Side effects of androgen deprivation therapy
- Matthew R Smith, MD, PhD
Matthew R Smith, MD, PhD
- Professor of Medicine
- Harvard Medical School
- Massachusetts General Hospital Cancer Center
- E David Crawford, MD
E David Crawford, MD
- Professor of Surgery, Urology and Radiation Oncology
- University of Colorado Denver School of Medicine
- Section Editors
- Nicholas Vogelzang, MD
Nicholas Vogelzang, MD
- Section Editor — Prostate Cancer
- Professor of Medicine
- University of Nevada School of Medicine
- US Oncology Research
- W Robert Lee, MD, MS, MEd
W Robert Lee, MD, MS, MEd
- Section Editor — Prostate Cancer
- Professor of Radiation Oncology
- Duke University Medical Center
- Jerome P Richie, MD, FACS
Jerome P Richie, MD, FACS
- Section Editor — Cancer of the Urethra, Penis, and Ureter; Urologic Surgery; Prostate Cancer
- Elliott Carr Cutler Professor of Surgery
- Harvard Medical School
Androgen deprivation therapy (ADT) is the main therapeutic approach for men with metastatic prostate cancer. ADT is also frequently used in patients whose only manifestation of disseminated disease is a rising or elevated serum PSA and as adjuvant or neoadjuvant therapy in conjunction with initial treatment of men with intermediate or high risk prostate cancer. (See "Initial systemic therapy for castration sensitive prostate cancer" and "Initial management of regionally localized intermediate, high, and very high-risk prostate cancer" and "Rising serum PSA after treatment for localized prostate cancer: Systemic therapy".)
Despite the potential benefits associated with its use, ADT can cause a range of side effects that negatively affect quality of life and may necessitate a change in therapy. The side effects of hormone therapy for prostate cancer, their prevention and management, and the potential role of an alternative hormonal strategy are discussed here.
The vast majority of men receiving continuous ADT who are potent prior to therapy develop sexual dysfunction. Loss of libido in men receiving gonadotropin-releasing hormone (GnRH) agonists usually develops within the first several months, and erectile dysfunction follows. Sexual dysfunction should be anticipated and couples counseled before ADT is started. Sex therapists may be helpful in managing these issues once they become problematic.
Recovery of erectile function is possible after discontinuation of short-term ADT (eg, in men who receive neoadjuvant and adjuvant ADT with radiation therapy for high-risk localized or locally advanced disease). However, it may be delayed and incomplete .
OSTEOPOROSIS AND BONE FRACTURES
ADT increases bone turnover, decreases bone mineral density, and increases the risk of bone fractures in men with prostate cancer . Loss of bone mineral density can be detected after six to nine months of ADT, and longer therapy confers a higher risk [3-6]. Osteoporotic skeletal fractures occur in up to 20 percent of men within five years of starting ADT [3,7].
- Wilke DR, Parker C, Andonowski A, et al. Testosterone and erectile function recovery after radiotherapy and long-term androgen deprivation with luteinizing hormone-releasing hormone agonists. BJU Int 2006; 97:963.
- Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol 2015; 67:825.
- Smith MR, Lee WC, Brandman J, et al. Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol 2005; 23:7897.
- Saad F, Adachi JD, Brown JP, et al. Cancer treatment-induced bone loss in breast and prostate cancer. J Clin Oncol 2008; 26:5465.
- Diamond T, Campbell J, Bryant C, Lynch W. The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer 1998; 83:1561.
- Krupski TL, Smith MR, Lee WC, et al. Natural history of bone complications in men with prostate carcinoma initiating androgen deprivation therapy. Cancer 2004; 101:541.
- Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352:154.
- Segal RJ, Reid RD, Courneya KS, et al. Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol 2003; 21:1653.
- Ross RW, Small EJ. Osteoporosis in men treated with androgen deprivation therapy for prostate cancer. J Urol 2002; 167:1952.
- Bae DC, Stein BS. The diagnosis and treatment of osteoporosis in men on androgen deprivation therapy for advanced carcinoma of the prostate. J Urol 2004; 172:2137.
- Saad F, Olsson C, Schulman CC. Skeletal morbidity in men with prostate cancer: quality-of-life considerations throughout the continuum of care. Eur Urol 2004; 46:731.
- Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001; 345:948.
- Smith MR, Eastham J, Gleason DM, et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003; 169:2008.
- Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med 2007; 146:416.
- Klotz LH, McNeill IY, Kebabdjian M, et al. A phase 3, double-blind, randomised, parallel-group, placebo-controlled study of oral weekly alendronate for the prevention of androgen deprivation bone loss in nonmetastatic prostate cancer: the Cancer and Osteoporosis Research with Alendronate and Leuprolide (CORAL) study. Eur Urol 2013; 63:927.
- Choo R, Lukka H, Cheung P, et al. Randomized, double-blinded, placebo-controlled, trial of risedronate for the prevention of bone mineral density loss in nonmetastatic prostate cancer patients receiving radiation therapy plus androgen deprivation therapy. Int J Radiat Oncol Biol Phys 2013; 85:1239.
- Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009; 361:745.
- Smith MR, Saad F, Egerdie B, et al. Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. J Urol 2009; 182:2670.
- http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site (Accessed on August 20, 2012).
- Frisk J. Managing hot flushes in men after prostate cancer--a systematic review. Maturitas 2010; 65:15.
- Vitolins MZ, Giffin L, Tomlinson WV, et al. Randomized Trial to Assess the Impact of Venlafaxine and Soy Protein on Hot Flashes and Quality of Life in Men With Prostate Cancer. J Clin Oncol 2013.
- Irani J, Salomon L, Oba R, et al. Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for prostate cancer: a double-blind, randomised trial. Lancet Oncol 2010; 11:147.
- Loprinzi CL, Dueck AC, Khoyratty BS, et al. A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB). Ann Oncol 2009; 20:542.
- Harding C, Harris A, Chadwick D. Auricular acupuncture: a novel treatment for vasomotor symptoms associated with luteinizing-hormone releasing hormone agonist treatment for prostate cancer. BJU Int 2009; 103:186.
- Beer TM, Benavides M, Emmons SL, et al. Acupuncture for hot flashes in patients with prostate cancer. Urology 2010; 76:1182.
- Ashamalla H, Jiang ML, Guirguis A, et al. Acupuncture for the alleviation of hot flashes in men treated with androgen ablation therapy. Int J Radiat Oncol Biol Phys 2011; 79:1358.
- Alibhai SM, Breunis H, Timilshina N, et al. Impact of androgen-deprivation therapy on physical function and quality of life in men with nonmetastatic prostate cancer. J Clin Oncol 2010; 28:5038.
- Smith MR, Saad F, Egerdie B, et al. Sarcopenia during androgen-deprivation therapy for prostate cancer. J Clin Oncol 2012; 30:3271.
- Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 2002; 87:599.
- Smith MR, Lee H, Fallon MA, Nathan DM. Adipocytokines, obesity, and insulin resistance during combined androgen blockade for prostate cancer. Urology 2008; 71:318.
- Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol 2009; 27:3452.
- Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006; 24:4448.
- Keating NL, O'Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 2010; 102:39.
- Tsai HT, 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; 193:1956.
- Keating NL, Liu PH, O'Malley AJ, et al. Androgen-deprivation therapy and diabetes control among diabetic men with prostate cancer. Eur Urol 2014; 65:816.
- Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 2006; 91:1305.
- Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol 2006; 24:3979.
- Braga-Basaria M, Muller DC, Carducci MA, et al. Lipoprotein profile in men with prostate cancer undergoing androgen deprivation therapy. Int J Impot Res 2006; 18:494.
- Yannucci J, Manola J, Garnick MB, et al. The effect of androgen deprivation therapy on fasting serum lipid and glucose parameters. J Urol 2006; 176:520.
- Reis C, Liberman S, Pompeo AC, et al. Body composition alterarions, energy expenditure and fat oxidation in elderly males suffering from prostate cancer, pre and post orchiectomy. Clinics (Sao Paulo) 2009; 64:781.
- Saigal CS, Gore JL, Krupski TL, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007; 110:1493.
- Tsai HK, D'Amico AV, Sadetsky N, et al. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007; 99:1516.
- Nanda A, Chen MH, Braccioforte MH, et al. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA 2009; 302:866.
- Crawford ED, Moul JW. ADT risks and side effects in advanced prostate cancer: cardiovascular and acute renal injury. Oncology (Williston Park) 2015; 29:55.
- O'Farrell S, Garmo H, Holmberg L, et al. Risk and Timing of Cardiovascular Disease After Androgen-Deprivation Therapy in Men With Prostate Cancer. J Clin Oncol 2015.
- Nguyen PL, Je Y, Schutz FA, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 2011; 306:2359.
- Bosco C, Bosnyak Z, Malmberg A, et al. Quantifying observational evidence for risk of fatal and nonfatal cardiovascular disease following androgen deprivation therapy for prostate cancer: a meta-analysis. Eur Urol 2015; 68:386.
- Albertsen PC, Klotz L, Tombal B, et al. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol 2014; 65:565.
- Klil-Drori AJ, Yin H, Tagalakis V, et al. Androgen Deprivation Therapy for Prostate Cancer and the Risk of Venous Thromboembolism. Eur Urol 2016; 70:56.
- Ehdaie B, Atoria CL, Gupta A, et al. Androgen deprivation and thromboembolic events in men with prostate cancer. Cancer 2012; 118:3397.
- Van Hemelrijck M, Adolfsson J, Garmo H, et al. Risk of thromboembolic diseases in men with prostate cancer: results from the population-based PCBaSe Sweden. Lancet Oncol 2010; 11:450.
- Lapi F, Azoulay L, Niazi MT, et al. Androgen deprivation therapy and risk of acute kidney injury in patients with prostate cancer. JAMA 2013; 310:289.
- Gandaglia G, Sun M, Hu JC, et al. Gonadotropin-releasing hormone agonists and acute kidney injury in patients with prostate cancer. Eur Urol 2014; 66:1125.
- Smith MR. Androgen deprivation therapy and acute kidney injury. JAMA 2013; 310:2313.
- Stone P, Hardy J, Huddart R, et al. Fatigue in patients with prostate cancer receiving hormone therapy. Eur J Cancer 2000; 36:1134.
- Beer TM, Tangen CM, Bland LB, et al. The prognostic value of hemoglobin change after initiating androgen-deprivation therapy for newly diagnosed metastatic prostate cancer: A multivariate analysis of Southwest Oncology Group Study 8894. Cancer 2006; 107:489.
- Joly F, Alibhai SM, Galica J, et al. Impact of androgen deprivation therapy on physical and cognitive function, as well as quality of life of patients with nonmetastatic prostate cancer. J Urol 2006; 176:2443.
- Haliloglu A, Baltaci S, Yaman O. Penile length changes in men treated with androgen suppression plus radiation therapy for local or locally advanced prostate cancer. J Urol 2007; 177:128.
- Nelson CJ, Lee JS, Gamboa MC, Roth AJ. Cognitive effects of hormone therapy in men with prostate cancer: a review. Cancer 2008; 113:1097.
- Gonzalez BD Jim HS, Booth-Jones M, et al. Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison. J Clin Oncol 2015.
- Nead KT, Gaskin G, Chester C, et al. Association Between Androgen Deprivation Therapy and Risk of Dementia. JAMA Oncol 2016.
- Khosrow-Khavar F, Rej S, Yin H, et al. Androgen deprivation therapy and the risk of dementia in patients with prostate cancer. J Clin Oncol 2016.
- Alibhai SM, Breunis H, Timilshina N, et al. Impact of androgen-deprivation therapy on cognitive function in men with nonmetastatic prostate cancer. J Clin Oncol 2010; 28:5030.
- Khosrow-Khavar F, Rej S, Yin H, et al. Androgen Deprivation Therapy and the Risk of Dementia in Patients With Prostate Cancer. J Clin Oncol 2017; 35:201.
- Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of the "androgen deprivation syndrome" in men receiving androgen deprivation for prostate cancer. Arch Intern Med 2006; 166:465.
- Dinh KT, Reznor G, Muralidhar V, et al. Association of Androgen Deprivation Therapy With Depression in Localized Prostate Cancer. J Clin Oncol 2016; 34:1905.
- Gardner JR, Livingston PM, Fraser SF. Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: a systematic review. J Clin Oncol 2014; 32:335.
- Smith MR, Goode M, Zietman AL, et al. Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition. J Clin Oncol 2004; 22:2546.
- Sieber PR, Keiller DL, Kahnoski RJ, et al. Bicalutamide 150 mg maintains bone mineral density during monotherapy for localized or locally advanced prostate cancer. J Urol 2004; 171:2272.
- Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000; 132:566.
- Hussain M, et al. Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial (abstract #4). J Clin Oncol 2012.
- Moinpour C, Berry DL, Ely B, et al. Preliminary quality-of-life outcomes for SWOG-9346: Intermittent androgen deprivation in patients with hormone-sensitive metastatic prostate cancer (HSM1PC)—Phase III. J Clin Oncol 2012; 30: (suppl; abstr 4571)
- Klotz L, O'Callaghan CJ, Ding K. A phase III randomized trial comparing intermittent versus continuous androgen suppression for patients with PSA progression after radical therapy: NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013 (abstract #3). J Clin Oncol 2011.
- SEXUAL DYSFUNCTION
- OSTEOPOROSIS AND BONE FRACTURES
- - Lifestyle modification
- - Osteoclast inhibition
- VASOMOTOR SYMPTOMS
- - Alternative strategies
- BODY COMPOSITION AND METABOLISM
- POTENTIAL CARDIOVASCULAR HARM
- Cardiac disease
- Venous thromboembolism
- KIDNEY INJURY
- ISSUES RELATED TO BODY IMAGE
- Decreased penile and testicular size
- Thinning of body hair
- EMOTIONAL AND COGNITIVE CHANGES
- ROLE OF STRUCTURED EXERCISE
- ALTERNATIVE HORMONE STRATEGIES
- Antiandrogen monotherapy
- Intermittent androgen deprivation