Department of Surgery, Division of Urology, McMaster University, Hamilton, ON, Canada.
Research Institute of St. Joe's, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
Prostate Cancer Prostatic Dis. 2021 Jun;24(2):389-397. doi: 10.1038/s41391-020-00288-y. Epub 2020 Sep 28.
Unlike in other mouse models of atherogenesis, it has recently been suggested that orchiectomy plays a role in accelerating atherosclerosis and inhibiting the progression of cardiovascular disease in the ApoE:Ins2 mouse model of hyperglycemia. Androgen-deprivation therapy (ADT) is a common treatment for prostate cancer, a population with high prevalence of cardiovascular disease and its risk factors. Our objectives were to test and further characterize the effects of pharmacological castration which is currently the acceptable modality to deliver ADT in the clinic.
Male ApoE:Ins2 mice received one of three modes of ADT (gonadotropin-releasing hormone (GnRH)-antagonist (degarelix), GnRH-agonist (leuprolide), or bilateral orchiectomy) and were compared to corresponding untreated control mice (n = 9-13/group). Mice were followed for 5 months. Body weight, fasting blood glucose, glucose tolerance, serum C-peptide, leptin, and testosterone levels along with atherosclerotic aortic plaque size and characteristics were determined. In a separate experiment, the survival of mice, untreated and on ADT, was determined.
Castration was achieved for all three modes of ADT. However, degarelix-treated mice gained significantly less weight, had lower serum leptin levels and systolic blood pressure compared to orchiectomy and leuprolide-treated mice. ADT improved dysglycemia and atherosclerotic burden. GnRH-antagonist significantly improved survival compared to GnRH-agonist but not compared to orchiectomy.
Further characterization of the ApoE:Ins2 mouse model confirms that pharmacological ADT ameliorated metabolic syndrome and cardiovascular complications. Improved dysglycemia and atherosclerosis associated with increased survival which was longest after degarelix followed by orchiectomy.
与其他动脉粥样硬化的小鼠模型不同，最近有人提出，去势在加速 ApoE：Ins2 小鼠模型的高血糖性动脉粥样硬化和抑制心血管疾病进展方面发挥作用。雄激素剥夺疗法（ADT）是治疗前列腺癌的常用方法，而前列腺癌患者具有较高的心血管疾病及其危险因素患病率。我们的目的是测试和进一步描述目前临床上可接受的 ADT 给药方式——药物去势的作用。
雄性 ApoE：Ins2 小鼠接受三种 ADT 模式之一（促性腺激素释放激素（GnRH）拮抗剂（degarelix）、GnRH 激动剂（leuprolide）或双侧睾丸切除术），并与相应的未治疗对照小鼠进行比较（n = 9-13/组）。小鼠随访 5 个月。测定体重、空腹血糖、葡萄糖耐量、血清 C 肽、瘦素和睾酮水平以及主动脉粥样硬化斑块大小和特征。在一个单独的实验中，确定未治疗和接受 ADT 的小鼠的存活率。
所有三种 ADT 模式均实现了去势。然而，与睾丸切除术和 leuprolide 治疗的小鼠相比，degarelix 治疗的小鼠体重增加显著减少，血清瘦素水平和收缩压降低。ADT 改善了糖代谢紊乱和动脉粥样硬化负担。与 GnRH 激动剂相比，GnRH 拮抗剂显著提高了存活率，但与睾丸切除术相比则没有提高。
对 ApoE：Ins2 小鼠模型的进一步特征分析证实，药物 ADT 改善了代谢综合征和心血管并发症。改善糖代谢紊乱和动脉粥样硬化与存活率增加相关，degarelix 后其次是睾丸切除术，存活率最长。
