HIGHLIGHTS. From Testosterone Update Disease State Theater. American Urological Association and Endocrine Society Annual Meetings

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1 HIGHLIGHTS From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings Jointly sponsored by the Annenberg Center for Health Sciences and CogniMed Inc. This activity is supported by an independent educational grant provided by

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3 Section 1: Considerations for Diagnosis of Hypogonadism Richard Sadovsky, MD Section 2: Impact of Hypogonadism on Men s Health Robert S. Tan, MD Section 3: Testosterone Treatment Options for Hypogonadism Christina Wang, MD Section 4: Adherence Considerations With Testosterone Therapy Ronald S. Swerdloff, MD Section 5: Testosterone Therapy and Prostate Health Abraham Morgentaler, MD Section 6: Optimal Monitoring for Hypogonadal Men Receiving Testosterone Therapy Martin M. Miner, MD Intended Audience This activity was developed for endocrinologists, urologists, primary care clinicians, and other health care professionals who treat patients with hypogonadism. Statement of Need Hypogonadism, defined as abnormally low testosterone levels in the presence of signs and symptoms, affects an estimated 4 to 5 million men in the United States. Hypogonadism is associated with a number of common medical conditions that negatively affect overall health and well-being but is underdiagnosed and undertreated. To diagnose and appropriately treat hypogonadism, physicians should maintain a high index of suspicion and be able to recognize the often nonspecific signs and symptoms of hypogonadism, understand the medical conditions that might affect testosterone levels, be able to classify hypogonadism by etiology, and be familiar with recommendations about when and how to screen for low testosterone levels. Recent evidence is reversing many of the traditional beliefs about the relationship of testosterone and men s health, particularly cardiovascular disease and prostate cancer. It is now clear that testosterone therapy can safely be offered to men with hypogonadism as long as proper medical monitoring is performed. Successful testosterone treatment requires appropriate follow-up and management of patient expectations on the part of the physician and adherence to the treatment regimen by the patient. Adherence, in turn, depends on satisfaction with treatment outcomes and the prescribed testosterone formulation. To ensure that patients make informed choices and adhere to the treatment regimen, physicians must understand and be able to educate their patients about the medical risks associated with untreated hypogonadism and the many potential benefits of testosterone treatment as well as the class- and formulation-specific adverse effects. This CME activity has been designed to assist physicians in recognizing, diagnosing, and managing hypogonadism in their male patients. 1

4 Learning Objectives Upon completion of this activity, participants should be better able to: 1. Recognize the broad physiologic effects of low testosterone levels on men s health 2. Describe recent data that are reversing traditional paradigms about the relationship of testosterone with cardiovascular disease and prostate health 3. Identify and appropriately screen patients who may be hypogonadal 4. Diagnose and determine the etiology of hypogonadism and appropriately treat men who are found to be hypogonadal 5. Educate and counsel patients who are hypogonadal about the benefits and risks of the various testosterone treatment options 6. Follow-up and monitor therapy to enhance patient satisfaction, improve adherence, and increase the likelihood of successful testosterone treatment Accreditation and Certification This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Annenberg Center for Health Sciences at Eisenhower and CogniMed Inc. The Annenberg Center is accredited by the ACCME to provide continuing medical education for physicians. The Annenberg Center designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. The Annenberg Center for Health Sciences is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. A maximum of 1.5 contact hours may be earned for successful completion of this activity. AAPA accepts Prescribed credit from AAFP and Category 1 CME credit for the PRA from organizations accredited by ACCME. Course meets qualifications for 1.5 hours of continuing education credit for MFTs and/or LCSWs as required by the California Board of Behavioral Sciences. Provider #PCE2048. This activity is cosponsored by the Annenberg Center for Health Sciences at Eisenhower and CogniMed Inc. The Annenberg Center is approved by the American Psychological Association to sponsor continuing education for psychologists. The Annenberg Center maintains responsibility for this activity and its content. This activity is designated for 1.5 hours of credit. There is no charge for this activity. Statements of Credit will be provided by mail following activity participation and upon completion and return of the evaluation form to: TestosteroneUpdate, c/o CogniMed Inc., 70 South Orange Avenue, Suite 200, Livingston, NJ or by fax to Please allow 4 to 6 weeks for the delivery of your statement. Disclosure It is the policy of the Annenberg Center to ensure fair balance, independence, objectivity, and scientific rigor in all programming. All faculty and planners participating in sponsored programs are expected to identify and reference off-label product use and disclose any significant relationships with those supporting the activity or any others whose products or services are discussed. The faculty for this activity have disclosed that there will be discussion about the use of products for non FDA-approved indications. In accordance with the Accreditation Council for Continuing Medical Education standards, parallel documents from other accrediting bodies, and Annenberg Center policy, the following disclosures have been made: Martin M. Miner, MD, receives research support from Auxilium Pharmaceuticals, Inc., and Indevus Pharmaceuticals, Inc., and is a consultant for Sanofi-Aventis. Abraham Morgentaler, MD, is a consultant for Indevus Pharmaceuticals, Inc., and Slate Pharmaceuticals, Inc. He receives research support from GlaxoSmithKline and Indevus Pharmaceuticals, Inc., and lecture honoraria from Auxilium Pharmaceuticals, Inc.; Eli Lilly and Company; Indevus Pharmaceuticals, Inc.; Pfizer Inc; Solvay S.A.; and Watson Pharmaceuticals, Inc. Richard Sadovsky, MD, is a consultant for Eli Lilly and Company and Pfizer Inc and serves on the speakers bureau of Pfizer Inc. Ronald S. Swerdloff, MD, receives research support from and is a consultant for Auxilium Pharmaceuticals, Inc.; GlaxoSmithKline; Indevus Pharmaceuticals, Inc.; Repros Therapeutics, Inc.; and Solvay S.A. Robert S. Tan, MD, has received research grants from Solvay Pharmaceuticals and serves on the speakers bureau of Lilly ICOS LLC. Christina Wang, MD, receives research support from Acrux Ltd., Bristol-Myers Squibb Company, GlaxoSmithKline, and Indevus Pharmaceuticals, Inc. The ideas and opinions presented in this educational activity are those of the faculty and do not necessarily reflect the views of the Annenberg Center and/or its agents. As in all educational activities, we encourage the practitioners to use their own judgment in treating and addressing the needs of each individual patient, taking into account that patient s unique clinical situation. The Annenberg Center disclaims all liability and cannot be held responsible for any problems that may arise from participating in this activity or following treatment recommendations presented. This activity is supported by an independent educational grant provided by Indevus Pharmaceuticals, Inc. This activity is an enduring material and consists of a printed monograph. Successful completion is achieved by reading the material, reflecting on its implications in your practice, and completing the assessment component. The estimated time to complete this activity is 1.5 hours. This activity was originally released December 15, 2008, and is eligible for credit through December 15, This piece is based on presentations from faculty members and was written by a medical writer. Faculty have final editorial control for the piece. 2

5 Section 1 Considerations for Diagnosis of Hypogonadism Richard Sadovsky, MD Associate Professor of Family Medicine State University of New York Health Science Center at Brooklyn Brooklyn, New York 3

6 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings Hypogonadism is a highly prevalent but underdiagnosed and undertreated condition affecting an estimated 4 to 5 million men in the United States. 1,2 Aging is associated with the progressive decline of physiologic functions, including the production of testosterone 3,4 (Figure I.1). Among men aged 45 years or older (mean, 60.5 y) presenting for routine care to 95 primary care practices throughout the United States, 38.7% were hypogonadal, with 80 (3.7%) receiving testosterone therapy for a prior diagnosis of hypogonadism. 5 In that study, the prevalence of hypogonadism increased 17% with each 10-year increase in age. 5 Hypogonadism is clinically defined as a constellation of signs and symptoms in the presence of a low level of testosterone (< ng/dl); low testosterone alone is insufficient for a diagnosis. 6-9 Vigilance and a high index of suspicion on the part of physicians are necessary because symptoms may be nonspecific with insidious onset and are often denied by patients. 10 Because treatment is not recommended for asymptomatic men with low testosterone levels, 6,8 screening of testosterone levels among the general population of men is not recommended. The signs and symptoms suggesting hypogonadism that should prompt 4

7 determination of testosterone levels are elicited by a thorough history and physical examination (Figure I.2). 6 A history should include evidence of decreased libido or sexual activity as well as disturbances of mood or cognition. The physical examination should encompass secondary sex characteristics, gynecomastia, testicular size and consistency, prostate parameters, and baseline body mass index (BMI). Low libido and sexual dysfunction are perhaps the most common reasons for measuring testosterone levels, but physicians should be alert for other signs and symptoms that suggest hypogonadism 6,8,10,11 (Table I.1). Screening for hypogonadism is also suggested for men with certain physiologic conditions, such as type 2 diabetes or moderate to severe chronic obstructive pulmonary disease, in which low testosterone levels are prevalent (Table I.2). 6 For men suspected of being hypogonadal, the Endocrine Society suggests measuring testosterone levels in the morning, when levels are highest, and confirming the results with at least one more determination. 1,6 A total testosterone level of <200 ng/dl is unequivocally hypogonadal. The normal range in most laboratories is >300 to <1000 ng/dl. 10 Only 2% of circulating testosterone is free; 58% to 68% is weakly bound to albumin, and the remaining 30% to 40% is strongly bound to sex hormone-binding globulin (SHBG). 1,10 When SHBG concentrations are altered, total testosterone levels may not accurately reflect gonadal status. SHBG concentrations rise with age and may be increased with Klinefelter syndrome, hyperthyroidism, liver disease, severe androgen deficiency, or estrogen excess. This might result in a normal total testosterone concentration even in hypogonadal men. Free or bioavailable testosterone concentrations should be obtained, therefore, in patients with an equivocal total testosterone level ( ng/dl) or with normal total testosterone concentrations in the presence of signs and symptoms of hypogonadism. The normal concentrations of free and bioavailable testosterone are 6.5 ng/dl and 15 ng/dl, respectively. If not available from the laboratory or not reimbursed by the patient s insurance company, free testosterone can be calculated using the values for total testosterone, SHBG, and albumin by a formula available on the Internet from the International Society for the Study of the Aging Male at For more complicated cases, the ratio between total testosterone and SHBG may be useful. Once hypogonadism is identified, reversible causes (illness, drugs, or nutritional deficiency) should be excluded. To determine appropriate treatment, hypogonadism must be classified according to etiology. Primary, or hypergonadotropic, hypogonadism is due to disorders of the testes, including Klinefelter syndrome, orchitis, congenital or acquired anorchia, and testicular tumors. 6,10 Secondary, or hypogonadotropic, hypogonadism results from disorders of the hypothalamus (eg, Kallmann syndrome, chronic illnesses) or pituitary gland (eg, hypopituitarism, pituitary tumors). In secondary Table I.1. Clinical Manifestations of Hypogonadism 6,10-12 Physical and Metabolic Psychological Sexual Decreased BMD Gynecomastia Mild anemia Increased body fat and BMI Decreased muscle mass Reduced strength or endurance Insulin resistance Sleep disturbance or increased sleepiness Depressed mood Diminished energy, sense of vitality, or well-being Impaired cognition or memory Diminished libido ED Difficulty achieving orgasm Decreased spontaneous erections BMD, bone mineral density; BMI, body mass index; ED, erectile dysfunction. 5

8 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings hypogonadism, gonadotropin levels fail to rise as testosterone levels decline. Measurement of the gonadotropins serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are recommended to distinguish between primary and secondary hypogonadism. 6 Hypogonadism may also be of mixed etiology, as with hemochromatosis, sickle cell disease, thalassemia, glucocorticoid treatment, or alcoholism. Even with mixed disorders, however, a predominantly primary or secondary phenotype can usually be determined by the hormonal pattern. For men with secondary hypogonadism, further individualized evaluation is suggested that may include measurement of prolactin and iron saturation, pituitary function testing, and magnetic resonance imaging, a karyotype to exclude Klinefelter syndrome, or seminal fluid analysis. 6 In most cases, hypogonadism can be comfortably diagnosed and treated in a primary care setting. Referral to a urologist for further evaluation should be considered for patients with a prostate-specific antigen (PSA) level >4.0 ng/ml, PSA increases >1.4 ng/ml in any 12-month period, prostatic abnormality detected by digital rectal examination (DRE), or an American Urological Association symptom score >19. Referral to an endocrinologist for further evaluation should be considered for patients with signs and symptoms of a pituitary tumor (ie, visual field abnormalities, headaches, hyperprolactinemia or hypopituitarism, and testosterone level <150 ng/dl with normal LH and FSH), other pituitary abnormalities, or unclear etiology. Unless contraindicated by an unacceptably high risk of adverse outcomes, treatment of symptomatic men with hypogonadism is recommended to induce and maintain secondary sex characteristics and to improve sexual function, sense of well-being, and bone mineral density (BMD). 6,10 Testosterone therapy for hypogonadism has been shown to improve mood and scores in most domains of psychological testing 6,8,10 and may reduce the risk of cardiovascular disease (CVD) and normalize growth-hormone levels in elderly men. 10 In conclusion, hypogonadism is a common condition that too often goes undiagnosed and untreated. It is associated with a number of common medical conditions that negatively affect overall health and well-being. The appropriate identification and screening of men with symptomatic testosterone deficiency is necessary to improve outcomes. Table I.2. Conditions for Which Screening for Low Testosterone Levels Is Recommended Sellar mass; radiation to or diseases of the sellar region Treatment with medications that affect testosterone production Glucocorticoids Ketoconazole Opioids HIV-associated weight loss End-stage renal disease and maintenance hemodialysis Moderate to severe COPD Infertility Osteoporosis or low-trauma fracture a Type 2 diabetes a Particularly if occurring in a young man. COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus. Adapted with permission. 6 6

9 Section 2 Impact of Hypogonadism on Men s Health Robert S. Tan, MD Director, OPAL Medical Center Associate Professor of Medicine Baylor College of Medicine Clinical Associate Professor of Family Medicine University of Texas Health Science Center Houston, Texas 7

10 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings Testosterone affects not only the sex organs, but also many other biological systems, including brain, bone, muscle, and fat. Although the relationship is not cause and effect, the prevalence of hypogonadism is dramatically higher in men with common medical conditions than in the general population, with the highest prevalence among men who are obese or have diabetes. 5,12 Levels of total and free testosterone decline with increasing BMI (Figure II.1). 13 In the Hypogonadism in Males (HIM) study, the prevalence of hypogonadism among obese men was 52.4%, and the risk of having hypogonadism was 2.4-fold higher for obese men compared with the general population. 5 Total testosterone levels have been positively correlated with high-density lipoprotein levels and negatively correlated with triglycerides in men with or without diabetes. 14,15 Hypogonadism is associated with metabolic syndrome and appears to predispose men to insulin resistance, abnormal lipid profiles, and borderline or overt hypertension, as well as obesity. Furthermore, hypogonadism appears to predict the subsequent development of metabolic syndrome and diabetes in middle-aged men 16,17 (Figure II.2). In a populationbased cohort study of 702 men, 147 men developed metabolic syndrome and 57 men developed diabetes after 11 years of follow-up. After adjustment for CVD, 8

11 smoking, alcohol intake, socioeconomic status, and physical activity, men with total testosterone and SHBG in the lowest quartile at baseline were significantly more likely to develop metabolic syndrome or diabetes. Lower baseline concentrations of calculated free testosterone were significantly associated with development of metabolic syndrome but not diabetes. Traditionally, the greater risk of heart disease among men compared with that for women was blamed on testosterone. New data are turning that assumption upside down. In fact, normal levels of testosterone appear to be protective, whereas abnormally low levels increase the risk. Studies in men with prostate cancer have shown that extremely low testosterone levels induced by LH-releasing hormone agonists increase the risk of CVD and sudden cardiac death. 18 Data from the population-based Rotterdam Study (n=504 men) showed that low levels of testosterone are inversely associated with severe aortic atherosclerosis and progression of aortic atherosclerosis in nonsmoking men 55 years of age or older (mean, 67.9 y; Figure II.3). 19 Men with testosterone concentrations in the lowest tertile had a significantly elevated risk of having severe aortic atherosclerosis compared with men with higher testosterone levels. Men with testosterone levels in the two upper tertiles were protected against progression of aortic atherosclerosis measured after 6.5 years compared with those in the lowest tertile. A recent Italian trial that evaluated 129 men undergoing coronary angiography for suspected coronary artery disease (CAD) found significantly lower testosterone levels in the patients than in matched healthy control subjects: 282 ng/dl vs 389 ng/dl, respectively (9.8 vs 13.5 nmol/l); P < Furthermore, when hormone concentrations were compared in patients with 1-, 2-, or 3-vessel disease, decreasing hormone levels were significantly associated with increasing severity of CAD. Like that with CVD, traditional thinking about the relationship between testosterone and prostate cancer has been reversed. In a biopsy study of 345 hypogonadal men with a mean age of 59 years who had PSA levels 4 (mean, 1.44), lower total testosterone levels ( 250 mg/dl vs >250 mg/dl) were associated with a higher rate of prostate cancer (21.1% vs 12.3%, respectively; Figure II.4). 21 When stratified by free testosterone levels, men in the lowest tertile had nearly twice the risk of prostate cancer compared with those in the combined upper tertiles. The two groups did not differ with regard to age, PSA level, findings on DRE, or Gleason score. 9

12 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings Another remarkable finding within the past 5 years is that low testosterone levels appear to have a negative impact on overall survival. One study of 858 men from a Veterans Administration hospital in Washington state, matched for comorbidities, found mortality at a younger age in men with low to intermediate testosterone levels compared with men with normal testosterone levels. 22 After adjusting for age, medical morbidity, and other clinical covariates, men with both low and equivocal testosterone levels continued to be associated with a nearly 2-fold increased mortality compared with men with normal testosterone levels. Low testosterone was defined as a total testosterone level of <250 ng/dl (<8.7 nmol/l) or a free testosterone level <0.75 ng/dl (<0.03 nmol/l). In summary, below-normal testosterone levels are associated with chronic medical conditions that may negatively affect men s overall health and well-being and may also negatively affect duration of survival. 10

13 Section 3 Testosterone Treatment Options for Hypogonadism Christina Wang, MD Director, General Clinical Research Center Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Torrance, California 11

14 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings The goals of treatment for hypogonadism are to restore serum testosterone into the normal adult (eugonadal) range and reduce or eliminate the signs and symptoms of hypogonadism. The benefits of testosterone therapy include 2,6,8-10,23 : restoring sexual function and libido producing and maintaining virilization optimizing bone density and preventing osteoporosis increasing energy, vitality, and well-being improving mood and cognition promoting weight maintenance and preserving or increasing lean body mass in human immunodeficiency virus infected men or men who are taking glucocorticoids restoring fertility in men with hypogonadotropic hypogonadism possibly normalizing growth hormone levels in elderly men potentially reducing the risk of CVD In individual men, testosterone therapy may result in all, some, or none of these benefits and to varying degrees. 9 The benefits of testosterone therapy must be weighed against the potential risks 2,6,9,10,24-30 (Table III.1). Some of the risks are rare, and those that occur frequently can generally be easily managed. The optimal testosterone formulation would achieve and maintain relatively stable physiologic levels of testosterone over time without supraphysiologic spikes at the beginning or hypogonadal nadirs before the end of the dosing period. 2 Importantly, the agent should be effective in reducing signs and symptoms of hypogonadism with a favorable safety profile. Finally, the ideal formulation would have a convenient dosing schedule and an easy route of administration at a reasonable cost to the patient. Table III.1. Potential Class Adverse Effects of Testosterone Treatment 6,9,24-30 Adverse Effect Comment Adverse Effect Comment Testicular atrophy, infertility Acne, oily skin Edema, fluid retention Gynecomastia Common, especially in young men, but not usually noticeable by patient; usually reversible with cessation of therapy Infrequent with steady-state concentrations Rarely clinically relevant except for at-risk patients a Infrequent and then usually just at initiation of therapy; usually reversible Benign prostatic hyperplasia Prostate cancer New, subclinical Progression Increased cardiac risk Infrequently worsened with mild or moderate LUTS b Theoretical, controversial c Established; testosterone should not be prescribed for men with active prostate cancer Controversial; most studies show a neutral or beneficial effect; large controlled trials are needed Erythrocytosis Depends on level achieved; relevant primarily in those at risk for erythrocytosis Sleep apnea Infrequent; weak evidence for induction; may aggravate sleep apnea at high doses a Men with preexisting class III or IV heart failure, chronic renal insufficiency, or severe liver disease. b Some weak evidence suggests that testosterone therapy should be avoided in men with severe LUTS. c For more detailed discussion, see Testosterone Therapy and Prostate Health in this issue. LUTS, lower urinary tract symptoms. 12

15 Table III.2. Dosing Schedule and Route of Administration of Available Testosterone Formulations 2,6,24-29 Route/Application Formulation Dosage Intramuscular injection Testosterone cypionate Testosterone enanthate mg every 2-4 wk Subcutaneous implant Pellets mg (2-6 pellets) every 3-6 mo Topical a Gel Skin patch Buccal patch 5-10 g daily 5 mg daily 30 mg every 12 h a Transdermal or transbuccal absorption. Table III.3. Formulation-Specific Adverse Effects of Available Testosterone Therapies 6 Formulation Adverse Effect Formulation Adverse Effect Injectable Topical Pellet implants Potential infections Expulsion of implant Gel Skin-to-skin transference to others Testosterone cypionate or testosterone enanthate Mood fluctuations Changes in libido Injection-site pain Increased hemoglobin and hematocrit Patch system Buccal system Application-site skin reactions Alterations in taste Irritation of gums and oral mucosa The testosterone products available in the United States include testosterone esters that are given by deep intramuscular injection, topical transdermal gels and patches, a transbuccal patch, and implantable pellets. 2,6,10 These agents vary widely in routes of administration and dosing schedules (Table III.2) as well as in pharmacokinetics and formulation-specific adverse effects 2,6,24-31 (Table III.3). Both available hydroalcoholic topical gel formulations deliver steady-state serum testosterone levels, and the pharmacokinetic profiles are similar. 2,26,30,32 After a single application, concentrations of testosterone rise 2- to 3-fold within approximately 2 hours, continue to rise to a 4- to 5-fold increase after 24 hours, then begin to decline. With daily application, testosterone concentrations remain in the normal range over time (Figure III.1). 32 The gels have the advantage of flexible dosing and ease of administration, particularly using the pump, and are well tolerated with minimal skin irritation. 2,26,30,32 The primary disadvantages of the gels are the expense and the potential for skin-to-skin transfer to anyone who comes in physical contact with the application site. Men using topical gels must wash their hands and either wear clothing over or wash the application site before physical contact with others. 13

16 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings Transdermal patches are available for application to scrotal or nonscrotal skin. 2,10,27 Scrotal skin must be dry-shaved before application of the scrotal patches. Patients may find them uncomfortable and awkward to use, and they are less often used today than the nonscrotal patches. 2 Applied at the appropriate time (morning for scrotal patches, evening for nonscrotal patches), the patches achieve the normal circadian rhythm and testosterone concentrations of healthy young men. Serum testosterone concentrations reach a maximum within 2 to 4 hours after application and remain in the normal range for approximately 24 hours. 2 With continued dosing, testosterone concentrations remain in the low-normal range (Figure III.1). 32 The primary adverse effect with transdermal patches is skin irritation after 3 to 4 weeks of use. The patches are much more likely to produce skin irritation than topical gels. 10,33 Application of corticosteroid cream can reduce irritation and contact dermatitis, but up to 45% of patients discontinue testosterone patch treatment because of skin irritation. 33 A transbuccal tablet, about the size of a contact lens, is placed in the depression of the gum above the incisor tooth and replaced every 12 hours. 2,28 After the first application, serum testosterone reaches maximum concentration within 10 to 12 hours. 28,34 Steady-state levels are reached after the second dose. Maximum and mean concentrations remain within the normal physiologic range for the duration of the dosing period. Disadvantages with this formulation are the need for twice-daily dosing and the gum-, mouth-, and tasterelated adverse effects, which can include gingivitis, edema, blistering, inflammation, persistent bitter taste, dry mouth, toothache, gum erythema, stomatitis, and stinging of the lips. 2 Gum-related effects occur early in treatment, are generally mild to moderate in intensity, and are usually transient, resolving within 1 to 2 weeks. 14

17 Pellets containing testosterone propionate are cylindrically shaped, approximately 3.2 mm in diameter and 8 to 9 mm in length. 29 They are surgically implanted subdermally through a small incision, usually in the lower abdominal wall, using a large trocar and cannula in a 15- to 20- minute outpatient procedure. Approximately one-third of the testosterone is absorbed in the first month, onefourth in the second month, and one-sixth in the third month. Adequate clinical effect usually continues for 3 to 4 months and may last for up to 6 months. Because dosage adjustment is less flexible with implanted pellets than with other formulations, great care must be used in estimating the dosage. Disadvantages with this formulation include the inability to easily adjust the dosage, the potential for infection, and occasional extrusion of the pellets. Although still available, pellets are seldom prescribed in the United States. Injectable testosterone enanthate 24 and testosterone cypionate 25 are the most affordable of all the treatment options if self-administered, but the least efficacious. 1,2 These testosterone esters are suspended in oil to prolong absorption and duration of effect. Testosterone levels rise rapidly after injections and may be supraphysiologic for 1 to 3 days, peaking about 72 hours after injection, then falling gradually for the next 1 to 2 weeks, often into the lower limit of the physiologic range. 1,10 Testosterone concentrations remain relatively normal when 50- to 100-mg injections are given every 7 to 10 days, but longer intervals and higher doses are associated with greater fluctuation. 10 The usual compromise dosage of 200 mg every 2 weeks may result in wide fluctuations (Figure III.2), resulting in mood swings. 1,12 Starting at a low dose and titrating upward according to tolerability may reduce these effects

18 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings A new long-acting injectable formulation of testosterone undecanoate is available in Europe, and a New Drug Application has been filed in the United States. The proposed dosing schedule is 750 mg in 3 ml of castor oil given on days 1 and 28 and every 10 weeks thereafter. 36 In a recent trial, testosterone was restored to normal physiologic levels in 94% of patients and maintained in that range for the entire 10-week dosing period with less fluctuation than the other injectable testosterone formulations. 36 Treatment was well tolerated, with fewer than 5% of patients experiencing adverse events. Efficacy appears at least comparable to other preparations, with significant improvements in all International Index of Erectile Function domains of sexual desire and function (including erectile function), psychosexual function, mood states (including tension, depression, anger), energy, and cognition. Like other injectable testosterones, the primary disadvantage is the need for injections requiring an office visit; however, the need for only 5 injections per year of this treatment may mitigate the disadvantage. In summary, testosterone therapy for hypogonadism is associated with a number of clinical benefits, but some adverse effects about which patients should be made aware before choosing a therapy. The ideal therapy should provide a steady state of testosterone in the normal (eugonadal) adult range over time. An increasing number of different formulations of testosterone are available in the United States. Awareness of the benefits and risks, including both class- and formulation-specific adverse effects, is necessary for patients and physicians to make optimal individual treatment choices. 16

19 Section 4 Adherence Considerations With Testosterone Therapy Ronald S. Swerdloff, MD Chief, Division of Endocrinology LA BioMedical Research Institute at Harbor-UCLA Medical Center David Geffen School of Medicine at UCLA Torrance, California 17

20 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings Among men 45 years of age and over visiting a primary care physician in the United States, an estimated 13.8 million men may be hypogonadal, but only 1.3 million (9%) are being treated. 5 Reasons for this may be patient-related or physician-related. Most men are unaware of the potential for low testosterone or the problems it can cause, or believe that low testosterone and its symptoms are a natural part of the aging process. 37 In an Alliance for Aging Research survey of 522 men 40 years of age or older, 62% said they would be uncomfortable talking to their physician about hypogonadism. Although one-third of respondents had experienced 2 or more symptoms, 95% of them said their physicians never mentioned low testosterone as a possible cause. 37 Even when informed about testosterone deficiency, some men refuse treatment for a variety of reasons (Table IV.1). Because many symptoms of hypogonadism are nonspecific, physicians must maintain a high level of suspicion for hypogonadism among their older male patients. Table IV.1. Perceived Obstacles to Seeking Testosterone Therapy Predominantly patient-related obstacles Fear of steroids Association with widely publicized anabolic steroid abuse, deaths, and testosterone rage Insufficient education about risks of testosterone deficiency and benefits of therapy Predominantly physician-related obstacles Fear of prostate cancer Inconclusive efficacy 18

21 Table IV.2. Advantages and Disadvantages of Testosterone Formulations: Characteristics That May Affect Patient Adherence 1,2,6,10 Formulation Advantages Disadvantages Injectable testosterone cypionate, testosterone enanthate Least expensive if self-administered Less-frequent dosing (7-14 d) Requires deep intramuscular injection of large volume May require office visit Fluctuating testosterone levels and symptoms Topical gels Well tolerated Easy to use Daily application 10- to 15-minute drying time Potential for transference Very expensive Transdermal patch (nonscrotal) Easy to apply Mimics normal circadian rhythm of testosterone Skin irritation Daily application May require 2 patches for optimal dosing Expensive Transdermal patch (scrotal) Mimics normal circadian rhythm of testosterone Same as above, plus Requires dry shaving before application Uncomfortable and awkward for some men Expensive Buccal system Generally well tolerated Mouth and gum irritation and taste alterations Twice-daily application Loss of adhesion, possibility of swallowing Expensive Pellets Longest duration of effect (4-6 mo) 15- to 20-minute outpatient surgical procedure Infection Extrusion of pellets 19

22 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings Issues regarding adherence to the prescribed treatment are similar to those encountered with other chronic therapies for which adherence is quite poor. Patients will usually take the medication as prescribed for a short time, but after 6 months to a year, adherence is poor. Health care providers should periodically reinforce the importance of continuing treatment and following the treatment schedule even though the patient may be feeling better or, alternatively, not experiencing the hoped-for degree of improvement. Testosterone plays an important role in many biological systems, and the benefits of testosterone therapy are far beyond restoring libido and sexual function, potentially including decreased fat mass; increased lean mass, hand-grip strength, and vitality; stabilized or increased bone density; and improved mood. 4,6,8,10,23 Patients should be reminded of the many medical benefits without raising unrealistic expectations. Not every patient experiences all the potential benefits of testosterone therapy, some improvements may be only partial, and some men may experience adverse effects. Sufficient time should be allowed to discuss, and ensure that the patient understands, both the risks and benefits. Discussion of potential risks should include information about how they can be managed and reassurance that the therapy will be carefully monitored for potential adverse effects. Many treatment options are available, varying by delivery system, frequency of dosing, and pharmacokinetics, each offering a different spectrum of advantages and disadvantages 1 (Table IV.2). (See Testosterone Treatment Options for Hypogonadism in this issue.) Patients should be presented with all options and encouraged to choose the one that best fits their individual needs based on their age, symptom profile, existing medical conditions, lifestyle, personal preference, and financial situation. They should also be counseled that the decision is not irrevocable: If one formulation does not work for them, they can switch. 1 In summary, hypogonadism is an underdiagnosed and undertreated disorder associated with aging in men. Physicians should maintain a high degree of suspicion for signs and symptoms of hypogonadism in their male patients who are aging or have other conditions that might affect testosterone levels. Men in whom hypogonadism has been diagnosed need education about the medical risks associated with untreated hypogonadism and a balanced discussion of the potential multiple benefits and risks of testosterone therapy. The success of treatment requires appropriate follow-up to therapy and management of patient expectations. Adherence to the treatment regimen depends on satisfaction with treatment outcomes and the prescribed formulation. Testosterone therapy is available in many formulations, providing options for health care providers and patients. 20

23 Section 5 Testosterone Therapy and Prostate Health Abraham Morgentaler, MD Associate Clinical Professor of Surgery (Urology) Harvard Medical School Men s Health Boston Boston, Massachusetts 21

24 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings The belief that higher testosterone levels are bad for prostate health dates back to an observation in 1941 that suppression of testosterone levels caused regression of prostate cancer, and it is so ingrained that it persists despite never having been proved in 65 years. 9,38 Recent evidence is slowly chipping away at that historical belief, however. We know that if we lower testosterone in patients with prostate cancer, the tumor shrinks, but that the opposite is not true. At all but the near-castrate range, increases in serum testosterone levels have little if any impact on prostate health. 39 It appears that the prostate needs a certain minimal amount of testosterone; beyond that, neither the prostate nor the cancer is affected by increasing serum testosterone levels. Therefore, testosterone therapy may safely be offered to men with testosterone deficiency as long as proper medical monitoring is performed. (See Optimal Monitoring for Hypogonadal Men Receiving Testosterone Therapy in this issue.) The current paradigm is that testosterone does not cause prostate diseases but rather plays more of a permissive role. 4 The presence of microscopic prostate cancer and precancer increases with age to a prevalence of 33% to 50% among men 60 to 70 years of age, but clinically detectable prostate cancer will develop in only 4% to 5% of these men in their lifetimes. 40,41 One of the greatest concerns is that testosterone therapy will stimulate the development and growth of such undiagnosed prostate cancers. 1 In fact, age-related increases in the prevalence of prostate diseases occur while endogenous androgen levels are decreasing 4 (Figure V.1). 22

25 Some of the most important data on testosterone and prostate health comes from a recent study by the Endogenous Hormones and Prostate Cancer Collaborative Group. 42 They performed a meta-analysis on results of 18 prospective trials that had evaluated the effects of a number of hormones, including serum testosterone and free testosterone, dihydrotestosterone (DHT), and estradiol (E2), in 3886 men with prostate cancer and 6438 control subjects matched for age and BMI. Individually, the studies, conducted between 1961 and 2001, were somewhat inconsistent in their results, and many had limited power to identify statistically significant differences. Together, however, the results unequivocally demonstrated that neither serum testosterone nor serum E2 at any level was associated with an increased risk of development or progression of prostate cancer. In direct contrast to the traditional paradigm, it is men with lower not higher levels of testosterone who appear to have the highest risk of prostate cancer. In a retrospective study of 345 hypogonadal men with PSA levels 4.0 ng/ml, Morgentaler et al showed that a substantial proportion of hypogonadal men had a biopsy-detectable prostate cancer despite normal PSA levels and that lower testosterone levels were associated with a greater risk of prostate cancer (Figure V.2). 21 (See Impact of Hypogonadism on Men s Health in this issue.) Overall, prostate cancer was detected in 15.1% of men, rising significantly with increasing PSA level, from 5.6% at a PSA level of 0 to 1.0 ng/ml to 36.4% at 3.1 to 4.0 ng/ml (P<.05). The combination of low serum testosterone and PSA level >2.0 ng/ml may be particularly worrisome, because 30.2% of such men had positive biopsies. 21 These results are very similar to those of men in the placebo group of the Prostate Prevention Trial with PSA level 4.0 ng/ml. 43 Testosterone levels were not assayed in that study, but the men were between 62 and 91 years of age, suggesting that many may have been hypogonadal. Similarly, recent reports have not demonstrated any causal relationship between testosterone therapy and prostate health. Studies have shown that prostate size, International Prostate Symptom Score (IPSS), and the incidence of diagnosed prostate cancer among men taking testosterone does not differ significantly from that in a matched control population. 4,30,34,44-51 A randomized, controlled trial in 40 men aged 44 to 78 23

26 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings years with late-onset symptomatic hypogonadism, for example, evaluated the effect of testosterone therapy (testosterone enanthate) on prostate tissue. 51 Although serum testosterone levels increased to the mid-normal range in the treated patients, biopsies performed at baseline and after 6 months of therapy showed no significant rise in median levels of testosterone and DHT within the prostate; no change in prostate volume, histology, tissue markers, or gene expression; and no increase in the incidence or severity of prostate cancer. Serum PSA levels increased significantly with testosterone therapy but were still relatively low after 6 months (total PSA level, 2.29 ng/ml; free PSA level, 0.68 ng/ml). These PSA level results are similar to those reported by others. 30,47,52 Mild increases (10%-25%) in PSA levels were reported to occur during the first 3 months of therapy, followed by stabilization for up to 42 months. 30,47 Additionally, a 2005 review of 19 randomized trials published between 1966 and 2004 found the rates of PSA level >4.0 ng/ml, prostate biopsies, and prostate cancer were numerically higher in the treatment group (n=651) than in the placebo group (n=433), but the differences were not statistically significant. However, the combined rate of all prostate adverse events in men receiving testosterone therapy was significantly higher in the treatment group than in the placebo group. 53 In addition to its association with an increased risk of prostate cancer, low levels of testosterone have been linked to high-grade prostate cancer. 48,54 One-third of patients (52 of 156) in a study of men with newly diagnosed prostate cancer had partial androgen deficiency, defined as testosterone levels <300 mg/ml. Mean Gleason score was higher (7.4 vs 6.2) and PSA levels lower (25.3 vs 31.9 ng/ml) in this group than in patients with testosterone concentrations in the normal range. Low testosterone levels have also been correlated with more aggressive disease, 55 advanced pathologic stage at radical prostatectomy, 56,57 and shorter survival in patients with metastatic prostate cancer. 58 In summary, higher testosterone levels are not associated with an increased risk of prostate cancer. In contrast to the traditional paradigm, evidence strongly suggests that men with testosterone levels below the normal physiologic range are at higher risk for prostate cancer. Additionally, increasing serum testosterone levels with androgen therapy does not appear to raise intraprostatic androgen concentrations or affect the risk or progression of prostate cancer. Finally, prostate cancer, when it develops, appears to occur in men with normal PSA levels and to be high-grade and more aggressive. Therefore, testosterone therapy can safely be offered to men with testosterone deficiency as long as proper medical monitoring is performed. 24

27 Section 6 Optimal Monitoring for Hypogonadal Men Receiving Testosterone Therapy Martin M. Miner, MD Director, Men s Health Center Miriam Hospital Clinical Associate Professor of Family Medicine Warren Alpert Medical School of Brown University Providence, Rhode Island 25

28 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings Periodic follow-up of patients taking testosterone is necessary. 10 Once the decision to treat is made and specific therapy chosen, a monitoring plan can be prepared. 6 The monitoring plan will include assessment of the effectiveness of treatment by routine measuring of testosterone levels and reviewing the signs and symptoms of hypogonadism. 6,9,10 (See Considerations for Diagnosis of Hypogonadism in this issue.) Clinical response and adverse effects should be monitored every 3 to 4 months during the first year of treatment. 10 The schedule for measuring testosterone levels will depend on the type of therapy 6,9 (Table VI.1). Sexual function should be evaluated as part of symptom review, which would include asking questions about libido and erectile function. Because hypogonadism is associated with osteopenia and osteoporosis, bone densitometry tests (eg, dual-energy x-ray absorptiometry scans) are advisable to determine BMD of the lumbar spine, femoral neck, and hip at baseline, after 1 to 2 years, and every 1 to 2 years thereafter. 6,10 Because BMD does not change rapidly, scanning more frequently than once a year is not useful. Improvement in BMD is sufficiently important that patients should be urged to continue treatment even if they are not experiencing improvement in sexual function. Other potential causes of osteoporosis should be evaluated and treated, if appropriate. It is important to ensure that patients have adequate vitamin D levels, are obtaining enough calcium in their diet, and have an activity level sufficient to increase muscle mass. A healthful lifestyle should be recommended and periodically evaluated and reinforced. Table VI.1. Monitoring Testosterone Levels in Men Receiving Testosterone Therapy Formulation Testosterone Monitoring Injectable Testosterone cypionate, testosterone enanthate Midway between injections If >700 ng/dl or <350 ng/dl, adjust dose or frequency of injections Topical Gel Patch system Buccal system Anytime after patient has been taking testosterone for at least 1 wk 3-12 h after application Immediately before application of fresh system Adapted with permission. 6 26

29 Patients should be evaluated for signs and symptoms of both class- and formulation-specific adverse effects at each visit. 6 (See Testosterone Treatment Options for Hypogonadism in this issue.) This is a good time to remind patients using gels of the importance of covering the application site with clothing and washing the skin before having skin-to-skin contact with others. 6 Because testosterone affects various organs and tissues, men receiving testosterone therapy should be evaluated at baseline and at regular follow-up visits 6 (Table VI.2). Proper monitoring of the prostate by DRE and measurement of PSA level should allow for early diagnosis, treatment, and cure of any occult prostate cancers that may be uncovered by testosterone treatment. 9 Prostate-related symptoms should be assessed at baseline and routinely thereafter with the IPSS or simple questioning about nocturia and voiding problems. 10 Table VI.2. Monitoring Safety of Testosterone Therapy 1,6,8-10 Parameter Frequency Comment/Action DRE At baseline and 3 mo, a,b then according to guidelines for prostate cancer screening (eg, yearly for men >50 y of age) To detect prostate cancer Biopsy if abnormal Voiding/IPSS At baseline and every 6-12 mo To detect BPH If warranted by symptoms, measure urine flow rate and post-void residual urine in bladder by ultrasonography PSA At baseline and 3 mo, a,c then according to guidelines for prostate cancer screening (eg, yearly for men >50 y of age) To detect prostate cancer Biopsy if >4.0 ng/ml or increased 1.0 ng/ml in any 12-mo period Repeat PSA in 3-6 mo if increased ng/ml in any 12-mo period Hemoglobin/hematocrit At baseline and 3 mo, a,b,d then yearly To detect erythrocytosis If >54%, stop therapy until normal, reinstate at reduced dose, and continue monitoring Breast At baseline and follow-up visits To detect gynecomastia Sleep apnea At baseline and follow-up as needed Ask about daytime fatigue and disordered sleep Discontinue treatment until the problem is adequately addressed Conduct a sleep study if symptoms persist a Rhoden et al recommend follow-up visits at 1 to 2 mo, at 3- to 6-mo intervals for the first y, and yearly thereafter. 9 b The International Society of Andrology, International Society for the Study of the Aging Male, and European Association of Urology recommend DRE and measurements of PSA, hemoglobin, and hematocrit at baseline, every 3 mo for the first y, and yearly thereafter. 8 c Dobs recommends DRE and PSA measurement at baseline, 3 mo, and 6 mo, and then annually in patients >50 y of age. 1 d The American Association of Clinical Endocrinologists recommends determination of hematocrit every 6 mo for the first 18 mo and yearly thereafter. 10 BPH, benign prostatic hyperplasia; DRE, digital rectal examination; IPSS, International Prostate Symptom Score; PSA prostate-specific antigen. 27

30 Highlights From Testosterone Update Disease State Theater Presentations held at the 2008 American Urological Association and Endocrine Society Annual Meetings Testosterone therapy increases hemoglobin and hematocrit, which is depressed in men with hypogonadism. 9 Although usually only increased to normal levels, erythrocytosis has been reported in clinical trials, particularly in older men, which could result in hyperviscosity side effects. 6,9,12,59 Injectable testosterone cypionate and testosterone enanthate are associated with the highest risk of erythrocytosis: up to 44% vs 3% to 18% with topical transdermal formulations. 12 Monitoring, therefore, should include hemoglobin and hematocrit testing 1,6,8,10 (Table VI.2). In conclusion, monitoring of patients receiving testosterone therapy should include review of hypogonadal signs and symptoms. Consideration should be given to discontinuing treatment if no benefit is seen. Measurement of serum testosterone levels is necessary for both the diagnosis and monitoring of hypogonadism. Adjustment of the dose or schedule of administration may be necessary to avoid supra- or subphysiologic testosterone concentrations. Monitoring of men taking testosterone should include both class- and formulation-specific adverse effects. Prostate health should be evaluated before initiation of therapy and monitored routinely during treatment. 28

31 References 1. Dobs AS, Myneni A. Hypogonadism and testosterone replacement therapy. Business Briefing US Endocr Rev. 2005: Edelstein D, Dobs A, Basaria S. Emerging drugs for hypogonadism. Expert Opin Emerging Drugs. 2006;11(4): Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab. 2001;86(2): Gooren L. Androgen deficiency in the aging male: benefits and risks of androgen supplementation. J Steroid Biochem Mol Biol. 2003;85(2-5): Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7): Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2006;91(6): Sadovsky R, Dhindsa S, Margo K. Testosterone deficiency: which patients should you screen and treat? J Fam Pract. 2007;56(5 suppl):s1-s Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment and monitoring of lateonset hypogonadism in males: ISA, ISSAM, and EAU recommendations. Eur Urol. 2005;48(1): Rhoden EL, Morgentaler A. Risks of testosteronereplacement therapy and recommendations for monitoring [review]. N Engl J Med. 2004;350(5): AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients 2002 update. Endocrine Pract. 2002;8(6): Morley JE, Charlton E, Patrick P, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism. 2000;49(9): Miner MM, Sadovsky R. Evolving issues in male hypogonadism: evaluation, management, and related comorbidities. Cleve Clin J Med. 2007;74 (suppl 3):S38-S Isidori AM, Caprio M, Strollo F, et al. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab. 1999;84(10): Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men: a 13- year follow-up of former Multiple Risk Factor Intervention Trial participants. Am J Epidemiol. 1997;146(8): Barrett-Connor E, Von Mühlen DG, Kritz-Silverstein D. Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. J Clin Endocrinol Metab. 1999;84(2): Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004;27(5):

32 References 17. Stellato RK, Feldman HR, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results form the Massachusetts Male Aging Study. Diabetes Care. 2000;23(4): Keating NL, O Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24 (27): Hak AE, Witteman JCM, De Jong FH, Geerlings MI, Hofman A, Pols HAP. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam Study. J Clin Endocrinol Metab. 2002;87(8): Rosano GMC, Sheiban I, Massaro R, et al. Low testosterone levels are associated with coronary artery disease in male patients with angina. Int J Impot Res. 2007;19(2): Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostatespecific antigen levels of 4.0 ng/ml or less. Urology. 2006;68(6): Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166(15): Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc. 2003;51(1): Delatestryl [package insert]. Lexington, MA: Indevus Pharmaceuticals Inc.; Depo-Testosterone [package insert]. Kalamazoo, MI: Pharmacia Corporation; AndroGel [package insert]. Marietta, GA: Solvay Pharmaceuticals Inc; Androderm [package insert]. Corona, CA: Watson Pharmaceuticals Inc; Striant [package insert]. Livingston, NJ: Columbia Laboratories Inc; Testopel [package insert]. Rye, NY: Bartor Pharmacal Co Inc; Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89(5): Testim [package insert]. Malvern, PA: Auxilium Pharmaceuticals Inc; Swerdloff RS, Wang C, Cunningham G, et al; Testosterone Gel Study Group. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab. 2000;85(12): Wang C, Swerdloff RS, Iranmanesh A, et al; Testosterone Gel Study Group. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):

33 References 34. Wang C, Swerdloff R, Kipnes M, et al. New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men. J Clin Endocrinol Metab. 2004;89(8): Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab. 1980;51(6): Morgentaler A, Dobs AS, Kaufman JM, et al. Safety, efficacy, and pharmacokinetics of testosterone undecanoate long-acting injection in the treatment of hypogonadism: results of a phase 3 clinical trial [poster]. Presented at: Annual Meeting of the American Urological Association; May 17-22, 2008; Orlando, FL. 37. Alliance for Aging Research. Low testosterone men s health condition in the shadows: survey highlights. Alliance for Aging Research Web site. April article/detail/714. Accessed August 18, Huggins C, Stevens RE Jr, Hodges CV. Studies on prostatic cancer: II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43: Cited by Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring [review]. N Engl J Med. 2004;350(5): Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin North Am. 2007; 34(4): Marcelli M, Cunningham GR. Hormonal signaling in prostatic hyperplasia and neoplasia [commentary]. J Clin Endocrinol Metab. 1999;84(10): Sakr WA, Grignon DJ, Crissman JD, et al. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases. In Vivo. 1994;8(3): Endogenous Hormones and Prostate Cancer Collaborative Group. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100(3): Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level 4.0 ng per milliliter. N Engl J Med. 2004;350(22): Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched controls. Clin Endocrinol (Oxf). 1994;40(3): Wallace EM, Pye SD, Wild SR, Wu FC. Prostatespecific antigen and prostate gland size in men receiving exogenous testosterone for male contraception. Int J Androl. 1993;16(1): Holmäng S, Mårin P, Lindstedt G, Hedelin H. Effect of long-term oral testosterone undecanoate treatment on prostate volume and serum prostatespecific antigen concentration in eugonadal middle-aged men. Prostate. 1993;23(2): Dean JD, Carnegie C, Rodzvilla J Jr, Smith T. Long-term effects of Testim 1% testosterone gel in hypogonadal men. Rev Urol. 2004;6(suppl 6): S22-S29.

34 References 48. Schatzl G, Madersbacher S, Thurridl T, et al. Highgrade prostate cancer is associated with low serum testosterone levels. Prostate. 2001;47(1): Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab. 2004;89(2): Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. 2001;56A(5):M266-M Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 2006;296(19): Swerdloff RS, Wang C. Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel. Aging Male. 2003;6(3): Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol Ser A Biol Sci Med Sci. 2005;60(11): Hoffman M, DeWolf WC, Morgentaler A. Is low serum free testosterone a markerfor high grade prostate cancer? J Urol. 2000;163(3): Ribeiro M, Ruff P, Falkson G. Low serum testosterone and a younger age predict for a poor outcome in metastatic prostate cancer. Am J Clin Oncol. 1997; 20(6): Massengill JC, Sun L, Moul JW, et al. Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. J Urol. 2003;169(5): Isom-Batz G, Bianco FJ Jr, Kattan MW, Mulhall JP, Lilja H, Eastham JA. Testosterone as a predictor of pathological stage in clinically localized prostate cancer. J Urol. 2005;173(6): Chodak GW, Vogelzang NJ, Caplan RJ, Soloway M, Smith JA; Zoladex Study Group. Independent prognostic factors in patients with metastatic (stage D2) prostate cancer. JAMA. 1991;265(5): Palacios A, Campfield LA, McClure RD, Steiner B, Swerdloff RS. Effect of testosterone enanthate on hematopoiesis in normal men. Fertil Steril. 1983; 40(1):

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