Peter J. Burrows MD FACS

Transcription

1 Testosterone Supplementation, Prostate Cancer Screening and Vitamins Peter J. Burrows MD FACS Clinical Assistant Professor of Urology University of Arizona, College of Medicine Adjunct Assistant Professor of Urology USC Department of Urology, USC/Keck School of Medicine International Center for Vasectomy Reversal Arizona Center for Vasectomy and Urology

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4 Testosterone Key information on Testosterone and it s impact on Men s Health

5 Testosterone s impact on the Male Body Skin Hair growth, balding, sebum production Brain Libido, mood Liver Synthesis of serum proteins Muscle Increase in strength and volume Bone Accelerated linear growth, closure of epiphyses Male sexual organs Penile growth, spermatogenesis, prostate growth and function Kidney Stimulation of erythropoietin production Bone marrow Stimulation of stem cells Morley JE, et al. Metab 2000;49: AACE Hypogonadism Task Force Endocrinol Pract 2002;8:

6 Age related Changes in Testo Total and Free T decline with age By 75 ys, T (total) is 2/3 T at age 20 and Free T drops by 40% Circadian rhythms of T drop as age DHT and Estradiol levels remain the same with age.

7 ANDROGENS AND BODY COMPOSITION Androgen replacement in hypogonadal men leads to: Decreased % body fat Increased lean body mass Reduced bone remodeling Increased trabecular bone density Bhasin et al., Issues in Testosterone Replacement in Older Men, J. Clin Endocrin. Metab., 1998.

8 The prevalence of Low Testosterone increases with age (<300 ng/dl) 70 The relative risk was greater with each 10-year increase in age ( ) Prevalence of Low T in All Enrolled Patients (%, 95%CI) ( ) ) 39.9 ( ) 45.5 ( ) 38.7 ( ) 45 to to to to Total Patient Age Range Mulligan, et al. Int J Clin Pract Jul;60(7):

9 UNITED STATES AGE DEMOGRAPHICS 70 # men > 65 years old (millions) Year

10 LONGITUDINAL CHANGES IN SERUM TESTOSTERONE LEVELS IN 4 AGE COHORTS Adapted from Morley JE et al, Metabolism 46:410, 1997.

11 Male Brain

12 Benefits and Risks of TRT

13 EFFECTS OF AGING ON THE MALE Decline in testosterone production 1 Decreased testosterone levels Long-term complications due to low testosterone levels 1 Increased body fat mass Decreased muscle mass Decreased bone mass Increased incidence of osteoporosis Decline in libido, erectile function 1. Tenover JL. Endocrinol Metab Clin North Am. 1998;27:

14 Other Effects of TRT: Changes in Bone Mineral Density Changes in Lumbar Spine Bone Mineral Density 14 BMD (% Change) T only T+F Placebo -2-4 Mean +/- SEM * Testosterone (T) and finasteride (F) Study Month Amory, et al. J Clin Endocrinol Metab 2004; 89:

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17 VIAGRA AND TESTOSTERONE DEFICIENCY Viagra is not a treatment for testosterone deficiency Viagra does not improve libido Testosterone deficiency should be treated before Viagra is prescribed Viagra and testosterone replacement may have beneficial effects in men who have testosterone deficiency and vascular disease

18 PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION Insufficient arterial flow Venous leakage Neurologic damage (autonomic, sensory) Testosterone deficiency Medications Psychogenic (depression, anxiety)

19 Management of ED: Lifestyle Modification Stop smoking 1,2 Limit or avoid alcohol 1 Follow healthy diet 2 Exercise regularly 3 1. Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A et al, eds. Erectile Dysfunction. Plymouth, UK: Health Publication, Ltd; 2000: Feldman HA et al. Prev Med. 2000;30: Derby CA et al. Urology. 2000;56:

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21 IDENTIFICATION AND DIAGNOSIS OF LOW T

22 SYMPTOMS/CONSEQUENCES OF TESTOSTERONE DEFICIENCY Adolescent (prepubertal) Nonvirilization, decreased bone density, eunuchoidal proportions, psychosocial problems Adult (postpubertal) Decreased libido, fatigue, erectile dysfunction, depressed mood, hot flashes Aging men Decreased strength/muscle mass/body hair, osteoporosis, increased abdominal fat Miscellaneous Autoimmune problems, mild anemia

23 Conditions in which Low T is significantly more likely to occur A prospective analysis of 2162 men over 45 years of age demonstrated that men with these conditions were significantly more likely to have testosterone levels below 300 ng/dl than in men without these conditions Condition Odds Ratio (95% CI) Obesity 2.38 ( ) Diabetes 2.08 ( ) Hypertension 1.84 ( ) Hyperlipidemia 1.47 ( ) Asthma/COPD 1.40 ( ) Prostatic disease/disorder 1.29 ( ) Mulligan, et al. Int J Clin Pract 2006 Jul;60(7):

24 Prevalence of Low Testosterone in Other Conditions (%) Chronic Opioid Use Obesity Diabetes AIDS HIV = 30%. ED = erectile dysfunction. Bodie J, et al. J Urol. 2003;169: ; Daniell HW. J Pain. 2002;3: ; Dobs AS. Baillière s Clin Endocrinol Metab. 1998;12: ; Grinspoon S, et al. Ann Intern Med. 1998;129:18-26; Mulligan T, et al. Int J Clin Pract. 2006;60: Hypertension Other Conditions Hyperlipidemia 19 ED

25 Percentage rates of Low Testosterone in selected conditions Prevalance of Low Testosterone 1 52% 50% 42% 40% Other Areas of Concern HIV/AIDS 30% of HIV-infected men and 50% of men with AIDS may have low testosterone. 2 Obesity Diabetes Hypertension Hyperlipidemia Chronic Pain 74% of men consuming sustained-action oral opioids may have low testosterone Mulligan, et al. Int J Clin Pract 2006 Jul;60(7): Dobs A.S. Clin Endocrinol Metab 1998;12: Daniell HW. J Pain 2002 Oct;3(5):377-84

26 Mechanism of drug-induced hypogonadism 1-3 Opiate compounds Glucorticoids and anabolic steroids Ketoconazole Cyclophosphamide Phenothiazines, H 2 blockers Inhibit gonadotropin-releasing hormone Reduce gonadotropic secretion Inhibits gonadal steroid production Inhibits gonadal steroid production Increase prolactin 1 Glass, J Clin Endocrinol Metab. 1986;63: Grinspoon. Clin Endocrinol Metab 1994;79: Hofbauer. Medicine 1996;75:

27 Low Testosterone and Body Composition Associated with Increase in body fat Decrease in lean body mass (muscle) Decrease in bone mineral density (BMD) Hijazi RA, et al. Annu Rev Med. 2005;56: ; Szulc P, et al. Am J Clin Nutr. 2004;80:

28 Testosterone and Metabolic Syndrome Connection Metabolic Syndrome defined as: 1. Insulin resistance 2. HTN 3. Dyslipidemia 4. Central Obesity Leads to endothelial dysfunction and Oxidative stress. Obesity is likely the common link. Adipose cells produce Leptin, which decreases T

29 Low T levels may predict future onset of Type II Diabetes or Metabolic Syndrome Author / Publication N Age Results/Conclusions Laaksonen, et al Diabetes Care 2004: 27(5): Men with low testosterone were significantly more likely to develop either metabolic syndrome or diabetes Among men monitored for 11 years, those in the lowest testosterone quartile had a 2.3-fold higher risk of both outcomes Muller, et al J Clin Endocrinol Metab 2005: 90(5): Levels of testosterone and SHBG were inversely associated with metabolic syndrome and insulin resistance Each unit increase (1 SD or 5.3 nmol/l) in total testosterone level reduced the risk of metabolic syndrome by 57% Kupelian, et al J Clin Endocrinol Metab 2006: 98(13): Low total testosterone and low serum SHBG are associated with increased risk of developing MetS over time, particularly non-overweight, middle-aged men (BMI<25)

30 Testosterone and Mortality

31 VA database 2006 Subject Group: 858 veterans older than 40 years with repeated T levels obtained from October 1, 1994 to December 31, 1999 and without diagnosed prostate cancer Low testosterone level = total testosterone less than 250 ng/dl or a free T level of less than 0.75 ng/dl Low: 166 (19.3%) Equivocal*: 240 (28.0%) Normal: 452 (45.7%) * Equivocal levels indicated equal number of low and normal levels Shores M., et al. Arch Intern Med. 2006; 166:

32 Study Results Testosterone Level Normal Mortality 20.1% 95% CI % Equivocal Low 24.6% 34.9% % % After adjusting for age, medical morbidity and other clinical covariates, low testosterone levels continued to be associated with increased mortality. Hazard Ratio: % CI: P < Shores M., et al. Arch Intern Med. 2006; 166:

33 Testo less than 200ng/dl associated with serious health risks (2005 Mass Aging Study) Over 17 years of T less than 200 vs men with T above 400 2x risk of death 3x risk of cancer death 2x risk of CV death

34 Why are men with these comorbid conditions NOT being screened and diagnosed for low T?

35 TESTOSTERONE SCREENING CONSIDERATIONS Mass screening for hypogonadism with serum testosterone is costly Screen only if considering replacement Swerdloff RS et al: Summary of the Consensus Session from the 1st Annual Andropause Consensus 2000 Meeting. The Endocrine Society, April 2000.

36 Measuring Testosterone Morning lab draw.

37 What Is Considered a Low Serum T-Level? Total Testosterone <300 ng/dl* FT <50 pg/ml Bioavailable Testosterone <70 ng/dl *Most frequently used lab test for the diagnosis of hypogonadism. AACE Hypogonadism Task Force. Endocrinol Pract. 2002;8: ; Bhasin S, et al. J Clin Endocrinol Metab. 1997;82:3-8.

38 What labs are relevant Total T= SHBG T +AlbuminT +free T ½ T bound to SHBG- this T is functionally unaval. Free T = Albumin bound T and unbound T Older men have more SHBG, thus less Free T No true threshold of hypogonadal cutoff Guidelines that if Total <300 = hypogonadal or Total > 400 is not hypogonadal. Rest is up for interpretation and trial

39 Contraindications for TRT Androgens are contraindicated in men with known or suspected carcinoma of the prostate or carcinoma of the breast. Androgens are not indicated for use in women Obstructive Sleep Anpea Optimal spermatogenesis

40 Known Adverse Effects of TRT and Dogma KNOWN Erythorcytosis More common with IM administration (44% vs 5% of transdermal preparations) Gynecomastia (T E) BPH- 15% increase in prostate volume but minimal change on AUA Sx score DOGMA: Lipids- no adverse effects! Liver- not with IM or dermal Cardiac- Protective! Better angina free exercise when replaced Injection of T into coronaries- dilation and improved blood flow Endocrine Society Guidelines. July 2006

41 Prostate volume and male hormones No significant differences in prostate events betw T replacement and placebo Typically no change in AUA Sx score while on T replacement Men with severe AUA Sx scores (>21) should avoid any additional prostate growth

42 PSA on TRT Normal rise of PSA on TRT= 0.2 while T increased from Small prostate volumes had greater relative rise of PSA vs larger glands Younger men had greater PSA increase than older men

43 Monitoring Men while on Testosterone Replacement Maximal PSA elevation is achieved at T at the lower end of normal Higher doses of T should not increase PSA after initial elevation Therefore, increase of PSA more than 1.0, regardless of starting point is concerning

44 Low Testo is a risk factor for prostate cancer Men with severely reduced testosterone levels had a significantly higher prostate cancer rate of 20%. 1. Morgentaler A, et al. JAMA. 1996;276: Rhoden EL, Morgentaler A. J Urol. 2003;169:S Thompson IM, et al. N Engl J Med. 2004;350(22):

45 TRT and prostate cancer TRT in men with PIN did not have increased development of PCA Maximal prostatic saturation of T reached within the prostate at low levels of T

46 Post-prostatectomy and TRT (Baylor 2007) Qualifications: Negative surgical margins. PSA undetectable None (N=21) had PSA increase from undetectable over 5 ys when receiving Testo replacement

47 TREATMENT OPTIONS

48 OBJECTIVES OF TESTOSTERONE REPLACEMENT THERAPY IN MEN Provide physiological amounts of testosterone on a daily, consistent basis Restore serum levels of testosterone and active metabolites, DHT and E 2, to normal physiologic ranges Be safe and well tolerated by patient and partner Be comfortable to administer and convenient to use

49 TESTOSTERONE REPLACEMENT: CURRENT THERAPIES Oral: 3-4 times daily IM injection: every 1-2 weeks Patch: once daily Absorbable Gels: once daily Bucal: Twice daily

50 CURRENT TREATMENT OPTIONS (LISTED IN CHRONOLOGICAL ORDER) Intramuscular depot testosterone esters (enanthate and cypionate) Orally active testosterone derivatives (alkylated and esterified compounds*) Testosterone patch (Androderm ) Transdermal testosterone gel (AndroGel, Tetsim ) Buccal pellet (Striant )

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53 Testosterone Levels After Replacement With Gel, Patch, or Injection Patch or Gel Normal Range Injection T ng/dl Normal range Time (d) Adapted from Bhasin S, et al. J Clin Endocrinol Metab. 1997;82:3-8; Testosterone gel (AndroGel 1%) Unimed Pharmaceuticals and Solvay Pharmaceuticals, 2007.

54 INTRAMUSCULAR INJECTION OF TESTOSTERONE ESTERS Positives Negatives Large clinical experience Infrequent administration Not visible to others Low cost Supraphysiological levels of T, BT, DHT and E 2 Roller-coaster effects on libido, energy, and mood Gynecomastia common Abnormal elevations in hematocrit are common No diurnal cycle* Painful administration *Clinical significance of diurnal cycle is unknown

55 ORALLY ACTIVE TESTOSTERONE DERIVATIVES (ALKYLATED AND ESTERIFIED*) Positives Oral administration Not visible to others *Not approved in US Alkylated (eg, methyl T) Negatives Potentially hepatotoxic Markedly lowers HDL Not metabolized to T Esterified* (eg, undecanoate) Low bioavailability, T levels TID, QID dosing No diurnal cycle

56 Testim and AndroGel : Key Points of Differentiation Acrylates Carbopol Testim X X AndroGel Uniquely formulated Only 3 common ingredients with AndroGel. Glycerin Pentadecalactone Polyethylene glycol Propylene glycol Tromethamine Alcohol Purified Water Testosterone Carbomer 940 Isopropyl Myristate Sodium Chloride X X X X X X X X X X X X X X Not bioequivalent The FDA has classified TESTIM as not bioequivalent with AndroGel. In the only head to head PK study, Testim patients demonstrated 47% higher free testosterone and 30% higher total testosterone Non-substitutable TESTIM cannot be substituted without physician approval. Marbury et al. Biopharm Drug Dispos 2003;24:

57 Recommendations for Monitoring Older Men During Testosterone Replacement Baseline Evaluation Follow-up at 3, 6, 12 mo and then annually DRE PSA, Testo, CBC AUA Sx score Bhasin et al. 2003

58 Indications for Urologic Evaluation PSA >4.0 Increase of PSA >1.0 after 3 or 6 months of T therapy PSA velocity >.4ng/ml/yr after 6 months of T therapy Change of DRE AUA Sx score >21 Bhasin et al. 2003

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60 Prostate Cancer Screening Prevention Treatment options

61 Prostate Cancer Screening in Men Over 75 Recent recommendation to stop screening at age 75 Cancers found at this age are insignificant! Testing/biopsy and treatment more harmful than ignoring cancer Maybe reasonable if mens life expectancy remained that is was 40 ys ago (life expectancy = 72) Just an ignorant, cost saving ill-advised RETRACTED

62 Prostate Cancer Screening 244,000 new cases a year with 38,000 deaths a year Death rate down 25% since mass screening with PSA in 1980 s PSA blood test Raw numbers less important than rate of change. PSA velocity is the most important So what does a PSA more than 4.0 mean?

63 PSA Screening Screening began 1986 High PSA still best predictor for cancer PSA detects cancer 5-10 ys before exam Most cancer found by PSA is curable Regular PSA tests eliminates dying of advanced prostate cancer.

64 Prostate Cancer Screening 1in 4 men found to have cancer with elevated PSA (25%) PSA not specific for prostate cancer and predicts benign growth more accurately DNA markers are the next wave: EPCA-2. Blood test. Not yet avaliable. PCA-3: Urine marker. 55% predictive if (+) 78% negative if (-)

65 Prostate Cancer Prevention Prostate Cancer Rate not the same between races in USA White: 101 per 100,000 Black: 137 per 100,00 Asian: 40 per 100,000 Cancer rates are different from nation to nation and from region to region within this nation

66 Dietary Fat and Prostate Cancer American diet: 30-40% fat Associated with lower intake of fruits and vegies, no soy, little fish Japanese diet: 15% fat Higher Omega-3 fats (anti-inflammatory) Soy products, fish NOT meat

67 Fruits and Vegetables 28 servings of veg/wk 35% reduction of prostate cancer Soy products: Increase estradiol: testo Lycopene: effective antioxidant Best source: Cruciferous vegetables: Broccoli, cabbage Men who ate 3 or more servings of crucif veg has 41% reduction of prostate cancer

68 Vitamins and Prostate Cancer Calcium High calcium INCREASED prostate cancer 2x Rec no more than 500mg/day Vitamin D (sunlight) Protective 15 min a day without sunscreen 400 IU/day vit D

69 Exercise and obesity For men over 65 ys: 70% reductive effect with vigorous exercise Diet with more than 2400Kcal/day 4x risk of prostate cancer

70 SUMMARY: TESTOSTERONE DEFICIENCY Testosterone deficiency may affect as many as 8 million men in the US of all ages Testosterone deficiency is observed in men with diabetes, HIV infection, renal failure, cancer and obesity Erectile dysfunction may be a symptom of testosterone deficiency Viagra is not a treatment for testosterone deficiency A variety of modalities for treating testosterone deficiency are currently available in the US

71 CONCLUSIONS Testosterone replacement therapy can increase hormone levels to normal ranges and improve these symptoms Transdermal formulations provide testosterone at more natural levels and rhythms compared with oral and intramuscular formulations Careful follow-up of PSA levels and hematocrit is an important component of testosterone replacement

72 ANDROGEN REPLACEMENT: Conclusions: Gestalt Replacement has wide benefits for men with TDS Improved: Mood, behavior, muscle mass, fat distribution, bone density, cardiovascular risk, sexual response. Testim has 30% better absorption than other topical options and can salvage non-responders 15% of men will not absorb either gel due to skin enzymatic breakdown and will require IM shots.

73 Female Brain

74 THANK YOU! Peter Burrows, MD Office:

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76 Which condition(s) has been assocaited with Low testosterone? A) Obesity B) Elevated Cholesterol C) Diabetes D) Chronic Pain E) All of the above

77 What is the main difference between the American diet and Japanese A) Greater calories B) More carbohydrate calories C) Greater Fat calories D) More Alcohol