Search Results (30)

Objectives: Our aim is to report an uncommon pituitary activation occurring during the desensitization phase of the gonadotropin-releasing hormone agonist (GnRHa) long protocol, a cornerstone of medically assisted reproduction (MAR) therapy, in a young woman. Results: We present a case of a 33-year-old female patient with secondary infertility, who exhibited a prolonged and asynchronous follicular development during ovarian stimulation using the GnRH antagonist protocol. Therefore, during a repeat attempt, the long GnRH agonist protocol was employed. Surprisingly, rather than achieving suppression with the agonist, ultrasound detected many large follicles in both ovaries, accompanied by extremely elevated estrogen levels, indicating imminent ovarian hyperstimulation syndrome (OHSS). This unusual phenomenon was also observed during a subsequent attempt using the long protocol in another reproductive center. As part of the work-up to identify the underlying etiology, contrast-enhanced magnetic resonance imaging (MRI) of the sella turcica was performed, which revealed an 11 × 13 × 10 mm pituitary macroadenoma without evidence of pathological hormone secretion. The luteinizing hormone-releasing hormone (LHRH) stimulation test showed a normal luteinizing hormone and follicle-stimulating hormone response. Other abnormalities of the hypothalamo–hypophyseal–target-organ axis were not found. Neurosurgical intervention was deemed unnecessary; radiological follow-up of the lesion was recommended. Conclusions: In this case, the clinical presentation was markedly different from the expected suppressive effects of GnRH agonist therapy, with profoundly elevated estrogen levels and clinical signs of imminent OHSS. Notably, hypersensitivity of the adenohypophysis was not demonstrated following a single physiological LHRH stimulation test. However, the presence of a pituitary adenoma identified on MRI raises the possibility that gonadotropin receptor function was altered by the lesion—an effect revealed only after repeated GnRH agonist exposure, resulting in a paradoxical stimulatory response. Full article

Gonadotropin-Releasing Hormone (GnRH) is a crucial neuropeptide that regulates reproductive functions in vertebrates. The study identifies and characterizes (GnRH) in the brain of Tenualosa ilisha, an iconic and lucrative Clupeiform fish from River Ganga, India. The current study aimed to analyze the GnRH gene in T. ilisha using an in silico study. The GnRH gene of T. ilisha comprises a full-length nucleotide sequence of 605 base pairs with an open reading frame of 312 base pairs, which encodes 103 deduced amino acids (aa), respectively. It was found that leucine (L) is the most abundant amino acid in the GnRH protein. Additionally, the ligand interactions of the GnRH were analyzed using computational approaches. The structural validation showed an excellent stereochemical quality of the GnRH protein sequence, with over 88% of residues in Ramachandran plot-favored regions. The binding site prediction revealed 6 ligand-binding pockets, with the largest pocket containing 12 amino acids. After ADME screening, 16 drug-like compounds were docked to GnRH protein. Top five ligands N-Ac-(4-Cl-Phe)-Trp-Lys-AlaNH2, LHRH_LYS (6), Seabream_GnRH, Leuprolide, and LHRH_Des-tyr (5) had binding affinities ranging from −7.5 to −5.6 kcal/mol. The stable binding site was confirmed by 100 ns molecular dynamics simulations, with RMSD values below 10 Å and key residues retaining ligand contacts. The GnRH-protein resulted in the development of a suitable peptide sequence of T. ilisha, showing similarity with the similar anadromous American shad (Alosa sapidissima). This will certainly aid in future therapeutic and captive breeding advances, thereby fostering the culture and conservation of the wild species. Full article

Background/Objectives: Several drugs used to treat prostate cancer have been reported to cause cardiovascular adverse events, and this study sought to identify the real-world risk. Methods: This study utilized real-world data from the FAERS to analyze the association between prostate cancer treatment and cardiovascular adverse events. It evaluated men treated with LHRH agonists and antagonists, antiandrogens, androgen synthesis inhibitors, and PARP inhibitors from 2003 to 2023. This study included patients treated with leuprolide, goserelin, triptorelin, degarelix, relugolix, bicalutamide, flutamide, apalutamide, nilutamide, abiraterone, enzalutamide, olaparib, rucaparib, talazoparib, and niraparib. The main outcome measure was the reported odds ratio (ROR) of adverse cardiovascular event associated with these treatments. Results: Among the 4,049,329 unique adverse event reports, 4391 cardiovascular events were identified. Leuprolide (ROR 0.481, 95% CI: 0.423–0.547), triptorelin (ROR 0.527, 95% CI: 0.305–0.909), enzalutamide (ROR 0.393, 95% CI: 0.341–0.452), and olaparib (ROR 0.145, 95% CI: 0.054–0.386) reduced the risk of myocardial infarction. Goserelin increased the risk of myocardial infarction (ROR 2.235, 95% CI: 1.367–3.654). Degarelix and relugolix both increased the risk of heart failure (ROR 3.136, 95% CI: 2.186–4.497), and enzalutamide was associated with an increased risk of heart failure (ROR 1.305, 95% CI: 1.135–1.501). Bicalutamide increased the risk of unstable angina (ROR 3.019, 95% CI: 1.621–5.622) and heart failure (ROR 3.730, 95% CI: 3.085–4.510). Niraparib increased the risk of hypertension (ROR 4.154, 95% CI: 1.709–10.092). Conclusions: These findings underscore the need for clinicians to monitor cardiac complications in patients undergoing these therapies. Full article

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. Full article

Background: The co-treatment of androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) with the fetal estrogen estetrol (E4) may further inhibit endocrine PCa tumor stimulators. We previously reported the suppression of follicle-stimulating hormone (FSH), total and free testosterone, and prostate-specific antigen by ADT+E4. Here, we provide more detailed data on FSH suppression by E4 and present new findings on the effect of ADT+E4 on insulin-like growth factor-1 (IGF-1). Methods: A Phase II, double-blind, randomized, placebo-controlled study (the PCombi study) was conducted in advanced PCa patients treated with ADT. The study assessed the effect of E4 co-treatment with LHRH agonist ADT on tumor stimulators, including FSH and IGF-1. Patients starting ADT were randomized 2:1 to receive either 40 mg E4 (n = 41) or placebo (n = 21) for 24 weeks. Non-parametric analyses were performed on the per-protocol population (PP) and individual changes were visualized. Results: The PP included 57 patients (37 ADT+E4; 20 ADT+placebo). ADT+E4 almost completely suppressed FSH in all patients (98% versus 37%; p < 0.0001). IGF-1 levels decreased by 41% with ADT+E4 versus an increase of 10% with ADT+placebo (p < 0.0001). Conclusions: The almost complete suppression of the tumor stimulator FSH using ADT plus E4 observed in all individual patients in this study, along with the augmented suppression of IGF-1 versus an increase by ADT only, may be clinically relevant and suggest the enhanced anti-cancer treatment efficacy of E4 in addition to the previously reported additional suppression of total and free T and PSA. Full article

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. Full article

Managing breast cancer in premenopausal women poses unique challenges due to its considerable effect on both morbidity and mortality. Goserelin, a gonadotropin-releasing hormone agonist, has emerged among the various modalities as a preferred option for ovarian function suppression, owing to its efficacy in reducing ovarian estrogen production in premenopausal women with hormone receptor-positive breast cancer. Recent studies have affirmed the efficacy and safety of long-acting (LA) goserelin 10.8 mg every 12 weeks, offering comparable outcomes to monthly injections. This flexibility enables personalized treatment approaches, potentially enhancing patient satisfaction. Off-label utilization of goserelin LA surged during the coronavirus disease pandemic, prompting initiatives to broaden its use for breast cancer treatment. Switching to goserelin LA can streamline treatment, boost adherence, and optimize resource utilization. With the recent approval of goserelin 10.8 mg LA by Health Canada on 6 May 2024, for use in breast cancer, Canada is the latest to join over 60 countries worldwide to expand the accepted indications for goserelin LA and ensure its availability to potentially enhance healthcare delivery, patient care, and breast cancer outcomes. Goserelin LA offers premenopausal patients a means to more effectively manage the constraints imposed by breast cancer treatment and its impact on survivorship. Full article

Background: Although metastatic hormone-sensitive prostate cancer (mHSPC) treatments have evolved, androgen deprivation therapy (ADT) remains a widely used regimen. Therefore, this study sought patients who did not progress to castration-resistant prostate cancer (CRPC) but received ADT monotherapy and factors affecting overall survival (OS) in de novo mHSPC. Methods: De novo mHSPC patients who received ADT treatment were included. ADT included luteinizing hormone-releasing hormone agonists with or without anti-androgen. The total cohort was divided into two groups relative to CRPC progression within two years. Logistic analysis was used to identify factors that did not progress CRPC within two years. Cox regression was used to assess the independent predictors for OS. Results: The total cohort was divided into the no-CRPC within two years group (n = 135) and the CRPC within two years group (n = 126). Through multivariate logistic analysis, the life expectancy (odds ratio [OR] 0.95, 95% CI 0.91–0.99, p = 0.014) and Gleason scores (≥9 vs. ≤8; OR 0.43, 95% CI 0.24–0.75, p = 0.003) were associated with the group without castration-resistant prostate cancer progression within two years. The multivariate Cox model revealed that life expectancy (hazard ratio [HR] 0.951, 95% CI 0.904–0.999, p = 0.0491), BMI (HR 0.870, 95% CI 0.783–0.967, p = 0.0101), and CCI (≥2 vs. <2; HR 2.018, 95% CI 1.103–3.693, p = 0.0227) were significant predictive factors for OS. Conclusions: Patients with long life expectancy and a Gleason score of 9 or more were more likely to develop mCRPC while alive. Patients with short life expectancy, low BMI, and worsening comorbidity were more likely to die before progressing to CRPC. Although intensified treatment is essential for oncologic outcomes in mHSPC, shared decision making is integral for patients who may not benefit from this treatment. Full article

The escalating problem of copper (Cu) and cadmium (Cd) pollution in aquatic environments poses a significant threat to the ovarian tissue and reproductive capacity of fish, hindering the development of the aquaculture industry. However, the combined effects of Cu and Cd on fish gonadal development remain unclear. In this study, the fish species Nile tilapia was stressed with rearing water containing 300 μg/L Cu²⁺ and 100 μg/L Cd²⁺ for 30 days, followed by an intraperitoneal injection of luteinizing hormone-releasing hormone (LHRH-α) and human chorionic gonadotropin (HCG) at various concentrations. We investigated the ovarian transcriptome profiles before and after injection. Prior to injection, combined treatment with Cu and Cd resulted in reproductive dysfunction and metal ion imbalance in tilapia. Transcriptomic profiling revealed differential gene annotation concentrated in the MAPK signaling pathway and regulation of GTPase activity. Post-injection, all concentrations of LHRH-α and HCG groups showed an upregulated gonadosomatic index (G.S.I) and higher levels of vitellogenin (VTG), gonadotropin-releasing hormone (GnRH), gonadotropin (GTH), and estrogen (E2) in serum compared to the negative control group. Transcriptomic analysis revealed alterations in various ovarian signaling pathways, preliminarily revealing the in vivo molecular mechanisms and differences in LHRH-α and HCG. The findings from this study could help us better understand how to counteract the effects of combined Cu and Cd exposure on tilapia ovarian development, which has significant implications for the Nile tilapia aquaculture industry. Full article

Background and Objectives: The gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard method for diagnosing central precocious puberty (CPP), although it requires multiple blood samplings over 120 min. This study aimed to evaluate if a shorter test may have an equivalent diagnostic accuracy. Materials and Methods: We retrospectively reviewed the GnRH tests of 188 consecutive pediatric patients (169 females) referred for signs of early pubertal development. The diagnostic accuracy of the hormonal levels was evaluated at different time points (15, 0, 60, 90, and 120 min after the GnRH stimulus). Results: A diagnosis of CPP was made in 130 cases (69%), with 111 (85%) being female. Sensitivity and specificity ratings higher than 99% for the diagnosis of CPP were achieved for LH levels ≥4.7 mU/mL at 30 and 60 min after the stimulus (area under the ROC curve (AUC) = 1), with no further increase in the diagnostic accuracy in the remaining time points. No sex differences in diagnostic accuracy were found. The LH/FSH ratio at 30 min showed a sensitivity of 94.9%, with an AUC of 0.997 and a value ≥0.76. Conclusions: A short-duration GnRH test of 60 min provided optimal results for the diagnosis of CPP. Extending the test for an extra hour is therefore unnecessary and inadvisable. Full article

Prostate cancer (PCa) used to be one of the most common nondermatologic cancers in men that can be treated only with surgery. However, a revolutionary breakthrough came in the 1980s with the introduction of long-acting luteinizing hormone-releasing hormone (LHRH) agonists for the curative treatment of PCa. This paradigm shift contributed to the combined use of androgen deprivation therapy (ADT), chemotherapy, and radiotherapy for the treatment. The latest data highlight the use of treatment intensification (TI), i.e., combined use of radiotherapy (RT) and hormonal or drug treatments, for localized or locally advanced PCa. Indeed, the results of combined modality treatments have shown a reduction in disease-specific mortality and improved overall survival. Although TI seems promising, more research studies are warranted to confirm its efficacy. This review summarizes the latest available outcome results of pivotal trials and clinical studies on the efficacy of TI. Full article

Background: Androgen deprivation therapy (ADT) is a mainstay of prostate cancer in both adjuvant and palliative settings. Since androgens are crucial for functional status and psychological functions, we evaluated whether blood testosterone, androstenedione, or DHEA concentrations were associated with functional status and psychological alterations in patients with localised (PCa) or metastatic prostate cancer (mPCa) receiving ADT with analogues of luteinising hormone-releasing hormone (LHRH). Methods: The five Fried criteria were considered to identify frailty syndrome. In addition, complementary evaluations were carried out to measure other variables of interest. Sleep quality was assessed using the Athens Insomnia Scale, cognitive functions were assessed using the Mini-Mental State Examination, and symptoms of depression were measured using the Yesavage Geriatric Depression Scale. Logistic regression analysis was performed to determine if the androgens level could be related to frailty syndrome, sleep impairment, depressive symptoms, and cognitive functions. Results: The results of the multivariate analyses show that high concentrations of androstenedione were significantly associated with frailty syndrome in both groups (p = 0.018; odds ratio = 4.66, 95% confidence interval [1.30–16.6]). There were significant relationships between frailty syndrome and the systemic concentration of androstenedione (p = 0.01), but not the concentration of testosterone (p = 0.60) or DHEA (p = 0.42). In addition, the results of the non-parametric tests show significant results between a decreased gait speed in the two groups (metastatic and localised) and the concentration of androstenedione (p = 0.015). High androstenedione levels were associated with a slow walking speed in the mCaP group (p = 0.016), while high testosterone levels were associated with a better walking speed in the localised CaP group (p = 0.03). For the concentration of androstenedione in plasma, the area under the curve was 0.72, with a 95% CI of 0.55–0.88 with acceptable values, and with a cut-off point of 4.51 pg/mL, a sensitivity of 82.9%, and specificity of 53.8%. No relationships between the concentration of androgens in plasma and sleep quality, cognitive functions, or symptoms of depression suggest that the changes were specific to frailty syndrome. Conclusions: Further research into the role of androstenedione should be evaluated in follow-up studies in order to recommend its use as a suitable biomarker of frailty syndrome in prostate cancer patients. Full article

Background: Prostate cancer (PCa) is considered one of the most important medical problems in the male population, with a very high incidence after the age of 65. Frailty represents one of the most critical issues facing healthcare due to its inherent relationship with poor healthcare outcomes. The physical phenotype of frailty syndrome based on Fried criteria has been associated with poor outcomes, morbidity, and premature mortality. To date, there are few studies that have analyzed frailty syndrome in patients with localized and advanced (mPCa) disease under androgen-deprivation therapy. Objective: Our goal was to assess whether there are differences in frailty criteria between mPCa and localized PCa. We also evaluated the role of other geriatric variables such as depressive and insomnia symptoms, which are frequently reported in cancer patients. Methods: In this cross-sectional study, frailty syndrome was evaluated in both groups, as well as its possible relationship with cognitive functions, depressive and insomnia symptoms, and other clinical variables related to PCa and its treatment. Frailty was defined on Fried’s criteria: low lean mass, weakness, self-reported exhaustion, low activity level, and slow walking speed; prefrailty was defined as having one or two of those criteria and frailty as having three or more, depressive symptoms were defined by the Yesavage scale, cognitive functions with the Mini-Mental examination test, and insomnia symptoms by the Athens scale and self-reported health status. Results: The prevalence of prefrailty/frailty was slightly higher in mPCa compared to localized PCa (81.5% versus 72.3%, respectively), however by analyzing each of the frailty criteria, two of them were significantly reduced in mPCa compared to localized PCa patients, e.g., gait speed (p = 0.001) and muscle strength (p = 0.04). The reduced gait speed and muscle strength in mPCa were not due to the increased age in mPCa group, or to an increase in comorbidities or shorter time under androgen-deprivation therapy. The symptoms of insomnia were significantly higher in mPCa patients compared to those with localized PCa (p < 0.05) whereas cognitive functions or depressive symptoms were not significantly different between the two groups. Conclusion: Patients with mPCa under androgen-deprivation therapy display higher alterations in gait speed and muscular strength and insomnia symptoms, thus interventions should be aimed to reduce these alterations in order to limit adverse outcomes related to them and to improve quality of life in these patients. Full article

Background: This retrospective single-center cohort study evaluated the efficacy and safety of a combination of neoadjuvant luteinizing hormone-releasing hormone (LHRH) antagonist and tegafur-uracil (UFT) therapy (NCHT) and investigated the medical records of patients with high-risk PCa who underwent robot-assisted radical prostatectomy (RARP). The therapy was followed by RARP for high-risk PCa. Materials and Methods: The enrolled patients were divided into two groups: low-intermediate-risk PCa patients who underwent RARP without neoadjuvant therapy (non-high-risk) and those who underwent NCHT followed by RARP (high-risk group). This study enrolled 227 patients (126: non-high-risk and 101: high-risk group). Patients in the high-risk-group had high-grade cancer compared to those in the non-high-risk-group. Results: At the median follow-up period of 12.0 months, there were no PCa deaths; two patients (0.9%) died of other causes. Twenty patients developed biochemical recurrence (BCR); the median time until BCR was 9.9 months after surgery. The 2-year biochemical recurrence-free survival rates were 94.2% and 91.1% in the non-high-risk and high-risk-group, respectively (p = 0.465). Grade ≥3 NCHT-related adverse events developed in nine patients (8.9%). Conclusions: This study indicates that combining neoadjuvant LHRH antagonists and UFT followed by RARP may improve oncological outcomes in patients with high-risk PCa. Full article

Breast cancer is one of the most common cancers in women worldwide. Conventional cancer chemotherapy always has adverse side effects on the patient’s healthy tissues. Consequently, combining pore-forming toxins with cell-targeting peptides (CTPs) is a promising anticancer strategy for selectively destroying cancer cells. Here, we aim to improve the target specificity of the BinB toxin produced from Lysinibacillus sphaericus (Ls) by fusing a luteinizing hormone-releasing hormone (LHRH) peptide to its pore-forming domain (BinB_C) to target MCF-7 breast cancer cells as opposed to human fibroblast cells (Hs68). The results showed that LHRH-BinB_C inhibited MCF-7 cell proliferation in a dose-dependent manner while leaving Hs68 cells unaffected. BinB_C, at any concentration tested, did not affect the proliferation of MCF-7 or Hs68 cells. In addition, the LHRH-BinB_C toxin caused the efflux of the cytoplasmic enzyme lactate dehydrogenase (LDH), demonstrating the efficacy of the LHRH peptide in directing the BinB_C toxin to damage the plasma membranes of MCF-7 cancer cells. LHRH-BinB_C also caused MCF-7 cell apoptosis by activating caspase-8. In addition, LHRH-BinB_C was predominantly observed on the cell surface of MCF-7 and Hs68 cells, without colocalization with mitochondria. Overall, our findings suggest that LHRH-BinB_C could be investigated further as a potential cancer therapeutic agent. Full article