1. A Patient Centered Approach to the Treatment of Hypogonadism: Consensus Recommendations from an Expert Panel Richard Sadovsky, MD Associate Professor of Family Medicine, Department of Family Medicine, SUNY-Downstate Medical Center, Brooklyn, New York

2. Disclosures Richard Sadovsky has served as a consultant for Endo Pharmaceuticals and, Eli Lilly & Co. All conflicts of interest have been resolved according to the NJAFP Conflict of Interest Policy

3. This program has been made possible through an unrestricted educational grant from Abbott Laboratories.

4. Describe Your Practice 1.I do not, and have no plans to treat hypogonadism 2.I have not treated hypogonadism but I am considering doing so 3.I treat men for primary, but not secondary, hypogonadism 4.I routinely treat men for hypogonadism but would like more guidance on diagnosis and treatment options 5.I routinely treat men for hypogonadism and am comfortable with my knowledge about the subject

5. Learning Objectives At the conclusion of this program you should be able to: 1.Identify patients for assessment of serum testosterone levels to determine if testosterone replacement therapy (TRT) is indicated 2.Recognize link between hypogonadism and obesity, diabetes, and other chronic conditions 3.Articulate current opinions about relationship between TRT and prostate cancer 4.Follow evidence-based practice for the treatment of hypogonadism 5.Understand the role of patient-centered, culturally appropriate communication in arriving at shared decisions about TRT

6. Overview TRT is becoming more popular New TRT formulations are available Men are more comfortable seeking counsel for sexual dysfunctions Low T is associated with increased risk of CVD Physicians increasingly likely to encounter men presenting with symptoms of low T Family physicians must remain current in their knowledge Dandona P, Rosenberg M. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64:682-696.

7. Overview This program will review: Testosterone physiology Symptoms of low T Treatment options Possible risks and benefits of TRT Consensus recommendations

8. Pop Quiz Q: Free (unbound) testosterone represents approximately what fraction of total serum testosterone? a. 1-2 % b. 10-20% c. 45% d. 65%

9. Pop Quiz Answer: 1-2% Dandona P, Rosenberg M. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64:682-696.

10. Testosterone Physiology Testosterone levels peak ~ 20 yrs, then decline ~1%/yr. Normal T levels are regulated by hypothalamic-pituitary- testicular axis Dysfunction manifests as different forms of hypogonadism Dandona P, Rosenberg M. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64:682-696.

11. Biochemical Definition of Hypogonadism Hypogonadism refers to any state of reduced testicular function, impaired sperm production, and low T Agreement on two thresholds for total testosterone (TT): >350 ng/dL (normal) and <230 ng/dL (low) Borderline TT : 230 – 345 ng/dL Buvat J, Maggi M, Guay A, Torres LO. Standard Operating Procedures for Diagnosing and Treating Testosterone Deficiency in Men. Journal of Sexual Medicine. In press.

12. Types of Hypogonadism Primary: abnormalities at testicular level  Examples: cryptorchidism, mumps orchitis, genetic conditions Secondary: abnormalities at hypothalamus or pituitary  Examples: pituitary tumors, medications, systemic disease Mixed: defects at both levels  Examples: aging, alcohol abuse, chronic infections Dandona P, Rosenberg M. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64:682-696.

13. Clinical Definition of Hypogonadism Requires below-normal TT and signs/ symptoms MMAS, using this definition, found prevalence in general population ranging from 7% (ages 48-59) to 23% (ages 70-80) No evidence that prevalence differs between racial and ethnic groups 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;89:5920-5926.

14. Nomenclature Terms used to describe primarily age-related, below-normal T-levels with associated clinical symptoms:  Androgen deficiency  Andropause  Age-related hypogonadism  Testosterone deficiency (TD) Testosterone deficiency (TD) describes patients family physicians are likely to encounter in daily practice

15. TD-Related Comorbidities Obesity Metabolic syndrome Diabetes Cardiovascular disease Hypertension Autoimmune diseases COPD Long-term opiate use Associations are bidirectional and complex! Miner MM. Low Testosterone Medscape CME Expert Column Series. Issue 2: Screening and Workup for Testosterone Deficiency. 2011. Available at: http://www.medscape.org/viewarticle/749240?src=emailthis

16. Expert Panel Recommendation TD does not always need to be treated first in patients with associated comorbidities. To the extent testosterone levels can be raised by successful treatment or resolution of comorbid conditions, these approaches should be attempted first.

17. TD and Cardiovascular Disease Recent observational studies suggest that lower T is associated with higher risk of CVD No randomized controlled trials of TRT and CVD Routine testosterone measurement is not recommended for men with cardiovascular disease unless they also have symptoms of TD Buvat J, Maggi M, Gooren L, et al. Endocrine Aspects of Male Sexual Dysfunctions. J Sex Med. 2010;7:1627-1656.

18. TD and Erectile Dysfunction ED is a common “portal” to T assessment Relationship between ED and TD often unclear TD usually only one element of ED in older patients ED may be caused by vascular or smooth muscle dysfunctions, which is why TRT is generally ineffective for treating ED There may be a beneficial synergy between TRT and phosphodiesterase inhibitors in men with both ED and TD Buvat J, Maggi M, Gooren L, et al. Endocrine Aspects of Male Sexual Dysfunctions. J Sex Med. 2010;7:1627-1656.

19. TD Screening Guidelines 2010 Endocrine Society Guidelines recommend against screening non-symptomatic patients for TD Testing reserved for men with signs/symptoms Serum TT levels should be taken in a.m. Positive findings must be repeated T levels should not be assessed during times of patient illness, malnutrition, or other physiologic stressors Buvat J, Maggi M, Guay A, Torres LO. Standard Operating Procedures for Diagnosing and Treating Testosterone Deficiency in Men. Journal of Sexual Medicine. In press.

20. TD Symptoms and Signs TD is a challenging diagnosis Some signs/symptoms are much more suggestive of TD than others Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6): 2536-2559. Symptoms & Signs More Specific to TD Incomplete or delayed sexual development Reduced sexual desire (libido) and activity Decreased spontaneous erections Breast discomfort, gynecomastia Loss of axillary and pubic hair, reduced shaving Very small (<5 mL) or shrinking testes Inability to father children, low or zero sperm count Hot flushes, sweats

21. TD Symptoms and Signs TD is a challenging diagnosis Some signs/symptoms are much more suggestive of TD than others Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6): 2536-2559. Symptoms & Signs Less Specific to TD Decreases energy, motivation, and initiative Feeling sad or blue, depressed mood, dysthymia Poor concentration and memory Sleep disturbance, increased sleepiness Mild anemia Reduced muscle bulk and strength Increased body fat, body mass index Diminished physical or work performance Height loss, low trauma fracture, low BMD

22. Expert Panel Recommendation Family physicians should probe for non- physiological causes of low libido by asking questions such as, “Are you still sexually attracted to your partner?” or “Are you comfortable with your sexuality?” Referral to therapy may be appropriate if non-medical factors are involved.

23. Prostate Cancer and Testosterone Recent analyses refute earlier positive associations between T levels and risk of prostate cancer Most observational studies found no correlation Case-control studies find correlations between PC and low T Low T also associated with high Gleason scores, more advanced stages, higher recurrence rates, and worse survival rates Herman LM, Miner MM, Quallich SA. Practicing Clinicians Exchange. 2010;1(2):1-8. Endogenous Hormones and Prostate Cancer Collaborative Group. J Natl Cancer Inst. 2008;100:170-183. Morgentaler A, Rhoden EL. Urology. 2006;68:1263–1267. Morgentaler A. Eur Urol. 2007;52:623–625.

24. Prostate Cancer and Testosterone T suppression can reduce prostate growth and symptoms in locally advanced and metastatic prostate cancer Explanation: PC may be very sensitive to changes in serum T at low concentrations but insensitive at higher concentrations Currently no conclusive evidence that TRT in testosterone-deficient men increases PC risk TRT may, however, stimulate growth of metastatic prostatic cancers Buvat J, Maggi M, Gooren L, et al. Endocrine Aspects of Male Sexual Dysfunctions. J Sex Med. 2010;7:1627-1656. Dandona P, Rosenberg M. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64:682-696.

25. Prostate Cancer and Testosterone International guidelines: hypogonadal men w/Hx of PC and no residual disease may be considered for TRT AUA suggests urological consult prior to TRT if:  PSA > 4 ng/mL  PSA > 3 ng/mL in high-risk men (i.e. African- Americans, men w/family history of PC)  PSA velocity change is 0.75 ng/mL or more in 1 yr. Carroll P, Coley C, McLeod D et al. Prostate-specific antigen best practice policy – part I: early detection and diagnosis of prostate cancer. Urology. 2001;57:217–224.

26. TRT Contraindications Metastatic prostate cancer Breast cancer Patient desire to maintain fertility Moderate-high risk of adverse outcomes:  Unevaluated prostate nodule or induration  PSA > 4ng/mL or > 3 ng/mL in high-risk men  Hematocrit >50%  Severe LUTS  Uncontrolled or poorly-controlled heart failure Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6): 2536-2559.

27. TRT Goals Safe restoration of normal physiologic T levels Reduction or elimination of symptoms Target T levels vary—most authors suggest a mid-range value of ~500 ng/dL For T injections, ES recommends 350-750 ng/dL at midpoint between injections Dose escalations beyond normal range are not recommended Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6): 2536-2559. Dandona P, Rosenberg M. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64:682-696.

28. TRT and Therapeutic Lifestyle Changes T levels have a synergistic relationship with lifestyle issues such as obesity, lack of exercise, and diabetes T levels often rise after weight loss Important to address T-related health issues either prior to or concurrent with a trial of TRT Emerging evidence suggests TRT may have positive synergistic effect on therapeutic lifestyle changes Niskanen L, et al. Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome. Diabetes Obes Metab. 2004;6:208-215. Heufelder AE, et al. Fifty-two-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;30:726-733.

29. Expert Panel Recommendation Family physicians considering TRT for a patient should incorporate therapeutic lifestyle changes such as weight loss with exercise, healthy dietary choices, and avoidance of smoking, into the overall treatment plan.

30. Diagnosis and Management of TD Buvat J, Maggi M, Gooren L, et al. Endocrine Aspects of Male Sexual Dysfunctions. J Sex Med. 2010;7:1627-1656.

31. TRT Formulations Available in US

32. Potential Adverse Effects of TRT AEs associated with all types of TRT:  Erythrocytosis  Acne and oily skin  Reduced sperm production and fertility Less common AEs:  Gynecomastia  Exacerbation of male pattern balding  Growth of breast cancer  Induction or worsening of obstructive sleep apnea Bhasin S, et al. J Clin Endocrinol Metab. 2010;95(6): 2536-2559.

33. Monitoring Patients on TRT

34. Expert Panel Recommendation Initial treatment with TRT should be viewed as a trial of therapy, with continuation dependent on satisfactory response and an absence of adverse effects. Patients should be evaluated 3-6 months after treatment start. If symptoms have not improved, or if unacceptable adverse effects are apparent, treatment should be withdrawn. If symptoms have improved and therapy is well-tolerated, patients should be evaluated annually.

35. Patient-Centered Management of TD Suggestions for improving patient care: Ask patients about the non-medical aspects of their lives Provide culturally-specific educational materials written or produced at an appropriate reading level Consider adopting the “medical home” model of health care delivery Set small, easily-achievable goals for lifestyle changes Make follow-up calls

36. Expert Panel Recommendation Family physicians must take the time to clearly explain to patients the risks and benefits of TRT, help them set realistic expectations for symptom improvement, and talk to them about the psychological and emotional components of healthy sexual relationships.

37. Case Study #1: Brad Age: 48 Height: 5’ 10” Weight: 227 lbs Non-smoker, moderate alcohol consumption Comorbid conditions: hypertension, dyslipidemia, insulin resistance is increasing. Complaint: physically inactive, feels tired, rarely has sex and is not particularly interested in it

38. Case Study #1: Brad Current medications: Lisinopril 20 mg/d Simvastatin 40 mg/d Labs: Fasting Glu: 118 mg/dL A1C: 6.4% Liver function: normal Total cholesterol: 213 mg/dL LDL: 124 mg/dL TG: 190 mg/dL HDL: 30 mg/dL Total testosterone: 290 ng/dL PSA: 1.2 ng/mL (unchanged from previous year)

39. Case Study #1: Brad Question 1: Brad meets the criteria for which conditions? a) Hypolipidemia/metabolic syndrome b) Type 2 diabetes/testosterone deficiency c) Metabolic syndrome/testosterone deficiency d) Testosterone deficiency/major depressive disorder

40. Case Study #1: Brad Question 1: Brad meets the criteria for which conditions? a) Hypolipidemia/metabolic syndrome b) Type 2 diabetes/testosterone deficiency c) Metabolic syndrome/testosterone deficiency d) Testosterone deficiency/major depressive disorder Answer: C

41. Case Study #1: Brad Brad agrees to a trial of a 1.62% testosterone gel. As part of the “prescription” you strongly urge Brad to become more physically active and lose at least 10 pounds. Question 2: Before he begins TRT, what additional test should you order for Brad? a) Repeat TT b) Hematocrit c) LH d) Prolactin e) All of the above

42. Case Study #1: Brad Brad agrees to a trial of a 1.62% testosterone gel. As part of the “prescription” you strongly urge Brad to become more physically active and lose at least 10 pounds. Question 2: Before he begins TRT, what additional test should you order for Brad? a) Repeat TT b) Hematocrit c) LH d) Prolactin e) All of the above Answer: E

43. Case Study #1: Brad At 3 mo. follow-up, Brad reports he is walking daily, eating better, has lost 9 pounds and his blood pressure is lower. His overall energy level is higher, he says, and he and his wife are having more regular sex. Labs: Fasting Glu: 105 mg/dL A1C: 6.0% Total cholesterol: 190 mg/dL LDL: 112 mg/dL TG: 165 mg/dL HDL: 41 mg/dL Total testosterone: 460 ng/dL PSA: 1.3 ng/mL Hematocrit: 50%

44. Case Study #1: Brad Question 3: If at Brad’s next follow-up appointment his hematocrit is found to be 56%, what course of action is indicated? a) No change in Brad’s regimen is indicated since his hematocrit level is not above the recommended cut-off point for stopping TRT. b) Brad’s TRT can continue, but he should be advised to drink plenty of fluids to avoid dehydration. c) Brad’s TRT can continue, but his hematocrit level should be re-checked in 3 weeks to see if it has declined to a safer level. d) Brad’s TRT should be stopped or decreased, his hematocrit should be monitored, and the dose of T adjusted until it is in the normal range.

45. Case Study #1: Brad Question 3: If at Brad’s next follow-up appointment his hematocrit is found to be 56%, what course of action is indicated? a) No change in Brad’s regimen is indicated since his hematocrit level is not above the recommended cut-off point for stopping TRT. b) Brad’s TRT can continue, but he should be advised to drink plenty of fluids to avoid dehydration. c) Brad’s TRT can continue, but his hematocrit level should be re-checked in 3 weeks to see if it has declined to a safer level. d) Brad’s TRT should be stopped or decreased, his hematocrit should be monitored, and the dose of T adjusted until it is in the normal range. Answer: D

46. Case Study #2: Dominic Age: 17 Complaint: Mother concerned he is not developing secondary sex characteristics Physical exam: little facial or body hair, slightly enlarged breasts, and under-sized and firm testicles for his age. History: Dominic is successful in school, though he prefers non- athletic extracurricular activities and is prone to a depressed mood.

47. Case Study #2: Dominic Question 1: Dominic’s presentation is consistent with which clinical condition? a) Hypogonadotropic hypogonadism b) Klinefelter’s Syndrome c) Fragile X Syndrome d) Edwards Syndrome

48. Case Study #2: Dominic Question 1: Dominic’s presentation is consistent with which clinical condition? a) Hypogonadotropic hypogonadism b) Klinefelter’s Syndrome c) Fragile X Syndrome d) Edwards Syndrome Answer: B

49. Case Study #2: Dominic Karyotype confirms XXY chromosomal pattern of Klinefelter’s Syndrome. Dominic’s TT level is found to be 225 ng/dL. Question 2: Testosterone replacement therapy is likely to induce secondary sex characteristics in Dominic, may improve his mood, and may have a beneficial effect on other health parameters. What parameter, however, is TRT not likely to improve? a) Sexual function b) Muscle mass c) Fertility d) Libido

50. Case Study #2 Karyotype confirms XXY chromosomal pattern of Klinefelter’s Syndrome. Dominic’s TT level is found to be 225 ng/dL. Question 2: Testosterone replacement therapy is likely to induce secondary sex characteristics in Dominic, may improve his mood, and may have a beneficial effect on other health parameters. What parameter, however, is TRT not likely to improve? a) Sexual function b) Muscle mass c) Fertility d) Libido Answer: C

51. Conclusions TD is a complex, multi-factorial disease state bi-directionally related to several common conditions Because signs and symptoms of TD may be non-specific a diagnosis of TD must be made cautiously Prior to (or concurrent with) a trial of TRT, family physicians should encourage therapeutic lifestyle changes Decisions about TRT must rest on good patient education about risks and benefits

52. Conclusions New TRT formulations and delivery systems may allow more accurate dosing and may reduce risk of adverse events Long-term, high-quality data documenting the benefits and risks of TRT are lacking Nonetheless, available knowledge and guidelines can allow providers to assess and treat TD with greater confidence

53. Discussion

54. Post-Presentation Question 1. I do not, and have no plans to treat hypogonadism. 2. I have not treated hypogonadism but I am considering doing so now. 3. I treat men with primary hypogonadism and am considering also treating men with secondary hypogonadism. 4. While I currently treat hypogonadism, I may change my approach to treatment following this presentation. 5. I routinely treat men for hypogonadism and this presentation confirmed that I do not need to change my treatment method.