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

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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

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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 α), 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, insulin-like growth factor-1 (IGF-1),

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 α 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 α, 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

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Table 1: Hormones Involved in CHF11 Hormones Metabolic axis Relationship/

Clinical effect Clinical effect Therapies available

Angiotensin II Renin-Angiotensin

Increased Vasoconstriction, myocardial fibrosis

Angiotensin converting enzyme inhibitor/ angiotensin receptor blocker

Aldosterone Renin-Angiotensin

Increased Myocardial fibrosis Spironolactone, eplerenone

Adrenaline Catecholamine Increased Tachycardia, arrhythmias

Beta blocker

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 Hormone

Somatotropic Decreased Catabolism Growth hormone

Insulin-like growth factor I

Somatotropic Resistance Catabolism None

Tumor necrosis factor

Immune/Cytokine Increased Catabolism Biologicals

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 failure

None

B: Structural heart disease but without signs or symptoms of heart failure I: No limitation of physical activity. Ordinary physical

activity does not cause symptoms of heart failure

C: Structural heart disease with prior or current symptoms of heart failure

II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of heart failure

III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of heart failure

D: Refractory heart failure requiring specialized interventions

IV: Unable to carry on any physical activity without symptoms of heart failure, or symptoms of heart failure 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

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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 lifestyle Prevent vascular coronary disease Prevent LV structural abnormalities

Prevent heart failure symptoms Prevent further cardiac remodeling

Preserved Ejection Fraction

Reduced Ejection Fraction

Control symptoms Control HRQOL Reduce hospital readmission Establish end of life goals

Control symptoms Improve HRQOL Prevent hospitalization Prevent mortality

Control symptoms Patient education Prevent hospitalization Prevent mortality

ACEI/ARB Statin

ACEI/ARB Beta Blocker

Diuretics Diuretics ACEI/ARB Beta Blocker Aldosterone Antagonist In certain patients Hydralazine/isosorbide dinitrate Digoxin

Chronic inotropes

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

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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

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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 <5 ml) or shrinking testes Inability to father children, low or zero sperm count Height loss, low trauma fracture, low bone mineral density Hot flashes, sweats

Other less specific symptoms and signs Decreased energy, motivation, initiative, and self-confidence Feeling sad or blue, depressed mood, dysthymia Poor concentration and memory Sleep disturbance, increased sleepiness Mild anemia (normochromic, normocytic, in the female range)

c. Other effects i. Decrease in testosterone results in decreased lean body mass, increased fat mass,

decreased bone mineral density, impaired mood, and decreased facial/body hair 1. Associated with obesity and predisposes men to develop type 2 diabetes

mellitus and increased mortality due to cardiovascular disease V. Diagnosis:

Figure 3: Diagnosis of Hypogonadism

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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%

Testim®

50 mg or 40.5 mg daily 5 g daily

Slight odor; unable to shower/swim 6 hours after application; potential transfer to others by direct-skin-to skin contact

Topical Transdermal Systems

Androderm®

4 mg patch daily May cause rash, erythema, induration

Buccal System StriantTM 30 mg twice daily Gum related tenderness and pain; bitter taste

Subcutaneous testosterone implants

Testopel® testosterone pellets

150-450 mg every 3-6 months

Minor bleeding, fibrosis, infection; longest acting formulation available; surgical insertion

Intramuscular depot testosterone

Delatestryl: testosterone enanthate Depo-testosterone: testosterone cypionate

50-400 mg IM every 2-4 weeks 50-400 mg IM every 2-4 weeks

Edema, erythropoiesis, gynecomastia , phlebitis, acne, hair loss, virilization; most potent; least expensive; given 1 or 2 week 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

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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)

Testosterone’s 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

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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 TNFα, C-reactive protein, IL-1β, 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

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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

Author’s Conclusion

• 12 weeks of treatment with testosterone was safe, well tolerated, and led to significant improvements in physical capacity and symptoms.

Critique Strengths • Study design • Appropriate timing of monitoring

testosterone levels between 8:00-9:30AM

Limitations • Small number of patients • No baseline characteristics described • Did not determine testosterone level in

patients • No identified primary outcome • NYHA functional class not reported

Take Home Points

• Significant increase in distance walked with those receiving testosterone • 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

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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 Analysis

• 66 subjects required to achieve 90% power and 5% significance • 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)

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Treatment Effects of Testosterone

Parameter

Change from baseline: effect of testosterone at 12 month

Change from baseline: effect of placebo at 12 months

P-value

BMI (kg/m2) −0.09±1.7 +3.8±3.1 0.5 Dominant handgrip strength (kg) +1.0±4.0 −0.6±5.3 0.04

Ejection fraction (%) +1.8±13.1 +0.95±13.6 0.7 LV length (mm) +0.26±0.7 −0.58±1.6 0.0001 Total testosterone (nmol/L) +5.7±10.8 +0.4±3.6 0.0001

Hematocrit (L/L) +0.009±0.3 −0.005±0.003 0.03 PSA (ng/mL) +0.08±0.7 −0.08±0.5 0.19 TNFα (pg/mL) 2.53±3.55 1.91±2.19 0.85 Systolic BP (mmHg) +1.6±17.4 −4.4±13.9 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) Author’s Conclusion

• The study demonstrated a significant benefit in functional capacity and symptoms in men with moderately severe heart failure by raising the serum levels of testosterone by almost 40% and within the normal physiological range.

Critique Strengths • Study design • Good monitoring of patients (baseline,

3, 6, 12 months)

Limitations • No data on the effects of testosterone

replacement therapy on endpoints 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 Points

• This study showed improvement in NYHA class in 13 patients (35%) • Testosterone patch caused many skin reactions

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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 <40%, symptomatic heart failure with NYHA

functional class II or III, clinical stability without hospital admission for heart failure in previous 3 months

• Exclusion: Unstable angina, recent acute myocardial infarction, history of severe liver or kidney diseases, uncontrolled hypertension, significant pulmonary disease, erythrocytosis (hematocrit >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 Spearman’s rank test for

non-normally distributed data • Two tailed p value of <0.05 considered significant

Results

• Baseline characteristics: no statistically significant differences • Active group median age 71 vs placebo group 69 years • Active group NYHA functional class II/III 18/17 vs placebo group 20/15 • 21 patients had testosterone levels below normal range (total testosterone <3.5 ng/ml)

Cardiorespiratory and Muscular Results Changes After Three Months of Testosterone Therapy

Variables Testosterone Placebo BMI (kg/m2) 2.4 ± 0.2* 0.5 ± 0.06 Body weight (kg) 0.5 ± 0.02 0.3 ± 0.02 Peak VO2 (ml/kg/min) 2.9 ± 0.8* 0.3 ± 0.07 VE/VCO2 −4.4 ± 1.0* −1.5 ± 0.4 Peak workload 9.9 ± 2.4* 2.0 ± 0.7 6MWT(m) 86.2 ± 14.5* 37.3 ± 8.7 MVC (Nm) 18.9 ± 3.3* 3.0 ± 1.1 Ejection fraction (%) 0.6 ± 0.04 −1.0 ± 0.03

Metabolic and Hormonal Changes After Three Months of Testosterone Supplementation Therapy

Variables Testosterone Placebo Fasting glycemia (mg/dl) 4.4 ± 1.3 5.2 ± 2.0 HOMA-IR −0.8 ± 0.02* 0.1 ± 0.06 HDL Cholesterol (mg/dl) −0.3 ± 0.05 −0.4 ± 0.02 Total Testosterone (ng/ml) 2.9 ± 0.6* 0.2 ± 0.1 Total PSA (ng/ml) 0.1 ± 0.02 0.1 ± 0.04

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Table 9. Toma M, et al. Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail. 2012;5:315-321.35

Purpose • To assess the effects of testosterone therapy on exercise capacity in patients with heart failure.

Included Trials

• Four randomized controlled trials with a total of 198 subjects • Pugh ,et al. 2004 • Malkin, et al. 2006 • Caminiti, et al. 2009 • Iellamo, et al. 2010 • Inclusion criteria: randomized, double blind trials, patients with heart failure of any age

and sex Outcomes • Differences for the pooled estimates for exercise capacity (6MWT, ISWT, VO2) before and

after testosterone intervention

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<0.05 BRS increased in testosterone group by 3.7+0.9 mg/mm Hg vs 0.3+0.8 ms/mm Hg; p=0.01 Adverse effects • Testosterone group showed a significant increase in hematocrit vs placebo group (2.3 ±

0.8% vs. 0.8 ± 0.2%, p=0.001). • No side effect requiring discontinuation of testosterone supplementation occurred

throughout the study Author’s Conclusion

• Long term testosterone supplementation improves functional capacity and baroreflex control of heart rate, muscle strength, and glucose metabolism in elderly men with moderately severe CHF.

Critique Strengths • Study design • Evaluated both static and dynamic muscular

performance • Fairly good compliance (dropout of 8%)

Limitations

• Small sample size • Short length of duration • Failure to properly mask injection

vs NS injection • Androgen deficiency status was

not inclusion criteria Take Home Points

• Administration of testosterone for twelve months shows improvements in elderly male with heart failure in a variety of outcomes

• No effects on left ventricular ejection fraction suggesting testosterone does not affect myocardial function

• Study found significant reduction of insulin resistance with testosterone • Those with lower testosterone levels did show more improvement in oxygen consumption

and static muscle endurance

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Results

Forest Plot of Four Studies Evaluating Exercise Capacity Critique Strengths

• Randomized, double-blind trials • All studies incorporated evaluated exercise

capacity

Limitations • Small sample sizes • None used baseline testosterone

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)

Author’s Conclusion

• In patients with moderate to severe heart failure, testosterone supplementation improves 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

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Appendices

Table 10. Endocrine Society Guidelines for the Monitoring of Testosterone Therapy17

Start of treatment (baseline)

Each visit 3 months Annually 1–2 years

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

Topi

cal

appl

icat

ion

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® 1%

50 mg (4 pump actuations from the 75 g multidose pump delivering 50 mg) applied topically once daily (preferably in the morning) to clean, dry, intact skin of the shoulders and upper arms or abdomen

Androgel® 1.62%

40.5 mg (2 pump actuations) applied topically once daily in the morning to clean, dry, 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

Bucc

al

muc

osa

StriantTM

One buccal system (delivering 30 mg) applied to the gum region twice daily in the morning and evening (approximately 12 hours apart)

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Table 12: Select Tests Used in Heart Failure Trials with Testosterone Therapy 36-38

Incremental Shuttle Walk Test (ISWT)

Subjects walk along a level 10 m course at a previously determined speed 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 subject’s own pace over a course of six minutes.

Minnesota Living with Heart Failure (MLHF) Questionnaire

Designed for use in heart failure to assess the patients' perception of the effects of CHF on the physical, socioeconomic, and psychological aspects of their life.

Homeostatic Model Assessment- Insulin Resistance (HOMA IR)

Measures peripheral insulin resistance. It is calculated multiplying fasting 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 Dioxide Production (VE/VCO2)

Prognostic indicator in CHF indicating liters of air breathed to eliminate 1 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.

Intr

amus

cula

r in

ject

ion

Testosterone Cypionate

50 to 400 mg IM every 2 to 4 weeks as replacement therapy

Testosterone Enanthate

50 to 400 mg IM every 2 to 4 weeks as replacement therapy

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

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Table 13. Testosterone Treatment in Patients with Stable, Moderate Heart Failure Study Design Intervention Outcome Conclusions

Pugh, et al. (2005)39

n=27

Randomized, double-blind, PB-controlled

Effects of testosterone on pro-inflammatory cytokine production in vitro (n=27) Effects of acute (6 hours) testosterone admission on TNF alpha production in vivo (buccal; two 30 mg tablets) (n=12) Effects of 3 months testosterone administration on TNF alpha production in vivo (IM Sustanon 100) (n=20) Effects of 3 months testosterone administration on TNF alpha production in vivo (transdermal androderm 5 mg) (n=62)

Effects of testosterone on pro-inflammatory cytokine production in vitro - Serum TNF alpha reduced (p<0.01 with 1µM; p<0.0001 with 100µM)

TNF α (pg/ml)

Baseline TNF α (pg/ml) 12 weeks

P value

Effects of acute (6 hours) testosterone admission on TNF alpha production in vivo (buccal)

1.70 + 0.23 2.06 + 0.39 0.18

Effects of 3 months testosterone administration on TNF alpha production in vivo (IM Sustanon)

1.54 + 0.26 1.81 + 0.22 0.28

Effects of 3 months testosterone administration on TNF alpha production in vivo (androderm)

3.31 + 1.56 1.91 + 0.38 0.44

In vitro testosterone reduces TNFα production at levels outside physiologic range. Administration of physiologic concentrations to male patients with CHF have no effect on serum concentrations

Pugh, et al. (2003)40

n=12

Randomized, double-blind, PB-controlled, cross over trial

Subjects received treatment with two tablets of testosterone 30 mg or placebo via buccal route At end of each study period, second drug administered and measurements repeated

Primary outcome was cardiac output • Cardiac index reduction was attenuated by testosterone treatment

o Bioavailable testosterone level correlation with cardiac index rs= 0.276, p=0.006

• Rise in systemic vascular resistance (SVR) decreased by testosterone treatment o Inverse relationship between bioavailable testosterone level and SVR

rs=-0.293, p=0.004 • No significant change in heart rate or mean arterial blood pressure compared

with placebo

Testosterone administration acutely increases cardiac output, via reduction of left ventricular afterload

Malkin, et al. (2007)41

n=14

3 month, single-blind, PB controlled, crossover study

Patients had two treatment phases, 4 weeks duration with a 4 week washout period between the treatment phases

Sustanon 250 (testosterone propionate 30 mg, testosterone phenylpropionate 60 mg, testosterone isocaproate 60 mg, and testosterone decanoate 100 mg/ml)

Two IM injections given 2 weeks apart; PB given as 0.9% NS

Primary outcome: insulin resistance Mean effect p HOMA index −1.9±0.8 0.03 Fasting glucose (mmol/L) −0.61±0.2 0.03 Fasting insulin (mIU/L) −5.4±2.7 0.06

Secondary outcomes: anthropomorphic measures of body mass (body mass index, lean mass, and percent fat mass derived from bioelectrical impedance)

Mean effect p Total body mass (kg) +1.5±0.5 0.008 Percent body fat (%) −0.8±0.3 0.02

Testosterone improves fasting insulin sensitivity and may also increase lean body mass, suggesting a favorable effect of testosterone

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Iellamo, et al. (2010)42

n=32

24 week, randomized, double-blind, PB controlled

Transdermal patch (300 µg Intrinsa) or PB transdermal patch twice/week to abdominal skin between 8:00 AM and 10:00 AM for 24 weeks (6 months)

Primary outcome: Δ 6MWT distance in meters and insulin resistance Testosterone Placebo 6MWT (m) 96.6 ± 14.5* 36.4 ± 11.9 Fasting insulinemia (µU/ml)

–1.9 ± 0.06* 0.9 ± 0.02

HOMA-IR –0.57 ± 0.03* 0.17 ± 0.02 Secondary outcomes: Δ 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<0.05

Testosterone supplementation therapy improves functional capacity, insulin sensitivity, and muscle strength in elderly female patients with CHF

Stout, et al. (2012)43

n=41

12 week, randomized, double-blind, PB controlled

Exercise training (aerobic and resistance exercises); intramuscular Sustanon 100 injection once every two weeks for 12 weeks vs intramuscular saline

Incremental shuttle walk test, peak oxygen uptake, muscular strength, echocardiographic measures, N-terminal pro–brain natriuretic peptide, inflammatory markers, depression (Beck Depression Inventory), and health-related quality of life

*p<0.05 **p<0.01

Testosterone (n = 15) Placebo (n = 13)

Baseline Baseline Endpoint Baseline Endpoint Shuttle walk distance (m)

418.7 ± 153.7

492.7 ± 215.3*�

556.2 ± 112.1

661.5 ± 158.8*�

Peak Vo2 (mL/ kg/min) 15.0 ± 4.4 18.2 ± 4.8** 17.4 ± 3.6 18.8 ± 3.4 Handgrip strength (kg) 38.6 ± 8.6 40.7 ± 7.1 44.5 ± 7.6

47.0 ± 9.0*�

TNFα± (pg/mL) 1.44 ± 0.77 1.32 ± 0.53 1.95 ± 1.97 1.69 ± 1.67*

IL-6 (pg/mL) 6.57 ± 9.56 5.63 ± 7.52 3.48 ± 2.72 3.45 ± 2.09

NYHA 2.5 + 0.5 1.8 + 0.7* 2.5 + 0.5 1.8 + 0.7* ADAM 6.2 ± 1.7 4.6 ± 2.5* 4.1 ± 2.3 4.0 ± 3.1 BDI 10.4 ± 8.7 6.6 ± 3.8* 7.1 ± 5.2 4.6 ± 3.4

Testosterone supplementation during a program of exercise rehabilitation is feasible in elderly patients with CHF who have a low testosterone status and can have a positive impact on a range of health outcomes

ADAM: Androgen Deficiency in Aging Males; BDI: Beck Depression Inventory; IM: intramuscular; MLHFQ: Minnesota Living with Heart Failure Questionnaire; NYHA: New York Heart Association; NS: normal saline; PB: placebo, PTmax: isokinetic power torque, rs: Spearman’s rank correlation

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