1 Other Side Effects: Perception vs. EvidenceNeal D. Shore, MD Atlantic Urology Clinic, LLC Myrtle Beach, SC

2 Common Adverse Effects of Androgen Deprivation TherapyHot flashes Loss of libido/ED Fatigue Anemia Muscle loss Gynecomastia Obesity/Sarcopenia Diabetes Cardiovascular disease Osteoporosis/fracture Psychological: depression, memory difficulties, emotional liability

3 Testosterone: Target Organsbrain libido, mood, cognition heart cardiovascular health liver protein synthesis kidney stimulation of erythropoietin production male sexual organs penile growth spermatogenesis, erection prostate growth and function bone marrow stimulation of stem cells skin hair growth, balding, sebum production muscle strength, volume, energy reduction in visceral fat bone strength and density

4 Androgen Deprivation Therapy“Androgen Deprivation Syndrome” “Androgen Withdrawal Syndrome” “LHRH Syndrome” “Medical Andropause” Constellation of symptoms and conditions ADT now used more in non-metastatic prostate cancer, exposing men to ADT for longer periods Concerns growing over ADT side effects Arch Intern Med. 2006;166: ; Oncologist. 2003;8:

5 ADT Causes a Variety of Specific Adverse EffectsCentral nervous system Fatigue Musculoskeletal system Osteoporosis/fractures Obesity Sarcopenia Hematologic system Anemia Endocrine Vasomotor flushing Lipid alterations Insulin resistance Reproductive system Decreased libido Erectile dysfunction

6 ADT has been Associated with Metabolic ChangesMetabolic syndrome is a disorder of energy utilisation and storage, diagnosed by co-occurrence of any 3 of: Abdominal (central) obesity Elevated blood pressure Elevated fasting plasma glucose High serum triglycerides Low high-density (HDL) cholesterol levels Metabolic syndrome increases the risk of developing CVD ADT leads to: Insulin resistance Accumulation of subcutaneous fat and decreased lean body mass Increased glucose levels Abnormalities in lipid levels Kelly DM, Jones TH. J Endocrinol 2013;217:R25-45

7 Metabolic Syndrome and Metabolic Changes Induced by ADT are DifferentMetabolic changes with ADT Increased triglycerides Increased visceral fat Increased subcutaneous fat Reduced HDL Increased HDL Hypertension Increased fasting glucose Decreased adiponectin Increased adiponectin Increased C-reactive protein Normal C-reactive protein

8 Abdominal Obesity and Sarcopenia During ADTEugonadal young man Saylor and Smith. J Urol. 2009;181:

9 GnRH Agonists Significantly Increase Serum Lipids in Men with CaPSmith MR et al. J Clin Endocrinol Metab. 2002;87:

10 GnRH Agonists Decrease Insulin Sensitivity in Nondiabetic Men with PCaSmith MR et al (2006) J Clin Endocrinol Metab 91:1305-8

11 ADT and Diabetes: Consistency Between Forms of ADTKeating, O’Malley, and Smith (2006) J Clin Oncol 24(27):

12 Consistency Between Population-Based StudiesADT and Diabetes: Consistency Between Population-Based Studies Hazard Ratio Confidence Intervals SEER-Medicare (n= 73,196; 7055 events) 1.44 ( ) Ontario registry (n= 39,418; 2573 events) 1.24 ( ) Veterans Administration (n= 37,433, 4967 events) 1.28 ( ) References: Keating et al (2006) JCO; Alibhai et al (2009) JCO; Keating et al (2010) JNCI

13 Causal Association Between ADT and Diabetes is PlausibleSmith MR et al (2002) JCEM 87: Smith MR et al (2006) JCEM 91:1305-8

14 Practical Recommendations: DiabetesScreening Consider testing in all men treated with ADT at baseline and yearly thereafter while receiving ADT Recommended test: glycated hemoglobin (HbA1c) Prediabetes=HbA1c %; diabetes=HbA1c >7% Management of pre-diabetes Treat other CHD risk factors Repeat testing at least yearly Lifestyle interventions (with follow-up counseling): 5–10% weight loss ≥150 min/week of moderate physical activity Saylor PJ et al. J Gen Intern Med. 2009;24 Suppl 2:S389-S394.

15 Other Recommendations based on RCTFatigue Aerobic and resistance exercise Gynecomastia RT and tamoxifen both reduce gynecomastia compared with observation, but tamoxifen reduces it more Sexual dysfunction - Intermittent ADT and Aerobic and resistance exercise Nguyen PL Eur Urol Aug 2. [Epub ahead of print].

16 Analyses based on 125 new diagnoses of Alzheimer’s diseaseNead et al. JCO 2016;34:

17 ADT and Alzheimer’s DiseaseADT Users and Non-ADT Users were dramatically different at baseline Kevin T. Nead et al. JCO 2016;34:

18 ADT and Alzheimer’s DiseaseKevin T. Nead et al. JCO 2016;34:

19 Lack of specificity suggests NO causal link between ADT and dementia

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22 Why Intermittent Androgen Deprivation?Androgen Deprivation Therapy (ADT) is associated with adverse events: Holzbeierlein JM Urol Clin NA 2006,33:181-90; Spry NA et al BJUI (2009) Epub; Gomella, et al Urology May;73:S28-35 Short-term: hot flushes, loss of libido, ED, fatigue Long-term: bone demineralization, anemia, muscle wasting, metabolic syndrome, depression development of hormone resistance Intermittent Androgen Deprivation (IAD) therapy aims to: Minimize adverse events Maximize quality of life (QoL) Delay development hormone resistant prostate cancer (HRPC) Reduction of non-oncologic morbidity/mortality and cost of care Tunn U. BJU Int 2007;99 (Suppl 1):19-22; Boccon-Gibod L et al. BJU Int 2007;100:738-43 Gleave M et al Urol Oncol 2009,27:81-86

23 Conclusions ADT causes specific harmsHot flashes, fatigue, anemia, sexual dysfunction, sarcopenia, obesity, osteoporosis, and greater risks for fractures and diabetes Not all harms associated with ADT are causal Cardiovascular disease, dementia, colorectal cancer, others When considering harms linked ADT, consider strength, consistency, and biological plausibility of the association

24 Thank you!