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Expert Opinion on Pharmacotherapy Dec 2021Androgen deprivation therapy (ADT) is currently the backbone treatment of metastatic prostate cancer and is also used in combination with external beam radiotherapy...
Androgen deprivation therapy (ADT) is currently the backbone treatment of metastatic prostate cancer and is also used in combination with external beam radiotherapy (EBRT). Castration may be achieved either by bilateral orchiectomy or by administration of LHRH agonists or GnRH antagonists.: In this article, the authors assess the current and emerging role of GnRH antagonists for the treatment of prostate cancer focusing on oncological results and safety (i.e. cardiovascular risk). In addition, updated data regarding the first orally administered GnRH antagonist, relugolix, is presented.: Studies demonstrate that GnRH antagonists are at least equal with LHRH agonists in terms of testosterone suppression and PSA progression free survival with a major advantage being rapid testosterone suppression. Thus, the optimal group of patients included symptomatic metastatic prostate cancer patients especially if cardiovascular comorbidities or LUTS are also present. Emerging data regarding benefit of the use of GnRH antagonists in patients with concomitant cardiovascular disease are of great interest. Relugolix has emerged as the first orally administered GnRH antagonist able to achieve and maintain testosterone castration levels and it is associated with a profound reduction of major cardiovascular events.
Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Orchiectomy; Prostatic Neoplasms
PubMed: 34187259
DOI: 10.1080/14656566.2021.1948012 -
American Journal of Physiology.... Jul 2020We have previously shown that systemic injection of erythropoietin-producing hepatocellular receptor A7 (EPHA7)-Fc raises serum luteinizing hormone (LH) levels before...
We have previously shown that systemic injection of erythropoietin-producing hepatocellular receptor A7 (EPHA7)-Fc raises serum luteinizing hormone (LH) levels before ovulation in female rats, indicating the induction of EPHA7 in ovulation. In this study, we aimed to identify the mechanism and hypothalamus-pituitary-ovary (HPO) axis level underlying the promotion of LH secretion by EPHA7. Using an ovariectomized (OVX) rat model, in conjunction with low-dose 17β-estradiol (E) treatment, we investigated the association between EPHA7-ephrin (EFN)A5 signaling and E negative feedback. Various rat models (OVX, E-treated OVX, and abarelix treated) were injected with the recombinant EPHA7-Fc protein through the caudal vein to investigate the molecular mechanism underlying the promotion of LH secretion by EPHA7. was observed strongly expressed in the arcuate nucleus of the female rat by using RNAscope in situ hybridization. Our results indicated that E, combined with estrogen receptor (ER)α, but not ERβ, inhibited and gonadotropin-releasing hormone 1 ( expressions in the hypothalamus. In addition, the systemic administration of EPHA7-Fc restrained the inhibition of and by E, resulting in increased and expressions in the hypothalamus as well as increased serum LH levels. Collectively, our findings demonstrated the involvement of EPHA7-EFNA5 signaling in the regulation of LH and the E negative feedback pathway in the hypothalamus, highlighting the functional role of EPHA7 in female reproduction.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Ephrin-A5; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Feedback, Physiological; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Hypothalamo-Hypophyseal System; Hypothalamus; Luteinizing Hormone; Oligopeptides; Ovariectomy; Ovary; Protein Precursors; Rats; Receptor, EphA7; Recombinant Proteins
PubMed: 32396496
DOI: 10.1152/ajpendo.00046.2020 -
Expert Review of Pharmacoeconomics &... Oct 2017Recently, LHRH antagonists have been established in the management of advanced prostate cancer, although the vast majority of Medical Oncologists and Urologists still... (Comparative Study)
Comparative Study Review
Recently, LHRH antagonists have been established in the management of advanced prostate cancer, although the vast majority of Medical Oncologists and Urologists still prefer the LHRH agonists. Areas Covered: In this article we assess the therapeutic outcomes and the safety of the LHRH antagonists (mainly degarelix) compared to the LHRH agonists. Expert Commentary: Relevant studies demonstrated that LHRH antagonists are at least non-inferior to the LHRH agonists regarding therapeutic efficacy and safety, while there is potential benefit over the LHRH agonists in terms of cardiovascular morbidity and disease control. Disadvantages regarding formulation and frequency of administration are currently seem to be improving, as a 3-month depot of degarelix is evaluated and relugolix, an investigational orally administered is undergoing phase I studies, while the results of relative comparative studies are warranted.
Topics: Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones
PubMed: 28870102
DOI: 10.1080/14737167.2017.1375855 -
The Canadian Journal of Urology Apr 2014Androgen deprivation therapy (ADT) is the lynchpin of treatment for advanced prostate cancer. Prescribing physicians and patients have a choice between orchiectomy,... (Review)
Review
INTRODUCTION
Androgen deprivation therapy (ADT) is the lynchpin of treatment for advanced prostate cancer. Prescribing physicians and patients have a choice between orchiectomy, luteinizing hormone releasing hormone (LHRH) agonists, combined androgen deprivation (CAD) or LHRH antagonists.
MATERIALS AND METHODS
Literature relating to the use of LHRH antagonists in the management of prostate cancer was reviewed.
RESULTS
Abarelix was the first-in-class LHRH pure antagonist that was Food and Drug Administration (FDA) approved in 2003. Due to a variety of concerns including hypersensitivity reactions it was withdrawn from the United States (U.S.) market in 2005. The only currently commercially available LHRH antagonist in the U.S. is degarelix available as a once-a-month depot injection. The potential clinical advantage of degarelix compared to the LHRH agonists is the very rapid and sustained testosterone suppression with no identifiable physiological or clinical testosterone surge or flare. The main disadvantage of degarelix compared to the LHRH agonists is the monthly dosing and the inconvenience for some patients and practices. Recent studies tout improved disease control for degarelix compared to monthly leuprolide acetate; however, these results remain controversial.
CONCLUSIONS
The rapid T-suppression achieved with degarelix may provide a clinical benefit for various groups of men with advanced or locally advanced disease.
Topics: Antineoplastic Agents; Cost-Benefit Analysis; Disease Progression; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Staging; Oligopeptides; Prostatic Neoplasms; Testosterone
PubMed: 24775720
DOI: No ID Found -
Reproduction in Domestic Animals =... Dec 2012Gonadotrophin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinizing and follicle-stimulating hormones, and thus controls the hormonal and... (Review)
Review
Gonadotrophin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinizing and follicle-stimulating hormones, and thus controls the hormonal and reproductive functions of the gonads. GnRH analogs, which include agonists and antagonists, have been produced by amino acid substitutions within the native GnRH molecule resulting in greater potency and a longer duration of effectiveness. While the initial antagonists produced significant side effects, more recent potent, long-acting, water-soluble, low histamine-release third-generation compounds such as cetrorelix, abarelix, azaline B and acyline have appeared. Differently to GnRH agonists, antagonists competitively block and inhibit GnRH-induced GnRH receptor gene expression leading to an immediate, dose-dependent, pituitary suppression without an initial stimulation of the gonadal axis. The aims of this review are to compare the effects of GnRH agonists vs antagonists and to describe the existing literature concerning new antagonists in domestic carnivores. In male dogs, a single subcutaneous dose of acyline safely and reversibly decreased serum gonadotrophins and testosterone concentrations for 9 days and prevented physiological response of gonadal the axis to agonistic challenge for 14 days. The same protocol reversibly impaired spermiogenesis, spermatocytogenesis and semen quality in both cats and dogs. In females, third-generation GnRH antagonists prevented ovulation and interrupted pregnancy in canids but not in felids. During anestrus, a single acyline injection exhibited limited prevention of the 'flare-up' effect in GnRH agonist-implanted bitches. Although GnRH antagonists appear to have a promising future in domestic carnivores reproduction, the information is still scarce and further work is needed before they can be widely recommended.
Topics: Animals; Cats; Dogs; Gonadotropin-Releasing Hormone; Reproduction
PubMed: 23279542
DOI: 10.1111/rda.12025 -
BJU International Jun 2012Since Huggins and Hodges demonstrated the responsiveness of prostate cancer to androgen deprivation therapy (ADT), androgen-suppressing strategies have formed the... (Review)
Review
Since Huggins and Hodges demonstrated the responsiveness of prostate cancer to androgen deprivation therapy (ADT), androgen-suppressing strategies have formed the cornerstone of management of advanced prostate cancer. Approaches to ADT have included orchidectomy, oestrogens, luteinizing hormone-releasing hormone (LHRH) agonists, anti-androgens and more recently the gonadotrophin-releasing hormone antagonists. The most extensively studied antagonist, degarelix, avoids the testosterone surge and clinical flare associated with LHRH agonists, offering more rapid PSA and testosterone suppression, improved testosterone control and improved PSA progression-free survival compared with agonists. The clinical profile of degarelix appears to make it a particularly suitable therapeutic option for certain subgroups of patients, including those with metastatic disease, high baseline PSA (>20 ng/mL) and highly symptomatic disease. As well as forming the mainstay of treatment for advanced prostate cancer, ADT is increasingly used in earlier disease stages. While data from clinical trials support the use of ADT neoadjuvant/adjuvant to radiotherapy for locally advanced or high-risk localized prostate cancer, it remains to be established whether specific ADT classes/agents provide particular benefits in this clinical setting.
Topics: Androgen Antagonists; Disease-Free Survival; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Neoadjuvant Therapy; Oligopeptides; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Testosterone; Treatment Outcome
PubMed: 22672120
DOI: 10.1111/j.1464-410X.2012.11215.x -
International Journal of Urology :... Jul 2012Gonadotropin-releasing hormone agonists and antagonists provide androgen-deprivation therapy for prostate cancer. Unlike agonists, gonadotropin-releasing hormone... (Comparative Study)
Comparative Study Review
Gonadotropin-releasing hormone agonists and antagonists provide androgen-deprivation therapy for prostate cancer. Unlike agonists, gonadotropin-releasing hormone antagonists have a direct mode of action to block pituitary gonadotropin-releasing hormone receptors. There are two licensed gonadotropin-releasing hormone antagonists, degarelix and abarelix. Of these, degarelix is the more extensively studied and has been documented to be more effective than the well-established, first-line agonist, leuprolide, in terms of substantially faster onset of castration, faster suppression of prostate-specific antigen, no risk for testosterone surge or clinical flare, and improved prostate-specific antigen progression-free survival, suggesting a delay in castration resistance. Other than minor injection-site reactions, degarelix is generally well tolerated, without systemic allergic reactions and with most adverse events consistent with androgen suppression or the underlying condition. In conclusion, degarelix provides a rational, first-line androgen-deprivation therapy suitable for the treatment of prostate cancer, with faster onset of castration than with agonists, and no testosterone surge. Furthermore, data suggest that degarelix improves disease control compared with leuprolide, and might delay the onset of castration-resistant disease. In view of these clinical benefits and the lack of need for concomitant anti-androgen treatment, gonadotropin-releasing hormone antagonists might replace gonadotropin-releasing hormone agonists as first-line androgen-deprivation therapy in the future.
Topics: Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone
PubMed: 22416801
DOI: 10.1111/j.1442-2042.2012.02997.x -
BJU International Mar 2012
New treatment paradigm for prostate cancer: abarelix initiation therapy for immediate testosterone suppression followed by a luteinizing hormone-releasing hormone agonist.
Topics: Antineoplastic Agents, Hormonal; Humans; Male; Oligopeptides; Prostatic Neoplasms
PubMed: 22360806
DOI: 10.1111/j.1464-410X.2012.10983.x -
Nature Reviews. Urology Jan 2012
Topics: Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Oligopeptides; Prostatic Neoplasms
PubMed: 22289702
DOI: 10.1038/nrurol.2012.5 -
BJU International Aug 2012Study Type - Therapy (prospective cohort). Level of Evidence 2a. What's known on the subject? and What does the study add? The sequential administration of a GnRH... (Clinical Trial)
Clinical Trial
New treatment paradigm for prostate cancer: abarelix initiation therapy for immediate testosterone suppression followed by a luteinizing hormone-releasing hormone agonist.
UNLABELLED
Study Type - Therapy (prospective cohort). Level of Evidence 2a. What's known on the subject? and What does the study add? The sequential administration of a GnRH antagonist followed by an LHRH agonist in the management of prostate cancer patients has not been studied, but such a program would provide a more physiologic method of achieving testosterone suppression and avoid the obligatory testosterone surge and need for concomitant antiandrogens that accompany LHRH agonist therapy. The current study which uses abarelix initiation therapy for 12 weeks followed by either leuprolide or goserelin demonstrates the ability to more rapidly achieve testosterone suppression, avoid the obligatory LHRH induced testosterone surge, avoid the necessity of antiandrogens, all of which were accomplished safely, without inducing either additional or novel safety issues.
OBJECTIVE
• To demonstrate the safety and endocrinological and biochemical efficacy of initiating treatment with the gonadotropin-releasing hormone (GnRH) antagonist, abarelix, followed by administration of an luteinizing hormone-releasing hormone (LHRH) agonist in patients with advanced and metastatic prostate cancer.
PATIENTS AND METHODS
• A multicentre, open-label design study was conducted at 22 centres in the US involving patients with: localized, locally advanced or metastatic disease; with a rising prostate-specific antigen (PSA) after definitive local treatment; patients undergoing neoadjuvant hormonal therapy before local therapy (radical prostatectomy, radiation therapy or cryosurgery); and patients in whom intermittent therapy was the planned treatment. • All patients received abarelix for 12 weeks followed by an LHRH agonist (either leuprolide or goserelin) for 8 weeks • The primary efficacy endpoint was achievement and maintenance of castration defined as testosterone <50 ng/dL from day 29 through to day 141 and whether abarelix initiation therapy could eliminate the testosterone surge after two consecutive doses of LHRH agonist therapy. • PSA, LH and follicle-stimulating hormone (FSH) levels were measured and adverse events were monitored.
RESULTS
• A total of 176 patients were enrolled into the present study, the majority of whom had localized prostate cancer (82%) and a PSA level <10 ng/mL (62%). • At the end of the abarelix treatment period (day 85), 93.8% of patients achieved castrate levels; during the first week of switch over to the LHRH agonist therapy (days 85-92) the rate was 86.5% and during the week after the second LHRH agonist injection (days 114-12) it was 93.3%. • A small, transient increase in testosterone occurred during the first injection of the LHRH agonist; mean (standard deviation [sd]) values increased from 17 (17.8) ng/dL at day 85 to 37.3 (51.07) ng/dL at day 86. • Mean (sd) PSA levels decreased from 20.5 (56.6) ng/mL at baseline to 3.7 (23.5) ng/mL on day 85 and remained stable throughout the LHRH agonist treatment phase. • Treatment-related adverse events occurred in 84% of patients overall; a similar incidence was reported during the two treatment phases.
CONCLUSIONS
• Abarelix initiation therapy results in the desired effect of achieving rapid testosterone suppression; testosterone surges after subsequent LHRH agonist therapy are greatly abrogated or completely eliminated. • This treatment paradigm (abarelix initiation followed by agonist maintenance) obviates the need for an antiandrogen. • Abarelix was well tolerated and no clinically meaningful or novel adverse events were observed during abarelix treatment or in the transition to LHRH agonist maintenance therapy.
Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Goserelin; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; United States
PubMed: 22093775
DOI: 10.1111/j.1464-410X.2011.10708.x