AUANEWS. Testosterone Replacement Therapy AUA 2014 ANNUAL MEETING HIGHLIGHTS ANNUAL MEETING HIGHLIGHTS Testosterone Replacement Therapy

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1 American Urological Association AUANEWS THE OFFICIAL NEWSMAGAZINE OF THE AMERICAN UROLOGICAL ASSOCIATION 2014 ANNUAL MEETING HIGHLIGHTS Testosterone Replacement Therapy Course #017PG Male Health: Strategies for Managing Lifelong Wellness Course #025IC Building a Comprehensive Men s Health Program that Addresses the Changing Clinical Environment, Regulations and Practices Course #050IC Testosterone Therapy: New Concepts for a Rapidly Changing Field Course #065IC Testosterone: Diagnosis and Management of the Hypogonadal Male AUANews Editor Gopal H. Badlani, MD Publisher American Urological Association 1000 Corporate Boulevard Linthicum, MD AUA 2014 ANNUAL MEETING HIGHLIGHTS Testosterone Replacement Therapy Copyright 2014 by American Urological Association None of the contents may be reproduced in any form without prior written permission of the publisher. The opinions expressed in this publication are those of the speakers and do not necessarily reflect the opinions or recommendations of their affiliated institutions, the publisher, the American Urological Association or any other persons. Some articles in this publication may discuss unapproved or off-label uses of products. Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients conditions and of possible contraindications or dangers in use, review of any applicable manufacturers product information and comparison with the recommendations of the authorities. Support provided by educational grants from: AbbVie Lilly CME Credit

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3 CME INFORMATION Method of Participation To claim CME credit/hours of participation, the learner must read the overview of courses 017PG, 025IC, 050IC, and 065IC, complete the posttest, passing with 80% accuracy, and submit the evaluation and credit request form by visiting TRT14. Estimated time to complete this activity: 1.25 hours Release Date: October 2014 Expiration Date: October 31, 2015 Software Requirements for Online Test A PC-compatible computer running Windows XP or later, or a Macintosh computer running OS X 10.4 or later. Internet access. Adobe Acrobat Reader 9 or newer. AUA Disclosure Policy All persons in a position to control the content of an educational activity (i.e., activity planners, presenters, authors) participating in an educational activity provided by the AUA are required to disclose to the provider any relevant financial relationships with any commercial interest. The AUA must determine if the individual s relationships may influence the educational content and resolve any conflicts of interest prior to the commencement of the educational activity. The intent of this disclosure is not to prevent individuals with relevant financial relationships from participating, but rather to provide learners information with which they can make their own judgments. Resolution of Identified Conflict of Interest All disclosures will be reviewed by the program/course directors or editors for AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS AUA Annual Meeting Highlights: Testosterone Replacement Therapy identification of conflicts of interest. Peer reviewers, working with the program directors and/or editors, will document the mechanism(s) for management and resolution of the conflict of interest and final approval of the activity will be documented prior to implementation. Any of the mechanisms below can/will be used to resolve conflict of interest: Peer review for valid, evidence-based content of all materials associated with an educational activity by the course/program director, editor, and/ or Education Content Review Committee or its subgroup Limit content to evidence with no recommendations Introduction of a debate format with an unbiased moderator (point-counterpoint) Inclusion of moderated panel discussion Publication of a parallel or rebuttal article for an article that is felt to be biased Limit equipment representatives to providing logistics and operation support only in procedural demonstrations Divestiture of the relationship by faculty Accreditation Statement The American Urological Association (AUA) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Credit Designation The American Urological Association designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This enduring material credit is valid only for content reformatted from courses 017PG, 025IC, 050IC and 065IC. Planners Gopal H. Badlani, MD Professor of Urology, Vice Chair of Clinical Affairs, Director of Urogynecology Regenerative Medicine Program Wake Forest Baptist Medical Center Winston-Salem, NC Disclosures: Lithotripsy Group: Investment Interest; Society of University Urologists: Leadership Position; NIDDK: Leadership Position; Endourology Society: Other Elspeth M. McDougall, MD, FRCSC, MHPE Professor of Urologic Sciences Provincial Coordinator for Health Simulation Education University of British Columbia Chair, AUA Office of Education Gordon & Leslie Diamond Health Care Centre Vancouver, B.C., Canada Disclosures: Nothing to disclose Tracey Krupski, MD Associate Professor, Department of Urology University of Virginia Charlottesville, VA Disclosures: Nothing to disclose J. Kellogg Parsons, MD Associate Professor, Department of Surgery UC San Diego Moores Cancer Center San Diego, CA Disclosures: AMS: Meeting Participant or Lecturer; Sophiris: Consultant or Advisor; Watson: Consultant or Advisor; Myriad: Consultant or Advisor Statement of Need There is an unmet need to educate health practitioners on male gender-specific issues in dealing with men's health issues and potentially initiate men's health programs and clinics. The AUA Annual Meeting courses on testosterone therapy Continued on page 2

4 2 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS CME Information Continued from page 1 address these needs by introducing and reviewing new concepts and areas of controversy in the exciting and rapidly evolving field of testosterone therapy as well as increasing awareness of the link between hypogonadism, metabolic function, and sexual function, which can result in improved screening and treatment outcomes. Target Audience Urologists, urologists in training and nonphysician providers involved in urology. Course #017PG: Male Health: Strategies for Managing Lifelong Wellness Learning Objectives After participating in this activity, participants should be able to: 1. Describe what should be recognized at each of the decades of the male health continuum and major risk factors 2. Cite the decade of life which supports each preventive service 3. Identify at-risk males and the appropriate evaluation 4. Indicate treatment needs and/or appropriate referral 5. Integrate male health into practice models from solo providers to large groups Faculty Richard S. Pelman, MD, Course Director Clinical Professor of Urology, Department of Urology University of Washington Seattle, WA Disclosures: Astellas Pharmaceuticals: Consultant or Advisor, Meeting Participant or Lecturer; Pfizer: Investment Interest; Johnson and Johnson: Investment Interest Mark A. Moyad, MD, MPH Jenkins Pokempner Director of Preventive & Alternative Medicine, Department of Urology University of Michigan Medical Center Ann Arbor, MI Disclosures: Abbvie: Consultant or Advisor, Meeting Participant or Lecturer; Farr Labs: Consultant or Advisor; Spry Publishing: Health Publishing; MAX International: Consultant or Advisor Martin M. Miner, MD Co-Director Men s Health Center The Miriam Hospital Clinical Associate Professor of Family Medicine and Urology Warren Alpert School of Medicine of Brown University Providence, RI Disclosures: Forest Pharmaceuticals: Scientific Study or Trial; Actient: Scientific Study or Trial Kevin R. Loughlin, MD, MBA Professor of Surgery, Department of Urology Harvard Medical School Director of Urologic Research and Senior Surgeon Brigham and Women s Hospital Boston, MA Disclosures: Nothing to disclose Stacy Loeb, MD, MSc Assistant Professor of Urology and Population Health New York University New York, New York Disclosures: Nothing to disclose Course #025IC: Building a Comprehensive Men s Health Program that Addresses the Changing Clinical Environment, Regulations and Practices Learning Objectives After participating in this activity, participants should be able to: 1. Evaluate and treat the primary conditions of sexual dysfunction and hypogonadism in a progressive manner 2. Monitor comorbidities as part of treatment protocols 3. Understand the cofactors that may influence the disease discussion and treatment options 4. Apply and provide an individualized, comprehensive and effective men s health program in their clinical practice Faculty Rafael E. Carrion, MD, Course Director Associate Professor, Department of Urology University of South Florida Tampa, FL Disclosures: American Medical Systems: Consultant or Advisor, Meeting Participant or Lecturer; Coloplast: Consultant or Advisor, Meeting Participant or Lecturer; Auxilium: Consultant or Advisor Mark J. Swierzewski, MD Director of Men s Health Florida Urology Partners, LLP Tampa, FL Disclosures: Nothing to disclose Course #050IC: Testosterone Therapy: New Concepts for a Rapidly Changing Field Learning Objectives After participating in this activity, participants should be able to: 1. Diagnose testosterone deficiency 2. Interpret the true relationship between serum testosterone and prostate cancer 3. Differentiate appropriate treatment choices on an individualized basis Faculty Abraham Morgentaler, MD, Course Director Associate Clinical Professor of Urology Harvard Medical School Boston, MA Disclosures: Auxilium: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Sprout: Continued on page 3

5 CME Information Continued from page 2 Investment Interest; Warner Chilcott: Scientific Study or Trial Abdulmaged M. Traish, PhD, MBA Professor of Biochemistry and Urology Boston University School of Medicine Boston, MA Disclosures: Nothing to disclose Course #065IC: Testosterone: Diagnosis and Management of the Hypogonadal Male Learning Objectives After participating in this activity, participants should be able to: 1. Review presentation and diagnostic methods for male hypogonadism/ testosterone deficiency syndrome 2. Interpret the link between hypogonadism (physiological or acquired through androgen deprivation therapy for metastatic prostate cancer) and cardiovascular disease (coronary artery disease, myocardial infarction and sudden cardiac death) 3. Appraise the controversy regarding testosterone supplementation and prostate cancer 4. Describe the shortcomings of current assay methodologies 5. Devise a cost-effective treatment and follow-up algorithm for the hypogonadal male Faculty AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 3 Wayne J.G. Hellstrom, MD, FACS, Course Director Professor of Urology Chief, Section of Andrology Department of Urology Tulane University School of Medicine New Orleans, LA Disclosures: Andromedical: Consultant or Advisor; Endo: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Slate-Actient Pharmaceutical: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Theralogix: Leadership Position; Coloplast: Consultant or Advisor, Meeting Participant or Lecturer; Lilly: Consultant or Advisor, Meeting Participant or Lecturer; American Medical Systems: Consultant or Advisor; Cook: Consultant or Advisor, Meeting Participant or Lecturer; NIH: Leadership Position; Allergan: Consultant or Advisor, Scientific Study or Trial; Vivus: Consultant or Advisor, Scientific Study or Trial; Auxilium: Consultant or Advisor, Scientific Study Andre T. Guay, MD, FACP, FACE Director, Center for Sexual Function and Endocrinology Lahey Clinic Northshore Peabody, MA Disclosures: Endo Pharmaceuticals: Consultant or Advisor Mohit Khera, MD, MBA, MPH Associate Professor of Urology Division of Male Reproductive Medicine and Surgery Scott Department of Urology Baylor College of Medicine Houston, TX Disclosures: Auxilium/Slate Pharmaceuticals: Consultant or Advisor, Meeting Participant or Lecturer; Allergan: Scientific Study or Trial; MEDA: Consultant or Advisor, Meeting Participant or Lecturer; Lilly: Meeting Participant or Lecturer; Coloplast: Consultant or Advisor, Meeting Participant or Lecturer; Merck: Consultant or Advisor, Meeting Participant or Lecturer; Endo Pharmaceuticals/ American Medical Systems: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Sprout Pharmaceuticals: Investment Interest; Journal of Sexual Medicine: Health Publishing; Sexual Medicine Society of North America: Leadership Position Acknowledgements The AUA Office of Education would like to thank the companies who support continuing education of physicians. The AUA recognizes the following companies for providing educational grant support: AbbVie Lilly American Urological Association Education & Research, Inc. ensures that all educational activities are developed and implemented independent of the control and/or influence of any commercial interests (ACCME: SCS1). Evidence-Based Content It is the policy of the AUA to ensure that the content contained in this CME activity is valid, fair, balanced, scientifically rigorous, and free of commercial bias. Off-label or Unapproved Use of Drugs or Devices It is the policy of the AUA to require the disclosure of all references to off-label or unapproved uses of drugs or devices prior to the presentation of educational content. The audience is advised that this continuing medical education activity may contain reference(s) to off-label or unapproved uses of drugs or devices. Please consult the product prescribing information for full disclosure of approved uses. Disclaimer The opinions and recommendations expressed by faculty, authors and other experts whose input is included in this program are their own and do not necessarily represent the viewpoint of the AUA. Reproduction Permission Reproduction of written materials developed for this AUA course is prohibited without the written permission from individual authors and the American Urological Association. AUA Privacy and Confidentiality Policy Access the AUA Privacy and Cofidentiality Policy online at education/confidentiality-statement.cfm.

6 4 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS COURSE #017PG Male Health: Strategies for Managing Lifelong Wellness Richard S. Pelman, MD, Course Director; Kevin R. Loughlin, MD, MBA, Mark A. Moyad, MD, MPH, Martin M. Miner, MD and Stacy Loeb, MD, MSc, Faculty Men s health has different connotations and applications for physicians, the public and health care organizations. To some, men s health may represent a reproductive clinic, to others it may represent a sexual health clinic and to others it may represent a testosterone (T) replacement clinic. In this course we emphasized the integration of male health into the practice of urology, shaping it with the future of male cardiometabolic health and sexual functioning. This integration should help reduce the disparity in health needs that men face and allow for better integration of care. Urology can and should recognize men with urinary disorders that place them at risk for associated or related medical conditions. Urologists need to understand the bidirectional nature of disease so that they can facilitate appropriate health care delivery for their patients. Testosterone replacement therapy (TRT) is reviewed as an important aspect of male health. Appropriate diagnosis, monitoring and replacement are key, along with education of our colleagues and patients as to what appropriate replacement actually entails. During the last several months there has been a firestorm of negative media attention regarding testosterone deficiency and its treatment, precipitated by a study reporting an increased rate of nonfatal myocardial infarction (MI) associated with testosterone prescriptions. 1 Class action suits against pharmaceutical companies for cardiovascular (CV) events are advertised nightly on television. This public judgment of T therapy demands a response. As researchers and clinicians with extensive experience with T deficiency and its treatment, we disagree that the recent study published in PLoS One presents any credible evidence that T prescriptions increase health risks, 1 and we find baseless the general assertion that testosterone is prescribed to men who are simply reluctant to accept the fact that they are getting older. 2 We object to comments questioning whether T deficiency is real, regardless of whether it is called hypogonadism or low T as used in advertisements. Clinicians who diagnose and treat testosterone deficiency conscientiously and appropriately do not deserve this criticism, and over-the-top comments scare patients and physicians alike, thereby hampering our goal of providing patients with the best available care. The Food and Drug Administration (FDA) announcement that it is investigating reports of increased CV risks of testosterone therapy has only added to the impression that a major study has determined serious problems with testosterone therapy. Let us examine carefully the publications at the heart of this firestorm. Benefits of Testosterone Repletion TRT is associated with improvements in many domains of sexual function, including sexual desire, sexual activity and sleep related erections. 3, 4 Erectile dysfunction itself may not respond as well to TRT if vascular disease is also present, a finding that is more common in older men. Testosterone replacement also improves bone mineral density, chiefly in the spine and femoral neck. 5 Testosterone therapy is associated with reduced body fat mass, improved muscle mass and strength, and a possible positive effect on lipid levels and glucose control. One does not often note a change in body mass index as fat mass is replaced by lean muscle mass. Functionally important changes in strength have been reported, particularly for older, frail, hypogonadal men and those with mobility limitations. 6 Improved mood, cognition, energy and quality of life have also been credited to TRT. 7 TRT and Cardiovascular Risk In the first of the 2 recent studies reporting the risks of testosterone prescriptions, Vigen et al performed a retrospective analysis of a data set of 8,709 men in the Veterans Administration health system who had undergone coronary angiography. 8 Among men with testosterone concentrations less than 300 ng/ dl, the authors reported an increased rate of heart attacks, strokes and deaths in those who received a testosterone prescription compared with those who did not. No significant differences in event rates were noted for any year of followup. However, the overall event curves demonstrated that the significantly increased risk of suffering an event was actually lower by half for the testosterone group compared with the no testosterone group (10.1% vs 21.2%) based on the raw data. 8 The authors came to the opposite conclusion resulting from complex statistical modeling based on more than 50 variables. This modeling failed to include substantially lower baseline testosterone levels in the T group, despite evidence that lower T values are associated with increased CV risk and mortality. In addition, the authors improperly excluded 1,132 men from study who suffered a stroke or heart attack before receiving a testosterone prescription. Without that exclusion, the rate of events in the no testosterone group would have been increased by 71%, reversing the results. It is impossible to conclude from this study that testosterone prescrip- Continued on page 5

7 Course #017IC Continued from page 4 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 5 tions increase the rates of cardiovascular events. In the second study Finkle et al performed a retrospective analysis of insurance claims data in 55,593 men for whom the only information available was diagnosis codes, procedure codes and prescription data. 1 The primary reported result was an increased rate of nonfatal MI within 90 days after filling a testosterone prescription compared with the prior 12 months. The authors also compared these rates with pre- and postprescription rates for phosphodiesterase type 5 inhibitors (PDE5is), reporting no increase in MI after PDE5i prescription. Analyses of subgroups by age revealed an increased risk of MI in men older than 65 years without a history of heart disease and for men younger than 65 with a history of heart disease. The authors concluded that the risk of MI is substantially increased in older men and in younger men with preexisting known heart disease. 1 This study received even greater media attention, and appears to have led to the FDA decision to review CV risks with testosterone. Neither the study by Vigen et al 8 nor the more recent publication by Finkle et al 1 provide any credible evidence that testosterone use is associated with increased cardiovascular risk. Both studies were retrospective and highly statistical, and reported only a minor effect size. These study characteristics make it unlikely that these results are reproducible or accurate. Even if the results were exactly as described, both studies could more plausibly be interpreted as showing the cardiovascular benefits of T therapy and the risks of untreated low T, as demonstrated repeatedly by numerous studies during the last 30 years. An unbiased examination of the literature reveals a much different result. An abundance of evidence indicates that low levels of testosterone are associated with CV risks and known risk factors for cardiovascular disease such as obesity, diabetes and the metabolic syndrome. Two retrospective studies demonstrated reduced mortality, by half, in men with T less than 300 ng/dl who received a testosterone prescription vs those who did not. 9, 10 To date, there is not a single study that provides any definitive evidence that T therapy increases cardiovascular risk, and a wealth of information suggests that testosterone may be beneficial for cardiovascular health. Therefore, we await a randomized, placebo controlled effort in process of more than 900 men placed on testosterone and placebo examining cardiovascular safety for 1 year to conclusively examine cardiovascular trends. Of note, on July 16 the FDA rendered a decision to deny the public citizen s petition written by Drs. Sidney Wolfe and Michael Carome to add a black box warning about the increased risk of heart attacks and other cardiovascular dangers to the product labels of all testosterone containing drugs presently on the market in the United States, and warn all physicians of these serious adverse effects. The FDA has concluded that it is difficult to attribute the increased risk of non-fatal MI seen in one study to testosterone alone when the study did not consider that the participants might have suffered from testosterone deficiency and [were] thus at higher risk for non-fatal MI. In addition, the FDA noted the lack of accountability for the significantly lower baseline testosterone level in the testosterone group, which was viewed by the authors peers as a significant oversight. This inconsistent and inaccurate methodology throughout the publication has resulted in a distinguished group of more than 150 physician-scientists from 32 countries and 29 medical societies with testosterone expertise to seek retraction of the publication by Vigen et al. 8 Dietary Supplements and Testosterone Numerous dietary supplements have been commercially touted as increasing testosterone (ashwagandha, dehydroepiandrosterone, tongkat ali, tribulus etc) with minimal to no evidence, especially in men with low testosterone. Still, no supplement has been publicized and has arguably profited more recently than fenugreek (Trigonella foenum-graecum). Aromatase inhibition has been a commonly suggested mechanism of action, 11 but human studies have failed to demonstrate that this supplement increases testosterone significantly or consistently. For example, in one clinical study often not recognized or cited, fenugreek (standardized to 70% trigimannose) actually significantly reduced levels of free testosterone. 12 Men had a 40 ng/ml free testosterone at baseline, reduced to 33 ng/ml at 4 weeks and then to 36 ng/ ml at 8 weeks (p=0.02) with 500 mg per day. Other small studies have demonstrated that fenugreek causes no change or minimally increases testosterone in men with an already normal testosterone at baseline. 13, 14 Fenugreek has been used as a spice, and is used in Indian Ayurvedic medicine and in Chinese medicine as a stimulus for lactation for breastfeeding women. 11, 15 This supplement also has a notorious history of being touted as a breast enhancement supplement for women without human research to support this claim. 11 Allergic reactions to the powder and mild gastrointestinal upset are not uncommon side effects, and increased bleeding can occur beyond what is expected in those on aspirin or anti-inflammatory drugs. 15 One ancillary health advantage of fenugreek is that the natural seeds can be purchased at health food stores and used in most diet plans (soups, yogurt, oatmeal etc). In fact, they may slightly lower blood sugar and cholesterol because they are a good source of fiber (1 tablespoon=3 gm fiber). 11, 16 Continued on page 6

8 6 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS Course #017IC Continued from page 5 Nevertheless, clinicians need to emphasize and refer to the consistent data regarding minimal to moderate weight loss in men and the significant increases in testosterone that can occur which far surpass the results of any current available dietary supplement. 11 Thus, the controversy over testosterone supplements actually represents an ideal opportunity to discuss heart healthy and testosterone healthy lifestyle changes with your patients. 1. Finkle WD, Greenland S, Ridgeway GK et al: Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014; 9: e Editorial Board: Overselling testosterone, dangerously. The New York Times, February 4, Available at opinion/overselling-testosterone-dangerously.html. Accessed February 24, Bassil N and Morley JE: Late-life onset hypogonadism: a review. Clin Geriatr Med 2010; 26: 197. COURSE #025IC 4. Bhasin S, Cunningham GR, Hayes FJ et al: Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: Isidori AM, Giannetta E, Greco EA et al: Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf) 2005; 63: Srinivas-Shankar U, Roberts SA, Connolly MJ et al: Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2010; 95: Zitzmann M, Faber S and Nieschlag E: Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab 2006; 91: Vigen R, O Donnell CI, Barón AE et al: Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310: Shores MM, Smith NL, Forsberg CW et al: Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012; 97: Muraleedharan V, Marsh H, Kapoor D et al: Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 2013; 169: Moyad MA: Complementary and Alternative Medicine for Prostate and Urologic Health. New York: Springer Poole C, Bushey B, Foster C et al: The effects of a commercially available botanical supplement on strength, body composition, power output, and hormonal profiles in resistance-trained males. J Int Soc Sports Nutr 2010; 7: Steels E, Rao A and Vitetta L: Physiological aspects of male libido enhanced by standardized Trigonella foenum-graecum extract and mineral formulation. Phytother Res 2011; Epub ahead of print. 14. Wilborn C, Taylor L, Poole C et al: Effects of a purported aromatase and 5α-reductase inhibitor on hormone profiles in college-age men. Int J Sport Nutr Exerc Metab 2010; 20: Tiran D: The use of fenugreek for breast feeding women. Complement Ther Nurs Midwifery 2003; 9: Hannan JM, Ali L, Rokeya B et al: Soluble dietary fibre fraction of Trigonella foenum-graecum (fenugreek) seed improves glucose homeostasis in animal models of type 1 and type 2 diabetes by delaying carbohydrate digestion and absorption, and enhancing insulin action. Br J Nutr 2007; 97: 514. Building a Comprehensive Men s Health Program that Addresses the Changing Clinical Environment, Regulations and Practices Rafael E. Carrion, MD, Course Director; Mark J. Swierzewski, MD, Faculty There is increased interest in the urological community in incorporating men s health into the clinical practice of urology. Testosterone deficiency (TD) and testosterone replacement therapy (TRT) are central to any urology based men s health program (MHP), but are only components of a comprehensive program. In this instructional course we discussed men s health assessment, and treatment plans to optimize TRT outcomes and meet the requirements of medical necessity and medical complexity in these times of ever changing medical requirements, regulations and practices. Men s Health Program The development of a MHP is not an attempt to replace or take on the role of a primary care physician. Most urologists do not have the skill base nor is it an efficacious use of time to become a treating primary care physician. However, urologists often have the unique opportunity to evaluate and monitor men on a consistent or even a more frequent basis than a primary care physician. This occurs especially when treating men with TRT. The degree of involvement can be divided into an observational role as a watchman or an active role in which the urologist initiates or participates in the treatment of comorbid conditions in men with TD. The watchman approach is purely observational. There is a great opportunity to have a role in identifying or diagnosing new conditions. There is a role in monitoring the stability of and compliance with ongoing treatment plans through objective parameters. There is also a supportive role in terms of patients understanding how conditions impact urological conditions and treatments. This type of approach involves routine data collection at an initial or followup encounter to identify and monitor medical conditions. The data are then used to establish new diagnoses or acknowledge changes in a current diagnosis, which can then be remitted to the appropriate treating physician or be used to initiate a referral. With an active role the urologist becomes involved in the management of cofactors and diseases that affect the treatment of ongoing urological issues as well as overall patient health. For example, with the advent of meaningful use, tobacco abuse counseling (V65.42, Z71.6) has already been incorporated into most urological practices. Dietary Continued on page 7

9 Course #025IC Continued from page 6 counseling (V65.3, Z71.3), exercise counseling (V65.41, Z71.89) and general health counseling (V65.4, Z71.9) are 3 additional examples of active interventions with specific and measurable end points. The use of counseling as an adjunct to TRT is important to maximize the benefits the patient can obtain from the therapy. We outlined ways to incorporate counseling into the treatment of TD. Men s Health Urological Assessment The men s health urological assessment (MHUA) is the cornerstone of every urology based MHP. Much of the information in the MHUA is already being gathered in the traditional urology practice. The difference is that the information is used and acknowledged in a manner that improves not just the patient s urological health but also his overall health. In addition, findings are recorded with diagnosis codes not typically used by urologists in their practices. The ability to make the proper diagnosis and use the correct diagnosis codes allows the urologist to justify and document medical necessity and medical complexity. A portion of the Affordable Care Act (ACA) involves the implementation and use of preventive services in the care of patients. Benchmarks will be set to track and validate outcomes and performance in groups and types of patients. Proper diagnosis coding with the implementation of the electronic medical record affords the opportunity to track outcomes on key parameters and diseases that have been earmarked in the ACA. Testosterone Deficiency TD (257.2, E29.1) is a diagnosis whose initial evaluation is based primarily on the symptoms of hypogonadism and confirmed with laboratory data. Additionally, there are many comorbidities and cofactors that lend themselves to hypogonadism. The ability to initially recognize and document these symptoms, comorbidities and cofactors helps AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 7 reduce denial for medical necessity, and more adequately reflect the medical complexity of the evaluation and treatment plan. Subjective Data Fatigue (780.79, R53.81) and irritability (799.22, R45.4) are 2 common initial complaints that warrant a TD evaluation. Decreased libido (799.81, R68.82) and symptoms of sexual dysfunction (607.84, N52.9) may or may not be present in every patient. Validated questionnaires can be used to gather the symptomatic data to assist in making the diagnosis of hypogonadism as well as in identifying common comorbid diseases. This includes screening for obstructive sleep apnea (OSA) (780.50, G47.9). OSA not only has a role in testosterone deficiency but it can also complicate the use of TRT. Objective Data Many medical diseases are associated with TD, including the comorbidities of cardiac disease, diabetes mellitus and obesity. The successful diagnosis and monitoring of these diseases have an impact on the success of TRT, and are important to overall patient health. Vital signs are a crucial part of the MHUA. The most important of these is likely the blood pressure (BP) reading. It allows the opportunity to identify men with undiagnosed hypertension or to monitor men who are already diagnosed. Normal BP is below 120/80 mm Hg and high BP (hypertension; 401.9, I10) is a reading of greater than 140/90 mm Hg. Values between normal and high are called prehypertension, and can be labeled elevated blood pressure reading without diagnosis of hypertension (796.2, R03.0). Body mass index (BMI) is the accepted standard to assess subjects as being overweight or obese. It helps establish those individuals at risk for diseases associated with obesity. Dated height, weight and BMI are required to code for dietary and exercise counseling. A BMI of 25 to 29.9 kg/m 2 is overweight (278.02, E66.3), 30 to 34.9 kg/m 2 indicates obesity (278.00, E66.9), 35 to 39.9 kg/m 2 severe obesity (278.01, E66.01), and 40 kg/m 2 or greater, extreme obesity (278.01, E66.01). Waist circumference (WC) is an additional measurement used to assess the degree of fat in the midsection. WC greater than 40 inches is strongly associated with an increased risk of hypertension, heart disease and type 2 diabetes. The assessment of BMI and subsequent nutritional and exercise counseling are key components of the MHP. The type of physical examination is individualized to the preference of the treating physician. However, the physical examination should be appropriate to the level of medical necessity and complexity of the visit. Cofactors There are men who seek alternative options to improve TD and health. These alternatives involve physiological factors such as sleep, exercise, weight loss, stress and sex. Additionally, nutritional factors such as carbohydrates, amino acids, lipids, zinc, vitamin D and alcohol have been claimed to have an impact on testosterone levels. Finally, there are supplements that may or may not improve testosterone levels. We examined the evidence-based science behind these alternatives, separating myth from fact. Many of these factors do influence testosterone levels and might be an appropriate alternative when discussing treatment options in men with TD. Estrogen There is increasing interest in the clinical relevance of estrogen and the role of estrogen levels in the treatment of men with testosterone deficiency. Unfortunately much of the readily available information about estrogen levels in men is based on speculation and studies with poorly defined or misleading parameters. This has led to the potential misuse and overuse of aromatase inhibitors. 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10 8 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS Course #025IC Continued from page 7 A basic understanding of estrogen and the treatment of estrogen levels is imperative when developing a MHP. Estrogen is an important hormone in men and should be a component of a MHUA. We reviewed evidence-based medicine that supports the conclusion that overtreatment can be detrimental. Additionally, we reviewed mounting evidence that high serum estradiol levels may lead to an increased risk of adverse outcomes including mortality. The appropriate use of aromatase inhibitors was also reviewed. Summary In this course we discussed the evaluation and treatment of the primary conditions of sexual dysfunction and hypogonadism in a progressive manner. We outlined the details of the monitoring of comorbidities as part of treatment protocols. We emphasized the importance of understanding and knowledge of the cofactors that may influence disease discussion and treatment options. These cofactors and treatments include behavioral, environmental and nutritional factors, and supplements, rehabilitation, pharmaceuticals and surgical options. Ultimately the course provided the attendee with the tools and building blocks to develop an individualized, comprehensive and effective men s health program. COURSE #050IC Testosterone Therapy: New Concepts for a Rapidly Changing Field Abraham Morgentaler, MD, Course Director; Abdulmaged M. Traish, PhD, MBA, Faculty Introduction As far back as 1940 testosterone (T) therapy in men with testosterone deficiency (TD) (also called hypogonadism) was deemed beneficial to overall health and no demonstrable adverse effects were reported. 1 In the more than 70 years since that time T therapy fell out of favor and it is only within the last 10 to 15 years that it has been used more extensively. Today it has become a controversial topic associated with considerable misinformation. Given the growth in recognition and treatment of TD, we believe there is considerable value in educating clinicians on this topic. Physiology and Pathophysiology of Testosterone Testosterone biosynthesis is a highly regulated process controlled by feedback mechanisms through the hypothalamic-pituitary-gonadal axis. The majority of T and 5α-dihydrotestosterone (5α-DHT) circulates in the plasma bound to sex hormone-binding globulin (SHBG) and only a small fraction remains unbound to proteins (free T). T and 5α-DHT interact with the androgen receptor (AR), leading to the formation of hormone-ar complexes which interact with androgen response elements and initiate gene activation. Testosterone Deficiency TD is characterized by low serum T combined with several suggestive clinical signs and symptoms. 2-5 TD is divided into primary (testicular dysfunction), secondary (pituitary or hypothalamic failure) or mixed hypogonadism (a combination of testicular failure and pituitary hypothalamic failure). 2 Decreased sexual desire and nocturnal penile erections are strongly suggestive of TD. 2 TD is associated with loss of lean body mass, decreased muscle volume and strength, decreased bone mineral density, increased body weight, adiposity and increased waist circumference. 4, 5 TD is also associated with insulin resistance and type 2 diabetes mellitus, hypertension, inflammation, altered lipid profile, the metabolic syndrome, atherosclerosis, and an increased risk of cardiovascular (CV) disease and incidence of mortality (see figure). 6 The overall prevalence of TD increases with age, 7 and TD is observed in about 20% of men older than 60 years, 30% older than 70 and 50% older than 80 years. 8, 9 TD and Increased Risk of Vascular Disease and Mortality Ohlsson et al reported that after 5-year followup in 2,416 men (age 69 to 81 years), total T levels were inversely associated with CV event risk. 10 The risk of death nearly doubled in subjects with low levels of T compared to those within quartiles 2 to 4 of T after a mean followup of 4.5 years. 11 In a cohort of 1,568 men there was a significant increase in all cause mortality risk for men with free T in the lowest quartile. 12 Men with coronary artery disease (930) followed for a mean of 6.9±2.1 years showed increased mortality in the TD group (21%) compared to those with normal T levels (12%). 13 Among 1,954 men followed for an average of 7.2 years, those with low T had a signifi- Continued on page 9

11 Course #050IC Continued from page 8 cantly higher mortality from all causes compared to men with higher T levels. 14 TD and Sexual Dysfunction The relationship between TD and sexual function has been recognized for some time. Many studies have documented that androgens are critical to maintain sexual function in men and that TD contributes to sexual dysfunction. 15 Indeed, men with TD exhibit symptoms of low libido and erectile dysfunction, and T therapy improves sexual desire and erectile function in men with TD. 16 Making the Diagnosis The diagnosis of T deficiency requires the presence of symptoms and/or signs, combined with a confirmatory blood test result indicating a decreased serum androgen concentration. 3, 4, 6 Symptoms may be categorized as sexual and nonsexual. Sexual symptoms include diminished or absent libido, reduced erectile rigidity, difficulty achieving orgasm, reduced intensity of the orgasm experience and reduced sexual sensitivity to touch. 17 Nonsexual symptoms include fatigue, lack of energy or pep, reduced sense of well-being, depressive symptoms, irritability, decreased muscle strength or mass, and increased waist circumference and fat. Objective signs suggestive of T deficiency include anemia, reduced bone mineral density and gynecomastia. The symptoms of T deficiency are fairly characteristic in an otherwise healthy individual, although none are pathognomonic. Decreased or absent libido is the most specific symptom, as well as the most likely to respond to treatment. 18 There is no universal agreement on what blood test results indicate T deficiency, nor whether total or free testosterone is more useful. 18 Medical groups or expert opinion has recommended making the diagnosis for total T concentrations below a threshold that ranges from 280 to 400 ng/dl. 3, 4, 18 Free T may be a more useful indicator of androgen status because it is not confounded by AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 9 binding to SHBG. In our practice symptomatic men are considered candidates for a trial of T therapy if they have calculated free T values less than 100 pg/ml or radioimmunoassay values less than 1.5 ng/dl. 17, 18 Additional blood tests of value during evaluation include luteinizing hormone, prolactin, SHBG, hematocrit and prostate specific antigen (PSA). Estradiol and follicle-stimulating hormone tests are optional. We perform bone density testing (DXA) at baseline and followup. The goal of treatment is improvement in symptoms and/or signs. Except in the most severe cases of T deficiency, treatment should be considered a 3 to 6-month trial, with continuation beyond that point only if warranted by response to treatment. 18 Benefits of T Therapy T therapy in men with TD restores physiological T levels, and results in a significant increase in muscle mass, reduction in fat mass, weight loss, and reduction in waist circumference and in body mass index. T therapy reduces inflammatory cytokines and fasting blood glucose and hemoglobin A1c levels concomitant with increased insulin sensitivity. 5, 6 More importantly, T therapy reduces total cholesterol, lowdensity lipoprotein cholesterol and triglycerides, and increases high-density lipoprotein levels and improves systolic and diastolic blood pressure. 19, 20 T therapy also improves mineral bone density, increases energy and vitality, and improves mood, sexual function and overall quality of life. 21, 22 T therapy to restore physiological levels ameliorates components of the metabolic syndrome. 23 Hackett et al demonstrated that T significantly improved all domains of the International Index of Erectile Function. 24 Improvement was most marked in less obese patients and those without coexisting depression. Corona et al reported that T therapy has positive effects on male sexual function in hypogonadal subjects. 25 Risks, Monitoring and Concerns Regarding Prostate Cancer and CV Disease All men receiving T therapy need to be monitored while receiving treatment. The goals of monitoring are to ensure adequate levels for treatment efficacy as well as to ensure safety. Office evaluations are recommended at least 2 to 3 times in the first year, and then 1 to 2 times per year thereafter in the absence of any concerns. 17 We recommend obtaining blood tests for testosterone within 2 to 4 weeks of initiating treatment to gauge the adequacy of the biochemical response. Adjustments may then be made in dose or in treatment interval for injections and pellets. Testing should be done several hours after application of topical T therapies, and at mid cycle or nadir for injections. We obtain blood tests at 1 month and 3 months after initial pellet implantation, and then 2 to 4 times per year thereafter. Safety monitoring should include hematocrit due to the risk of erythrocytosis and PSA due to historical concerns that higher serum T concentrations may precipitate prostate cancer growth. A digital rectal examination to assess new prostate abnormalities is recommended 1 to 2 times in the first year and annually thereafter. Risks of therapy include testicular atrophy, suppression of spermatogenesis leading to infertility, gynecomastia, pedal edema and acne. There is weak literature supporting concerns of exacerbation of sleep apnea and worsening of lower urinary tract symptoms. Research revealed the origin of the concern that raising T would cause rapid prostate cancer growth was based on erratic serum acid phosphatase concentrations in a single patient with metastatic disease who received T injections over 14 days. 26 Subsequent experiences revealed that T administration was problematic in androgen deprived men but not in hormonally intact men. 26 Evidence in humans, animals and prostate cancer cell lines reveals that prostate Continued on page 10

12 10 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS Course #050IC Continued from page 9 tissue, malignant and benign, reaches maximal androgen mediated growth at relatively low concentrations, consistent with a saturation effect. 27 Today T therapy is offered at some centers to selected men with a history of prostate cancer. However, this is controversial and safety has not been established. 28 The new concern regarding T therapy and CV risk is based on 2 articles published in the last year. 29, 30 Both were retrospective analyses of large data sets with major limitations. One group acknowledged large data errors after publication 29 and the methodology of the second study was highly questionable. 31, 32 The U.S. Food and Drug Administration concluded that neither study provided compelling evidence of increased CV risk with T therapy. Summary Testosterone deficiency is an increasingly recognized medical condition that negatively impacts the health of men in important ways. The treatment of these men often provides considerable symptom relief as well as improved sexual function and quality of life. Clinicians with an interest in this area should become familiar with current indications, risks and treatment options. 1. Aub JC: Endocrines: the use of testosterone. N Engl J Med 1940; 222: Buvat J, Maggi M, Guay A et al: Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J Sex Med 2013; 10: Wang C, Nieschlag E, Swerdloff R et al: Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol 2008; 159: Bhasin S, Cunningham GR, Hayes FJ et al: Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: Buvat J, Maggi M, Gooren L et al: Endocrine aspects of male sexual dysfunctions. J Sex Med 2010; 7: Traish AM, Miner MM, Morgentaler A et al: Testosterone deficiency. Am J Med 2011; 124: Wu FC, Tajar A, Beynon JM et al: Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010; 363: Araujo AB, O Donnell AB, Brambilla DJ et al: Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2004; 89: Harman SM, Metter EJ, Tobin JD et al: Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001; 86: Ohlsson C, Barrett-Connor E, Bhasin S et al: High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol 2011; 58: Tivesten A, Vandenput L, Labrie F et al: Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab 2009; 94: Vikan T, Johnsen SH, Schirmer H et al: Endogenous testosterone and the prospective association with carotid atherosclerosis in men: the Tromsø study. Eur J Epidemiol 2009; 24: Malkin CJ, Pugh PJ, Morris PD et al: Low serum testosterone and increased mortality in men with coronary heart disease. Heart 2010; 96: Haring R, Völzke H, Steveling A et al: Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged Eur Heart J 2010; 31: Isidori AM, Buvat J, Corona G et al: A critical analysis of the role of testosterone in erectile function: from pathophysiology to treatment a systematic review. Eur Urol 2014; 65: Finkelstein JS, Lee H, Burnett-Bowie SA et al: Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013; 369: Rhoden EL and Morgentaler A: Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004; 350: Morgentaler A, Khera M, Maggi M et al: Commentary: Who is a candidate for testosterone therapy? A synthesis of international expert opinions. J Sex Med 2014; 11: Traish AM, Haider A, Doros G et al: Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract 2014; 68: Traish AM: Testosterone and weight loss: the evidence. Curr Opin Endocrinol Diabetes Obes 2014; 21: Haider A, Meergans U, Traish A et al: Progressive improvement of T-scores in men with osteoporosis and subnormal serum testosterone levels upon treatment with testosterone over six years. Int J Endocrinol 2014; 2014: Zitzmann M, Mattern A, Hanisch J et al: IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. J Sex Med 2013; 10: Saad F, Haider A, Doros G et al: Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring) 2013; 21: Hackett G, Cole N, Bhartia M et al: Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and qualityof-life parameters vs. placebo in a population of men with type 2 diabetes. J Sex Med 2013; 10: Corona G, Isidori AM, Buvat J et al: Testosterone supplementation and sexual function: a metaanalysis study. J Sex Med 2014; 11: Morgentaler A: Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol 2006; 50: Morgentaler A and Traish AM: Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol 2009; 55: Khera M, Crawford D, Morales A et al: A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol 2014; 65: Vigen R, O Donnell CI, Barón AE et al: Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310: Finkle WD, Greenland S, Ridgeway GK et al: Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS One 2014; 9: e Morgentaler A: Testosterone, cardiovascular risk, and hormonophobia. J Sex Med 2014; 11: Seftel AD and Morgentaler A: Does testosterone increase the risk of a cardiovascular event? J Urol 2014; 192: 13.

13 Course #065IC Continued from page 10 COURSE #065IC AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 11 Testosterone: Diagnosis and Management of the Hypogonadal Male Wayne J.G. Hellstrom, MD, FACS, Course Director; Andre T. Guay, MD, FACP, FACE and Mohit Khera, MD, MBA, MPH, Faculty In 2012 testosterone was one of the fastest growing medications in the United States, with studies showing that testosterone use during the last decade has increased almost fivefold (fig. 1). 1 The dramatic increase in testosterone use has also been seen in the younger population, many of whom do not realize that exogenous testosterone is a natural contraceptive. 1 There are still many controversies associated with testosterone replacement therapy (TRT), including the risk of prostate cancer, benign prostatic hyperplasia (BPH), infertility and cardiovascular disease. The prevalence of hypogonadism increases with age. In fact, men lose 1% to 2% of testosterone every year starting at approximately 30 years old. 2 Long-term complications due to low testosterone levels include increased body fat, decreased muscle mass, decreased bone mineral density, fatigue, depression, memory loss, and decline in libido and erectile function (fig. 2). 3 There are certain medical conditions that are associated with a higher incidence of hypogonadism. These conditions include diabetes, AIDS, alcohol abuse, chronic liver disease and chronic obstructive pulmonary disease. 4 While the normal secretion of testosterone in men is 3 to 10 mg per day, the highest levels of serum testosterone levels are in the morning, due to diurnal variation. 5 Raising serum testosterone levels has been shown to improve depression, erectile function, bone mineral density, and decrease fat deposition and increase muscle mass. The diagnosis of hypogonadism can be challenging, as patients must have androgen deficiency (ie testosterone less than 300 ng/dl) and the signs and symptoms of androgen deficiency. The problem is that the signs and symptoms of androgen deficiency are nonspecific and can be found in numerous other conditions. In fact, the use of hypogonadal screening questionnaires is not recommended because of their low specificity. In addition, the results of testosterone assays vary significantly among laboratories, 6 and the 300 ng/dl serum testosterone cutoff is not sensitive or specific for hypogonadal symptoms, further complicating the diagnosis. The threshold testosterone level below which symptoms of androgen deficiency and adverse health outcomes occur, and at which TRT results in improved outcomes, has not been established. There are data to suggest that genetic variations in androgen receptor sensitivities may explain the variability in hypogonadal symptoms at different serum testosterone levels. 7 Finally, most testosterone reference ranges are not age adjusted. Most of testosterone is bound tightly to sex hormone-binding globulin (SHBG) or loosely to albumin and, thus, about 2% of testosterone is free. 8 Certain conditions that increase SHBG levels include HIV, liver disease and hyperthyroidism. Patients with low normal testosterone levels and signs and symptoms of low testosterone should have their free testosterone levels evaluated. During the last decade there has been a significant increase in available testosterone treatment options. While 10 years ago we only had 2 testosterone gels on the market, today we have 5 testosterone gels and 1 testosterone solution. In 2008 U.S. Food and Drug Administration (FDA) approved Figure 1. Increasing use of testosterone among younger and older men. T, testosterone. Reprinted with permission. 1 Figure 2. Physical signs and symptoms of androgen deficiency. BMI, body mass index. Continued on page 12

14 12 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS Course #065IC Continued from page 11 testosterone pellets were introduced. Testosterone patches have now been modified to cause less skin irritation. Finally, a new, long-acting testosterone undecanoate injection was approved by the FDA in March New testosterone therapies on the horizon include oral testosterone undecanoate, intranasal testosterone sprays and the use of nanotechnology for a long-acting testosterone delivery system. Patients should be carefully monitored after TRT initiation. Patients should be evaluated at 3 months after the start of TRT and then every 6 to 12 months thereafter to assess serum testosterone levels, symptomatic improvement, prostate specific antigen (PSA) and digital rectal examination changes, and changes in hematocrit. If a hematocrit level increases to more than 54%, TRT should be discontinued until the hematocrit decreases, or the patient should consider a therapeutic phlebotomy. A patient receiving injectable testosterone might consider switching to another TRT formulation that has a lower risk of erythrocytosis. Repeat DEXA scan is advisable after 1 to 2 years of TRT in hypogonadal men with osteoporosis or low-trauma fractures. With an increasing number of young men being diagnosed with hypogonadism, alternative treatment options to raise endogenous testosterone levels have become more popular. While exogenous testosterone can decrease a man s sperm count, raising endogenous testosterone not only preserves fertility, but also possibly enhances a man s fertility. Clomiphene citrate is a selective estrogen receptor modulator that results in increased levels of follicle-stimulating hormone and luteinizing hormone and, thus, improves sperm count and serum testosterone levels. Aromatase inhibitors block the conversion of testosterone to estradiol and increase serum testosterone levels. Finally, human chorionic gonadotropin is a LH analogue and directly increases Leydig cell production of testosterone. This year there has been significant attention turned toward the link between testosterone and cardiovascular disease (CVD). 9 During the last 10 years there have been numerous articles demonstrating that low serum testosterone levels are associated with an increase in CVD. In fact, several articles have shown that testosterone supplementation is associated with a lower risk of CVD. 10 Earlier this year the FDA initiated an investigation of the effects of TRT on CVD based on articles by Vigen 11 and Finkle 12 et al. However, there are significant limitations to each of these articles. Neither of the studies was randomized or placebo controlled. Moreover, the study by Finkle et al did not have a control group. 12 Due to these and other significant study limitations it is believed that there is no convincing evidence to support the idea that testosterone leads to CVD. Low testosterone levels represent a risk factor for insulin resistance and type 2 diabetes, and approximately 50% of patients with diabetes are found to have androgen deficiency. 13 Low testosterone has been shown to increase fasting insulin, glucose and hemoglobin A1c (HbA1C) levels, and possibly to predict the onset of diabetes. 14 The exact mechanism by which diabetes and insulin resistance impair testosterone production, and how decreased testosterone levels increase the risk of diabetes and insulin resistance, are poorly understood. 14 TRT has been shown to improve insulin sensitivity, fasting glucose and HbA1c levels A prospective, randomized, doubleblind study of 220 hypogonadal men with type 2 diabetes and the metabolic syndrome showed that 12 months of TRT resulted in improvements in insulin resistance, total and low-density lipoprotein cholesterol, and lipoprotein(a). 17 In a similar study Heufelder et al found that a 52-week treatment with diet and exercise plus transdermal testosterone reversed the metabolic syndrome, and improved glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone levels. 16 This study also demonstrated reductions in waist circumference and improvements in HbA1c levels and fasting glucose levels in hypogonadal men receiving TRT. Most clinicians throughout the world still do not prescribe testosterone due to the concern that TRT may cause prostate cancer. 18 Despite these persistent concerns, there are still no convincing data to indicate that TRT increases the risk of prostate cancer. However, to date there are no prospective, controlled studies with adequate sample size and duration to definitively assess the relationship of TRT to the risk of prostate cancer. Calof et al performed a metaanalysis of 19 placebo controlled TRT trials in men with hypogonadism and found no greater risk of prostate cancer in men being treated with testosterone than in those receiving a placebo. 19 The saturation model helps us understand why, at even supraphysiological doses of testosterone, there are no changes in serum PSA or prostate growth, and why androgen deprivation therapy in these patients results in a decrease in PSA and prostate size. 20 The saturation model describes a threshold effect in which increasing androgen concentrations reach a limit (the saturation point) beyond which there is no further ability to induce androgen driven changes in prostate tissue growth. Finally, testosterone also has an important role in penile rehabilitation after radical prostatectomy (RP). There are data to suggest that a hypogonadal man may be at a disadvantage in recovering erectile function compared to a eugonadal man after RP. 21 Thus, this factor should also be considered when deciding whether to offer TRT to hypogonadal men after RP. With the rapid growth of TRT in recent years, it is increasingly important for urologists to become familiar with the diagnosis and management of TRT as well as the impact of TRT on prostate cancer, BPH and male fertility. Hypo- Continued on page 13

15 Course #065IC Continued from page 12 gonadism can be easily diagnosed with a serum testosterone evaluation and assessment of the signs and symptoms of hypogonadism. Clinicians should be aware of the various treatment options for hypogonadism and the adverse effects associated with each of these formulas. Choosing the right formula is based on compliance, convenience, efficacy, cost, tolerability, and patient and physician preference. While low testosterone levels may result in an increase in diabetes/metabolic syndrome, CVD and osteoporosis, TRT has been shown to potentially improve these conditions. 1. Baillargeon J, Urban RJ, Ottenbacher KJ et al: Trends in androgen prescribing in the United States, 2001 to JAMA Intern Med 2013; 173: Leifke E, Wichers C, Gorenoi V et al: Low serum levels of testosterone in men with minimal traumatic hip fractures. Exp Clin Endocrinol Diabetes 2005; 113: Tenover JL: Male hormone replacement therapy including "andropause". Endocrinol Metab Clin North Am 1998; 27: Kaufman JM and Vermeulen A: Declining gonadal function in elderly men. Baillieres Clin Endocrinol Metab 1997; 11: 289. AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS Bremner WJ, Vitiello MV and Prinz PN: Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab 1983; 56: Lazarou S, Reyes-Vallejo L and Morgentaler A: Wide variability in laboratory reference values for serum testosterone. J Sex Med 2006; 3: Schneider G, Nienhaus K, Gromoll J et al: Aging males' symptoms in relation to the genetically determined androgen receptor CAG polymorphism, sex hormone levels and sample membership. Psychoneuroendocrinology 2010; 35: Winters SJ, Kelley DE and Goodpaster B: The analog free testosterone assay: are the results in men clinically useful? Clin Chem 1998; 44: Morgentaler A: Testosterone, cardiovascular risk, and hormonophobia. J Sex Med 2014; 11: Shores MM, Smith NL, Forsberg CW et al: Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012; 97: Vigen R, O'Donnell CI, Barón AE et al: Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310: Finkle WD, Greenland S, Ridgeway GK et al: Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014; 9: e Mulligan T, Frick MF, Zuraw QC et al: Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006; 60: Traish AM, Saad F and Guay A: The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl 2009; 30: Guay AT and Traish A: Testosterone deficiency and risk factors in the metabolic syndrome: implications for erectile dysfunction. Urol Clin North Am 2011; 38: Heufelder AE, Saad F, Bunck MC et al: Fiftytwo-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009; 30: Jones TH, Arver S, Behre HM et al: Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011; 34: Khera M, Crawford D, Morales A et al: A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol 2014; 65: Calof OM, Singh AB, Lee ML et al: Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005; 60: Song W and Khera M: Physiological normal levels of androgen inhibit proliferation of prostate cancer cells. Asian J Androl 2014; Epub ahead of print. 21. Khera M: Androgens and erectile function: a case for early androgen use in postprostatectomy hypogonadal men. J Sex Med, suppl., 2009; 6: 234.

16 14 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS SAVE THE DATE! Registration opens December 3,