Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

Abstract

BackgroundTreatment of prostate cancer often involves androgen deprivation therapy (ADT) by gonadotropin‐releasing hormone (GnRH) receptor agonists, GnRH receptor antagonists, or orchiectomy. ADT may increase the rate of cardiovascular disease events, but recent clinical studies suggested that not all means of ADT carry the same risk, raising the possibility of non–testosterone‐mediated effects of different forms of ADT on atherosclerosis. Here we compared effects of ADT on atherosclerosis in intact and orchiectomized Apoe‐deficient mice.Methods and ResultsChow‐fed Apoe‐deficient mice were allocated to orchiectomy and/or monthly injections with the GnRH receptor agonist leuprolide or the GnRH receptor antagonist degarelix. Atherosclerosis was quantified at 26 weeks of age in the aortic arch by en face examination and in the aortic root by histology. In intact Apoe‐deficient mice, all types of ADT reduced testosterone production to castration levels. Although hypercholesterolemia was accentuated in leuprolide‐treated mice, the amount and composition of atherosclerosis was not different between the different types of ADT. In orchiectomized Apoe‐deficient mice, leuprolide, but not degarelix, augmented hypercholesterolemia, changed body, thymus, and spleen weights, and increased atherosclerosis in the aortic root. No direct effects of the drugs were detectable on cytokine secretion from murine bone marrow–derived macrophages or on splenocyte proliferation.ConclusionsNo differences in the development of atherosclerosis were detected among groups of intact Apoe‐deficient mice treated with different types of ADT. A pro‐atherogenic, possibly cholesterol‐mediated, effect of leuprolide was seen in orchiectomized mice that might be relevant for understanding the potential cardiovascular risk associated with GnRH agonist‐based ADT.

Endothelial dysfunction after androgen deprivation therapy and the possible underlying mechanisms

“…Another study in ApoE knockout mice using a longer treatment scheme similar to ours showed that leuprolide increased hypercholesterolemia, whereas the effect on enhancing atherosclerotic plaque formation are similar among leuprolide, degarelix, and orchidectomy. 28 This is also in agreement with our results which showed that leuprolide increased LDL and TC, whereas degarelix, and orchidectomy did not show obvious change.…”

Effects of castration on atherosclerosis in Yucatan minipigs with genetic hypercholesterolemia

“…Overall, we found modest effects of castration on plasma lipids and plaque burden in minipigs compared to what has been reported in mice and rabbits [4][5][6][7][8]. As an investigation into the human association of hypogonadism and coronary events, our investigation is unfortunately limited by the scarcity of advanced coronary lesions in the present study.…”

“…One prevailing hypothesis is that hypogonadism may increase cardiovascular risk through atherogenesis. This has been explored in mouse and rabbit models, where castration changes fat distribution, evokes more atherogenic lipid profiles, increases atherogenesis, and leads to changes in plaque composition with increased necrosis [4][5][6][7]. Recent studies in Apoe-deficient mice showed that loss of testosterone signaling in thymic epithelium was responsible for part of the pro-atherogenic effect [8].…”

Novel model to study the physiological effects of temporary or prolonged sex steroid deficiency in male mice

“…1B). Based on these findings, we chose 2 mg/kg as the low DGX dose (LD) to mimic a delay in puberty and compared this group with vehicle-treated control mice (C) as well as with mice receiving a 25 mg/kg high DGX dose (HD) to model complete and persistent suppression of puberty 33 .…”

“…We hypothesized that the use of a low dose of GnRH analogue administered at the start of puberty would be able to induce transient sex steroid deficiency, allowing to study the timing of sex steroid action as well as introducing a novel animal model of delayed puberty. In addition, a high dose of GnRH analogue would be suitable for complete and persistent suppression of pubertal sex steroid secretion 33 , allowing to assess the effects of chemical castration -as opposed to surgical castration -on bone and body composition. As a GnRH analogue, we decided to use a GnRH antagonist because this does not cause an initial flare-up response by means of a surge in LH levels as observed with GnRH agonists 16,19 .…”