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Protective effect of pharmacological castration on metabolic perturbations and cardiovascular disease in the hyperglycemic male ApoE−/−:Ins2+/Akita mouse model

Prostate Cancer and Prostatic Diseases volume 24, pages 389–397 (2021)Cite this article

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A Correction to this article was published on 19 August 2021

This article has been updated

Abstract

Background

Unlike in other mouse models of atherogenesis, it has recently been suggested that orchiectomy plays a role in attenuating atherosclerosis and inhibiting the progression of cardiovascular disease in the ApoE−/−:Ins2+/Akita 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.

Methods

Male ApoE−/−:Ins2+/Akita 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.

Results

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.

Conclusions

Further characterization of the ApoE−/−:Ins2+/Akita 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.

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Fig. 1: Body weight gain and serum leptin in ApoE−/−:Ins2+/Akita mice receiving different modes of ADT.
Fig. 2: Glucose and related assessments in ApoE−/−:Ins2+/Akita mice receiving different modes of ADT.
Fig. 3: Blood lipids in ApoE−/−:Ins2+/Akita mice receiving different modes of ADT.
Fig. 4: Aortic atherosclerotic plaque in ApoE−/−:Ins2+/Akita mice receiving different modes of ADT (n = 7–8/group) after 5 months.
Fig. 5: Kaplan–Meier survival curves of ApoE−/−:Ins2+/Akita mice receiving different modes of ADT excluding mice that died of non-CVD causes (n = 4–11/group).

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Acknowledgements

Financial support provided by the CUA-CUOG Astellas Research Grant Program funded by Astellas Pharma Canada, Inc. (jointly established by Astellas Pharma Canada, Inc., Canadian Urological Association and the Canadian Urological Oncology Group) (to SD), McMaster Surgical Associates grant, Ferring Pharmaceuticals through an investigator-initiated grant to JHP. Ferring Pharmaceuticals had no involvement in study design, collection, analysis, and interpretation of data, writing of the report or the decision to submit for publication.

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Authors and Affiliations

  1. Department of Surgery, Division of Urology, McMaster University, Hamilton, ON, Canada

    Wilhelmina C. M. Duivenvoorden, Magda Naeim, Sarah N. Hopmans, Sadiya Yousef, Shawn Dason & Jehonathan H. Pinthus

  2. Research Institute of St. Joe’s, St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada

    Wilhelmina C. M. Duivenvoorden & Jehonathan H. Pinthus

  3. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada

    Geoff H. Werstuck

  4. Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, Canada

    Geoff H. Werstuck

  5. Department of Urology, The Ohio State University, Columbus, OH, USA

    Shawn Dason

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Correspondence to Jehonathan H. Pinthus.

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JHP has acted in a consulting role for Ferring Pharmaceuticals; has received research funding for projects from Ferring Pharmaceuticals. The remaining authors have no conflict of interest.

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The original online version of this article was revised: The original version of this article unfortunately contained a mistake in the first sentence of the Background section of the Abstract.

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Duivenvoorden, W.C.M., Naeim, M., Hopmans, S.N. et al. Protective effect of pharmacological castration on metabolic perturbations and cardiovascular disease in the hyperglycemic male ApoE−/−:Ins2+/Akita mouse model. Prostate Cancer Prostatic Dis 24, 389–397 (2021). https://doi.org/10.1038/s41391-020-00288-y

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