1. Louis B. Kasunic, DO, FACOFP Castle Rock Family Physicians May 3, 2014

2.  A few philosophical questions  A discussion of condition prevalence  Some screening suggestions  A brief review of testosterone physiology  Patient evaluation suggestions  Treatment options  Patient follow up suggestions

4.  Why should we care?  “Andropause” Medical condition or normal male aging? Is this a pharmaceutical industry construct or a valid male health issue? Have you ever asked yourself this question about female hormone replacement therapy?

5.  Low testosterone (T) in men is a common condition which often goes undiagnosed  Prevalence of low T in men over 45 years old in the U.S. estimated at about 40%  In studies of men with type 2 diabetes, about 50% have low T Mulligan T, et al. Int J Clin Pract. 2006;60(7):762-9. Dhindsa S, et al. J Clin Endocrinol Metab. 2004;89:5462-8.

6.  Increased body fat to lean body mass ratio  Decreased bone mass and bone mineral density  Decreased erectile function / sexual performance  Anemia  Decreased strength / vigor/ vitality  Decreased libido  Mood changes with an increase in depression  Decreased Leydig cell counts  Increased SHBG and lower Free (active) T

7.  2165 patients (45-96 yrs mean age 60 yrs) Pt age yrsLow T 45-5434% 55-6440% 65-7440% 75-8445% >8550%  Prevalence increases with aging

8.  Type II DM  Obesity  Chronic opiate use  COPD  Cancer  HIV  Rheumatoid Arthritis  Corticosteroid use  Chronic liver disease  Chronic Renal disease

9.  Dhindsa studies DM type II 33% low free T 44% low total T BMI correlates inversely with FT and TT inversely with LH and FSH Similar data demonstrated for insulin resistant and metabolic syndrome males

10. Body Fat Body Fat Insulin Sensitivity Insulin Sensitivity Altered Leydig cell function Endogenous T Endogenous T E2 T Aromatase E2 = Estradiol Kapoor et al. Clin Endocrinol 2005;63:239-250. Pitteloud et al. JCEM 2005;90:2636-2641. Dhindsa et al. Diabetes Care 2007;30:1860-2.

11. * p <0.001 † p = 0.013 Mulligan et al. Int J Clin Pract 2006;60(7):762-9. 70% 60% 50% 40% 30% 20% 10% 0% Hypertension*Hyperlipidemia* Diabetes*Obesity*Asthma/COPD † HypogonadalEugonadal OR 1.84 (1.53, 2.22) OR 1.47 (1.23, 1.76) OR 2.09 (1.70, 2.58) OR 2.38 (1.93, 2.93) OR 1.40 (1.04, 1.86)

12. The Androgen Deficiency in Aging Males (ADAM) Questionnaire 1.Do you have a decrease in libido (sex drive)? 2.Do you have a lack of energy? 3.Do you have a decrease in strength and/or endurance? 4.Have you lost height? 5.Have you noticed a decreased enjoyment of life? 6.Are you sad and/or grumpy? 7.Are your erections less strong? 8.Have you noticed a recent deterioration in your ability to play sports? 9.Are you falling asleep after dinner? 10.Has there been a recent deterioration in your work performance? If the answer is yes to question 1 or 7, or at least three of the other questions, low testosterone may be present. Morley J et al. Metabolism 2000;49:1239-42.

13. 13 Past Medical History – Type 2 diabetes – No neuropathy – Occasional ED – No retinopathy – Hypertension – COPD History of Present Illness –50 year-old male – ED, loss of libido x 2 years – Poor recovery with exercise –Always tired – Recent belly fat weight gain –Tobacco use 255,000 lifetime cigs

14. Medications – metformin – ipatroprium – simvastatin – valsartan – aspirin Q. What are the labs you would order? Physical Exam – BMI 32 kg/m 2 – Waist circumference 40 inches – BP 155/90 mm Hg

15.  Hgb and Hct Hgb 15 g/dL/ Hct 45%  Hemoglobin A1c 8%  Lipid ProfileTC 250 mg/dL, LDL 179 mg/dL, HDL 37 mg/dL, TG 220 mg/dL, LDL-p 2600  Serum Total Testosterone TT 205 ng/dL, FT 5.0 ng/dL  CIMT + 18 years and soft plaque  TSH 1.5mIU/ml  CMP normal  PSA 1.1 ng/mL

16.  Hgb and Hct not repeated  Hemoglobin A1c Not repeated  Lipid profile Not repeated at one week  Serum Total Testosterone (am) TT 195 ng/dL, FT 5.0 ng/dL  FSH and LH FSH 2.9 IU/L, LH 3.5 IU/L  SHBG 22 nmol/L  Serum Prolactin 12 ng/mL  TSH Not repeated  PSA Not repeated

17. Is the patient hypogonadal? Would you consider treatment with appropriate testosterone therapy?

19.  Normalizing T levels  Improved libido (? improve performance)  Improved energy level  Improved mood, sense of well-being  Increase in lean body mass and strength  Decrease in body fat mass  Improved bone mineral density (effects on fracture risk are currently unknown) Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(16):1995-2010. Wang C, et al. J Clin Endocrinol Metab. 2004;89:2085-2098. Petak SM, et al. AACE Clinical Practice Guidelines. Endocrine Practice. 2002;8(6):439-456. Wang C, et al. J Clin Endocrinol Metab. 2000;85:2839-2853.

20. Intramuscular ◦ Testosterone enanthate or cypionate ◦ 100-200 mg weekly or 200-400 mg every 2 weeks ◦ Testosterone undecanoate 750mg/3ml Q 10 weeks Transdermal Patches (Nonscrotal) ◦ 4 mg applied nightly for 24 hours* Transdermal Gels 1% ◦ 5- ? g applied daily Buccal Tablets ◦ 30 mg tablet applied every 12 hoursPellets ◦ 150-450 mg implanted SC every 3-6 months† Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(16):1995-2010. *Androderm® [package insert]. Corona, CA:Watson Pharma, Inc; February 2013 †Testopel in Drugs.com SC = Subcutaneous

21. Intramuscular ◦ Peaks and valleys in serum T levels ◦ Fluctuation in mood ◦ Office visits ◦ Pain at injection site ◦ Occasional excessive erythrocytosis ◦ Pulmonary oil microembolism Transdermal Patches ◦ Skin irritation at application site Transdermal Gels ◦ Risk for transfer ◦ odor Buccal Tablets ◦ Gum irritation ◦ Taste alterationPellets ◦ Infection ◦ Expulsion of pellet.

22.  Vigen et al Jama 2013  8709 T deficient men  1223 T therapy  20% untreated and 26% treated men death/MI/stroke  HR = 1.29  Finkle et al. PLoSOne 2014  Retrospective look 56K men T and 167K treated PDE5 inhibitor  T 1.36 nonfatal MI  >65yoa 2.19  <65 w cv dx 2.90  PDE5 1.1, 1.15, 1.4

23.  Xu et al. BMC Med 2013Meta analysis randomized placebo controlled trials of T therapy Odds ratio (OR) CV event = 1.54  Analysis by funding source Pharmaceutical funding OR = 0.89 Not funded by pharma OR = 2.06

24.  Cost Insurance coverage Testosterone therapy =$$$$ [female HRT =$]  Controlled substance Testosterone yes [female HRT no]  PO administration Testosterone no [female HRT yes]

25. Time (weeks) Serum testosterone concentration (ng/dL) 0 400 800 1000 1400 0315 200 600 1200 6912 Lower limit of normal range Upper limit of normal range IM = Intramuscular

26. Testosterone concentration (ng/dL) Time (hours) after application 04812162024 Lower limit of normal range Upper limit of normal range 5 g T-Gel 10 g T-Gel 0 400 800 1400 200 600 1000 1200 AndroGel ® [prescribing information]. Marietta, GA: Solvay Pharmaceuticals, Inc.; December 2007.

27.  Stimulation of growth in previously undiagnosed prostate cancer  Increased risk of bladder outlet symptoms due to increase in prostate volume  Erythrocytosis  Worsening of sleep apnea  Acne  Decreased sperm production  Edema in patients with preexisting cardiac, renal, or hepatic disease  Pulmonary Oil Microembolism Hijazi R, Cunningham G. Annu Rev Med. 2005;56:117-137 Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(16):1995-2010

28.  Known or suspected prostate cancer  Breast cancer  Use in pregnant or breastfeeding women  Unexplained PSA elevation  Hematocrit >50%  Severe BPH symptoms ◦ AUA prostate symptom score >19 (severe)  Unstable severe heart failure  Untreated prolactinoma  Untreated sleep apnea PSA = Prostate Specific Antigen, BPH = Benign Prostatic Hyperplasia, AUA = American Urological Association Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(16):1995-2010. Petak SM, et al. AACE Clinical Practice Guidelines. Endocrine Practice 2002 8(6): 439-456.

29.  Wolffian and mullerian ducts in utero prostate or uterus  Unopposed E2 on adult uterus inc risk of cancer -opposed by progesterone  Unopposed E2 on adult prostate inc risk of cancer -opposed by testosterone  If high T leads to prostate cancer (never proven) then why don’t 18 yr old males have prostate cancer?

30. Baseline 2-6 Months 2-6 MonthsAnnually T Concentrations Hematocrit PSA and DRE In accordance with your prostate cancer screening protocol BMD After 2 years of T therapy in hypogonadal men with osteoporosis or osteopenia Evaluate patient after testosterone initiation, then annually for response to treatment and symptom profile DRE = Digital Rectal Exam BMD = Bone Mineral Density

31. Serum PSA >4 ng/ml Increase in serum PSA >1.4 ng/mL within any 12 month period of T replacement PSA velocity of >0.4 ng/mL/yr Only applicable if PSA data are available for a period >2 years Prostatic abnormality on digital rectal exam If AUA prostate symptom score >19

32.  Low Testosterone is more common with increasing age and a number of other common medical conditions. It is characterized by serum concentrations below 300ng/ml ◦ With symptoms/ signs which may include changes in energy, libido, mood, body fat/lean mass ratio and bone mineral density  Replacement therapy can increase T levels to normal ranges which may improve symptoms  Multiple testosterone formulations are available  Testosterone replacement / supplementation may be indicated based upon patient and physician preference  Testosterone concentrations, PSA levels, DRE, hematocrit, AUA score, and BMD should be monitored during replacement supplementation therapy In Summary

33. Pearls?