GnRH Research Articles

Efficacy and safety of neoadjuvant chemohormonal therapy for high-risk prostate cancer treated with robot-assisted laparoscopic radical prostatectomy: a propensity score-matched analysis (the MSUG94 group).

The optimal neoadjuvant regimen before radical prostatectomy (RP) in patients with high-risk (HR) prostate cancer (PCa) remains to be determined. This retrospective multicenter cohort study assessed the effectiveness and safety of neoadjuvant chemohormonal therapy (NCHT) in patients with HR-PCa undergoing robot-assisted laparoscopic radical prostatectomy (RALP). We reviewed the datasets of 1023 subjects who underwent RALP at nine Japanese facilities between September 2012 and October 2023. The enrolled patients were divided into two groups using propensity score matching: a RALP-alone group and those who underwent NCHT followed by RALP (NCHT group). The NCHT regimen consisted of a luteinizing hormone-releasing hormone antagonist and tegafur-uracil for at least 3months before RALP. The primary endpoint was biochemical recurrence (BCR) after RALP. The secondary endpoint was the surgical specimen pathology findings. Propensity score matching identified 139 individuals for each group. Median follow-up was 18.2months. During follow-up, BCR was observed in 41 patients (29.5%) in the RALP-alone group and 22 patients (15.8%) in the NCHT group (p = 0.010). Pathological results showed significantly more organ-confined PCa and significantly fewer positive surgical margins or lymphovascular invasion in the NCHT group than in the RALP-alone group. The 2-yr biochemical recurrence-free survival (BRFS) was 72.7% and 74.7% in the RALP-alone and NCHT groups, respectively (p = 0.086). Two patients (1.4%) experienced grade 3 liver disorder as an NCHT-related adverse event. The results suggest that NCHT can safely treat HR-PCa and may reduce the incidence of BCR when combined with RALP.

Clinical evaluation and outcome in patients with heart failure receiving chemotherapy with different anti-cancer agents

Abstract Background Over the last few decades, advances in cancer therapy have prolonged the life expectancies of patients diagnosed with malignancies. Although traditional cytotoxic chemotherapy, molecularly targeted therapy, and immunotherapy have improved survival rates, off-target adverse effects such as complications of the cardiovascular system require attention. The optimal strategy for modern chemotherapy should be based on a comprehensive approach for patients with cancer and cardiovascular diseases. Therefore, cardio-oncology has received increasing attention owing to the cardiotoxic effects of anti-cancer therapies. Purpose To assess the clinical characteristics and outcomes of patients with heart failure (HF) who received chemotherapy compared with those of a matched cohort with HF who did not receive chemotherapy, using real-world HF data. Methods This study used the Diagnosis Procedure Combination database of the Japanese Registry of All Cardiac and Vascular Disease. We identified 1,328,113 patients hospitalized for HF between April 2012 and March 2021. We excluded 14,043 patients with unknown outcomes, non-emergency admissions, and unknown chemotherapy data. The primary endpoint was readmission. Thus, our study included 5,774 patients who received chemotherapy and 39,412 patients who did not. The propensity score (PS) was estimated using a logistic regression model, with chemotherapy as the dependent variable, and clinically score-matched analysis of 11,532 patients with HF with or without chemotherapy. Results Colon, lung, breast, and prostate cancers accounted for > 60% of all cancer types. After PS matching, 62.5% and 19.5% of patients with HF had prostate and breast cancer, respectively. After PS matching, readmission was more frequently observed in patients undergoing chemotherapy than those not undergoing chemotherapy (odds ratio [OR], 1.26; 95% confidence interval [CI] 1.17–1.36, p<0.0001). Treatment with genomic epidermal growth factor receptor tyrosine kinase inhibitors (OR, 1.69; 95% CI 1.39–2.07), taxane (OR, 2.95; 95% CI 2.11–4.12), anthracyclines (OR, 1.86; 95% CI 1.19–2.90), and fluorouracil agents (OR, 1.65; 95% CI 1.18–2.30) resulted in a significant risk of readmission. Moreover, patients treated with endocrine therapy before hospitalization had significantly higher readmission rates than the matched patients who did not receive chemotherapy (aromatase inhibitors: OR, 1.40; 95% CI 1.19–1.65: anti-androgens: OR, 1.39; 95% CI 1.27–1.52: luteinizing hormone-releasing hormone agonists: OR, 1.18; 95% CI 1.08–1.30 and gonadotropin-releasing hormone antagonists: OR, 2.17; 95% CI 1.68–2.79). Conclusions Medical providers need to monitor and follow-up patients with HF, depending on the characteristics of the anticancer agents and types of cancer. Furthermore, close collaboration among oncologists, cardiologists, and healthcare professionals will ensure the delivery of optimal care for patients with HF undergoing chemotherapy.

The Effect of Androgen Deprivation Therapy on the Cardiovascular System in Advanced Prostate Cancer

Androgen deprivation therapy (ADT) is a mainstay treatment for metastatic prostate cancer, improving progression-free survival. ADT suppresses the production of testosterone and reduces circulating levels of the hormone. Luteinizing hormone-releasing hormone (LH-RH) agonists are the most commonly used ADT modality. They can be given alone or in combination with androgen synthesis inhibitors or androgen receptor antagonists. An estimated 40% of prostate cancer patients will receive ADT as part of their therapy during their lifetime. However, ADT has numerous adverse effects, including an increased cardiovascular risk that impacts quality of life. Relugolix is an alternative form of ADT. It is the only oral gonadotropin-releasing hormone antagonist, circumventing injection site reactions, making it easier for patients to take, and thus increasing compliance. Testosterone suppression with relugolix is excellent and testosterone recovery after discontinuation is rapid. This paper reviews the ADT and anti-androgen treatment options for men with prostate cancer and the cardiovascular effects of these therapies. There is accumulating evidence that cardiovascular risk with relugolix is lower than with other ADT medications and also lower than with androgen synthesis inhibitors and androgen receptor antagonists. This paper provides insight into the use of different ADT regimens based on the cardiovascular status and circumstances. It explores strategies to mitigate negative cardiovascular consequences and highlights the need for further study.

Embryonic and larval development of black jewfish, Protonibea diacanthus: A new candidate for aquaculture in northern Australia

Black jewfish Protonibea diacanthus is a large, commercially important fish distributed across the tropical Indo-Pacific. In Australia, there is an established commercial wild fishery for the species but it’s aquaculture potential has not been investigated. This research presents hatchery production of native P. diacanthus in Darwin, Australia and documents ontogeny of early life stages of this species over three trial runs. Wild P. diacanthus were induced to spawn with luteinizing hormone-releasing hormone analog (LHRHa) and eggs were released approximately 25–28 h after injection (0.88 ± 0.01 mm in diameter with oil globule 0.24 ± 0.01 mm). Larvae hatched 12 h after spawning. At one day post hatch (dph) larvae were 2.68 ± 0.01 mm standard length with 0.15 ± 0.01 mm oil globule diameter. Larvae mouths opened at 31 h post hatch (hph) and first feeding was seen at 57 hph. Swim bladder inflation (92 %) occurred between 40 and 62 hph. Larvae were progressively fed rotifers, Artemia and Otohime microdiet, and metamorphosis occurred between 20 and 25 dph, completing as they reached over 13 mm standard length. Tail biting cannibalism began with the onset of metamorphosis and caused significant mortality until approximately 24 dph when metamorphosed juveniles could be handled and moved to low stocking density systems. This study demonstrates that northern Australian P. diacanthus is amenable to hatchery production and provides important foundational knowledge for this emerging aquaculture species.

7426 Tamoxifen-Induced Ovarian Hyperstimulation in a Pre-Menopausal Patient with Breast Cancer History: Spontaneous Resolution with Conservative Management

Abstract Disclosure: S. Gondi: None. M. Contento: None. A. Leiter: None. Background: Tamoxifen is a selective estrogen receptor modulator (SERM) that competitively binds to estrogen receptors (ER) on tumors and inhibits the effect of estrogen, which is used in the treatment and prevention of ER-positive breast cancer. Tamoxifen therapy has been reported to increase serum estrogens and cause ovarian hyperstimulation in premenopausal women, but knowledge on how to manage these conditions is limited. Clinical Case: A 36-year-old pre-menopausal female with history of malignant neoplasm of the right breast (ER positive) who completed neoadjuvant chemotherapy, lumpectomy, and radiation, on tamoxifen for seven years presented with new-onset oligomenorrhea. Laboratory testing done by the patient’s gynecologist revealed total estrogen 2,723 pg/mL (reference range [RR] 34-501), testosterone 132 ng/dL (RR 8-60), anti-Mullerian hormone 12.7 ng/mL (RR for age 0.66-8.75), ovulation-phase follicle stimulating hormone 11.5 mIU/mL (RR 4.7-21.5) and luteinizing hormone (LH) 63.3 mIU/mL (RR 14-95.6). Further workup revealed that ovarian tumor markers alpha-fetoprotein and serum human chorionic gonadotropin and other labs including dehydroepiandrosterone sulfate, progesterone 17-OH, lactate dehydrogenase, prolactin, and thyroid stimulating hormone were normal. Transvaginal ultrasound (TVUS) showed a new 2.8 x 1.9 x 2.3 cm complex left ovarian cyst, which, along with the elevated estrogen level, was concerning for ovarian hyperstimulation. Treatment with LH-releasing hormone (LHRH) agonists, surgical consultation, and discontinuation of tamoxifen were offered as potential management strategies, but the patient opted for observation and continued tamoxifen. Two months later, estradiol was 989 pg/mL (RR 85-498), and then three months later decreased to 152 pg/mL with repeat TVUS showing resolution of the left ovarian cyst. The patient’s oligomenorrhea resolved with resumption of regular menstrual cycles. Conclusion: While it is well-known that tamoxifen causes elevated serum estrogen levels and can lead to ovarian hyperstimulation, there is limited research on the management of these side effects. Treatment strategies in past cases have included oophorectomy or medical management with LHRH agonists or gonadotropin-RH agonists. However, this case demonstrates that a tamoxifen-induced ovarian cyst and high estrogen levels can resolve on its own with continued tamoxifen treatment. Conservative management with monitoring via imaging and repeat estrogen levels may be sufficient in management of pre-menopausal women with tamoxifen-induced ovarian hyperstimulation. Presentation: 6/1/2024

A randomized phase II trial on the addition of dutasteride to combined androgen blockade therapy versus combined androgen blockade therapy alone in patients with advanced or metastatic salivary duct carcinoma – the DUCT study protocol

BackgroundSalivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients.MethodsThis prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome.DiscussionThe DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial’s findings could be readily applied into clinical practice.Trial registrationClinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022.Protocol versionCurrent protocol version 4.0, February 21, 2024.

Effect of Administering Serially Diluted Suprecur and Motilium (Dopamine Blocker) on the Breeding Performance of Clarias gariepinus

This study was designed to determine the effect of using serially diluted Buserelin acetate (Suprecur), which is a luteinizing hormone-releasing hormone analogue (LHRHa) with dopamine antagonist (Motilium) on the latency period, fecundity, percentage fertilization and percentage hatching of Clarias gariepinus. Treatments administered include 50ug/l, 40ug/l, 20ug/l and 10ug/l of Suprecur in tandem with 5mg/kg of Motilium. Metrics obtained include egg numbers, latency period, fertilization rate, hatching rates, and survival to first feeding. The results obtained demonstrated that the use of Suprecur (LHRHa) together with dopamine antagonist (Motilium) successfully induced ovulation in the experimental Clarias gariepinus broodfish. The highest fecundity was from the treatment T40 There was no significant difference in egg weights stripped from each treated group. The application of 50 µg/kg of Suprecur with 5mg/kg of Motilium resulted in earlier synchronization of ovulation (Latency period; 12 hours). Results of the fertilization percentage indicated that an increase in the dose of LHRHa did not significantly affect the fertilization rate in treated groups of broodfish. Overall superiority of 50 µg/kg of Suprecur plus 5mg/kg of Motilium in spawning induction was proved by significantly high hatchability, 83.56%. Broodstock used for the 40µg/kg dose had the highest fecundity. There was no significant correlation (p>0.05) between the water quality parameters and the breeding parameters. In conclusion, the result obtained clearly indicates an overall superiority of using 50 µg/kg of Suprecur together with 5mg/kg of Motilium to induce spawning with regard to the recorded high hatchability percentage.

Effectiveness of surgical castration by bilateral subcapsular orchiectomy as monotherapy for the treatment of advanced prostate cancer.

Prostate cancer is the most common malignancy in men and the second cause of death due to cancer [1]. Treatment of prostate cancer has been a field of many progresses, but the discovery of the role of androgen in the genesis of prostate cancer by Hugins and Hodges is really a milestone in the treatment of advanced prostate cancer [2]. In patients with advanced prostate cancer, options for androgen ablation include bilateral orchiectomy, therapy with luteinizing hormone-releasing hormone (LHRH) analogues and antagonists, and combined androgen blockade (typically a LHRH analogue plus a first-generation anti-androgen). Although orchiectomy remains the historical gold standard for androgen ablation, LHRH therapy is considered to be equivalent therapeutically. Medical castration has the advantage to induce less psychological effects comparatively to the surgery, reason why in developed countries patients are managed with medical therapy [3]. However, LHRH agonists cannot induce a complete castration levels of testosterone in some patients [4]. Instead, surgical castration can completely eliminate remaining testosterone produced by the Leydig cells in testes [5]. According to the latest recommendations of the European Association of Urology (EAU), androgen deprivation therapy (ADT) is the firstline indication in patients with advanced and metastatic PCa [6]. This first line is made of LHRH agonists, surgical castration representing the second line [7] And Several techniques of surgical castration have been described with comparable results in terms of patient survival and quality of life, but the sub-capsular technique of preserving testicular albuginea and epididymis is the most commonly used [8]. The relatively high cost of chemical castration is a constraint in the therapeutic choice in developing countries [9]. Therefore, surgical castration is an interesting alternative because of its simplicity and affordability in patients, most of whom have no health insurance. In Togo, most patients diagnosed with prostate cancer are at the metastasis stage, and surgical castration is often used as first-line treatment [10]. The aim of this study was to assess the biological and clinical effectiveness of surgical castration as the sole treatment in patients with advanced prostate cancer.

Andrew Victor Schally: Pioneering Neuroendocrinologist and Architect of Luteinizing Hormone-Releasing Hormone Analogs.

Andrew Victor Schally is a pioneering figure in endocrinology and neuroendocrinology, whose work has fundamentally transformed the understanding and treatment of hormone-related disorders and cancer. His research, particularly in the isolation, characterization, and clinical application of hypothalamic hormones, has been instrumental in advancing medical science. Schally's early life, marked by the adversities of World War II, shaped his resilience and determination, driving him to pursue a career in medical research. His groundbreaking discovery of luteinizing hormone-releasing hormone (LHRH) and its analogs revolutionized the treatment of hormone-dependent cancers, especially advanced prostate cancer, by providing an effective alternative to surgical castration. Beyond LHRH, Schally's contributions to the development of somatostatin analogs have also had a significant impact on the management of acromegaly and neuroendocrine tumors. This article reviews Schally's life and work, emphasizing his contributions to endocrinology, particularly in the context of LHRH and its clinical applications. The review outlines his early life and education, his pioneering research on hypothalamic hormones, and the development of LHRH analogs that have become a cornerstone in the treatment of prostate cancer. Schally's ability to translate basic scientific discoveries into practical therapeutic strategies has earned him numerous accolades, including the Nobel Prize in Physiology or Medicine in 1977. His legacy continues to inspire and guide research in endocrinology and oncology, underscoring the lasting impact of his scientific achievements.

A practical guide for the use of apalutamide for non-metastatic castration-resistant prostate cancer in Australia.

Studies of patients with castrate-resistant prostate cancer at high risk of developing overt metastases but with no current evidence of evaluable disease on computed tomography or bone scan non-metastatic castrate-resistant prostrate cancer have demonstrated increased metastasis-free survival and overall survival following treatment with the next-generation oral anti-androgen apalutamide (in addition to therapies that aim to lower testosterone to castrate levels) or luteinizing hormone-releasing hormone antagonist or surgical castration. Patients receiving apalutamide can be managed by medical oncologists, radiation oncologists, or urologists, preferably as part of a multidisciplinary team. However, the importance of additional safety monitoring for significant adverse effects and drug interactions should not be underestimated. The toxicities of apalutamide are manageable with experience and should be managed proactively to minimize their impact on patients. Monitoring of patients for apalutamide-specific toxicities, including skin rash, hypothyroidism, and QT prolongation should be carried out regularly, particularly in the first few months following initiation. Monitoring should continue alongside monitoring for toxicities of androgen deprivation, including cardiovascular risk, hot flashes, weight gain, bone health, muscle wasting, and diabetic risk. This review is a practical guide to the use of apalutamide describing the management of patients including dosing and administration, toxicities, potential drug interactions, and safety monitoring requirements.

Luteinizing Hormone-Releasing Hormone (LHRH)-Conjugated Cancer Drug Delivery from Magnetite Nanoparticle-Modified Microporous Poly-Di-Methyl-Siloxane (PDMS) Systems for the Targeted Treatment of Triple Negative Breast Cancer Cells.

This study presents LHRH conjugated drug delivery via a magnetite nanoparticle-modified microporous Poly-Di-Methyl-Siloxane (PDMS) system for the targeted suppression of triple-negative breast cancer cells. First, the MNP-modified PDMS devices are fabricated before loading with targeted and untargeted cancer drugs. The release kinetics from the devices are then studied before fitting the results to the Korsmeyer-Peppas model. Cell viability and cytotoxicity assessments are then presented using results from the Alamar blue assay. Apoptosis induction is then elucidated using flow cytometry. The in vitro drug release studies demonstrated a sustained and controlled release of unconjugated drugs (Prodigiosin and paclitaxel) and conjugated drugs [LHRH conjugated paclitaxel (PTX+LHRH) and LHRH-conjugated prodigiosin (PG+LHRH)] from the magnetite nanoparticle modified microporous PDMS devices for 30 days at 37 °C, 41 °C, and 44 °C. At 24, 48, 72, and 96 h, the groups loaded with conjugated drugs (PG+LHRH and PTX+LHRH) had a significantly higher (p < 0.05) percentage cell growth inhibition than the groups loaded with unconjugated drugs (PG and PTX). Additionally, throughout the study, the MNP+PDMS (without drug) group exhibited a steady rise in the percentage of cell growth inhibition. The flow cytometry results revealed a high incidence of early and late-stage apoptosis. The implications of the results are discussed for the development of biomedical devices for the localized and targeted release of cancer drugs that can prevent cancer recurrence following tumor resection.

Optimization of a protocol for fertilized egg production in Japanese eel using recombinant gonadotropins, LHRHa, pimozide, and 17α-hydroxyprogesterone

Recently, two types of Japanese eel recombinant gonadotropins (rGths), recombinant follicle-stimulating hormone (rFsh) and luteinizing hormone (rLh), have been successfully produced. However, the protocol for obtaining fertilized eggs using rGths has not yet been optimized. In this study, to establish a new protocol for obtaining fertilized eggs from Japanese eel, we decided to use rFsh as an inducer of vitellogenesis and focused on optimizing the final oocyte maturation (FOM) and ovulation induction method using rLh, 17α-hydroxyprogesterone (OHP), Lh-releasing hormone analog (LHRHa), and pimozide. Our findings indicates that OHP injection is crucial for stable ovulation induction. Quality evaluations revealed that the FOM and ovulation induction methods using LHRHa, pimozide, and OHP significantly improved the egg quality (fertility, hatchability, and larval survival) better than the methods using rLh and OHP (P < 0.05). Furthermore, effects of different doses of LHRHa and pimozide on egg quality were examined. We found that 0.5 mg/kg BW LHRHa, 10 mg/kg BW pimozide, and 2.0 mg/kg BW OHP injections was an effective and economical induction method, and this method was defined as the rGths method. When comparing the quality and quantity of eggs and larvae obtained by the rGths method with those obtained by the conventional method, the former displayed superior quality. In addition, the number of eggs, fertilized eggs, and normal larvae at 6 days post hatch was significantly higher in broodstock matured by the rGths method compared to the conventional method (P < 0.05). These results suggest that the new rGths method is a promising alternative for the artificial sexual maturation Japanese eel, potentially leading to a higher yield of larvae.

A randomised trial of short- vs long-term androgen deprivation with salvage radiotherapy for biochemical failure following radical prostatectomy: URONCOR 06-24.

Salvage radiotherapy (SRT) and androgen-deprivation therapy (ADT) are widely used in routine clinical practice to treat patients with prostate cancer who develop biochemical recurrence (BCR) after radical prostatectomy (RP). However, there is no standard-of-care consensus on optimal duration ADT. Investigators propose three distinct risk groups in patients with prostate cancer treated with SRT in order to better define the indications and duration of ADT combined with SRT. The URONCOR 06-24 trial (ClinicalTrials.gov identifier NCT05781217) is a prospective, multicentre, randomised, open-label, phase III, clinical trial. The aim of the trial is to determine the impact of short-term (6 months) vs long-term (24 months) ADT in combination with SRT on distant metastasis-free survival (MFS) in patients with prostate cancer with BCR after RP (intermediate and high risk). The primary endpoint is 5-year MFS rates in patients with prostate cancer treated with long- vs short-term ADT in combination with SRT. Secondary objectives are biochemical-relapse free interval, pelvic progression-free survival, time to start of systemic treatment, time to castration resistance, cancer-specific survival, overall survival, acute and late toxicity, and quality of life. Total of 534 patients will be randomised 1:1 to ADT 6 months or ADT 24 months with a luteinizing hormone-releasing hormone analogue in combination with SRT, stratified by risk group and pathological lymph node status. The study is conducted under the guiding principles of the World Medical Association Declaration of Helsinki. The results will be disseminated at research conferences and in peer-reviewed journals. EudraCT number 2021-006975-41.

Cloning and expression patterns of espl1 gene in loach (Misgurnus anguillicaudatus) during gonad development

espl1 (extra spindle pole bodies like 1), a cysteine endopeptidase, is a mitotic key player in chromosomal segregation and centriole duplication during mitosis and meiosis. Considering the espl1 gene has not been reported in aquatic organisms, we reported the isolation and expression of the espl1 gene from loach. In this study, the full-length cDNA of espl1 was cloned for the first time in loach. In loach, the full-length cDNA of espl1 consisted of 6948 bp, the open reading frame (ORF) is 6240 bp, and the espl1 gene encodes 2139 amino acids. Moreover, the deduced amino acid sequences of espl1 in loach shared the highest identity with those of Cyprinus carpio (78.39%) and Sinocyclocheilus anshuiensis (78.27%), and the sequence homology among the various separases is confined to the C-terminal region. Furthermore, tissue-specific checking results indicated that the espl1 gene of the loach gene was highly expressed in the ovary and testis, especially in stage Ⅳ oocytes and stage Ⅳ testis by Real-time quantitative PCR (qPCR). Then, whole-mount in situ hybridization analyses revealed the expression of espl1 in the early development of loach. We found that the positive signal of espl1 was observed in the notochord during the early embryo development of loach. Last but not least, when treated with luteinizing hormone-releasing hormone analog (LHRH-A2), the mRNA expression of espl1 was significantly increased in the testes and ovaries. These observations suggest that the espl1 gene had a distinct and important role in the gonads of Loach. This study will be of value for further studies into the function of the espl1 gene in fish.

Reversible Sterilization of Channel Catfish via Overexpression of Glutamic Acid Decarboxylase Gene.

The confinement of transgenic fish is essential to prevent their escape and reproduction in natural ecosystems. Reversible transgenic sterilization is a promising approach to control the reproduction of transgenic fish. Therefore, the present study was conducted to develop a reversibly sterile channel catfish (Ictalurus punctatus) via the transgenic overexpression of the goldfish (Carassius auratus) glutamic acid decarboxylase (GAD) gene driven by the common carp (Cyprinus carpio) β-actin promoter to disrupt normal gamma-aminobutyric acid (GABA) regulation. Three generations of GAD-transgenic fish were produced. All studied generations showed repressed reproductive performance; however, this was not always statistically significant. In F1, 5.4% of the transgenic fish showed a sexual maturity score ≥ 4 (maximum = 5) at five years of age, which was lower (p = 0.07) than that of the control group (16.8%). In the spawning experiments conducted on F1 transgenic fish at six and nine years of age, 45.5% and 20.0% of fish spawned naturally, representing lower values (p = 0.09 and 0.12, respectively) than the percentages in the sibling control fish of the same age (83.3% and 66.7%, respectively). Four of six pairs of the putative infertile six-year-old fish spawned successfully after luteinizing hormone-releasing hormone analog (LHRHa) therapy. Similar outcomes were noted in the three-year-old F2 fish, with a lower spawning percentage in transgenic fish (20.0%) than in the control (66.7%). In one-year-old F2-generation transgenic fish, the observed mean serum gonadotropin-releasing hormone (GnRH) levels were 9.23 ± 2.49 and 8.14 ± 2.21 ng/mL for the females and males, respectively. In the control fish, the mean levels of GnRH were 11.04 ± 4.06 and 9.03 ± 2.36 ng/mL for the females and males, respectively, which did not differ significantly from the control (p = 0.15 and 0.27 for females and males, respectively). There was no significant difference in the estradiol levels of the female transgenic and non-transgenic fish in the one- and four-year-old F2-generation fish. The four-year-old F2-generation male transgenic fish exhibited significantly (p < 0.05) lower levels of GnRH and testosterone than the control fish. In conclusion, while overexpressing GAD repressed the reproductive abilities of channel catfish, it did not completely sterilize transgenic fish. The sterilization rate might be improved through selection in future generations.

Lipid-Based Nanocarrier by Targeting with LHRH Peptide: A Promising Approach for Prostate Cancer Radio-Imaging and Therapy.

Prostate cancer is a prevalently detected malignancy with a dismal prognosis. Luteinizing-hormone-releasing-hormone (LHRH) receptors are overexpressed in such cancer cells, to which the LHRH-decapeptide can specifically bind. A lipid-polyethylene glycol-conjugated new LHRH-decapeptide analogue (D-P-HLH) was synthesized and characterized. D-P-HLH-coated and anticancer drug doxorubicin (DX)-loaded solid lipid nanoparticles (F-DX-SLN) were formulated by the cold homogenization technique and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, differential scanning calorimetry, dynamic light scattering, electron microscopy, entrapment efficiency, and drug-release profile studies. F-DX-SLN allows site-specific DX delivery by reducing the side effects of chemotherapy. Cancer cells could precisely take up F-DX-SLN by targeting specific receptors, boosting the cytotoxicity at the tumor site. The efficacy of F-DX-SLN on PC3/SKBR3 cells by the MTT assay revealed that F-DX-SLN was more cytotoxic than DX and/or DX-SLN. Flow cytometry and confocal microscopic studies further support F-DX-SLNs' increased intracellular absorption capability in targeting LHRH overexpressed cancer cells. F-DX-SLN ensured high apoptotic potential, noticeably larger mitochondrial transmembrane depolarization action, as well as the activation of caspases, a longer half-life, and greater plasma concentration. F-DX-SLN/DX-SLN was radiolabeled with technetium-99m; scintigraphic imaging studies established its tumor selectivity in PC3 tumor-bearing nude mice. The efficacy of the formulations in cancer treatment, in vivo therapeutic efficacy tests, and histopathological studies were also conducted. Results clearly indicate that F-DX-SLN exhibits sustained and superior targeted administration of anticancer drugs, thus opening up the possibility of a drug delivery system with precise control and targeting effects. F-DX-SLN could also provide a nanotheranostic approach with improved efficacy for prostate cancer therapy.

Growth hormone increase by luteinizing hormone-releasing hormone reflects gonadotroph-related characteristics in acromegaly

PurposeWe previously showed the clinical characteristics of acromegaly with a paradoxical growth hormone (GH) response to oral glucose or thyrotropin-releasing hormone. However, the clinical characteristics of acromegaly with an increased GH response to luteinizing hormone-releasing hormone (LHRH responders) remain unclear. The aim of the present study was to evaluate the clinical characteristics, especially gonadotroph-related characteristics of LHRH responders in acromegaly.MethodsThe clinical characteristics of 33 LHRH responders and 81 LHRH nonresponders were compared.ResultsNo differences in age, sex or basal serum levels of GH, insulin-like growth factor-1 (IGF-1), and gonadotropin were observed between the two groups. Steroidogenic factor 1 (SF-1), gonadotropin-releasing hormone receptor (GnRHR), and LH expression was more frequently observed in LHRH responders (P < 0.05). In addition, a greater increased rate of GH after LHRH loading, and the proportion of GnRHR and gonadotropin expression was observed in pituitary tumor with SF-1 expression than that without the expression (P < 0.01). LHRH responders showed a greater GH decrease in the octreotide test and a greater IGF-1 decrease after first-generation somatostatin ligand than LHRH nonresponders (P < 0.05). Furthermore, the proportion of hypointense pituitary tumors on T2-weighted magnetic resonance imaging and tumors with densely granulated type was higher in LHRH responders than in LHRH nonresponders, respectively (P < 0.05). No difference between the two groups was observed in either somatostatin receptor 2 or 5 expression.ConclusionsThe increased GH response to LHRH is associated with the gonadotroph-related characteristics. This response may reflect the biological characteristics of somatotroph tumors.

Evaluation of the criteria for renewal of LHRH agonists in patients with prostate cancer: results of the ANAREN Study.

Injectable extended-release formulations of luteinizing hormone-releasing hormone agonists (LHRHa) have simplified the treatment of prostate cancer with a satisfactory level of androgen castration. This study aims to determine the percentage of patients whose initial LHRHa prescription was renewed during follow-up, how many changed formulation and how their quality of life evolved. This is an observational, prospective, multicentre study of men with prostate cancer who were to receive treatment with LHRHa (triptorelin every 3 or 6 months, leuprorelin every 3 or 6 months, or goserelin every 3 months) for 24 months. The treatment used was recorded and quality of life was assessed (QLQ-PR25 questionnaire) at four follow-up visits. A total of 497 men (median age 75 years) were evaluated. The median exposure to LHRHa was 24 months. The initial prescription was renewed in 95.7% at follow-up 1 and 75% at follow-up 4. The main reason for changing from a 6-month to a 3-month formulation was a preference for sequential treatment (according to the investigator) and to see the physician more frequently (according to the patient). The main reason for switching from the 3-month to 6-month formulation was simplification of treatment (according to the investigator) and for convenience (according to the patient). Findings in the QLQ-PR25 questionnaire revealed no changes in urinary or bowel symptoms, though an improvement in sexual activity was reported. Practically all investigators and patients were satisfied/very satisfied with the treatment. Changes in formulation were scarce and generally justified by convenience factors or personal preferences. Patients maintained a good health status, with a high rate of retention of LHRHa treatment. Study number: A-ES-52014-224.A plain language summary is provided as supplementary material (available at: https://www.drugsincontext.com/wp-content/uploads/2024/05/dic.2024-2-2-Suppl.pdf).

Fulvestrant with or without the cyclin-dependent kinase 7 (CDK7) inhibitor samuraciclib in advanced hormone receptor positive (HR+) breast cancer after CDK4/6 inhibition: Phase II SUMIT-BC study.

TPS1126 Background: CDK7 enhances oncogene transcription and upregulates anti-apoptotic genes, accelerates the cell cycle via CDK phosphorylation, and activates estrogen receptors (ERs) that can drive resistance to hormonal therapy in cancer. CDK7 inhibition therefore represents a potential anticancer strategy in cancer. Samuraciclib (CT7001) is a small molecule, ATP competitive, selective oral inhibitor of CDK7 that inhibits these key effects of CDK7. Samuraciclib had a favorable safety profile and showed clinical activity when combined with fulvestrant in a phase I study in patients with HR+/HER2− advanced breast cancer (BC) who had previously been treated with a CDK4/6 inhibitor. Patients with no detectable TP53 mutation in ctDNA at baseline and those without baseline liver metastases appeared to have better outcomes. The instant release capsule formulation of samuraciclib used in this study released large amounts of samuraciclib high in the gastrointestinal (GI) tract, which may have contributed to the observed low grade GI adverse events, which were managed with prophylaxis and counselling (1). Methods: A phase 2 open-label randomized study has been designed to evaluate the efficacy, safety, pharmacokinetics (PK), and quality of Life (QoL) of samuraciclib combined with fulvestrant compared to fulvestrant monotherapy (SUMIT-BC; NCT05963984). Eligible patients (n=60) are ≥18 years, have histologically or cytologically confirmed ER+/HER2− advanced or metastatic BC not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor combined with a CDK4/6 inhibitor in the adjuvant or advanced setting, are receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal, and have RECIST v1.1 evaluable disease. Prior SERD, mTOR inhibition, or chemotherapy for advanced BC are not permitted. All patients undergo baseline Guardant360 ctDNA analysis to establish TP53 and other mutation status. Patients are randomized 1:1:1 to fulvestrant alone (500 mg IM administered on days 1, 15 and 29 and then monthly), fulvestrant and samuraciclib 240 mg QD, or fulvestrant and samuraciclib 360 mg QD. In preparation for phase 3 development, a novel single tablet formulation of samuraciclib is used, which may enhance GI tolerability. Patients undergo RECIST v1.1 evaluation at baseline, every 8 weeks until week 48, and every 12 weeks thereafter. The primary endpoint is clinical benefit response at 24 weeks. Secondary endpoints are tolerability, progression free survival, overall response rate, duration of response, and PK of fulvestrant and samuraciclib. QoL (Functional Assessment of Cancer Therapy - Breast questionnaire [FACT-B]) and correlations between TP53 mutation and efficacy/safety will be assessed. 1. Coombes et al. Nature Comms 2023. Clinical trial information: NCT05963984 .

H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive (ER+), HER2 negative (–) breast cancer (BC).

1015 Background: H3B-6545 is a novel selective ER covalent antagonist (SERCA) that inactivates wild-type and mutant ERα. This phase 1/2 study aimed to identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and characterize safety and efficacy of H3B-6545 in women with advanced/metastatic ER+, HER2– BC. Methods: This multicenter, open-label study included dose-escalation [ph1] and -expansion [ph2] phases. Females (postmenopausal or concurrently receiving a luteinizing hormone-releasing hormone agonist) with ER+, HER2–BC who had disease progression on standard therapy were eligible. Prior therapy must have included a minimum of 2 hormonal therapies (HTs), or 1 HT + 1 chemotherapy, or 1 HT + a CDK4/6 inhibitor. H3B-6545 was administered orally QD at doses of 100-600 mg. The MTD was the highest dose at which ≤1 of 6 patients (pts) had a dose-limiting toxicity (DLT). In ph2, efficacy of the RP2D was examined. The primary endpoints were determination of RP2D (ph1) and efficacy (ph2; including objective response rate [ORR], duration of response [DOR], and progression-free survival [PFS] per RECIST v1.1 by investigator, and overall survival [OS]). Safety and PK were secondary endpoints. Results: At data cutoff (30 Nov 22), 151 pts received ≥1 dose of H3B-6545 during ph1 or ph2. Pts had a median (m [range]) of 2 (1-7) prior endocrine- and 1 (1-6) non-endocrine–containing therapies; 90.1% of pts received prior CDK4/6 inhibitors. During ph1, DLTs of grade (G) 3 rash (n=1) and G 3 fatigue (n=1) were observed at 600 mg; thus, 450 mg was determined to be the MTD/RP2D. In the full analysis set (N=151), 100% and 50.3% of pts had any grade and G ≥3 treatment-emergent adverse events (TEAEs), respectively. TEAEs leading to drug interruption, dose reduction, and withdrawal occurred in 38.4%, 20.5%, and 8.6% of pts, respectively. Nausea (45.7% [2.0% G ≥3]), sinus bradycardia (44.4% [0% G ≥3]), and diarrhea (41.1% [1.3% G ≥3]) were the most common TEAEs. QT prolongation occurred in 9.9% [3.3% G ≥3] of pts. Among 94 response-evaluable pts treated at 450 mg, ORR was 20.2% (95% CI 12.6–29.8) and clinical benefit rate (CBR) was 41.5% (95% CI 31.4–52.1); mPFS (95% CI) was 5.06 (3.15–7.26) months. Among all pts treated at 450 mg (n=115), mOS (95% CI) was 21.52 (16.56–25.46) months. Plasma concentration of H3B-6545 increased as dose increased. Additional results are shown (Table). Conclusions: H3B-6545 had a low rate of G ≥3 TEAEs and showed clinically meaningful antitumor activity in heavily pretreated female patients with ER+, HER2– BC. Clinical trial information: NCT03250676 . [Table: see text]