Testosterone Use in Heart Failure: The “Low T” Story

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1 Testosterone Use in Heart Failure: The Low T Story Pharmacotherapy Rounds Sumon K. Sen, PharmD PGY1 Pharmacy Practice Resident South Texas Veterans Health Care System, San Antonio, Texas Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center The University of Texas Health Science Center at San Antonio November 15, 2013 Learning Objectives 1. Investigate the incidence and complications of chronic heart failure 2. Examine hypogonadism and testosterone use as replacement therapy 3. Report testosterone use in chronic heart failure 4. Evaluate literature for evidence in testosterone therapy in chronic heart failure 5. Develop recommendations regarding use of testosterone in chronic heart failure Sen 1

2 Chronic Heart Failure (CHF) I. Epidemiology/Mortality1-3 a. More than 5 million Americans currently have heart failure b. Lifetime risk of developing heart failure is 20% for those over 40 years of age c. Each year, 990,000 patients are hospitalized with CHF as the primary diagnosis d. Nearly 50% of patients die within 5 years of the onset of symptoms e. Despite treatment, CHF is a progressive disease with high morbidity and mortality, suggesting that important pathogenic mechanisms remain unmodified by the present treatment modalities II. Pathophysiology3-8 Figure 1: Heart Failure Pathophysiology4 a. CHF is a metabolic and hormonal deficiency syndrome with anabolic/catabolic imbalances b. Functional impairment is a hallmark of heart failure and a prognostic marker of disease i. Cardiopulmonary exercise testing evaluates exercise capacity and predicts outcomes c. Peripheral skeletal muscles, neurohormonal, and metabolic systems are involved i. Skeletal muscles 1. Exercise intolerance results in poor quality of life, high morbidity, and high mortality a. Reduced muscle strength and endurance due to catabolic effects Sen 2

3 i. Imbalance of protein synthesis and proteolysis resulting in atrophy b. Impaired endothelial function results in reduced peripheral vasodilator capacity and muscle hypoperfusion 2. Fatigue does not necessarily relate to degree of myocardial dysfunction a. Chronic beta-adrenergic stimulation, enhanced angiotensin II activity, effects of inflammatory cytokines (tumor necrosis factor alpha (TNF ), interleukin (IL), reactive oxygen species) involved in fatigue 3. Insulin resistance (inability of insulin to promote glucose transport into skeletal muscles) is proposed as a mediator of skeletal muscle fatigue and wasting during heart failure d. Neurohormonal system i. Elevation of circulating catecholamines, cortisol, aldosterone, and plasma renin activity ii. Decreased anabolic factors (testosterone, insulinlike growth factor1 (IGF1), growth hormone (GH), and insulin) 1. Low levels are associated with greater cytokine and neurohormonal activation, reduced skeletal muscle performance, endothelial dysfunction, and poor outcome e. Metabolic system i. More than 40% with heart failure have glucose metabolism disorders ranging from diabetes to impaired insulin sensitivity ii. Increased levels of TNF and decreased levels of testosterone adversely affect insulin sensitivity in skeletal muscle III. Inflammation4,6, 9-10 a. CHF is considered a state of chronic inflammation as it activates neurohormones and pro- inflammatory cytokines b. Maladaptive response i. Cytokines and hormones lead to pro-inflammatory state favoring catabolism ii. Response is controlled by RAAS inhibition and sympathetic blockade to restore anabolic/catabolic balance c. Cytokines (TNF , IL1, IL6) are elevated and contribute to insulin resistance and cachexia (tissue wasting) d. Anabolic/catabolic imbalance is presented by multiple anabolic deficiency reflecting impairment of anabolic hormones (testosterone, dehydroepiandrosterone sulfate (DHEAS), IGF-1, insulin) i. Anabolic hormones are determinants of male exercise capacity 1. Age-related decline in testosterone, dehydroepiandrosterone sulfate (DHEAS), and IGF-1 contribute to impaired exercise tolerance 2. Adrenal axis suppression reflects observed functional impairment in CHF Sen 3

4 Table 1: Hormones Involved in CHF11 Hormones Metabolic axis Relationship/ Clinical effect Therapies available Clinical effect Angiotensin II Renin- Increased Vasoconstriction, Angiotensin converting Angiotensin myocardial fibrosis enzyme inhibitor/ angiotensin receptor blocker Aldosterone Renin- Increased Myocardial fibrosis Spironolactone, eplerenone Angiotensin Adrenaline Catecholamine Increased Tachycardia, Beta blocker arrhythmias Noradrenaline Catecholamine Increased Sudden death Beta blocker Cortisol Glucocorticoid Increased Catabolism None Insulin Endocrine Resistance Associated cachexia None Testosterone Androgen Decreased Catabolism Testosterone DHEA Androgen Decreased Catabolism DHEA Growth Somatotropic Decreased Catabolism Growth hormone Hormone Insulin-like Somatotropic Resistance Catabolism None growth factor I Tumor necrosis Immune/Cytokine Increased Catabolism Biologicals factor Interleukin 1 Immune/Cytokine Increased Catabolism Anti-TNF, anti-IL-1 recombinant antibodies IV. Stages of Heart Failure Table 2: Stages of Heart Failure2,11 ACC/AHA Stages of Heart Failure NYHA Functional Classification A: At high risk for heart failure but without structural heart disease or symptoms of heart None failure B: Structural heart disease but without signs or I: No limitation of physical activity. Ordinary physical symptoms of heart failure activity does not cause symptoms of heart failure II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms C: Structural heart disease with prior or current of heart failure symptoms of heart failure III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of heart failure IV: Unable to carry on any physical activity without D: Refractory heart failure requiring specialized symptoms of heart failure, or symptoms of heart failure interventions at rest V. Complications of CHF11, 13-15 a. Arrhythmias i. Atrial fibrillation is present in about a third (range 10-50%) of patients with chronic heart failure b. Thromboembolism i. Low cardiac output, endothelial dysfunction, abnormalities of blood constituents Sen 4

5 c. Cachexia i. Process of muscle wasting and weight loss occurring with heart failure ii. Definition: 1. At least 10% loss of lean tissue 2. Non-edematous weight loss of 6% or more over a period of at least 6 months iii. Undernutrition develops as a consequence of CHF 1. Occurs in 50% of CHF patients but not recognized due to edema iv. Mechanisms of the progression from heart failure to cardiac cachexia are not fully understood v. Anker, et al. proved that cardiac cachexia is a strong independent risk factor for increased mortality in CHF patients vi. Difficult to diagnose cachexia in heart failure as edema impairs body weight evaluation and other anthropometric measures vii. Presents with gastrointestinal protein loss and fat malabsorption d. Respiratory i. Pulmonary congestion, respiratory muscle weakness VI. Pharmacotherapy Table 3. Pharmacotherapy for Heart Failure2 Stage A Stage B Stage C Stage C Stage D Heart healthy Prevent heart Preserved Reduced Ejection Control symptoms lifestyle failure symptoms Ejection Fraction Fraction Control HRQOL Prevent vascular Prevent further Control symptoms Control symptoms Reduce hospital coronary disease cardiac Improve HRQOL Patient education readmission Prevent LV remodeling Prevent Prevent hospitalization Establish end of structural hospitalization Prevent mortality life goals abnormalities Prevent mortality ACEI/ARB ACEI/ARB Diuretics Diuretics Chronic inotropes Statin Beta Blocker ACEI/ARB Beta Blocker Aldosterone Antagonist In certain patients Hydralazine/isosorbide dinitrate Digoxin ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; HRQOL: health related quality of life; LV: left ventricle Male Hypogonadism I. General Information11,16-18 a. Hypogonadism refers to decreased functional activity of gonads and increases with age II. Classification18 a. Primary: testicular failure i. Klinefelter syndrome, toxin exposure, chemotherapy, testicular trauma, increased temperature of testis environment b. Secondary: hypothalamic-pituitary process failure i. Congenital disorders, medications (opioids, corticosteroids), obesity, aging, excess estrogen, anabolic steroid abuse, HIV, anorexia, alcohol abuse Sen 5

6 III. Pathophysiology Figure 2: Hormonal Control of Testosterone Secretion17 a. Hypothalamic-pituitary-gonadal axis18 i. Hypothalamus secretes (pulsatile) gonadotropin-releasing hormone (GnRH) which acts on the anterior pituitary to produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH) ii. LH stimulates the interstitial Leydig cells of the testes to produce testosterone iii. FSH stimulates spermatogenesis and Sertoli cell function iv. Secretion of LH from the pituitary is not constant 1. Estimated to have six bursts of secretion per day with early morning high and early evening low 2. A total of approximately 7 mg of testosterone is secreted each day, which decreases with age IV. Assessment of androgen deficiency19 a. Screening for androgen deficiency in the asymptomatic general population is not recommended b. Assess for signs and/or symptoms of androgen deficiency Sen 6

7 Table 4: Symptoms and Signs Suggestive of Androgen Deficiency in Men18 More specific symptoms and signs Incomplete or delayed sexual development, eunuchoidism Reduced sexual desire (libido) and activity Decreased spontaneous erections Breast discomfort, gynecomastia Loss of body (axillary and pubic) hair, reduced shaving Very small (especially

8 VI. Testosterone Therapy20-22 a. Became available since the 1930s to treat impaired libido and failure of secondary sexual development b. Morning levels of serum testosterone vary between 315 and 1000 ng/dl (11 and 35 nmol/liter) Table 5: Testosterone Replacement Therapies23,24 Formulation Name Dosing Adverse Effects/Comments Oral AndroxyTM 5-20 mg daily Hepatic events Topical Gels AndroGel 1% or 1.62% 50 mg or 40.5 mg daily Slight odor; unable to shower/swim 6 hours after 5 g daily application; potential transfer to Testim others by direct-skin-to skin contact Topical Androderm 4 mg patch daily May cause rash, erythema, Transdermal induration Systems Buccal System StriantTM 30 mg twice daily Gum related tenderness and pain; bitter taste Subcutaneous Testopel testosterone 150-450 mg every 3-6 Minor bleeding, fibrosis, infection; testosterone pellets months longest acting formulation implants available; surgical insertion Intramuscular Delatestryl: 50-400 mg IM every 2- Edema, erythropoiesis, depot testosterone enanthate 4 weeks gynecomastia , phlebitis, acne, hair testosterone loss, virilization; most potent; least Depo-testosterone: 50-400 mg IM every 2- expensive; given 1 or 2 week testosterone cypionate 4 weeks intervals c. Monitoring i. Levels are measured at baseline and then again at three months ii. Testosterone levels taken in morning (near 8 AM) d. Safety concerns20 i. Prostate carcinoma 1. Prostate carcinoma is androgen sensitive 2. No clear evidence testosterone initiates development of prostatic carcinoma ii. Benign prostatic hyperplasia 1. Increase in prostate volume, but no increase in voiding symptoms or residual urine volume iii. Erythropoiesis 1. Increased hematocrit a. Result in risk of stroke b. IM injection may be more associated with erythrocytosis than transdermal form 2. Monitor hematocrit or hemoglobin blood concentration iv. Sleep apnea 1. Liu, et al. observed decrease in sleep time and disrupted breathing pattern during sleep with prolonged hypoxemia with short term administration of high doses of testosterone v. Gynecomastia 1. Peripheral aromatization of testosterone in fat tissue Sen 8

9 vi. Cardiovascular events25-27 1. Anabolic steroids associated with left ventricular hypertrophy and systolic/diastolic dysfunction 2. Basaria, et al. (Testosterone in Older Men with Mobility Limitations (TOM) trial) evaluated the effect of testosterone supplementation in men 65 years of age or older with limitations in mobility and low serum levels of total or free testosterone a. Trial was stopped before enrollment had been completed due to incidence of adverse cardiovascular events that were higher in the testosterone group b. However, it is argued the baseline characteristics were more likely to be predisposed to cardiovascular events c. Doses of testosterone given were higher than usual doses given vii. Other adverse events 1. Breast carcinoma 2. Fluid retention 3. Lipid alterations 4. Atherosclerosis viii. Black box warning23,24 1. Virilization has been reported in children who were secondarily exposed to testosterone gel/solution (topical) ix. Contraindications23,24 1. Breast cancer (male) 2. Pregnant, may become pregnant, or breast feeding females 3. Hypersensitivity to testosterone 4. Prostate cancer (known or suspected) Testosterones Effects on Heart Failure I. Approximately 25% of men with CHF have testosterone deficiency3,8 II. Current ACC/AHA Heart Failure Guidelines do not recommend use of testosterone in heart failure2 III. Jankowska, et al. demonstrated a high prevalence of reduced serum were markers of poor prognosis28 a. Circulating levels of testosterone are related to peak oxygen consumption in men with CHF i. Low serum testosterone levels predict reduced peak oxygen consumption IV. Testosterone may worsen heart function7, 16, 29 a. Anabolic steroids were considered to have cardiac toxicity effects b. High doses cause myocardial hypertrophy and stiffness V. Testosterone may benefit heart function28 a. As testosterone levels decline, there is diminished vasoreactivity and increased vascular inflammation i. Coronary artery dilatation, resulting in a reduction of blood pressure ii. Increases coronary blood flow iii. Increases cardiac output by reduction of vascular resistance iv. Improvements in anginal symptoms Sen 9

10 b. Vascular effects i. Endothelial independent (vascular smooth muscle cells) 1. Ion channel modulation a. Testosterone inhibits voltage operated calcium channels or activates potassium channels on smooth muscle cells to induce vasodilation ii. Endothelial dependent 1. Increases expression of nitric oxide synthase and enhance nitric oxide (NO) production 2. Increased NO acts on smooth muscle cells to induce vasorelaxation by activating cyclic guanosine monophosphate dependent protein kinases, which activate sarcoplasmic reticulum calcium ATPase to increase uptake of calcium into sarcoplasmic reticulum and decreases calcium resulting in vasorelaxation iii. Anti-inflammatory mechanisms 1. Reduce TNF, C-reactive protein, IL-1, IL-6 c. Decrease peripheral vascular resistance and afterload i. Cardiac output increases as result of decreased systemic vascular resistance VI. Effects on skeletal muscles5,30,31 a. Promotes protein synthesis and blocking catabolic action i. Skeletal muscle hypertrophy 1. Accelerates fast to slow-oxidative fiber type conversion 2. Increases number and size of type I slow-oxidative fibers 3. Results in improved oxidative capacity higher aerobic potential with a delayed fatigue ii. Increased muscle bulk and strength 1. Increases in leg muscle strength and work output by decreasing the muscle metaboreflex overactivity a. Increase in sympathetic activity to heart and vasculature b. Anabolic hormones are determinants of exercise capacity. i. Age-related decline in circulating testosterone, DHEAS, and IGF-1 contribute to gradually impaired exercise tolerance in elderly men c. Improves insulin sensitivity i. Increases availability of glucose in skeletal muscle cells to reduce fatigue and promote vasodilation d. Testosterone therapy effects on exercise performance resulting in increased functional capacity and ventilatory efficiency i. Increased muscular performance ii. Increased oxygen availability to muscles iii. Decreased muscle metaboreflex activation VII. Testosterone deficiency in CHF and relation to poor prognosis encourages idea of replacement of testosterone VIII. There is a growing interest in possibility of testosterone administration to counteract catabolic/anabolic imbalance and improve exercise intolerance in CHF patients Sen 10

11 Literature Review Table 7. Pugh PJ, et al. Testosterone treatment for men with chronic heart failure. Heart. 2004;90:446- 7.32 Purpose To determine whether testosterone therapy can improve exercise capacity and symptoms in male patients with CHF. Design Randomized, double blind, placebo controlled trial Population Inclusion: Moderate impairment of left ventricular systolic function ejection fraction 35% and reduced exercise tolerance, with CHF at least six months without any other malignant or debilitating disease, ambulating Exclusion: High prostate specific antigen (PSA) concentrations or exercise limitation due to a non-cardiac cause Methods Patients given IM (Sustanon 100) or placebo injections every two weeks for twelve weeks Assessed between 8:00-9:30AM at baseline and then twelve weeks later Outcomes Improvements in exercise capacity and symptoms Statistics Kolmogorov-Smirnov test Group changes following treatment were analyzed with paired t tests for normal data and Wilcoxon matched pairs test for other data Independent samples t-tests or Mann Whitney U test used for between group comparisons Results Baseline characteristics: well matched without significant differences Mean increase in distance walked with incremental shuttle walk test 91.0 (19.7) m vs 26.0 (15.2) m, p=0.018 Minnesota Living with Heart Failure scores had greater reduction with testosterone 8.0 (3.2) vs placebo 1.3 (4.0), p=0.086 Authors 12 weeks of treatment with testosterone was safe, well tolerated, and led to significant Conclusion improvements in physical capacity and symptoms. Critique Strengths Limitations Study design Small number of patients Appropriate timing of monitoring No baseline characteristics described testosterone levels between 8:00- Did not determine testosterone level in 9:30AM patients No identified primary outcome NYHA functional class not reported Take Home Significant increase in distance walked with those receiving testosterone Points Treatment had no significant effect on skeletal muscle bulk and strength, heart rate, blood pressure, weight, left ventricular size and function, nor concentrations of plasma cytokines Found trend in positive effect on mood scores, which may be related to improved functional capacity Sen 11

12 Table 6. Malkin CJ, et al. Testosterone therapy in men with moderate severity heart failure: a double- blind randomized placebo controlled trial. Eur Heart J 2006;27:57-64.33 Purpose To determine if low dose physiological replacement with testosterone therapy may improve anabolic/catabolic imbalance and improve symptoms along with functional capacity. Design Randomized, double-blind, placebo-controlled parallel trial between November 2001 and February 2003 Population Inclusion: Ambulant male patients, stable CHF of at least 6 months duration, >18 years of age, impaired exercise tolerance limited by fatigue or dyspnea (cardiac origin), moderate left ventricular systolic dysfunction on 2D trans-thoracic echocardiography Exclusion: Use of sex hormone manipulating therapy, prostate specific antigen (PSA) level above the age adjusted normal range, exercise limitation due to a non-cardiac cause or malignancy Methods Subjects applied a 5 mg patch at night (n=37) vs placebo (n=39); replaced every 24 hours Subjects randomized were reviewed at baseline, three, six, and twelve months Stratified according to ischemic vs non-ischemic etiology Outcomes Primary outcome evaluated functional capacity as assessed by the incremental shuttle walk test at 12 months Statistical 66 subjects required to achieve 90% power and 5% significance Analysis All data compared with normal distribution using Kolmogorov-Smirnov test Intention-to-treat analysis P=0.01 considered significant Results Baseline characteristics: no differences in baseline characteristics Active group average age 63.1 years vs placebo group 64.9 years Active group total testosterone 13.9 nmol/L vs placebo group 12.1 nmol/L Active group NYHA class (II/III/IV) 21/14/2 vs placebo group 24/13/2 Primary outcome: Mean shuttle walk distance change at 12 months was +25+15 m (7- 56 m) (15+11% improvement from baseline) Sen 12

13 Treatment Effects of Testosterone Change from Change from baseline: effect of baseline: effect of Parameter P-value testosterone at 12 placebo at 12 month months BMI (kg/m2) 0.091.7 +3.83.1 0.5 Dominant handgrip +1.04.0 0.65.3 0.04 strength (kg) Ejection fraction (%) +1.813.1 +0.9513.6 0.7 LV length (mm) +0.260.7 0.581.6 0.0001 Total testosterone +5.710.8 +0.43.6 0.0001 (nmol/L) Hematocrit (L/L) +0.0090.3 0.0050.003 0.03 PSA (ng/mL) +0.080.7 0.080.5 0.19 TNF (pg/mL) 2.533.55 1.912.19 0.85 Systolic BP (mmHg) +1.617.4 4.413.9 0.013 No differences in Minnesota Living with Heart Failure (MLHF) or Beck Depression Inventory (BDI) between groups NYHA heart failure class at study completion improved by least one functional class in 13 (35%) patients in the testosterone group compared with three (8%) on placebo (p=0.01) Safety 19 patients withdrew due to skin reactions 42 patients (55%) experienced skin reactions (minor and reactions necessitating withdrawal) Authors The study demonstrated a significant benefit in functional capacity and symptoms in Conclusion men with moderately severe heart failure by raising the serum levels of testosterone by almost 40% and within the normal physiological range. Critique Strengths Limitations Study design No data on the effects of testosterone Good monitoring of patients (baseline, replacement therapy on endpoints 3, 6, 12 months) including hospitalization, deterioration in CHF, and death Analysis performed on 6 month data instead of 12 month data due to patient withdrawals Androgen deficiency was not inclusion criteria Take Home This study showed improvement in NYHA class in 13 patients (35%) Points Testosterone patch caused many skin reactions Sen 13

14 Table 8. Caminiti G, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure. J Am Coll Cardiol. 2009;54(10):919-27.34 Purpose To assess the effects of a long-acting testosterone treatment on functional capacity and ventilator efficiency in elderly male patients with moderate-to-severe heart failure. Design Randomized, double-blind, placebo-controlled study Population Inclusion: Left ventricular ejection fraction 50%), prostate cancer, prostate-specific antigen (PSA) >3ng/ml, severe lower urinary tract symptoms, any disease preventing a symptom limited exercise test Methods Patients randomly allocated to receive IM long acting testosterone undecanoate (1000mg) (n=35) or IM saline injection (n=35) at baseline, six, and twelve weeks Outcomes Effect of testosterone on functional capacity and ventilatory efficiency through improvement of muscle performance Effect of testosterone supplementation on vagally mediated arterial baroreceptor cardiac reflex sensitivity (BRS) Statistics Estimated 70 patients to obtain effect size with 80% power and 5% significance, assuming dropout rate of 15% Within group changes evaluated by paired t-test or Wilcoxon signed rank test for non- normally distributed variables Between group comparisons evaluated with unpaired t and Mann-Whitney rank sum tests Variables assessed by Pearson product moment correlation or Spearmans rank test for non-normally distributed data Two tailed p value of

15 Select Cardiorespiratory, Muscular, and Metabolic Changes After Three Months of Testosterone Therapy with Low vs Normal Baseline Testosterone Levels Variables Low Testosterone (n=12) Normal Testosterone (n=19) Peak VO2 (ml/kg/min) 4.0 1.8* 2.6 + 1.2 VE/VCO2 4.9 1.6 4.1 1.5 6MWT(m) 96.5 33 80.7 28 MVC (Nm) 39.1 6.2* 16.0 5.6 *p

16 Results Forest Plot of Four Studies Evaluating Exercise Capacity Critique Strengths Limitations Randomized, double-blind trials Small sample sizes All studies incorporated evaluated exercise None used baseline testosterone capacity level as inclusion/exclusion criteria Differing testosterone dosage forms Differing durations of therapy Variable patient population (sex) Exercise capacity evaluated differently in studies (ISWT vs 6MWT) Authors In patients with moderate to severe heart failure, testosterone supplementation improves Conclusion exercise capacity and metabolic indices. Conclusion I. Summary of evidence a. Randomized trials with small patient samples sizes b. Patient population i. Generally older age (65+ years) ii. Androgen deficiency was not inclusion criteria c. Testosterone dosage form and dose are variable i. Testosterone patch ii. Intramuscular injection (different injection forms) d. Safety outcomes i. Dropouts due to use of patches ii. No other safety issues were reported e. Limitations in length of therapy f. Long term effects are unknown II. Currently not enough evidence warrants use of testosterone in men with CHF Sen 16

17 Appendices Table 10. Endocrine Society Guidelines for the Monitoring of Testosterone Therapy17 Start of Each visit 3 months Annually 12 years treatment (baseline) Symptom response Adverse events Formulation-specific adverse events Testosterone levels Hematocrit* Bone mineral density of lumbar spine/femoral neck Digital rectal exam Prostate specific antigen *If hematocrit > 54%, discontinue therapy until hematocrit decreases to a safe level, evaluate the patient for hypoxia and sleep apnea, then reinitiate therapy with a reduced dose For patients with osteoporosis or low trauma fracture After 3 months, perform in accordance with guidelines for prostate cancer screening, depending on the age and race of the patient Table 11: Testosterone Monograph23,24 General Schedule III Indication FDA labeled: Hypogonadism Unlabeled: Osteoporosis, weight gain Androderm Initial, one 4 mg/day patch applied topically nightly for 24 hours to back, abdomen, upper arm, or thigh; may increase to 6 mg/day or decrease to 2 mg/day per serum testosterone levels Androgel 50 mg (4 pump actuations from the 75 g multidose pump delivering 50 mg) applied 1% topically once daily (preferably in the morning) to clean, dry, intact skin of the shoulders and upper arms or abdomen Androgel 40.5 mg (2 pump actuations) applied topically once daily in the morning to clean, dry, Topical application 1.62% intact skin of the shoulders and upper arms Axiron 60 mg (1 pump actuation of 30 mg to each axilla) applied topically once daily at the same time each morning to clean, dry, intact skin of the axilla FortestaTM 40 mg (4 pump actuations) applied topically once daily to clean, dry, intact skin of the front and inner thighs in the morning Testim 5 g (contains 50 mg testosterone) applied topically once daily (preferably in the morning) to clean, dry intact skin of the shoulders or upper arms; may increase dose to 10 g daily after 2 weeks StriantTM One buccal system (delivering 30 mg) applied to the gum region twice daily in the morning and evening (approximately 12 hours apart) mucosa Buccal Sen 17

18 Testosterone 50 to 400 mg IM every 2 to 4 weeks as replacement therapy Cypionate Intramuscular injection Testosterone 50 to 400 mg IM every 2 to 4 weeks as replacement therapy Enanthate Precautions Children and women; benign prostatic hyperplasia; cancer patients associated with risk of hypercalcemia; dyslipidemia; edema; gynecomastia; immobile; magnetic resonance imaging (aluminum in patch); polycythemia; prostate cancer; sleep apnea Pregnancy category X Adverse events Acne, gynecomastia, oral irritation (buccal), headache, enlarged prostate, edema, cholestatic jaundice syndrome, liver carcinoma (rare), liver neoplasm, peliosis hepatis, benign prostatic hyperplasia, prostate cancer Onset/Duration Transdermal: peak response 3-6 months (lean muscle mass, erythropoiesis, prostate volume, energy, and sexual function) Absorption Transdermal/Gel: 10% absorbed in 24 hour period Distribution Protein bound: Testosterone-estradiol binding globulin: 98% Sex hormone-binding globulin: 40% Free (bioavailable): 2% Volume of distribution: 74.9 to 122.5 L/kg Metabolism Liver Metabolites: estradiol and dihydrotestosterone (DHT); testosterone glucuronic conjugate; testosterone sulfuric acid conjugate Excretion Renal excretion: 90% Feces: 6% Elimination half life 10-100 minutes Table 12: Select Tests Used in Heart Failure Trials with Testosterone Therapy 36-38 Incremental Shuttle Walk Test Subjects walk along a level 10 m course at a previously determined speed (ISWT) dictated by signals from an audio tape recorder. The speed progressively increased at 1 min intervals. 6 Minute Walk Test (6MWT) Subjects walk from down one long corridor 30 m long from end to end at the subjects own pace over a course of six minutes. Minnesota Living with Heart Designed for use in heart failure to assess the patients' perception of the Failure (MLHF) Questionnaire effects of CHF on the physical, socioeconomic, and psychological aspects of their life. Homeostatic Model Assessment- Measures peripheral insulin resistance. It is calculated multiplying fasting Insulin Resistance (HOMA IR) plasma insulin by fasting plasma glucose, then dividing by the constant 22.5. HOMA IR values between 1.7 and 2.5 are considered normal glucose tolerance. Minute Ventilation-Carbon Prognostic indicator in CHF indicating liters of air breathed to eliminate 1 Dioxide Production (VE/VCO2) liter of CO2. Slope >34 associated with worse prognosis in CHF. Peak O2 Consumption (VO2) Prognostic indicator determining functional capacity in CHF. 10ml/kg/min to 18 ml/kg/min indicates moderate risk of cardiac events. Sen 18

19 Table 13. Testosterone Treatment in Patients with Stable, Moderate Heart Failure Study Design Intervention Outcome Conclusions Pugh, et al. Randomized, double-blind, Effects of testosterone on pro-inflammatory Effects of testosterone on pro-inflammatory cytokine production in vitro In vitro testosterone reduces (2005)39 PB-controlled cytokine production in vitro (n=27) - Serum TNF alpha reduced (p

20 Iellamo, et al. 24 week, randomized, Transdermal patch (300 g Intrinsa) or PB Primary outcome: 6MWT distance in meters and insulin resistance Testosterone supplementation (2010)42 double-blind, PB controlled transdermal patch twice/week to abdominal Testosterone Placebo therapy improves functional skin between 8:00 AM and 10:00 AM for 24 6MWT (m) 96.6 14.5* 36.4 11.9 capacity, insulin sensitivity, and weeks (6 months) Fasting insulinemia 1.9 0.06* 0.9 0.02 muscle strength in elderly female n=32 (U/ml) patients with CHF HOMA-IR 0.57 0.03* 0.17 0.02 Secondary outcomes: MVC and peak torque Testosterone Placebo MVC (n) 27.1 4.7* 4.5 2.1 PTmax (Nm) 32.9 + 8.4* 5.5 + 1.2 *p

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