryzias latipes)

Microplastics not only accumulate in the bodies of fishes and cause damage to the organs, but also cause many other problems, such as reduced reproductive capacity, by acting directly or indirectly on the hypothalamus-pituitary-gonad axis (HPG axis). In this study, we investigated the changes in HPG axis-related genes in male medaka (Oryzias latipes) exposed to fiber-type microplastics. We confirmed the progression of vitellogenesis, a sign of endocrine disruption, in male fish. In the microfiber-exposed group, microfiber accumulation was confirmed in the gills and intestines. One week after exposure to two different concentrations of microfibers (500 and 1,000 fibers/L), the fish showed increased expression of gonadotropin-releasing hormone (GnRH) and luteinizing hormone receptor (LH-R) mRNA. From day 10 of exposure to the microfibers, there was an increase in the expression of the gonadotropin-inhibitory hormone (GnIH) mRNA and a decrease in the expression of GnRH and LH-R mRNA. There was an increase in the cytochrome P450 aromatase (CYP19a) mRNA expression and plasma estradiol (E2) concentration in the 1,000 fibers/L exposure group. High vitellogenin (VTG) mRNA expression was confirmed seven days after exposure in the 1,000 fibers/L group, which was consistent with the VTG mRNA expression signals detected in the liver using in situ hybridization. These results suggest that microfiber ingestion may cause short-term endocrinal disruption of the HPG axis in male medaka, which in turn may interfere with their normal maturation process.

Effect of GnRH immunocastration on immune function in male rats.

The present study aimed to reveal the effects of immunocastration on the development of the immune system in rats. Seventy rats were randomly assigned into two groups: Control (n = 35) and immunized (n = 35). Twenty-day-old rats were immunized with gonadotropin-releasing hormone (GnRH) and booster immunization was administered every two weeks (three immunizations in total). From 20-day-old rats, we collected samples every two weeks, including five immunized rats and five control rats (seven collections in total). We collected blood samples, testicles, thymuses, and spleens. The results showed that GnRH immunization increased the GnRH antibody titers and reduced the testosterone concentration (both P < 0.05). Compared with the control group, the number of CD4+CD8- cells, CD4-CD8+ cells, and CD4+CD8+ cells increased (P < 0.05) whereas the number of CD4-CD8- cells and CD4+CD25+ cells reduced in the immunized group (P < 0.05) over time. GnRH immunization also increased the relative weights of thymus and spleen (P < 0.05), serum concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17 and Interferon-γ (IFN-γ) over time (P < 0.05), and changed the mRNA levels of IL-2, IL-4, IL-6. IL-10, IL-17, IFN-γ, CD4, D8, CD19 GnRH, and GnRH receptor (GnRH-R) in thymus and spleen. Thus, GnRH immunization enhanced the immune markers in thymus, spleen, and blood immune cytokines in rats.

Association of Gonadotropin-Releasing Hormone Receptor (GnRHR) gene (c.18085 T&gt;G) and litter size in Ettawa crossbreed goat

In the present study, the association of Gonadotropin-Releasing Hormone Receptor gene (GnRHR) and litter size were investigated using the PCR-RFLP method as a genetic marker candidate for litter size in 35 individuals from Ettawa crossbreed goats. This research has two steps conducted in the laboratory and in the field. Data on litter size and blood samples were collected from the field. In the laboratory was carried out DNA isolation, amplification, and restriction. Molecular analysis of DNA isolation were precise, the enzyme Msp1 (C*CGG) with a product length of 706 bp was used for amplification and restriction analysis, releaved TT genotype in GnRHR gene fragment. In the exon 3 of chromosome 6, the single nucleotide polymorphism (SNP) c.18085 T&gt;G was found. Ettawa crossbreed goat in calculations using the hardy-weinberg law, insignificant results are obtained because the value is more than &gt; 0.05 (db; 1) = 0.50. The genotypes and allele frequencies found in the Ettawa Crossbreed Goat GnRHR genes are monomorphic and the GnRHR gene did not associate with litter size. The conclusion is that GnRHR exon 3 gene (SNP) c.18085 T&gt;G did not associate with litter size and can not be used as a genetic marker on Ettawa crossbred goats.

Anti-GnRH Receptor Monoclonal Antibody, GHR106 is First-inClass GnRH Antagonist

During the last decade, a monoclonal antibody, GHR106 was generated and characterized extensively biologically and immunologically. This antibody targets specific human pan cancer marker and is being evaluated for potential therapeutic applications in cancer immunotherapy and fertility regulations. GHR106 was generated against N1-29 oligopeptide located in the extracellular domains of human GnRH receptor found either in the anterior pituitary or in most of cancer cells. In vitro culture of cancer cells revealed that this antibody can induce apoptosis of cancer cells following 24-48 hours incubations. Anti-tumor activities of GHR106 were evaluated by typical nude mouse experiments in which the effective volume reduction of implanted tumor was observed. Humanized forms of GHR106 were made available in CAR (chimeric antigen receptor) T-cell constructs. GHR106 was shown separately to induce cytotoxic killings of cancer cells in vitro by releasing cytokines following incubations of tumor cells with CAR-T cell constructs. In addition, GHR106 also acts as GnRH antagonist by a specific targeting to pituitary GnRH receptor for reversible suppressions of reproductive hormones. These were demonstrated in “Proof of Concept” rabbit experiments. A single subcutaneous injection with 1-3mg/kg of GHR106 to rabbits of either sex could result in 60 to 90% reductions of gonadotropins, estrogen and/or testosterone over a period of one to two weeks. Based on these preclinical assessments, it can be concluded that GHR106 is restricted in tissue expressions and suitable for cancer immunotherapy. It can also act as long-acting GnRH antagonist to target specifically on GnRH receptor in anterior pituitary for numerous gynecological diseases including ovulation inhibition in IVF/ART, endometriosis-premenstrual syndrome, precocious puberty, uterine fibroids and/or polycystic ovarian syndrome.