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.

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.

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.

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.• 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.• 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.• 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.• 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.

Androgen deprivation therapy (ADT) is the main treatment approach in advanced prostate cancer and in recent years has primarily involved the use of gonadotropin-releasing hormone (GnRH) agonists. However, despite their efficacy, GnRH agonists have several drawbacks associated with their mode of action. These include an initial testosterone surge and testosterone microsurges on repeat administration. GnRH antagonists provide an alternative approach to ADT with a more direct mode of action that involves immediate blockade of GnRH receptors. Antagonists produce a more rapid suppression of testosterone (and prostate-specific antigen [PSA]) without a testosterone surge or microsurges and appear to offer an effective and well tolerated option for the hormonal treatment of prostate cancer. Comparisons with GnRH agonists have shown GnRH antagonists to be at least as effective in achieving and maintaining castrate testosterone levels in patients with prostate cancer. Furthermore, with antagonists, the lack of an initial testosterone surge (which may cause clinical flare) may allow more rapid relief of symptoms related to prostate cancer, avoid the need for concomitant antiandrogens to prevent clinical flare (so avoiding any antiandrogen-associated adverse events) and allow GnRH antagonist use in patients with high tumour burden and/or acute problems such as spinal cord compression. Although several antagonists have been investigated, only degarelix and abarelix are currently available for clinical use in prostate cancer. Currently, degarelix is the most extensively studied and widely available agent in this class. Degarelix is one of a newer generation of antagonists which, in a comprehensive and ongoing clinical development programme, has been shown to provide rapid, profound and sustained testosterone suppression without the systemic allergic reactions associated with earlier antagonists. This review examines the currently available data on GnRH antagonists in prostate cancer.

Gonadotropin-releasing hormone (GnRH) receptors are not only detected in the central nervous system but also in tissues such as ovary, endometrium, breast, gastrointestinal system, placenta and malignant tumors of ovary and breast. The direct role of GnRH-antagonists in ovarian function, implantation, cancer pathogenesis and treatment is under extensive investigation. This study reviews the biochemistry and molecular and cellular biology of GnRH-antagonists as well as GnRH types and their receptors.The best clinical evidence with GnRH-antagonists has accumulated in controlled ovarian hyperstimulation protocols for prevention of premature luteinizing hormone surge (cetrorelix, ganirelix) and in the treatment of advanced-stage prostate cancer (abarelix and degarelix). GnRH-GnRH receptor pathways may have a role in the embryo implantation. The controversy still exists whether GnRH antagonist protocols result in slightly decreased clinical pregnancy rates compared with the GnRH agonist protocols. GnRH-antagonists could be used in the near future to treat some cancer types that express GnRH receptors.GnRH-antagonists have various clinical applications in gynecology, reproductive medicine, urology and oncology. The emergence of well tolerated, orally active GnRH-antagonists may provide an alternative to long-term injections and is likely to have a major impact on the utility of GnRH analogues in the treatment of human diseases.

Early studies on gonadotrophin-releasing hormone (GnRH) antagonists pointed out histamine-mediated anaphylactic reactions as a potential adverse effect of these drug candidates. In this study we have compared the histamine-releasing potential of four approved and marketed antagonists, degarelix, cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples.Human skin samples were obtained during cosmetic plastic surgery and kept in oxygenated saline solution. The samples were incubated either without or at different concentrations of the antagonists (3, 30 or 300 µg ml(-1) for all, except for ganirelix 1, 10 or 100 µg ml(-1) ). The drug-induced effect was expressed as the increase relative to basal release. The histamine-releasing capacity of the skin was verified by a universal histamine releaser, compound 40/80.Degarelix had no significant effect on basal histamine release in the 3 to 300 µg ml(-1) concentration range. The effect of ganirelix was moderate causing a nonsignificant increase of 81 ± 27% at the 100 µg ml(-1) concentration. At 30 and 300 µg ml(-1) concentrations abarelix (143 ± 29% and 362 ± 58%, respectively, P < 0.05) and cetrorelix (228 ± 111% and 279 ± 46%, respectively, P < 0.05) caused significantly increased histamine release.In this ex vivo human skin model, degarelix displayed the lowest capacity to release histamine followed by ganirelix, abarelix and cetrorelix. These findings may provide indirect hints as to the relative likelihood of systemic anaphylactic reactions in clinical settings.

Analogues of the gonadotropin releasing hormone (GnRH) inhibit the hypothalamic-pituitary-gonadal axis. This has provided treatment modalities for advanced and metastatic prostate cancer. The latest group of analogues, the GnRH antagonists, make promising treatments available that avoid the transient surge in testosterone that occurs with the use of GnRH agonists. Such surges may stimulate tumor growth, causing patients to experience new or worsening cancer symptoms and potential serious adverse effects, including increased bone pain, urinary retention, and spinal cord compression and consequently delay the therapeutic benefits of agonist therapy. Degarelix, an antagonist, recently approved in the United States and Europe, achieves faster, more profound and sustained testosterone suppression and with fewer adverse effects when compared with agonists and other antagonists. This review discusses and compares the compounds degarelix, abarelix, and cetrorelix.