cetrorelix and Prostatic-Hyperplasia

Benign prostatic hyperplasia (BPH) is the nonmalignant enlargement of the prostate gland caused by increases in number of both epithelial and stromal cells. Clinically, BPH leads to voiding dysfunction, which is most often referred to as lower urinary tract symptoms (LUTS). Historically, the only treatments for LUTS due to BPH were watchful waiting or surgery (transurethral or open prostatectomy). However, over the last 20 years medical therapy has taken a prominent role in the management of BPH. Current medical treatments for BPH include alpha-adrenergic receptor antagonists, inhibitors of the 5-alpha reductase enzyme and various phytotherapies. These agents are generally effective and safe; however, many patients are unable to tolerate the side effects or are refractory to medical management and require surgery. In light of this, many potential new therapies for the treatment of BPH are under development. Some represent a variation of current treatments, whereas others target novel molecular pathways within the prostate. The aim of this review is to examine current pharmacotherapies as well as to highlight emerging drugs that may improve our treatment of patients with LUTS secondary to BPH.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Antineoplastic Agents; Calcitriol; Cell Proliferation; Drug Therapy, Combination; Enzyme Inhibitors; Finasteride; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Indazoles; Male; Naphthalenes; Phytotherapy; Piperazines; Plant Extracts; Prostatic Hyperplasia; Randomized Controlled Trials as Topic; Receptors, Adrenergic, alpha-1; Serenoa

Early treatment of benign prostatic hyperplasia (BPH) helps to decrease the need for surgery and thus places the medical treatment at the forefront which implies, optimising its efficacy and tolerance. Alpha-blockers and 5-alpha-reductase inhibitors are the two main classes of currently used drugs. The role in the growth of glandular, muscular and fibroblastic tissues of the prostate of androgens, testosterone and especially intraprostatic dihydrotestosterone was properly established. These physiopathological data prompted to evaluate the efficacy of inhibition of the hypothalamic-pituitary-gonadal axis, by means of LH-RH analogues. The agonists lead to a biological castration associated with a significant improvement of BPH symptoms. Unfortunately clinical relapse is systematic when treatment is discontinued. The antagonists, particulary cetrorelix, improve BPH symptoms, with a persistant benefit after treatment, discontinuation, although the effect on the prostate volume reduction is transitory. It can be suggested that beside the well known hormonal action, there is a direct apoptic effect cells as well as inhibition of the intratissue growth factors. The LH-RH antagonists could thus become an alternative to the current drugs by offering a relatively short treatment with a prolonged benefit.

Topics: Apoptosis; Disease Progression; Drug Administration Schedule; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Prostatic Hyperplasia; Treatment Outcome

To compare the efficacy of 4 dosage regimens of cetrorelix pamoate, a sustained release formulation that allows for more convenient dosing, in patients with symptomatic benign prostatic hyperplasia (BPH). Repeated dosing with cetrorelix acetate was shown to be active in the treatment of BPH symptoms.. Double-blind, randomized, multicenter study was undertaken among patients with International Prostate Symptom Score (IPSS) ≥ 13. After a single-blind placebo run-in phase of 4 weeks, treatment was administered at 2-week intervals as follows: 30 + 30 mg, 30 + 30 + 30 mg, 60 + 30, 60 + 60 mg cetrorelix pamoate, or matching placebo. Patients were followed-up for 28 weeks after randomization.. A statistically significant overall difference was found with respect to the primary variable, the IPSS (P ≤ .001). Optimal results, a 4-point improvement in IPSS in excess of the changes observed in the placebo group, were achieved with a starting dose of 60 mg cetrorelix pamoate followed by a dose of 30 mg 2 weeks later. In all dosage groups, the symptomatic improvement was paralleled by an increase in uroflow. There was a marked dissociation between only moderate and transient testosterone suppression and the persisting effects on BPH signs and symptoms. Tolerability was good at all cetrorelix dosages.. Intramuscular injections of 60 and 30 mg of cetrorelix pamoate within 2 weeks provide rapid symptomatic improvements of BPH that are sustained for the following 6 months.

Topics: Aged; Aged, 80 and over; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Erectile Dysfunction; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Injections, Intramuscular; Male; Middle Aged; Prostatic Hyperplasia; Quality of Life; Receptors, LHRH; Severity of Illness Index; Single-Blind Method; Testosterone; Urination Disorders

Pilot studies with daily dosing suggested the use of the luteinizing hormone-releasing hormone antagonist cetrorelix (CET) for the treatment of symptoms from benign prostatic hyperplasia (BPH).. To assess efficacy and safety of three dosing schemes of CET in patients with symptomatic BPH.. After a run-in period with 4 weekly injections of placebo, 140 patients with an international prostate symptoms score (IPSS) > or =13 and a peak urinary flow rate (PFR) 5-13ml/s were randomly allocated to 4 treatment groups; patients with residual urine volume of >350ml were excluded.. Patients received either CET at dosages of 5mg/wkx4, 10mg/2 wkx2 or 10mg/wkx4 or placebo.. IPSS, PFR and mean uroflow, residual urinary volume, prostate volume, plasma testosterone, quality of life, and sexual function were evaluated over a total of 20 wk after randomization.. Of 140 randomized patients, one patient did not complete treatment, 5 others dropped out off-treatment, before week 12 evaluation of the primary end point. In all CET groups a rapid improvement in mean IPSS was obtained, with a peak effect of -5.4 to -5.9 (placebo: -2.8). After all dosages of CET given, changes from baseline and differences to placebo were statistically significant up to week 20. Similarly, secondary parameters showed a significant, rapid, and persistent improvement for all CET dosages. All dosage regimens were well tolerated. The study evaluated a single treatment course only; further studies with repeated treatment courses will be required to establish a dose regimen for long-term disease management.. At all dosage regimens tested, CET was safe and effective in patients with symptomatic BPH, with a trend towards a more rapid onset of effect for the CET 10mg/wkx4 regimen. Response persisted up to the end of follow-up, 16 wk after the last dose.

Topics: Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Injections, Subcutaneous; Male; Middle Aged; Prostatic Hyperplasia; Treatment Outcome

Among new highly potent antagonistic analogs of luteinizing hormone-releasing hormone (LH-RH), containing neutral hydrophilic D-ureidoalkyl amino acids such as D-Cit and D-Hci at position 6 and free of edematogenic and anaphylactoid reactions, Ac-D-Nal(2)1, D-Ph(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10 (LH-RH) (SB-75; Cetrorelix) was shown to be one of the most powerful. In this trial, we evaluated the response to 500 micrograms SB-75 given every 12 hr subcutaneously (sc) for 4 weeks in 11 patients with benign prostatic hyperplasia (BPH), and 6 weeks in 6 prostatic cancer patients (2 stage C, 4 stage D2). In patients with BPH presenting with prostatism and urinary outflow obstruction, there was a noticeable clinical improvement after the first week of SB-75 administration. This improvement continued during the course of treatment. Before therapy with SB-75, the serum levels of prostate-specific antigen (PSA) (6.73 +/- 1.46 ng/ml), acid phosphatases, total (12.67 +/- 1.15 U/l), and prostatic (2.27 +/- 0.34 U/l), were mildly elevated, but declined to normal values at 4 weeks: (2.13 +/- 0.59 ng/ml; P < 0.01), (7.68 +/- 0.89 U/l; P < 0.01), and (1.39 +/- 0.18 U/l; P < 0.01), respectively. Mean prostatic volume assessed by ultrasonography showed a significant decrease in all patients from 67.84 +/- 8.86 to 37.92 +/- 8.52 cm3; P < 0.01, which represents a reduction of 44%. In patients with prostate cancer, after the first week of therapy with SB-75, we observed a significant decrease in bone pain, relief in urinary outflow obstruction, and reversal of the signs of prostatism. Subjective improvement continued during the following weeks of treatment, so that the patients no longer needed analgesics. PSA, acid, and alkaline phosphatases gradually fell, achieving nearly normal values at 6 weeks. Initial serum testosterone levels in BPH and prostatic cancer patients were within normal limits, but during treatment with the antagonistic analog SB-75, fell to castration values. A major fall in free testosterone levels was observed after the first dose; the maximal inhibition was seen after 6-12 hr, with a simultaneous decrease in levels of both gonadotropins. Our results show that antagonist SB-75 can be safely administered for prolonged periods of time. The rapid shrinkage of the prostate and concomitant improvement in obstructive symptoms of prostatism obtained with antagonistic analog SB-75 in patients with BPH may decrease the morbidity of prostatic surgery and offer a th

Topics: Acid Phosphatase; Aged; Aged, 80 and over; Biomarkers, Tumor; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Infusions, Intravenous; Longitudinal Studies; Luteinizing Hormone; Male; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms; Testosterone; Ultrasonography; Urination

Benign prostatic hyperplasia (BPH) affects aging men. Combined therapy with antagonists of growth hormone-releasing hormone (GHRH) and of luteinizing hormone-releasing hormone (LHRH or GnRH) induces prostate shrinkage in rat models. We investigated the mechanisms of action of this combination on cell cycle traverse and expression of prostatic genes.. Effects of GHRH antagonist, JMR-132 (40 µg/day), the LHRH antagonist, cetrorelix (0.625 mg/kg), and their combination were evaluated on testosterone-induced benign prostatic hyperplasia in male Wistar rats. Influence of JMR-132, cetrorelix, and their combinations on cell viability was assessed by MTS assay in BPH-1 human prostate epithelial cells and WPMY-1 normal prostate stromal cells. Cell cycle was analyzed by laser flow cytometry. Real-time PCR arrays were performed.. The combination of antagonists caused marked shrinkage of rat prostate (29.5%). In vitro, JMR-132 plus cetrorelix (both 5µM) produced synergistic (57.4%) inhibition of growth of BPH-1 cells, but a lesser inhibition (46%) of WPMY-1 cells. Co-treatment of with JMR-132 plus cetrorelix induced a significant increase of BPH-1 cells blocked in S-phase plus cells with lower G0 /G1 and G2 /M DNA content. Significant changes in expression of >40 gene transcripts related to growth factors, inflammatory cytokines, and signal transduction were identified.. GHRH antagonist and LHRH antagonist combination potentiates rat prostate weight reduction and synergistically inhibits of growth of BPH-1 leading to cell cycle arrest in S-phase. These effects were lesser in normal stromal prostate cell line, WPMY-1. Our findings suggest that GHRH antagonists could be useful for BPH therapy, possibly in combination with LHRH antagonists.

Topics: Animals; Cell Cycle Checkpoints; Cell Line; Cell Survival; Down-Regulation; Drug Synergism; Gene Expression Profiling; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; Humans; Male; Organ Size; Prostatic Hyperplasia; Rats; Rats, Wistar; Sermorelin; Signal Transduction

Benign prostatic hyperplasia often affects aging men. Antagonists of the neuropeptide growth hormone-releasing hormone reduced prostate weight in an androgen induced benign prostatic hyperplasia model in rats. Luteinizing hormone-releasing hormone antagonists also produce marked, protracted improvement in lower urinary tract symptoms, reduced prostate volume and an increased urinary peak flow rate in men with benign prostatic hyperplasia. We investigated the influence of a combination of antagonists of growth hormone-releasing hormone and luteinizing hormone-releasing hormone on animal models of benign prostatic hyperplasia.. We evaluated the effects of the growth hormone-releasing hormone antagonist JMR-132, given at a dose of 40 μg daily, the luteinizing hormone-releasing hormone antagonist cetrorelix, given at a dose of 0.625 mg/kg, and their combination on testosterone induced benign prostatic hyperplasia in adult male Wistar rats in vivo. Prostate tissue was examined biochemically and histologically. Serum levels of growth hormone, luteinizing hormone, insulin-like growth factor-1, dihydrotestosterone and prostate specific antigen were determined.. Marked shrinkage of the rat prostate (30.3%) occurred in response to the combination of growth hormone-releasing hormone and luteinizing hormone-releasing hormone antagonists (p<0.01). The combination strongly decreased prostatic prostate specific antigen, 6-transmembrane epithelial antigen of the prostate, interleukin-1β, nuclear factor-κβ and cyclooxygenase-2, and decreased serum prostate specific antigen.. A combination of growth hormone-releasing hormone antagonist with luteinizing hormone-releasing hormone antagonist potentiated a reduction in prostate weight in an experimental benign prostatic hyperplasia model. Results suggest that this shrinkage in prostate volume was induced by the direct inhibitory effects of growth hormone-releasing hormone and luteinizing hormone-releasing hormone antagonists exerted through their respective prostatic receptors. These findings suggest that growth hormone-releasing hormone antagonists and/or their combination with luteinizing hormone-releasing hormone antagonists should be considered for further development as therapy for benign prostatic hyperplasia.

Topics: Animals; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; Male; Organ Size; Prostatic Hyperplasia; Rats; Rats, Wistar; Sermorelin

In the present study, we investigated the roles of TGF-β signaling pathway in a rat benign prostatic hyperplasia (BPH) model treated with cetrorelix. TGF-β1 and c-Myc expression were measured by qRT-PCR and Western blotting in the proximal and distal region of ventral prostatic lobes, respectively. We observed that treatment with cetrorelix led to a significant reduction of ventral prostate weight in a dose-dependent manner. In the proximal region, after cetrorelix treatment, the expression of TGF-β1 was dramatically increased (P<0.05), while the expression of c-Myc was significantly decreased (P<0.05). In comparison with the control group, the cetrorelix groups had more TUNEL-positive cells. Our findings strongly suggest that the TGF-β signaling pathway may be one of the major causes responsible for prostate volume reduction in BPH rats after cetrorelix treatment.

Topics: Animals; Atrophy; Disease Models, Animal; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Organ Size; Prostatic Hyperplasia; Proto-Oncogene Proteins c-myc; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1

The majority of men will develop symptoms of benign prostatic hyperplasia (BPH) after 70 years of age. Various studies indicate that antagonists of LHRH, such as cetrorelix, exert direct inhibitory effects on BPH mediated by specific LHRH receptors. Our aim was to investigate the mRNA for LHRH and LHRH receptors and the expression of LHRH receptors in specimens of human BPH.. The expression of mRNA for LHRH (n=35) and LHRH receptors (n=55) was investigated by RT-PCR in surgical specimens of BPH, using specific primers. The characteristics of binding sites for LHRH on 20 samples were determined by ligand competition assays. The LHRH receptor expression was also examined in 64 BPH specimens by immunohistochemistry.. PCR products for LHRH were found in 18 of 35 (51%) BPH tissues and mRNA for LHRH receptors was detected in 39 of 55 (71%) BPH specimens. Eighteen of 20 (90%) samples showed a single class of high affinity binding sites for [D-Trp(6) ]LHRH with a mean K(d) of 4.04 nM and a mean B(max) of 527.6 fmol/mg membrane protein. LHRH antagonist cetrorelix showed high affinity binding to LHRH receptors in BPH. Positive immunohistochemical reaction for LHRH receptors was present in 42 of 64 (67%) BPH specimens.. A high incidence of LHRH receptors in BPH supports the use of LHRH antagonists such as cetrorelix, for treatment of patients with lower urinary tract symptoms from BPH.

Topics: Aged; Aged, 80 and over; Binding, Competitive; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Immunohistochemistry; Male; Middle Aged; Molecular Targeted Therapy; Prostatic Hyperplasia; Radioligand Assay; Receptors, LHRH; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Recent findings suggest that BPH has an inflammatory component. Clinical trials have documented that therapy with LHRH antagonist Cetrorelix causes a marked and prolonged improvement in LUTS in men with symptomatic BPH. We investigated the mechanism of action and effect of Cetrorelix in a rat model of BPH.. Adult male Wistar rats were used. BPH was induced in rats by subcutaneous injections of TE 2 mg/day for 4 weeks. Control animals received injections of corn oil. After induction of BPH, rats received depot Cetrorelix pamoate at the doses of 0.625, 1.25, and 12.5 mg/kg on days 1 and 22 and TE-control rats received vehicle injections. Whole prostates were weighed and processed for RNA and protein. Real-time RT-PCR assays for numerous inflammatory cytokines and growth factors were performed. Quantitative analyses of prostatic LHRH receptor, LHRH, androgen receptor (AR) and 5α-reductase 2 were done by real-time RT-PCR and immunoblotting; serum DHT, LH, PSA, and IGF-1 by immunoassays.. mRNA levels for inflammatory cytokines IFN-γ, IL-3, IL-4, IL-5, IL-6, IL-8, IL-13, IL-15, and IL-17 and for growth factors EGF, FGF-2, FGF-7, FGF-8, FGF-14, TGF-β1, and VEGF-A were significantly reduced by Cetrorelix 0.625 mg/kg (P < 0.05). Prostate weights were also significantly lowered by any dose of Cetrorelix.. This study suggests that Cetrorelix reduces various inflammatory cytokines and growth factors in rat prostate and, at doses which do not induce castration levels of testosterone, can lower prostate weights. Our findings shed light on the mechanism of action of LHRH antagonists in BPH.

Topics: Animals; Cytokines; Disease Models, Animal; Gene Expression; Gonadotropin-Releasing Hormone; Hormone Antagonists; Male; Prostate; Prostatic Hyperplasia; Rats; Rats, Wistar; Receptors, LHRH; RNA, Messenger; Testosterone

To assess the mechanism by which the luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix exerts its effects in men with benign prostatic hyperplasia (BPH), as it produces a long-lasting improvement in lower urinary tract symptoms that is only partly accounted for by the transient reduction in testosterone levels, and the beneficial results could be due to direct inhibitory effects of cetrorelix on the prostate exerted through prostatic LHRH receptors.. Using the BPH-1 cell line we evaluated the effects of cetrorelix in vitro on the proliferation and the expression of receptors for LHRH, epidermal growth factor (EGF), α(1A) -adrenergic receptor, STAT-3 transcription factor and the response to growth factors insulin-like growth factor (IGF)-1 and -II and fibroblast growth factor (FGF)-2.. There was expression of LHRH receptors in the human BPH-1 cell line. Cetrorelix had inhibitory effects on the proliferation rate of BPH-1 cells, also reflected by the decrease in the expression of the proliferating cell nuclear antigen (PCNA). Cetrorelix inhibited the stimulatory effect of the growth factors IGF-I and -II and FGF-2 on the proliferation of this line. Cetrorelix also downregulated the expression of the receptors for LHRH and EGF, as well as of α(1A) -adrenergic receptors, and inhibited the activation of the STAT3 transcription factor.. The results show that in vitro cetrorelix can directly inhibit the proliferation rate of the human BPH-1 cell line by counteracting growth factors like IGF-I and -II and FGF-2, and downregulating the LHRH receptor and α-adrenergic receptors, as well as transcription factors.

Topics: Analysis of Variance; Blotting, Western; Cell Line; Down-Regulation; ErbB Receptors; Fibroblast Growth Factors; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Insulin-Like Growth Factor Binding Proteins; Male; Peptide Fragments; Prostatic Hyperplasia; Prostatism; Receptors, Adrenergic, alpha; Receptors, LHRH; Transcription Factors

Topics: Androgen Antagonists; Clinical Trials, Phase II as Topic; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Organ Size; Prostate; Prostatic Hyperplasia; Stem Cells

Topics: Dose-Response Relationship, Drug; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Prostatic Hyperplasia

Topics: Dose-Response Relationship, Drug; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Prostatic Hyperplasia

Topics: Dose-Response Relationship, Drug; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Prostatic Hyperplasia; Treatment Outcome

As the life expectancy for men increases, more cases of benign prostatic hyperplasia (BPH) will be expected. Symptomatic BPH causes morbidity and can lower the quality of life. We investigated whether short term administration of the LH-releasing hormone antagonist cetrorelix could provide an improved treatment for men with BPH. Thirteen patients with moderate to severe symptomatic BPH were treated with cetrorelix (5 mg, s.c., twice daily for 2 days followed by 1 mg/day, s.c., for 2 months). Patients were evaluated at baseline, during treatment, and up to 18 months after therapy. We determined the effects of cetrorelix on the International Prostate Symptom Score (IPSS), Quality of Life score, sexual function, prostate size, uroflowmetry, and hormonal levels. Treatment with cetrorelix produced a decline of 52.9% (P < 0.0001) in IPSS, a 46% improvement in the Quality of Life score (P < 0.001), a rapid reduction of 27% (P < 0.006) in prostatic volume, and an increase in peak urinary flow rates by 2.86 mL/s. Serum testosterone fell to castrate levels on day 2, but was inhibited only by 64-74% during maintenance therapy, and after cessation of treatment returned to normal. During long term follow-up, most patients continued to show a progressive improvement in urinary symptoms (decline in IPSS from 67% to 72% at weeks 20 and 85, respectively) and an enhancement of sexual function, and prostatic volume remained normal. Our study demonstrates that in patients with symptomatic BPH, treatment with cetrorelix is safe and produces long term improvement.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Middle Aged; Prostatic Hyperplasia; Quality of Life; Receptors, LHRH; Treatment Outcome