Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer: Contemporary Meta-Analyses

Jiun-Ruey Hu, Meredith S Duncan, Alicia K Morgans, Jonathan D Brown, Wouter C Meijers, Matthew S Freiberg, Joe-Elie Salem, Joshua A Beckman, Javid J Moslehi, Jiun-Ruey Hu, Meredith S Duncan, Alicia K Morgans, Jonathan D Brown, Wouter C Meijers, Matthew S Freiberg, Joe-Elie Salem, Joshua A Beckman, Javid J Moslehi

Abstract

Androgen deprivation therapy is a cornerstone of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, androgen receptor inhibition, and CYP17 (cytochrome P450 17A1) inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.

Keywords: androgen deprivation therapy; cardiooncology; cardiotoxicity; gonadotropin releasing hormone agonists; prostate cancer.

Figures

Figure 1:
Figure 1:
The hypothalamic-pituitary-gonadal axis and targets for androgen deprivation therapy in prostate cancer Abbreviations: 17-OHP5: 17α-hydroxypregnenolone; AE: androstenedione; AR: androgen receptor; DHEA: dihydroepiandrosterone; DHT: dihydrotestosterone; GnRH: gonadotropin releasing hormone; LH: luteinizing hormone; P5: pregnenolone; T: testosterone

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi:10.3322/caac.21492
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: A Cancer Journal for Clinicians. 2019;69(1):7–34. doi:10.3322/caac.21551
    1. Levine GN, D’Amico AV, Albertsen P, et al. Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk. Circulation. 2010;121(6):833–840. doi:10.1161/CIRCULATIONAHA.109.192695
    1. Beyer DA, Amari F, Thill M, et al. Emerging gonadotropin-releasing hormone agonists. Expert Opinion on Emerging Drugs. 2011;16(2):323–340. doi:10.1517/14728214.2010.547472
    1. Barber M, Nguyen LS, Wassermann J, Spano J-P, Funck-Brentano C, Salem J-E. Cardiac arrhythmia considerations of hormone cancer therapies. Cardiovasc Res. 2019;115(5):878–894. doi:10.1093/cvr/cvz020
    1. Shore ND, Abrahamsson P-A, Anderson J, Crawford ED, Lange P. New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists. Prostate Cancer and Prostatic Diseases. 2013;16(1):7–15. doi:10.1038/pcan.2012.25
    1. Van Poppel H Evaluation of degarelix in the management of prostate cancer. Cancer Manag Res. 2010;2:39–52.
    1. Tombal B, Berges R. Optimal Control of Testosterone: A Clinical Case-Based Approach of Modern Androgen-Deprivation Therapy. European Urology Supplements. 2008;7(1):15–21. doi:10.1016/j.eursup.2007.11.001
    1. Klotz L, Boccon‐Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU International. 2008;102(11):1531–1538. doi:10.1111/j.1464-410X.2008.08183.x
    1. Shore ND. Experience with degarelix in the treatment of prostate cancer. Therapeutic Advances in Urology. 2013;5(1):11–24. doi:10.1177/1756287212461048
    1. Gittelman M, Pommerville PJ, Persson B-E, Jensen J-K, Olesen TK, Degarelix Study Group. A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America. J Urol. 2008;180(5):1986–1992. doi:10.1016/j.juro.2008.07.033
    1. Rathkopf D, Scher HI. Androgen Receptor Antagonists in Castration-Resistant Prostate Cancer. The Cancer Journal. 2013;19(1):43. doi:10.1097/PPO.0b013e318282635a
    1. Yu J, Zhang L, Yan G, et al. Discovery and biological evaluation of novel androgen receptor antagonist for castration-resistant prostate cancer. European Journal of Medicinal Chemistry. 2019;171:265–281. doi:10.1016/j.ejmech.2019.03.041
    1. Vasaitis TS, Bruno RD, Njar VCO. CYP17 inhibitors for prostate cancer therapy. J Steroid Biochem Mol Biol. 2011;125(1–2):23–31. doi:10.1016/j.jsbmb.2010.11.005
    1. Keating NL, O’Malley AJ, Smith MR. Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy for Prostate Cancer. JCO. 2006;24(27):4448–4456. doi:10.1200/JCO.2006.06.2497
    1. Carneiro A, Sasse AD, Wagner AA, et al. Cardiovascular events associated with androgen deprivation therapy in patients with prostate cancer: a systematic review and meta-analysis. World J Urol. 2015;33(9):1281–1289. doi:10.1007/s00345-014-1439-6
    1. Meng F, Zhu S, Zhao J, et al. Stroke related to androgen deprivation therapy for prostate cancer: a meta-analysis and systematic review. BMC Cancer. 2016;16(1):180. doi:10.1186/s12885-016-2221-5
    1. Zhao J, Zhu S, Sun L, et al. Androgen Deprivation Therapy for Prostate Cancer Is Associated with Cardiovascular Morbidity and Mortality: A Meta-Analysis of Population-Based Observational Studies. PLOS ONE. 2014;9(9):e107516. doi:10.1371/journal.pone.0107516
    1. Bourke L, Kirkbride P, Hooper R, Rosario AJ, Chico TJA, Rosario DJ. Endocrine therapy in prostate cancer: time for reappraisal of risks, benefits and cost-effectiveness? British Journal of Cancer. 2013;108(1):9–13. doi:10.1038/bjc.2012.523
    1. Nguyen PL, Je Y, Schutz FAB, et al. Association of Androgen Deprivation Therapy With Cardiovascular Death in Patients With Prostate Cancer: A Meta-analysis of Randomized Trials. JAMA. 2011;306(21):2359–2366. doi:10.1001/jama.2011.1745
    1. Bosco C, Bosnyak Z, Malmberg A, Adolfsson J, Keating NL, Van Hemelrijck M. Quantifying Observational Evidence for Risk of Fatal and Nonfatal Cardiovascular Disease Following Androgen Deprivation Therapy for Prostate Cancer: A Meta-analysis. European Urology. 2015;68(3):386–396. doi:10.1016/j.eururo.2014.11.039
    1. Albertsen PC, Klotz L, Tombal B, Grady J, Olesen TK, Nilsson J. Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist. European Urology. 2014;65(3):565–573. doi:10.1016/j.eururo.2013.10.032
    1. Scailteux L-M, Naudet F, Alimi Q, Vincendeau S, Oger E. Mortality, cardiovascular risk, and androgen deprivation therapy for prostate cancer: A systematic review with direct and network meta-analyses of randomized controlled trials and observational studies. Medicine. 2016;95(24):e3873. doi:10.1097/MD.0000000000003873
    1. Jin C, Fan Y, Meng Y, et al. A meta-analysis of cardiovascular events in intermittent androgen-deprivation therapy versus continuous androgen-deprivation therapy for prostate cancer patients. Prostate Cancer and Prostatic Diseases. 2016;19(4):333–339. doi:10.1038/pcan.2016.35
    1. Iacovelli R, Ciccarese C, Bria E, et al. The Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer. Clinical Genitourinary Cancer. 2018;16(3):e645–e653. doi:10.1016/j.clgc.2017.12.007
    1. Moreira RB, Debiasi M, Francini E, et al. Differential side effects profile in patients with mCRPC treated with abiraterone or enzalutamide: a meta-analysis of randomized controlled trials. Oncotarget. 2017;8(48):84572–84578. doi:10.18632/oncotarget.20028
    1. Bretagne M, Lebrun-Vignes B, Pariente A, et al. Heart failure and atrial tachyarrhythmia on abiraterone: a pharmacovigilance study. Archives of Cardiovascular Diseases. 2019;In Press.
    1. Moslehi JJ. Cardiovascular Toxic Effects of Targeted Cancer Therapies. New England Journal of Medicine. 2016;375(15):1457–1467. doi:10.1056/NEJMra1100265
    1. D’Amico AV, Chen M-H, Renshaw A, Loffredo M, Kantoff PW. Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer. JAMA. 2015;314(12):1291–1293. doi:10.1001/jama.2015.8577
    1. Nathan L, Shi W, Dinh H, et al. Testosterone inhibits early atherogenesis by conversion to estradiol: Critical role of aromatase. Proc Natl Acad Sci U S A. 2001;98(6):3589–3593. doi:10.1073/pnas.051003698
    1. Bourghardt J, Wilhelmson ASK, Alexanderson C, et al. Androgen Receptor-Dependent and Independent Atheroprotection by Testosterone in Male Mice. Endocrinology. 2010;151(11):5428–5437. doi:10.1210/en.2010-0663
    1. Langer C, Gansz B, Goepfert C, et al. Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochemical and Biophysical Research Communications. 2002;296(5):1051–1057. doi:10.1016/S0006-291X(02)02038-7
    1. Hamilton EJ, Gianatti E, Strauss BJ, et al. Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy. Clinical Endocrinology. 2011;74(3):377–383. doi:10.1111/j.1365-2265.2010.03942.x
    1. Hara N, Ishizaki F, Saito T, Nishiyama T, Kawasaki T, Takahashi K. Decrease in Lean Body Mass in Men With Prostate Cancer Receiving Androgen Deprivation Therapy: Mechanism and Biomarkers. Urology. 2013;81(2):376–380. doi:10.1016/j.urology.2012.10.050
    1. Chazenbalk G, Singh P, Irge D, Shah A, Abbott DH, Dumesic DA. Androgens inhibit adipogenesis during human adipose stem cell commitment to predipocyte formation. Steroids. 2013;78(9):920–926. doi:10.1016/j.steroids.2013.05.001
    1. Gupta V, Bhasin S, Guo W, et al. Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytes. Mol Cell Endocrinol. 2008;296(1–2):32–40. doi:10.1016/j.mce.2008.08.019
    1. Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in Body Composition during Androgen Deprivation Therapy for Prostate Cancer. J Clin Endocrinol Metab. 2002;87(2):599–603. doi:10.1210/jcem.87.2.8299
    1. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer. 2006;106(3):581–588. doi:10.1002/cncr.21642
    1. Rubinow KB, Snyder CN, Amory JK, Hoofnagle AN, Page ST. Acute testosterone deprivation reduces insulin sensitivity in men. Clinical Endocrinology. 2012;76(2):281–288. doi:10.1111/j.1365-2265.2011.04189.x
    1. Tsai H-T, Keating NL, Van Den Eeden SK, et al. Risk of Diabetes among Patients Receiving Primary Androgen Deprivation Therapy for Clinically Localized Prostate Cancer. J Urol. 2015;193(6):1956–1962. doi:10.1016/j.juro.2014.12.027
    1. Keating NL, Liu P-H, O’Malley AJ, Freedland SJ, Smith MR. Androgen Deprivation Therapy and Diabetes Control among Diabetic Men with Prostate Cancer. Eur Urol. 2014;65(4):816–824. doi:10.1016/j.eururo.2013.02.023
    1. Chen X, Li X, Huang H, Li X, Lin J. [Effects of testosterone on insulin receptor substrate-1 and glucose transporter 4 expression in cells sensitive to insulin]. Zhonghua Yi Xue Za Zhi. 2006;86(21):1474–1477.
    1. Bosco C, Crawley D, Adolfsson J, Rudman S, Van Hemelrijck M. Quantifying the Evidence for the Risk of Metabolic Syndrome and Its Components following Androgen Deprivation Therapy for Prostate Cancer: A Meta-Analysis. PLoS One. 2015;10(3). doi:10.1371/journal.pone.0117344
    1. Braga-Basaria M, Muller DC, Carducci MA, Dobs AS, Basaria S. Lipoprotein profile in men with prostate cancer undergoing androgen deprivation therapy. International Journal of Impotence Research. 2006;18(5):494. doi:10.1038/sj.ijir.3901471
    1. Goldberg RB, Rabin D, Alexander AN, Doelle GC, Getz GS. Suppression of Plasma Testosterone Leads to an Increase in Serum Total and High Density Lipoprotein Cholesterol and Apoproteins A-I and B. J Clin Endocrinol Metab. 1985;60(1):203–207. doi:10.1210/jcem-60-1-203
    1. Moorjani S, Dupont A, Labrie F, et al. Increase in plasma high-density lipoprotein concentration following complete androgen blockage in men with prostatic carcinoma. Metabolism. 1987;36(3):244–250. doi:10.1016/0026-0495(87)90183-1
    1. Dockery F, Bulpitt CJ, Agarwal S, Donaldson M, Rajkumar C. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clinical Science. 2003;104(2):195–201. doi:10.1042/cs1040195
    1. Smith JC, Bennett S, Evans LM, et al. The Effects of Induced Hypogonadism on Arterial Stiffness, Body Composition, and Metabolic Parameters in Males with Prostate Cancer. J Clin Endocrinol Metab. 2001;86(9):4261–4267. doi:10.1210/jcem.86.9.7851
    1. Attard G, Reid AHM, Auchus RJ, et al. Clinical and Biochemical Consequences of CYP17A1 Inhibition with Abiraterone Given with and without Exogenous Glucocorticoids in Castrate Men with Advanced Prostate Cancer. J Clin Endocrinol Metab. 2012;97(2):507–516. doi:10.1210/jc.2011-2189
    1. Beckman JA, Doherty SP, Feldman ZB, et al. Comparative Transcriptomics of Ex Vivo, Patient-Derived Endothelial Cells Reveals Novel Pathways Associated With Type 2 Diabetes Mellitus. J Am Coll Cardiol Basic Trans Science. 2019;4(5):567–574. doi:10.1016/j.jacbts.2019.05.012
    1. Nguyen PL, Jarolim P, Basaria S, et al. Androgen Deprivation Therapy Reversibly Increases Endothelium‐Dependent Vasodilation in Men With Prostate Cancer. Journal of the American Heart Association. 2015;4(4):e001914. doi:10.1161/JAHA.115.001914
    1. Herman SM, Robinson JT, McCredie RJ, Adams MR, Boyer MJ, Celermajer DS. Androgen deprivation is associated with enhanced endothelium-dependent dilatation in adult men. Arterioscler Thromb Vasc Biol. 1997;17(10):2004–2009.
    1. Salem J-E, Yang T, Moslehi JJ, et al. Androgenic Effects on Ventricular Repolarization A Translational Study From the International Pharmacovigilance Database to iPSC-Cardiomyocytes. Circulation. 2019;(140).
    1. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female Gender as a Risk Factor for Torsades de Pointes Associated With Cardiovascular Drugs. JAMA. 1993;270(21):2590–2597. doi:10.1001/jama.1993.03510210076031
    1. Abehsira G, Bachelot A, Badilini F, et al. Complex Influence of Gonadotropins and Sex Steroid Hormones on QT Interval Duration. J Clin Endocrinol Metab. 2016;101(7):2776–2784. doi:10.1210/jc.2016-1877
    1. Salem Joe-Elie, Waintraub Xavier, Carine Courtillot, et al. Hypogonadism as a Reversible Cause of Torsades de Pointes in Men. Circulation. 2018;138(1):110–113. doi:10.1161/CIRCULATIONAHA.118.034282
    1. Gagliano-Jucá T, İçli TB, Pencina KM, et al. Effects of Testosterone Replacement on Electrocardiographic Parameters in Men: Findings From Two Randomized Trials. J Clin Endocrinol Metab. 2017;102(5):1478–1485. doi:10.1210/jc.2016-3669
    1. Kakar SS, Jennes L. Expression of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor mRNAs in various non-reproductive human tissues. Cancer Lett. 1995;98(1):57–62.
    1. Dong F, Skinner DC, Wu TJ, Ren J. The Heart: A Novel Gonadotrophin-Releasing Hormone Target. Journal of Neuroendocrinology. 2011;23(5):456–463. doi:10.1111/j.1365-2826.2011.02119.x
    1. Garnick MB, Pratt CM, Campion M, Shipley J. The effect of hormonal therapy for prostate cancer on the electrocardiographic QT interval: phase 3 results following treatment with leuprolide and goserelin, alone or with bicalutamide, and the GnRH antagonist abarelix. JCO. 2004;22(14_suppl):4578–4578. doi:10.1200/jco.2004.22.90140.4578
    1. Canpolat U, Tokgözoğlu L, Yorgun H, et al. The association of premature ovarian failure with ventricular repolarization dynamics evaluated by QT dynamicity. Europace. 2013;15(11):1657–1663. doi:10.1093/europace/eut093
    1. Libby P The vascular biology of atherosclerosis In: Bonow R, Mann D, Zipes D, Libby P, eds. Braunwald’s Heart Disease: Textbook of Cardiovascular Medicine. 9th ed Philadelphia, PA: Elsevier Saunders; 2012.
    1. Hajer GR, van Haeften TW, Visseren FLJ. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J. 2008;29(24):2959–2971. doi:10.1093/eurheartj/ehn387
    1. Tzortzis V, Samarinas M, Zachos I, Oeconomou A, Pisters LL, Bargiota A. Adverse effects of androgen deprivation therapy in patients with prostate cancer: focus on metabolic complications. Hormones. 2017;16(2):115–123. doi:10.14310/horm.2002.1727
    1. Bhatia N, Santos M, Jones LW, et al. Cardiovascular Effects of Androgen Deprivation Therapy for the Treatment of Prostate Cancer: ABCDE Steps to Reduce Cardiovascular Disease in Patients With Prostate Cancer. Circulation. 2016;133(5):537–541. doi:10.1161/CIRCULATIONAHA.115.012519

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