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1 7:45-9:00 AM Changing Paradigms in the Diagnosis and Management of Erectile Dysfunction and Hypogonadism SPEAKER Mohit Khera, MD, MBA, MPH Disclosures The following relationships exist related to this presentation: Mohit Khera, MD, MBA, MPH: Advisory Board for AbbVie Inc., Boston Scientific, Coloplast, and Endo Pharmaceuticals Inc. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Erectile Dysfunction Through the Ages ~2600 BC 1600 BC Eighth century BC Yellow Emperor s Classic of Internal Medicine: a potion with 22 ingredients to cure impotence Papyrus Ebers: topically applied baby crocodiles hearts mixed with wood oil Shah J. BJU Int. 2002;90(4): Samhita of Sushruta: consumption of goat testes th Century Varolio: described how impeded venous return is involved in erectile physiology Impotence Trials s-1960 s Eckhard: explored neurogenic erectile physiology Lydston: dorsal vein ligation procedures Artificially Intercorporeal synthesized prosthetic testosterone implants introduced Case Bill is a 59 y/o male with a 2 year history of worsening ED. He is unable to maintain his erections. He is happily married but ED causing stress in marriage PMH: HTN, gout PSx: hernia, TURP Social: smokes 2ppd, occ ETOH PE: testis- 18cc bilaterally, DRE- 50 grams and benign, B DP pulses 1+ Labs: PSA 2.5 Next step?

2 Massachusetts Male Aging Study (MMAS) Prevalence Feldman HA, et al. J Urol. 1994;151(1): Prevalence and Severity of ED by Age Group Severe Moderate Mild Age (y) Overall prevalence of ED among men aged 40 to 70 years (N=1290) was 52% The overall prevalence of mild, moderate, and severe ED was 17.2%, 25.2%, and 9.6%, respectively Vasculogenic Neurogenic Local penile (cavernous) factors Hormonal Drug-induced Psychogenic Etiologies of ED 1-3 Cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, smoking, major surgery (radical prostatectomy) or radiotherapy (pelvis or retroperitoneum) Spinal cord and brain injuries, Parkinson s disease, Alzheimer s disease, multiple sclerosis, stroke Peyronie s disease, cavernous fibrosis, penile fracture Hypogonadism, hyperprolactinemia, hyper- and hypothyroidism, hyper- and hypocortisolism Antihypertensives, antidepressants, antipsychotics, antiandrogens, recreational drugs Performance-related issues, traumatic past experiences, relationship problems, anxiety, depression, stress 1. Wespes E, et al. European Association of Urology Guidelines on Male Sexual Dysfunction: erectile dysfunction and premature ejaculation Accessed November 24, 2013; 2. Shamloul R, Ghanem H. Lancet. 2013;381(9861): ; 3. Grant P, et al. Clin Med. 2013;13(2): Most Men With ED Do Not Receive Treatment Erectile Dysfunction: Unmet Medical Need In a study of 6,228,509 men with ED % received treatment (ie, PDE5 inhibitor, injection or urethral prostaglandins or androgen replacement) 74.6% were untreated In a population-based study of men 40 years and older with ED, 77% were not receiving pharmacotherapy with a PDE5 inhibitor 2 Potential reasons for not seeking treatment 3 Feelings of shame Concern that the physician won t take the sexual problem seriously MD does not address the issue Most important considerations when staring ED medications: Most important reasons for discontinuing ED medications: 1.Cakir O, et al. J Urol. 2013;189(4S):e570; 2. Foster SA, et al. Curr Med Res Opin. 2013;1-9; 3. Gerster S, et al. Int J Impot Res. 2013;25(2): Hanson-Divers et al J Urol 1998;159: ;

3 Prior ED Treatment Paradigm 1 st line therapies Male patient diagnosed with ED ~75 % Oral ED therapies (PDE5i) Prescribed by both Urologists & PCPs ~5% <10% <5% 2 nd line therapies 3 rd line therapies Urethral suppository Penile implant ~5% Injectable <1% Corrective vascular surgery Vacuum pump Primarily prescribed by Urologists Source: Adapted from American Urologic Association Treatment of ED Guidelines, emedicine.com, L.E.K. Consulting Interviews and analysis. PDE5 Inhibitors: Pharmacokinetics Sildenafil 1 Tadalafil 2 Vardenafil 3 T max (min) Terminal t 1/2 (hrs) Impact of a high fat meal Mean delay in T max of 60 minutes; mean reduction in C max of 29% Rate and extent of absorption are not influenced by food Reduction in C max of 18-50% Recommended administration times ~60 minutes before sexual activity ~60 minutes before sexual activity Use as needed prior to sexual activity AUA ED Guidelines Viagra [package insert]. Pfizer Inc.; 2010; 2. Cialis [package insert]. Eli Lilly and Company; 2003; 3. Levitra [package insert]. Bayer Healthcare Pharmaceuticals Inc.; 2013.

4 Avanafil T max (min): 30-45min Terminal t 1/2 (hrs): 5 hours Impact of a high fat meal: Rate of absorption is reduced, Tmax of 1.12 to 1.25 hours and a mean reduction in Cmax of 39% (200 mg) 3.8% decrease in AUC Recommended administration times: 30 minutes prior to intercourse Testosterone to Treat ED * Androgens Enhance PDE5i Efficacy Shabsigh et al.¹ 75 hypogonadal men (T<400 ng/dl) failed sildenafil 100mg Randomize to testosterone gel or placebo All men received sildenafil 100 mg as needed for 12 weeks IIEF significantly improved in TRT vs placebo (4.4 vs 2.1, p=0.029) Rosenthal et al.² 24 hypogonadal men failed 3 trials of sildenafil 100mg within 3 months Started on 4 weeks of testosterone gel and then restarted on silendafil After 16 weeks, 92% of men who initially failed sildenafil therapy reported improvements in potency Khera et al. ³ Multicenter registry of hypogonadal men (n=849) treated with TRT and followed for 12 months Patients already on PDE5i therapy also had a significant increase in BMSFI scores after starting TRT Intracavernosal Injection Therapy (ICI) Caverject EDEX (Alprostadil) Trimix (PGE, Phentolamine, Papaverine) ¹Shabsigh et al. J Urol Aug;172(2): ²Rosenthal et al. Urology 2006 Mar; 67(3):571-4 ³ Khera et al JSM 2011 Nov;8(11):

5 MUSE Intraurethral Suppository 1 2 * 3 4 Corporal Blood Oxygen Saturation with VED Vacuum Erection Device Corporal blood gas obtained with men using VED immediately after ring applied, after 1 minutes, after 30 minutes Corporal blood gas results were compared to peripheral arterial and venous blood Results : VED results in 58% arterial blood and 42% venous blood Bosshardt et al. Br J Urol 1995; 75:786

6 Inflatable 3-Piece Penile Implant Reservoir Correlation Between ED and CVD Thompson et al. 2005¹ 4,247 men without ED followed prospectively 57% with ED at 5 years Men with ED had a significantly higher incidence of developing CVD Montorsi et al ² Prevalence of ED was 49% in men with symptomatic CAD. Patients noticed ED on average 39 months before the onset of angina. Cylinder Pump ¹ Thompson et al JAMA 2005; 294:2996 ² Montorsi et al Eur Urol 2003; 44:360 ³ Montorsi et al AJC 2005; 96(12): 19M Shockwave Therapy to Treat ED Shockwave Therapy to Treat Other Medical Conditions Plantar fasciitis Achilles tendonitis Myocardial revascularization

7 Different Forms of Shockwave Generators Radial pressure wave (RSWT) Electrohydraulic shockwave Electromagnetic shockwave Piezoelectric shockwave Pneumatic shockwave Cavernosal Tissue Response to Shockwaves Activate nerve repair Restore normal endothelial signaling Recruit immune cells, initiate wound healing Recruit stem cells Medispec Dornier Storz Renova Direx MTS Medical (TRT) Haibin medical equipment Activate resident stem cells Fode et al. Nat Rev Urol Jul 25. Courtesy of F. Giuliano Fode, M. et al. (2017Nat. Rev. Urol. doi: /nrurol AUA ED Guidelines: Low Intensity Show Wave Therapy RCTs have produced conflicting results, and have evaluated erectile function only a short time after treatment; several RCTs are highly biased No high-quality level 1a evidence is available and level 1b evidence is conflicting regarding the use of Li- ESWT for ED treatment CONCLUSION: Li-ESWT should be limited to clinical trials until large multi-centric RCTs have provided the necessary data to recommend the routine use of this promising novel technology as a first-line treatment For men with ED, low-intensity extracorporeal shock wave therapy (ESWT) should be considered investigational. (Conditional Recommendation; Evidence Level: Grade C) Fode, M. et al. (2017) Nat. Rev. Urol. doi: /nrurol

8 Emerging Tools for Erectile Dysfunction: A Role for Regenerative Medicine Effects of Mesenchymal Stem Cells on Cavernous Smooth Muscle Smooth muscle Fibrosis Nerve innervatio n b-actin nnos b-actin nnos Hakim et al.nat Rev Urol Sep;9(9): Albersen et al J Sex Med Oct;7(10): The Current Status of Stem Cell Therapy in Erectile Dysfunction Word of caution Only small number of clinical trials published in the literature No control group No randomization Numerous clinics throughout the world are offering penile injections of stem cells for monetary gain to treat ED Further larger randomized controlled trials are desperately needed in this field Reed-Maldanado A and Lue T World J Mens Health Dec;34(3): Khera et al. J Sex Med May;12(5):

9 AUA ED Guidelines: Stem cells For men with ED, intracavernosal stem cell therapy should be considered investigational. (Conditional Recommendation; Evidence Level: Grade C) Baylor College of Medicine Stem Cell and ED Studies Human trials: IRB and FDA approved clinic trial (NCT ) Randomized controlled trial Diabetic and radical prostatectomy patients Autologous adipose derived stem cells 30 patients completed study Animal experiments: IRB approved experiments Diabetic rat model Autologous adipose derived stem cells Assessing optimal dosing and frequency of intracavernosal stem cell injections

10 Platelet Rich Plasma PRP Statistics No studies listed on for PRP and ED Google Platelet rich plasma, erectile dysfunction : 147,000 results (10/2017) Website marketing (2015) bigger erections, improved sex life, improvement in climax/orgasm, increased sensation, increased libido and improved sensation even years after prostatectomy Cost: $1500 to $3000 cash per injection 2018 first PRP/ED study published (case series) Jenkins L et al JSM 12(12) Franco M, Garcia-Cruz E ESSM with ED only and 1 with ED and Peyronies disease Between 4 and 9 ml of PRP was injected in corpora cavernosa per treatment session. was A mean of 2.1 injection procedures per patient were performed IIEF-5 improvement of 4.14 AEs (in all patients): mild pain (23.5%) and bruising (5.9%) Matz et al Investig Clin Urol 2018;59:61-65.

11 AUA ED Guidelines: Platelet Rich Plasma For men with ED, platelet-rich plasma (PRP) therapy should be considered experimental. (Expert Opinion) Testosterone Testing and Initiation Thus, given the current lack of regulatory agency approval for any restorative (regenerative) therapies for the treatment of ED and until such time as approval is granted, SMSNA believes that the use of shock waves or stem cells or platelet rich plasma is experimental and should be conducted under research protocols in compliance with Institutional Review Board approval. Patients considering such therapies should be fully informed and consented regarding the potential benefits and risks. Finally, the SMSNA advocates that patients involved in these clinical trials should not incur more than basic research costs for their participation. March 2018 Layton et al. J Clin Endocrinol Metab 2014; 99(3):

12 FDA Label Venous Thromboembolism (VTE) Controversies? Testosterone Guidelines AUA 2018 Endocrine 2018 FDA Label (2005 and 2009): Venous Thromboembolism Adverse Reactions section of the label was amended to note that one patient during the open-label extension of the clinical trial had suffered a DVT New Medication Guide that listed Blood clots in the legs among the serious side effects FDA Label (2014): Venous Thromboembolism Warnings and Precaution Section

13 Venous Thromboembolism AUA 2018 Guidelines Patients should be informed that there is no definitive evidence linking testosterone therapy to a higher incidence of venothrombolic events (Moderate Recommendation; Evidence Level: Grade C) Endocrine 2018 Guidelines No guideline statement Case-control and pharmacoepidemiologic studies have not shown a consistent increase in the risk of venous thromboembolism (VTE) with T treatment. However, there are too few T- associated VTE events in RCTs to draw meaningful inferences. Cardiovascular Risk Aging Males and Mortality Low Serum T and Mortality in Male Veterans Men With a Normal T-Level (n = 452) Men With a Low T-Level (n = 166) Cumulative Survival Survival (y) Shores M, et al. Arch Intern Med. 2006;166: Survival 79.9% Survival 65.1% Low Testosterone and Increased Mortality (N >500) Recent Studies HR (95% CI) Nature Men, n Follow-Up, y Mortality Shores, ( ) Retrospective All-cause Laughlin, ( ) Prospective CVD Khaw, ( ) Prospective of 11,606 All-cause and CVD Haring, ( ) Prospective All-cause 2.56 ( ) CVD Malkin, ( ) Prospective All-cause in men with coronary disease Tivesten, ( ) Prospective All-cause Menke, ( ) Prospective All-cause Vikan, ( ) Prospective All-cause Corona, ( ) Prospective CVD HR=hazard ratio; CI=confidence interval.

14 Prior to 2010 Articles Demonstrating Beneficial Effects of T Against CVD Type of Article Number of Articles Low levels of endogenous testosterone and increased 8 mortality Low testosterone levels and increased incidence of 6 coronary artery disease Low testosterone level correlates with increased 4 severity of coronary artery disease Low endogenous testosterone level and increased 8 carotid intima-media thickness TRT decreases obesity 6 TRT improved cholesterol levels (meta- analysis) 3 TRT improves glycemic control 6 TRT decreases markers of inflammation 8 Review of all articles from relating to T and CVD Over 200 articles identified Only 4 articles suggesting increased CV risk with T Several dozen studies demonstrated beneficial effects of normal T on CV risk and mortality Low levels of T associated with increased risk of mortality and CVD (LOE IIa) Severity of CAD inversely correlated with serum T levels (LOE IIa) Morgentaler et al. Mayo Clin Proc Nov 1 Morgentaler et al. Mayo Clin Proc Nov 1 Basaria et al NEJM 2010 Vigen et al JAMA 2013 FDA Label (2015): Cardiovascular Risk RPCT frail elderly men 15 grams of testosterone CVD not an endpoint Treatment arm greater CV risks 5 vs 2 major CV events (ie MI) No difference if exclude CHF No randomization or placebo No control group or clinical info Health insurance database 90 days after start testosterone Pre-prescription MI rate 3.48/1000 Post-prescription MI rate 4.75/1000 Studies Claiming TTh Causes CVD No randomization or placebo 2 major corrections Absolute risk of MI (19.9 vs 25.7%) vs (21 vs 10%) Exclusion of 1132 men RETRACTION 29 societies Meta- analysis of CV events in 27 PC studies of >12 weeks Just 2 studies provided 1/3 of all CV events in T treat arm If exclude 2 studies CV events in T and placebo are identical Warnings and Precaution Section Finkle et al PLoS One 2014 Xu et al BMC 2013 European Medicines Agency (EMA) performed its own review and declined to add a new CV warning

15 T and CV studies from September 2014 to July studies (12 clinical trials, 11 observational studies) Results: No study reported increased MACE with TTh Men whose T normalized with TTh had reduced risk of MI and death compared with men whose T levels failed to normalize Miner et al. Clinical Endocrinology 2018 Cardiovascular Risk AUA 2018 Guidelines Clinicians should inform testosterone deficient patients that low testosterone is a risk factor for cardiovascular disease. (Strong Recommendation; Evidence Level: Grade B) Prior to initiating treatment, clinicians should counsel patients that, at this time, it cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events (e.g., myocardial infarction, stroke, cardiovascular-related death, allcause mortality). (Moderate Recommendation; Evidence Level: Grade B) Testosterone therapy should not be commenced for a period of three to six months in patients with a history of cardiovascular events. (Expert Opinion) Endocrine 2018 Guidelines We recommend against testosterone therapy in men with. heart failure, myocardial infarction or stroke within the last 6 months (Low quality evidence) there is no conclusive evidence that T supplementation is associated with increased cardiovascular risk in hypogonadal men. Thus, there are insufficient data to establish a causal link between T therapy and cardiovascular events. Indications for Testosterone Therapy FDA Androgen Class Labeling Guideline (1981) "Androgens are indicated for replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. a) Primary hypogonadism (congenital or acquired)-testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy. b) Hypogonadotropic hypogonadism (congenital or acquired) idiopathic gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation."

16 FDA Label (2015): Indications for Testosterone Therapy Prevalence of Hypogonadism Specific medical conditions Specific Medical Conditions Associated with Secondary Hypogonadism 79.4% Eugondal 3.2% Primary 17.4% Secondary 50.4% 49.6% Unknown 10.9% 89.1% Unknown 10.9% Specific medical conditions 89.1% Unknown 70.7% Associated with concomitant metabolic disease (Obesity, T2DM or Metabolic Syndrome) 29.3% Unknown Specific medical conditions Corona et al J Sex Med 2015; ) Corona et al J Sex Med 2015; )

17 AOH is a clinical and biochemical syndrome characterized by a deficiency of testosterone with signs and symptoms that can be caused by testicular and/or hypothalamic-pituitary dysfunction AOH is clinically distinct from classical primary and secondary hypogonadism AOH more often occurs in men who have chronic medical conditions AUA 2018 Guidelines The clinical diagnosis of testosterone deficiency is only made when patients have low total testosterone levels combined with symptoms and/or signs (Moderate Recommendation; Evidence Level: Grade B) Indications Endocrine 2018 Guidelines We recommend diagnosing hypogonadism in men with symptoms and signs of testosterone deficiency and unequivocally and consistently low serum total testosterone and/or free testosterone concentrations (when indicated) (Moderate quality evidence) Khera et al. Mayo Clin Proc Jul;91(7): At What Levels Should We Treat?: Total Testosterone For most symptoms, the average testosterone threshold corresponds to the lower limit of the normal (approximately 300 ng/dl), with a greater likelihood of having symptoms below this threshold than above it ¹² Threshold of testosterone levels vary for various symptoms of androgen deficiency and target organs, and among individuals ¹ ² Laboratory Diagnosis Problems with testosterone and free testosterone testing Variations between total testosterone assay methods Variation in reference ranges for total testosterone Study of 25 different testosterone reference labs² Lower reference value: 130 to 450 ng/dl (350% difference) Upper reference value: 486 to 1,593 ng/dl (325% difference) ¹ Menke et al Am J Epidemiol : ² Zitzmann et al J Clin Endocrinol Metab : Lazarou et al. J Sex Med Nov;3(6):1085-9

18 Prostate Cancer and BPH FDA Label: Prostate Cancer and BPH Warnings and Precaution Section Contraindications Section T and BPH T and Prostate Cancer DeLay KJ and Kohler TS Urol Clin North Am Aug;43(3): AUA 2018 Guidelines Clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer. (Strong Recommendation; Evidence Level: Grade B) Patients with testosterone deficiency and a history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy (Expert Opinion) Endocrine 2018 Guidelines We recommend against testosterone therapy in men with. prostate cancer, a palpable prostate nodule or induration, a prostatespecific antigen level >4 ng/ml, a prostate-specific antigen level >3 ng/ml combined with a high risk of prostate cancer (without further urological evaluation).severe lower urinary tract symptoms,. (Low quality evidence)

19 Khera M. J Sex Med 2009;6(suppl 3): Khera et al. Eur Urol Jan;65(1): Testosterone Alternatives: Future Therapies NanoTechnology Personalized Molecular Drug-delivery System (PMDS) CONSTRAINT CAUSES CONSTANT RELEASE Like an Hour Glass Nano Technology Stem Cells Drug Reservoir PMDS CHIP CROSS SECTION 1 of 1,000,000 Nanochannels on Chip High Concentration of Drug Formulation CONSTANT RELEASE No Burst or Bolus Effect Inlet (~µm) Nanochannel (~nm) DAILIY DOSING Outlet (~µm) PMDS RANGE THERAPEUTIC Body (bio-fluid) MONTHS

20 D ifferentiated Undifferentiated Leydig Stem Cell Isolation and Differentiation From Human Testis Biopsies: Potential Modality To Increase Serum Testosterone Eight days in Differentiation induction medium Replicate 2 Impact of differentiation on PDGFR (Stem cell marker) expression after 14 and 20 days in DIM Impact of differentiation on 3BHSD (differentiation marker) expression after 8 days in DIM Exposing Leydig stem cells to LH in vitro from human testis biopsies, we can differentiate them to adult Leydig cells that can express 3 - HSD make testosterone Conclusion Current ED therapies do not provide a cure for ED Penile rehabilitation may offer men faster and better recovery of erectile function following radical prostatectomy The mechanisms for how PRP, stem cells and LIST improve erectile dysfunction appear to be promising and some initial studies have demonstrated benefit At this time, the use of LIST, stem cells or PRP should be consider experimental until appropriate RCTs have demonstrated proven efficacy and safety Slide courtesy of Dr. Ranjith Ramasamy Conclusion Diagnosis of hypogonadism can be challenging with majority of men being treated off-label Clinicians prescribing testosterone therapy should be aware of the 2018 AUA and Endocrine Guidelines and the recent FDA label changes TTh has been shown to improve BPH and LUTS Low serum testosterone has been associated with an increased risk of MI and CV risk factors There is no convincing data to support that TTh causes prostate cancer Patients should be appropriately counseled on the risks of VTE, CVE, BPH, and prostate cancer when prescribing testosterone therapy