Treatment with a GnRH receptor agonist, but not the GnRH receptor antagonist degarelix, induces atherosclerotic plaque instability in ApoE−/− mice

Abstract

Androgen-deprivation therapy (ADT) for prostate cancer has been associated with increased risk for development of cardiovascular events and recent pooled analyses of randomized intervention trials suggest that this primarily is the case for patients with pre-existing cardiovascular disease treated with gonadotropin-releasing hormone receptor (GnRH-R) agonists. In the present study we investigated the effects of the GnRH-R agonist leuprolide and the GnRH-R antagonist degarelix on established atherosclerotic plaques in ApoE−/− mice. A shear stress modifier was used to produce both advanced and more stable plaques in the carotid artery. After 4 weeks of ADT, increased areas of necrosis was observed in stable plaques from leuprolide-treated mice (median and IQR plaque necrotic area in control, degarelix and leuprolide-treated mice were 0.6% (IQR 0–3.1), 0.2% (IQR 0–4.4) and 11.0% (IQR 1.0-19.8), respectively). There was also evidence of increased inflammation as assessed by macrophage immunohistochemistry in the plaques from leuprolide-treated mice, but we found no evidence of such changes in plaques from control mice or mice treated with degarelix. Necrosis destabilizes plaques and increases the risk for rupture and development of acute cardiovascular events. Destabilization of pre-existing atherosclerotic plaques could explain the increased cardiovascular risk in prostate cancer patients treated with GnRH-R agonists.

Current and future strategies for the nutritional management of cardiometabolic complications of androgen deprivation therapy for prostate cancer

“…Data taken from Nguyen et al (19) and Bosco et al (12) . that acute ADT promotes inflammation, atherosclerosis and destabilises plaque (16) , and that this relates specifically to GnRH agonists and not antagonists. A comparison between the components of classic MetS and ADT-induced cardiometabolic risk factors is shown in Table 1.…”

“…These findings were soon corroborated by further primary studies, and a highly publicised metaanalysis of observational prospective cohort studies that showed GnRH agonists to be associated, unequivocally, with an increased risk of fatal and non-fatal CVD (12) . These associations have been linked to the adverse effects of ADT on body composition, insulin sensitivity and other cardiometabolic risk factors described below (6) , and also to the specific effects of GnRH agonists in precipitating cardiac events by promoting vascular dysfunction (13)(14)(15) and destabilising atherosclerotic plaque (16) . Nevertheless, RCT have generally failed to substantiate a direct, and thus causal, link between ADT/GnRH agonists and cardiac mortality (17)(18)(19)(20)(21) (Fig.…”

Considerations for the use of gonadotropin‐releasing hormone agonists and antagonists in patients with prostate cancer

“…Compared with GnRH agonists in preclinical mouse models, GnRH antagonists were associated with less adiposity, and fewer characteristics of metabolic syndrome and atherosclerosis 55,56 . The effects of GnRH antagonists on glucose control and body composition have yet to be reported in human clinical trials 27 …”

Degarelix versus luteinizing hormone-releasing hormone agonists for the treatment of prostate cancer

“…[68,69] A mouse model of ApoE −/− fed a high-fat diet to induce carotid artery atherosclerosis noted that 4 weeks of LHRH agonist therapy was associated with an increase in the plaque necrosis and macrophage infiltration, theoretically making such plaques more susceptible to rupture, while treatment with degarelix was not associated with this histologic change. [70] Another possible biologic explanation may lie in the presence of FSH receptors within the endothelial surface of blood vessels. FSH receptors that would be stimulated by LHRH agonist therapy but would presumably be less stimulated through GnRH antagonist therapy which also suppresses FSH.…”