Testosterone Deficiency in Men More Common Than You Think

Transcription

1 Supplement to DECEMBER 2011 Testosterone Deficiency in Men More Common Than You Think Alfred Pasieka / Photo Researchers, Inc CPE grading online at This activity is supported by an educational grant from Abbott Laboratories and Lilly USA, LLC.

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3 CONTINUING EDUCATION INFORMATION Target Audience: Pharmacists Type of Activity: Knowledge Program Description: Testosterone deficiency is a highly prevalent condition among aging men, particularly among those who are obese and those with metabolic syndrome and type 2 diabetes. Increasingly recognized as more than a marker of sexual function, testosterone is an integral component of many metabolic pathways associated with body composition, cardiometabolic risk profile, and general well-being. Recently developed options in testosterone replacement therapy (TRT) are improving tolerability and safety, allowing patients to replace testosterone at near-normal physiologic levels with a low risk of adverse events. New developments in TRT include higher-potency, lower volume transdermal formulations that carry a lower risk of transference to partners. Successful treatment depends on matching the patient s needs, lifestyle, and preferences with specific formulations. Pharmacists play an essential role in educating patients about the value of TRT, explaining potential complications associated with its use, and setting treatment expectations to improve adherence and satisfaction with therapy. FACULTY Emily L. Knezevich, PharmD, BCPS, CDE Assistant Professor Department of Pharmacy Practice Creighton University School of Pharmacy and Health Professions Omaha, Nebraska Jon T. Knezevich, PharmD, BCPS Assistant Professor Department of Pharmacy Practice Creighton University School of Pharmacy and Health Professions Omaha, Nebraska ACCREDITATION Continuing Education Alliance is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is approved for 2.0 contact hours (0.2 CEUs). Universal Activity Number H01-P. The providers of this program have waived the processing fees. The estimated time to complete this activity is 2 hours. Release date: December 1, 2011 Expiration date: December 1, 2013 This activity is supported by an educational grant from Abbott Laboratories and Lilly USA, LLC. Faculty Disclosure: All faculty and planners participating in continuing education activities sponsored by Continuing Education Alliance are expected to disclose to the audience any significant support or substantial relationship(s) with providers of commercial products and/or devices discussed in this activity and/or with any commercial supporters of the activity. In addition, all faculty are expected to openly disclose any offlabel, experimental, or investigational use of drugs or devices discussed in this activity. The faculty and planning committee have been advised that this activity must be free from commercial bias, and based upon all the available scientifically rigorous data from research that conforms to accepted standards of experimental design, data collection, and analysis. Dr E. Knezevich has nothing to disclose with regard to commercial interests. Dr J. Knezevich has nothing to disclose with regard to commercial interests. The Planning Committee for this activity included Ruth Cohen and Margaret Inman of Continuing Education Alliance. The members of the Planning Committee have no significant relationships to disclose. Disclaimer: The opinions or views expressed in this CPE activity do not necessarily reflect the opinions or recommendations of Continuing Education Alliance, U.S. Pharmacist, Abbott Laboratories, or Lilly USA, LLC. How to Receive Credit: Participants wishing to earn CPE credit must: Read the supplement. Relate the content material to the learning objectives. Complete the self-assessment questions and evaluation form online at: After login, please enter the code: CAE76711 Successful completion of the self-assessment is required to earn CPE credit. Successful completion is defined as a cumulative score of at least 70%. A certificate of credit will be automatically generated upon successful completion of the activity. U.S. PHARMACIST CONTINUING EDUCATION Goals: To educate pharmacists about national and international standards for screening, evaluation, and treatment of testosterone deficiency, to delineate common comorbidities, to describe treatment options for TRT, and to provide strategies for patient education. Learning Objectives: After completing this activity, participants should be better able to: Discuss the important association of low testosterone with other comorbidities, including type 2 diabetes and metabolic syndrome Identify potential secondary causes of low testosterone levels using patient medication records Educate patients on the application/administration of TRT Copyright 2011 by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY No part of this publication may be reproduced or transmitted by any means, electronic or mechanical, or stored in any storage and retrieval system, without permission in writing from the publisher. U.S. PHARMACIST (ISSN ; USPS No ) is published monthly by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY Periodicals postage paid at New York, NY and additional mailing offices. Acceptance of advertising in U.S. PHARMACIST does not constitute endorsement of the advertiser, its products or services. The opinions, statements, and views expressed within this publication do not necessarily reflect those of Jobson Medical Information LLC or the editors of U.S. PHARMACIST. PHS1102 1

4 Testosterone Deficiency in Men More Common Than You Think INTRODUCTION Testosterone deficiency, or hypogonadism, is defined by low levels of serum total testosterone (TT) and the presence of associated signs and symptoms. 1 Hypogonadism is almost always a chronic and irreversible disorder that, left untreated, can compromise sexual function, body composition, cardiometabolic profile, and healthy aging. 2 Testosterone replacement therapy (TRT) can restore serum testosterone to normal physiologic levels and ameliorate many of the symptoms of hypogonadism. Pharmacists play an important role in the management of testosterone deficiency through patient education and counseling, screening for drug interactions and adverse events, and monitoring for adherence and therapeutic response. Emily L. Knezevich, PharmD, BCPS, CDE Creighton University School of Pharmacy and Health Professions Department of Pharmacy Practice Omaha, Nebraska Jon T. Knezevich, PharmD, BCPS Creighton University School of Pharmacy and Health Professions Department of Pharmacy Practice Omaha, Nebraska POP QUIZ Alfred Pasieka / Photo Researchers, Inc 2 Testosterone deficiency is defined by: A. TT levels B. Signs and symptoms C. Both of the above The biochemical definition of hypogonadism is controversial because there is no clear threshold for serum testosterone that distinguishes testosterone deficiency from normal levels. Moreover, endogenous serum testosterone levels vary widely as the result of circadian rhythms, episodic secretion, and fluctuations in sex hormone-binding globulin (SHBG) levels. Bioavailable or free testosterone (FT) appears to be a better indicator of testosterone status, but FT is more difficult to measure with current assays. 3 In the absence of a more conclusive diagnostic test for hypogonadism, the Endocrine Society defines the lower limit of normal TT as ~300 ng/dl (10.4 nmol/l). 1 As techniques for measuring serum testosterone improve, the threshold for normal may change. For example, in a recent analysis of data from the Framingham Heart Study, investigators used liquid chromatography tandem mass spectrometry to measure TT and FT in healthy nonobese men aged 19 to 40 years. 4 Values below the 2.5th percentile of TT (348.3

5 ng/dl) and FT (70 pg/ml) were considered low. When applied to cohorts from the Framingham Heart Study, European Male Aging Study, and Osteoporotic Fractures in Men Study, these TT and FT thresholds correctly identified men with a higher prevalence of sexual dysfunction, physical dysfunction, and diabetes. 4 POP QUIZ The prevalence of testosterone deficiency: A. Is highest in middle age B. Increases with common comorbidities such as obesity C. Is higher in ethnic minorities in the United States In the Hypogonadism in Males (HIM) study of men treated in the primary care setting, 38.7% of men aged 45 years tested positive for hypogonadism (TT <300 ng/ dl). 5 Applied to U. S. census data, these findings suggest that 13.8 million American men aged 45 years may be testosterone-deficient. 5 Furthermore, the prevalence of testosterone deficiency increases with age, reaching 50% for men aged 85 years. 5 As the population ages, the burden of testosterone deficiency is expected to grow. 6 The prevalence of low testosterone also increases in men with common comorbidities, such as obesity, diabetes, and metabolic syndrome. 7 Despite the availability of effective treatment, few patients with hypogonadism receive appropriate therapy. In the HIM study, <10% of men with biochemical hypogonadism were being treated with TRT. 5 Therefore, according to current estimates, 12.5 million American men aged 45 years have untreated testosterone deficiency. 5 Many factors contribute to poor recognition of hypogonadism. The symptoms of testosterone deficiency are nonspecific and may be attributed to other conditions. Patients may be reluctant to disclose sexual symptoms one of the most common presenting symptoms of low testosterone and physicians may be reluctant to ask. Clinicians also face diagnostic barriers that limit the timely recognition of hypogonadism, including lack of consensus on the biochemical definition of testosterone deficiency and unreliability of serum testosterone assays. 8 POP QUIZ Primary vs secondary hypogonadism can be distinguished by: A. TT and FT levels B. Leuteinizing hormone and folliclestimulating hormone levels C. Neither of the above PATHOPHYSIOLOGY Testosterone production is regulated by the hypothalamic-pituitary-testicular (HPT) axis. Testosterone deficiency can result from a disease of the testes (primary hypogonadism), defects of the pituitary or hypothalamus (secondary hypogonadism), or a combination of primary and secondary causes. 1 Measuring leuteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels can distinguish between these etiologies. 1 Men with primary hypogonadism are expected to have low testosterone in association with elevated LH and FSH levels. By comparison, men with secondary hypogonadism also called hypogonadotropic hypogonadism will have low testosterone and low or normal LH and FSH levels. 1 Testosterone levels may be adversely affected by acute illness, nutritional deficiency, excessive exercise, and certain medications, including opiates and glucocorticoids. Therefore, evaluation for testosterone deficiency should exclude conditions that cause transient fluctuations in testosterone. 1 For men with an initial TT measurement in the mildly hypogonadal range, a repeat TT measurement is necessary to confirm a low testosterone concentration. 1 Clinicians should also consider the potential effects of chronic health conditions and medications on a patient s testosterone level. 1,9 In addition, aging, obesity, diabetes, and other factors can alter SHBG and TT levels. In cases of suspected hypogonadism and borderline TT level, measuring or calculating bioavailable testosterone can clarify the diagnosis. 1,9 Additional diagnostic testing may be necessary to identify the cause of hypothalamic and/or pituitary dysfunction in men with secondary hypogonadism. These may include hyperprolactinemia, hemochromatosis, pituitary neoplasia, obstructive sleep apnea, and genetic diseases associated with gonadotropin deficiency. 1 For men with primary testicular failure of unknown etiology, genetic testing can exclude Klinefelter syndrome. 1 POP QUIZ What is the most common symptom associated with testosterone deficiency? A. Erectile dysfunction B. Loss of body hair C. Low libido D. Reduced vigor CLINICAL PRESENTATION Testosterone deficiency is associated with a spectrum of clinical signs and symptoms. Given uncertainty about the optimal biochemical threshold for hypogonadism, symptoms play an important role in determining the 3

6 Table 1. Signs and Symptoms Associated With Testosterone Deficiency Measure serum testosterone in men with these signs and symptoms Incomplete sexual development, eunuchoidism, aspermia Reduced libido and sexual activity Decreased spontaneous erections, poor morning erection Erectile dysfunction Reduced muscle bulk and strength Low BMD, height loss, low-trauma fracture Breast discomfort, gynecomastia Loss of body (axillary and pubic) hair, reduced shaving Very small or shrinking testes (especially <5 cm) Inability to father children, low or zero sperm counts Hot flushes, sweats Consider also measuring in men with Reduced vigor: decreased energy, motivation, initiative, aggressiveness, self-confidence Diminished physical or work performance Depressed mood: feeling sad or blue, dysthymia Poor concentration and memory Sleep disturbance, increased sleepiness Mild anemia (normochromic, normocytic, in the female range) Increased body fat or BMI BMD: bone mineral density; BMI: body mass index. Source: Reference 1. presence and severity of testosterone deficiency. 3 The Endocrine Society recommends measuring serum testosterone levels in men with clinical manifestations of low testosterone (TABLE 1) and in men with comorbid conditions associated with a high prevalence of androgen deficiency (TABLE 2). 1 Low libido is the most common presenting symptom of hypogonadism. 9 The association between hypogonadism and sexual dysfunction is well documented. Up to 35% of men with erectile dysfunction (ED) have low testosterone levels, which contribute to the underlying pathophysiology of ED. 10 Testosterone regulates nitric oxide and phosphodiesterase-5 (PDE5) levels, which are important for normal erectile function. 10 Normal testosterone levels also are important for other aspects of sexual function such as orgasm and ejaculatory volume. 11 Because of the mulitplicity of etiologies for ED, TRT does not always completely reverse symptoms of this disorder. Testosterone deficiency is also associated with a reduction in bone mineral density (BMD) in older ( 65 years) men. The Osteoporotic Fractures in Men Study Group reported that a comparison of osteoporotic men with men with normal BMD showed the prevalence of TT deficiency was 6.9% and 3.2% (P =.01). 12 Other changes in body composition, including decreased muscle mass and strength and increased body fat, also are symptoms of testosterone deficiency. 1 Memory, energy, and physical functioning also are impaired in men with testosterone deficiency, leading to an erosion in quality of life. 13 In addition, hypogonadism also adversely effects vitality, mood, and cognition, particularly in older men. 14 POP QUIZ Which is a common comorbidity of testosterone deficiency? A. Metabolic syndrome B. Rheumatoid arthritis C. Asthma D. Overactive bladder COMORBIDITIES Growing beyond its role as a sex hormone, testosterone is recognized increasingly as an important regulator of metabolic homeostasis. Testosterone deficiency is associated with an interrelated array of adverse metabolic parameters, including obesity, insulin resistance, hyperglycemia, hypertension, and dyslipidemia. 3,15 Low testosterone levels also are associated with increased inflammation and endothelial dysfunction, which are major risk factors for cardiovascular disease (CVD). 3 Evidence Table 2. Comorbid Conditions Associated With Elevated Risk of Hypogonadism Sellar mass, radiation to the sellar region, or other diseases of the sellar region Treatment with medications that affect testosterone production or metabolism, such as glucocorticoids, ketoconazole, and opioids HIV-associated weight loss End-stage renal disease and maintenance hemodialysis Moderate to severe chronic obstructive lung disease T2DM Metabolic syndrome Obesity Hemochromatosis HIV: human immunodeficiency virus; T2DM: type 2 diabetes mellitus. Source: Reference 1. 4

7 linking testosterone deficiency to a multitude of comorbidities and adverse outcomes mandates a comprehensive screening and workup that includes testosterone measurement in patients with these comorbidities. This should improve the under-recognition and undertreatment of testosterone deficiency. Obesity Several measures of obesity correlate strongly with testosterone deficiency in men. In the National Health and Nutrition Examination Survey (NHANES) III, TT and FT decreased significantly with increasing body mass index (BMI) (P <.05), waist circumference (P <.05), and body fat percentage (P <.05). 16 In the HIM study, obese men were more than twice as likely as nonobese men to have low testosterone levels (odds ratio [OR], 2.38). 5 Obesity, particularly the accumulation of excess visceral fat, appears to activate a self-perpetuating cycle of insulin resistance, systemic inflammation, and other metabolic derangements, including decreased testosterone. 17 Metabolic Syndrome Metabolic syndrome describes a cluster of related cardiometabolic risk factors, including visceral obesity, insulin resistance, hypertriglyceridemia, and hypertension. A recent meta-analysis of 20 testosterone studies evaluated the inverse relationship between metabolic syndrome and testosterone deficiency. 18 Controlling for age and BMI, metabolic syndrome was an independent risk factor for hypogonadism (P <.05). Low testosterone also predicted metabolic syndrome: baseline TT levels were significantly lower for men with new-onset metabolic syndrome than for controls (2.17 nmol/l; P <.0001). 18 Mechanisms underlying the interplay between testosterone and metabolic syndrome are not well understood. Testosterone deficiency may be a downstream consequence of obesity, or it may drive accumulation of visceral fat and reduction of insulin-sensitive muscle mass. 18 Whatever the mechanism, metabolic syndrome and testosterone deficiency are a particularly dangerous combination. In an analysis of men aged 40 years in the NHANES III study, Lin et al evaluated the effect of low testosterone defined as a calculated bioavailable testosterone level <3.54 ng/ml (354 ng/dl) in men with and without metabolic syndrome. 19 Men with metabolic syndrome and testosterone deficiency had nearly twice the risk of cardiovascular mortality (hazard ratio [HR], 1.90; P =.02) than men with metabolic syndrome alone (HR, 0.82; P =.95). Higher testosterone protected against cardiovascular death in patients with metabolic syndrome, with each log-ng/ml increase in bioavailable testosterone reducing cardiovascular mortality by 28% during the median follow-up of 15.6 years (HR, 0.72; P =.03). 19 Diabetes Type 2 diabetes mellitus (T2DM) affects one-third of men aged 65 years, and the prevalence is expected to increase 69% over the next 2 decades. 17 Observational studies consistently show that men with diabetes have lower TT levels than nondiabetic controls. 17 At least 25% of men with T2DM have evidence of secondary hypogonadism, and an additional 4% have primary hypogonadism. 20 Given the strong correlation between diabetes and testosterone deficiency, the Endocrine Society recommends the routine measurement of testosterone in patients with T2DM. 20 The relationship between testosterone and T2DM is complex and likely mediated by obesity. 20 Still, several studies suggest men with low testosterone are at a greater risk of developing T2DM, and low testosterone may even predict the onset of diabetes In a meta-analysis of 43 diabetes studies including 6427 men, men with TT levels to ng/dl had a 42% lower risk of T2DM compared with men with lower serum TT levels (RR, 0.58; 95% CI, ) independent of adiposity. 28 Furthermore, testosterone deficiency appears to worsen cardiovascular outcomes in men with T2DM. 29 Muraleedharan and colleagues recently evaluated the relationship between TT and cardiovascular mortality in a study of men with T2DM (N = 587). 30 At baseline, the mean age of patients was 61 years, and 42% had serum TT levels <300 ng/dl. Compared with normal TT levels, testosterone deficiency more than doubled the risk of cardiovascular death during the 6-year follow-up period, independent of age, BMI, HbA1c, pre-existing CVD, smoking status, and use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (HR, 2.2; P =.001). 30 Cardiovascular Disease Testosterone concentrations decline with aging, obesity, and other risk factors for cardiovascular morbidity and mortality. Low testosterone increases the risk of cardiovascular death in men with pre-existing metabolic syndrome and diabetes. 19,30 However, whether testosterone deficiency is itself a risk factor for CVD is not clear. Testosterone deficiency may be a marker of underlying disease processes associated with CVD rather than an independent predictor of adverse outcomes. 31 5

8 Few trials have been powered to examine the relationship between testosterone and CVD, and results of metaanalyses have been inconsistent. In 2011, Ruige and colleagues evaluated testosterone levels in 19 prospective studies of men who were at least 45 years of age and generally healthy at enrollment. Serum TT had a modest protective benefit against incident CVD, but only in men >70 years of age (RR, 0.84 for each standard deviation of TT; 95% CI, ). There was no apparent link between testosterone deficiency and incident CVD in men <70 years (RR, 1.01; 95% CI, ). In another meta-analysis, Corona et al examined 70 studies enrolling patients with and without established CVD. Men with any CVD had significantly lower mean serum TT levels than men without CVD ( 2.55 nmol/l; P <.0001). 32 Testosterone deficiency also was associated with overall and cardiovascular mortality. Baseline TT levels were significantly lower in men who died from any cause ( 1.53 nmol/l; 95% CI, 2.69 to 0.37) and in those who died from cardiovascular causes ( 0.97 nmol/l; 95% CI, 1.55 to 0.40). 32 In the Corona meta-analysis, certain comorbidities such as diabetes, obesity, and hypertension resulted in a more pronounced difference in TT levels between men with and without CVD. 32 Investigators also examined the role of obesity as a potential mediator of testosterone-related cardiovascular risk in a study of 1687 men with ED. 33 In this population, there was a significant interaction between hypogonadism and BMI as risk factors for major cardiovascular adverse events (MACE). Whereas testosterone deficiency significantly increased the risk of MACE in normal-weight men (HR, 6.361; P =.048), hypogonadism was paradoxically protective against MACE in obese men (HR, 0.097; P =.032). 33 These findings underscore the complexity of interactions among testosterone, obesity, and other pathways that contribute to cardiovascular risk, and the importance of tailoring treatment to individual patient needs. POP QUIZ What is the goal of TRT? A. Ameliorate symptoms of hypogonadism B. Raise serum testosterone to normal physiologic levels C. Both a and b TREATMENT OF TESTOSTERONE DEFICIENCY The goal of TRT is to ameliorate the symptoms of hypogonadism by restoring serum testosterone to normal physiologic levels. The optimal biochemical target, however, is controversial because the lower threshold of serum testosterone below which symptoms of hypogonadism are observed is not known. For most symptoms, the lower threshold of normal is approximately 300 ng/dl (10.4 nmol/l). 1 The Endocrine Society recommends TRT to restore serum testosterone levels to within a range that is midnormal for healthy young men ( ng/dl). 1 Some evidence suggests older hypogonadal men may need higher levels of testosterone, owing to age-related changes in the sensitivity of target tissues to serum testosterone. 2 Therefore, rather than aiming for specific biochemical goals, treatment should be designed to improve serum testosterone to levels sufficient to relieve the signs and symptoms of testosterone deficiency. 2 Although TRT was introduced into clinical practice to improve sexual function in hypogonadal men, there is increasing interest in the use of TRT to address the array of adverse metabolic issues associated with testosterone deficiency. Given the physiologic importance of testosterone to insulin sensitivity, inflammation, vasodilation, and endothelial function, restoring optimal testosterone levels has many potential benefits for men with hypogonadism. Lifestyle Interventions Lifestyle interventions aimed at weight loss are beneficial for patients with hypogonadism, particularly those with comorbid conditions that are exacerbated by obesity. In a study of obese men with hypogonadism, metabolic syndrome, and T2DM, a 52-week program of diet and exercise resulted in significant increase in serum testosterone level (P <.001) and improved glycemic control. 33 Additional lifestyle interventions, including smoking cessation and avoidance of excess alcohol intake, also correlated with higher TT levels. 34 POP QUIZ Formulations of TRT in the United States include all of the following except: A. Oral (swallowed) B. Oral (transbuccal) C. Transdermal (patch) D. Pellets TRT Administration Native testosterone is challenging to administer orally or parenterally because it is metabolized rapidly during first hepatic passage. To overcome this barrier, certain chemical modifications to the molecular structure of testosterone have been introduced to slow the rate of absorption and hepatic clearance (FIGURE). 35 Alkylation at the 17α position protects the testosterone molecule from being metabolized by the liver. 6

9 1α-alkylation retards hepatic catabolism O Testosterone 18 OH Esterification of 17β-hydroxil improves lipophilicity, enabling parental use 17α-alkylation retards hepatic catabolism Figure. Structural modifications associated with improved bioavailability and pharmacokinetics of testosterone. Source: Reference 35. However, this modification increases the risk of liver toxicity. Therefore, 17α-alkylated testosterone preparations such as methyltestosterone should be avoided 35 Alkylation at position 1 prevents premature metabolism without the risk of liver toxicity. Mesterolone is a 1-alkylated testosterone analogue available for oral administration 35 Esterification of the 17β-hydroxyl group prevents premature liver metabolism without the risk of liver toxicity. This modification also improves the lipophilicity of testosterone, enabling intramuscular administration in an oil solution. However, because the resulting analogue has the same short half-life of native testosterone, it must be delivered via a delayed-release depot injection to prolong its therapeutic effect. Several 17β-hydroxyl-ester preparations are available for intramuscular injection, including testosterone enanthate, testosterone cypionate, testosterone propionate, and testosterone undecanoate (TU) 35 Desirable Attributes of TRT Testosterone therapy is available in various formulations and delivery systems, each with advantages and disadvantages related to convenience, bioavailability, and tolerability (TABLE 3). 1,35-43 In 2011, Giagulli and colleagues described the ideal clinical and biochemical characteristics of TRT. 2 While no formulation fulfills all criteria, these properties provide a useful framework for evaluating available options. 2 Ideally, TRT should: Raise circulating testosterone levels to strictly normal physiologic ranges Provide a daily release of testosterone that is similar to normal endogenous production (3-10 mg/day) Reproduce testosterone fluctuations that match the circadian rhythm Deliver serum testosterone that can be converted to its metabolites at the desired concentrations, including conversion to dihydrotestosterone (DHT) by 5-alpha reductase activity (30-80 ng/dl) and to 17β-estradiol by aromatase activity (20-50 pg/ml) Induce little or no negative effects on the prostate, liver, or cardiovascular system Represent a convenient treatment option that hypogonadal men can manage autonomously OPTIONS FOR TRT Transdermal Formulations Transdermal testosterone preparations, including patches, gels, and sprays, are used daily to provide stable serum testosterone levels during treatment. Patches: Testosterone patches can deliver testosterone to the systemic circulation, increase testosterone levels to the normal physiologic range, and mimic the normal circadian rhythm of serum testosterone levels. Scrotal patches, which took advantage of rapid absorption through highly vascularized scrotal skin, were first introduced in the 1990s. More recently, nonscrotal patches were introduced and scrotal patches are no longer available. Nonscrotal patches require an alcohol base to enhance skin absorption. The use of transdermal patches is limited by adverse skin reactions at the patch site, including skin irritation in approximately 32% of patients and allergic contact dermatitis in 12%. 44 Pretreatment with triamcinolone 7

10 acetonide 0.1% under the patch can improve local tolerability. 44 However, skin irritation, as well as the obtrusive presence of patches on the skin, may reduce the acceptability of skin patches for many patients. Topical gel: Testosterone gel provides a transdermal system that avoids skin irritation associated with patches. Other advantages of testosterone gels include ease of use, invisibility of application, and flexible dosing. Gels are the most widely prescribed form of TRT for adult men in the United States, reflecting the favorable efficacy, safety, and tolerability of this testosterone delivery system. 39 Until recently, the standard formulation for testosterone gel contained 1% testosterone, and the gel was Table 3. TRT Formulations Frequency of Disadvantages, Formulation Administration Dose Advantages Side Effects, Precautions Transdermal Daily 5-10 g of a 1%-2% Serum TT Need for daily administration gel testosterone maintained Risk of transfer to partners and gel applied within normal children via skin-to-skin contact to shoulders, range (risk diminished by newer, highupper arms, Flexible dosing potency formulations applied to abdomen, Less risk of smaller skin area) or upper and skin irritation Patients should wash hands after inner thighs, compared with applying gel, cover skin with depending transdermal clothing, and wash skin before on product patches skin contact to minimize risk of secondary testosterone exposure Rate of application-site reactions varies from 2%-5% depending on product and dosage Transdermal Daily 1 pump actuation Higher potency, Need for daily administration spray of 30-mg smaller surface Absorption limited by small testosterone area surface area to each axilla Less messy ; applicator; does not touch hands Transdermal Every night One 5-mg, or one Mimics circadian Need for daily administration patch 5-mg plus one rhythm of Skin reactions at the application 2.5-mg patch(es) testosterone site: pruritus, 37%; burnlike applied over the release blister, 12%; erythema, 7%; skin of the back, Simple vesicles, 6%; burning, 3%; thigh, or upper administration induration, 3% arm, avoiding pressure points Buccal tablet Every 12 h One 30-mg bio- Serum TT Need for twice daily administration adhesive tablet maintained Gum or mouth irritation, 9.2%; applied to buccal within normal gum pain, 3.1%; gum tenderness, mucosa range 3.1%; gum edema, 2%; bitter taste, 4.1%; taste perversion, 2%. Subcutaneous Every 3-6 mo Implanted; dose Treatment only Invasive placement pellets and regimen vary twice per year Inflammation and pain at with formulation site of implantation used, patient age, Infection diagnosis Expulsion of pellet Intramuscular Every 1-2 wk mg, Low cost Associated with supraphysiologic injection testosterone testosterone levels that fall to enanthate or hypogonadal range by end of cypionate weekly dosing interval or mg Fluctuations in mood, libido; every 2 wk erythrocytosis (especially in older men); pain at injection site TT: total testosterone. Source: References 1,

11 applied to the shoulders, upper arms, or abdomen, depending on formulation and target dosage. The major limitation of testosterone gel is the risk of testosterone transfer from the patient to others via skin contact. 45 Men treated with testosterone gel should be advised to wash their hands after applying gel, cover medicated areas with clothing, and wash before skin contact to minimize risk of secondary testosterone exposure. 37,42 Newer formulations of transdermal testosterone diminish the risk of transfer by reducing the surface area of skin that must be treated or by targeting a more discreet application site. In 2011, the US Food and Drug Administration (FDA) approved a new formulation of 1.62% testosterone gel. With increased viscosity and permeation, the concentrated formulation delivers the desired testosterone dose within a lower volume of gel, reducing the total mass of gel applied per day from 5.0 to 10.0 g with 1.0% gel to 1.25 g and 5.0 g with 1.62% gel. 39 The 1.62% concentration testosterone decreases the overall surface area required for application. Another new transdermal formulation, a 2% testosterone gel, is applied directly to the front and inner thighs rather than the upper body. 40 The gel is supplied in a 60-g canister that uses a metered-dose pump to deliver 10 mg of testosterone per pump actuation. Doses can be adjusted between 10 mg (1 actuation) and 70 mg (7 actuations), with a recommended starting dose of 40 mg applied to the front and inner thighs once daily in the morning. 40 Underarm spray: Another recent addition to the transdermal arsenal is a 2% testosterone underarm spray, approved for the treatment of hypogonadism in 2010 and specifically designed to reduce the risk of testosterone transfer. 38 The delivery system uses a metered-dose pump with a no-touch applicator to titrate the testosterone dose from 30 mg (1 pump) to 120 mg (4 pumps). The recommended starting dose is 30 mg applied to each underarm (60 mg total) at the same time each morning, with or without prior use of deodorants or antiperspirants, and no shaving requirement. As with other topical testosterone products, the underarm spray carries a boxed warning regarding the potential for virilization in children with secondary exposure to treated skin. Patients who use the testosterone underarm spray should wash their hands immediately after application, and avoid skin-to-skin contact with the unwashed or unclothed application sites with others. 38 Transbuccal Testosterone Tablets Unlike traditional oral preparations, transbuccal systems are absorbed through the oral mucosa, avoiding intestinal absorption and hepatic clearance. The sustained-release, mucoadhesive tablets are applied twice daily to the upper gums, where they soften, mold to the shape of the gum, and gradually release unmodified testosterone with a halflife of 12 hours. 35 The most common side effects include gum or mouth irritation, pain, tenderness, and swelling; bitter taste; and taste perversion. 41 Subcutaneous Testosterone Pellets Subcutaneous testosterone pellets have been available since the 1940s, and although no longer frequently used, they remain the only long-acting testosterone treatment available in the United States. In the typical procedure, 8 to 12 testosterone 75-mg pellets (total dose, mg) are implanted under the skin of the lower abdomen, where they provide sustained release of unmodified testosterone for up to 6 months. 46 Testosterone pellets are associated with possible inflammation and pain at site of implantation, 43 infection, and expulsion of pellets. 1 Testosterone pellets are not the best choice for first-line testosterone therapy, given their long-lasting effects and the inconvenience of removing them. It may be preferable to reserve them for patients who have shown response to and tolerate TRT. 47 Testosterone pellets may be an appropriate alternative to testosterone gels for men who have a high risk of secondary testosterone exposure to young children, such as grandfathers who play a prominent caregiving role. Intramuscular Injection Intramuscular injection of testosterone esters may be an appropriate option for some patients, particularly when cost is an issue. Testosterone injections typically are given every 2 weeks, beginning with a lower dose and titrating upward. Testosterone injections are associated with fluctuating serum levels over time rising initially to supraphysiologic levels and declining gradually to hypogonadal levels by the end of the dosing interval leading to fluctuations in mood, libido, and general well-being. Although these fluctuations can be reduced by compressing the dosing interval to once a week, it may not be possible to achieve stable testosterone concentrations without unacceptably frequent injections of small doses of testosterone. In addition, the viscosity of the testosterone formulation used for intramuscular administration requires long (1.5 inch) and large-gauge (usually 21 or 23 G) needles that may cause pain at the injection site. An additional side effect includes erythrocytosis (especially in older men). 1 An investigational, long-acting depot formulation of 9

12 injectable testosterone undecanoate (TU) may be an option for avoiding frequent testosterone injections. After 2 initial loading doses, TU requires only 4 injections per year, compared with 26 injections for standard twice-weekly intramuscular testosterone. A recent longterm study demonstrated the sustained efficacy and safety of TU injections given every 10 weeks over 21 months. 48 If approved by the FDA, TU will be the first intramuscular testosterone formulation available for injection every 3 months. Oral Testosterone Preparations Oral TU is available in many countries and is under review in the United States. Oral testosterone bypasses hepatic clearance through lymphatic absorption to deliver testosterone to the systemic circulation. Lymphatic absorption of TU is highly dependent on the lipid content of the diet, however, and it must be taken with at least 20 g of fat. Oral TU has been available in capsule form dissolved in oleic acid since the 1970s and was recently reformulated in a mixture of castor oil and propylene glycol laureate. The half-life of TU is approximately 4 hours, requiring 2 to 3 daily doses that result in an irregular pattern of serum testosterone throughout the day. 35 A new formulation of oral TU, using a self-emulsifying drug delivery system (SEDDS) that promotes intestinal lymphatic absorption, is in development. In a phase 2 study, most hypogonadal men achieved stable testosterone levels in the normal physiologic range after 7 days of treatment with a SEDDS formulation of oral TU 200 mg twice daily, with no evidence of liver toxicity. 49 Alkylated oral testosterone derivatives such as methyltestosterone and oxandrolone are associated with liver toxicity and are not safe for long-term use. Novel formulations of non alkylated testosterone may provide a safer alternative for oral dosing. An investigational formulation of slow-release oral testosterone is in development. In a phase 1 study of healthy men with experimentally induced hypogonadism, treatment with slow-release oral testosterone 300 mg 3 times daily normalized serum testosterone levels after 9 days. 9 TREATMENT CONSIDERATIONS No TRT formulation perfectly replicates the daily endogenous production of testosterone. Treatment selection therefore depends on patient preference, cost, factors that may influence adherence, potential adverse effects, and other considerations. 1 The potential clinical benefits of TRT should be weighed against risks. In addition, the severity of testosterone deficiency should be considered when deciding whether testosterone therapy is appropriate, as this will help determine which patients will benefit the most from treatment. Patient Preference Successful TRT depends on matching the patient s lifestyle and treatment expectations with an appropriate method of delivery. Patients may have concerns about specific delivery options, such as an aversion to needles or gel odor. For some patients, cost may be an important factor, while others prioritize convenience. The patient s experiences with TRT or other therapies also may influence current preferences and priorities. Risk of Transference For patients who are considering transdermal testosterone, it is important to assess and manage risk of transference. Compared with traditional 1% testosterone gel formulations, new transdermal formulations reduce risk of transference by enabling patients to use a smaller volume of gel and/or apply gel to discreet application sites such as the underarms and upper and inner thighs. 39,40 All patients who initiate treatment with transdermal testosterone gel should be advised of the risk of transference and trained in appropriate safety precautions as described on product labeling. Adherence Poor medication adherence is a widespread problem in patients with chronic conditions. Nonadherence decreases therapeutic efficacy, leading to poor outcomes. Pharmacists can encourage adherence by explaining the value of treatment, keeping the regimen uncomplicated, and customizing treatment to fit the patient s lifestyle. Counseling patients on the correct usage of testosterone patches, gels, buccal tablets, and other delivery systems can increase the likelihood of successful treatment. Pharmacists can educate patients about expected side effects and options for managing adverse events. Adherence usually is better when the patient understands that treatment is important, perceives that the regimen is convenient, and is prepared to manage potential side effects of treatment. 50 Contraindications Men should be screened for absolute and relative contraindications before initiating TRT (TABLE 4). 1 Repeat screening is recommended throughout the treatment course, as new conditions can arise that warrant treatment modification or discontinuation. TRT is contraindicated 10

13 in men with hormone-dependent cancers, including breast cancer or metastatic prostate cancer, which may be stimulated during testosterone treatment. 1 The Endocrine Society also cautions against TRT in men with a moderate-to-high risk of adverse events, including men with an elevated risk of prostate cancer, erythrocytosis, untreated obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled/untreated severe heart failure, or men who wish to maintain their fertility. 1 BENEFITS OF TRT TRT has a range of potential beneficial effects in men with testosterone deficiency, including improved libido, erectile function, body composition (reduced fat mass, increased lean body mass), bone density, and mood Patients should understand these potential benefits when considering TRT. Sexual Function Restoring testosterone levels improves overall sexual function in men with testosterone deficiency. The Testim Registry in the United States (TRiUS) included 849 men with hypogonadism who were treated with testosterone 1% transdermal gel. 57 Sexual function was measured at baseline and during the 12-month follow-up by the selfreported Brief Male Sexual Function Inventory (BMSFI). With TRT, patients saw significant improvements in TT and FT levels (P <.001), with TT reaching a mean of ng/dl after 1 year. Testosterone normalization was Table 4. Contraindications and Precautions for TRT High risk of serious adverse events Male breast cancer Metastatic prostate cancer Moderate-to-high risk of adverse events Unevaluated prostate nodule or induration PSA >4 ng/ml for most men, or >3 ng/ml in men with a high risk of prostate cancer (eg, African American men and men with a first-degree relative with prostate cancer) Hematocrit >50% Severe lower urinary tract symptoms (AUA/IPSS score >19) Untreated obstructive sleep apnea Uncontrolled or poorly controlled congestive heart failure AUA: American Urological Association; IPSS: International Prostate Symptom Score; PSA: prostate-specific antigen. Source: Reference 1. associated with significant improvements in the total BMSFI score (P <.001) and in each of the individual domains of sex drive/libido, erectile function, ejaculatory function, and level of bother. Importantly, treatment with TRT significantly improved sexual function in the subgroup of men who were also taking PDE5 inhibitors (P <.001). Therefore, findings from TRiUS demonstrate the beneficial effects of 12 months of TRT on sexual function in hypogonadal men, including men receiving concomitant treatment for ED. 57 For some men with testosterone deficiency and comorbid vascular disease, TRT alone may not be sufficient to improve sexual function. For instance, in obese hypogonadal men with T2DM, TRT improves libido but does not universally improve ED. Additional treatment with PDE5 inhibitors may be necessary to fully restore sexual function. 47 Body Composition Treatment with TRT is associated with an overall improvement in body composition, including a decrease in fat mass and an increase in lean body mass and muscle strength. 1 Normalization of testosterone levels also appears to improve BMD in men with hypogonadism. 1 Improvements in body composition are observed in men of all ages. The Hormonal Regulators of Muscle and Metabolism in Aging (HORMA) study evaluated testosterone supplementation in 122 older community-dwelling men (mean age 70.8 years). 58 After 16 weeks of treatment with transdermal testosterone, patients had a significant increase in total lean body mass and appendicular lean tissue, as well as a significant decrease in total fat mass and abdominal fat. Moreover, composite upper and lower body muscle strength increased, as did aerobic endurance. 58 In a follow-up analysis of the HORMA study, patients who made the greatest gains in muscle strength and endurance during short-term treatment with TRT retained these benefits 3 months after treatment was discontinued. 59 Cardiometabolic Profile Several studies have identified favorable changes in lipid parameters and other markers of cardiometabolic risk in hypogonadal men undergoing treatment with TRT. One meta-analysis showed treatment with TRT corrected many components of metabolic syndrome, resulting in loss of visceral fat, improved glucose tolerance, and an increase in HDL. 18 However, while these markers of cardiovascular risk change favorably, whether these changes result in improved outcomes is being studied. 11

14 TRT and Prostate Cancer: Common Fears vs Clinical Evidence Some patients may ask about TRT and risk of prostate cancer. In a recent meta-analysis from the Endogenous Hormones and Prostate Cancer Collaborative Group, there was no evidence of a link between serum testosterone levels and prostate cancer risk. 68 In another recent meta-analysis of patients who received TRT for 3 months to 3 years, there was no relationship between testosterone therapy and prostate cancer, the need for prostate biopsy, or other prostatic and urologic outcomes, including PSA and lower urinary tract symptoms. 62 Protecting prostate health is an important component of TRT monitoring. The risk of prostate cancer must be assessed before starting TRT, and treatment should not be started without further urologic evaluation in patients with prostate cancer, a palpable prostate nodule or induration, or a PSA level >3 ng/ ml. 50 The Endocrine Society recommends PSA surveillance at baseline and again after 3 to 6 months in men aged 40 years with a baseline PSA >0.6 ng/ ml. Beyond 6 months of TRT, clinicians monitor prostate health according to current prostate cancer screening guidelines for the patient s age and race. Although the Endocrine Society suggests performing DRE as well as measuring PSA to monitor for prostate cancer, some experts disagree with this recommendation. 69 Patients should be referred for a urology consult if 1 : PSA concentration rises by >1.4 ng/ml within any 12-month period during TRT PSA velocity exceeds 0.4 ng/ml/y, using a PSA level after 6 months of TRT as a reference and based on >2 years of PSA measurements DRE reveals a prostatic abnormality Severe lower urinary tract symptoms are present Researchers continue to examine the relationship between testosterone deficiency and prostate health. The Registry of Hypogonadism in Men (RHYME) is an international registry of men with treated and untreated testosterone deficiency. 70 The registry will recruit 1000 men with primary hypogonadism, secondary hypogonadism, and late-onset hypogonadism receiving care in primary care and specialty practices. Patients will undergo clinical and laboratory evaluation at baseline, 3 to 6 months, 12 months, and 24 months. The primary end point of the RHYME registry study is the rate of positive prostate biopsy results in hypogonadal men. Secondary end points will include other measures of prostate health, such as benign prostatic hyperplasia (BPH), as well as sexual function, quality of life, and cardiovascular outcomes. Findings from the RHYME registry study will provide important information on the natural history of testosterone deficiency and the safety and efficacy of TRT in hypogonadal men. 70 The Testosterone Replacement in Hypogonadal Men With Type 2 Diabetes and/or Metabolic Syndrome (TIMES2) study evaluated the effects of TRT on insulin resistance and cardiovascular risk factors in 220 hypogonadal men with T2DM or metabolic syndrome. 60 Patients were randomly assigned to treatment with 3-g metered-dose 2% transdermal testosterone gel (60 mg testosterone) or placebo gel once daily for 1 year. Many patients also were taking concomitant oral antidiabetes drugs such as metformin. Main findings from the TIMES2 study included the following: Transdermal testosterone was associated with a reduction in insulin resistance of 15.2% at 6 months (P =.006) and 16.4% at 12 months (P =.006) compared with placebo In the subgroup of patients with diabetes, those in the TRT arm had significantly better glycemic control at 9 months, as measured by a greater reduction in mean HbA1c compared with placebo ( 0.446%; P =.035) TRT improved several lipid parameters in patients with metabolic syndrome, leading to greater reductions in lipoprotein a ( 0.31 µmol/i; P =.008), total cholesterol ( mmol/l; P =.003), and low-density lipoprotein cholesterol (LDL-C) ( mmol/l; P =.012) compared with placebo. However, in the overall study population, TRT decreased high-density lipoprotein cholesterol (HDL-C) compared with placebo (.049 mmol/l; P =.032). Improvements in lipid profiles among men treated with TRT may result from improvements in body composition, particularly loss of overall fat mass and reduction in abdominal obesity. However, beneficial changes in cardiometabolic profile also have been observed in patients who did not experience any significant changes in body composition. 60 Other studies of men undergoing treatment with TRT have found no changes in any lipid parameters, including total cholesterol, HDL, LDL, or triglyceride levels, between, before, and after TRT. 61 Another meta-analysis of TRT and cardiovascular safety found a modest decrease in HDL (.49 mg/ dl; 95% CI,.85 to.13 mg/dl), but no other adverse cardiovascular outcomes associated with testosterone therapy. 62 POP QUIZ Risks of TRT include: A. Erythrocytosis B. Hypersomnia C. Migraine headache D. Osteoporosis 12

15 POTENTIAL RISKS OF TRT Erythrocytosis Increases in hemoglobin and hematocrit are the most frequent adverse events observed with TRT. In a meta-analysis of 51 trials, TRT was associated with an increase in mean hemoglobin (0.80 g/dl, 95% CI, g/dl) and hematocrit (3.18%, 95% CI, 1.35%-5.01%) compared with placebo. 62 TRT also increased the risk of erythrocytosis compared with placebo (RR, 3.15; 95% CI, ), although this effect is dose-related and is often managed with dose reduction. 62 The clinical significance of these findings on patient outcomes is unclear. Cardiovascular Risk The role of TRT in men with cardiovascular disease remains contentious. It appears to reduce risk in advanced cardiac failure. 63 Adverse cardiovascular events, however, have been reported, including myocardial infarction (MI) and depressed ventricular function. These events typically occur in patients who take supraphysiologic testosterone doses, such as anabolic steroid users. 63 In general, it appears that testosterone can be used safely in hypogonadal men with established CVD. 63,64 Patients should be monitored during TRT to ensure that testosterone levels remain in physiologic ranges. 63 TRT may increase cardiovascular risk factors in certain high-risk populations. The Testosterone in Older Men with Mobility Limitations (TOM) trial evaluated safety and efficacy of treatment with 1% testosterone gel in a population of 209 older men (mean age, 74 years) with limited mobility and a high prevalence of chronic disease, including hypertension, diabetes, hyperlipidemia, and obesity. 65 Compared with men in the placebo group, men in the TRT group had significantly greater increases in leg-press strength, chest-press strength, and stair-climbing power while carrying a load. However, during the 6-month study period, 23 men in the testosterone group had cardiovascular-related adverse events, including hypertension and MI, compared with 5 men in the placebo group. The finding of excess cardiovascular risk in the TRT group mandated that the TOM study be discontinued early. 65 The study authors cautioned against extrapolating these findings to other patient populations, particularly to younger men with testosterone deficiency without established CVD or limitations in mobility. 65 Other Adverse Events Testosterone injections are associated with peak and trough serum testosterone concentrations, increasing the risk of mood swings. This may be an important consideration for patients with comorbid psychiatric illness. Hepatotoxicity is a concern with oral testosterone formulations, which are not available in the United States. Other adverse events include acne and reduced sperm production. 1 MONITORING RECOMMENDATIONS Monitoring Testosterone Levels The Endocrine Society recommends measuring testosterone levels 3 to 6 months after initiating therapy. 1 Endogenous testosterone levels follow a circadian rhythm, with highest levels in the morning. Therefore, Table 5. TRT Monitoring Strategies Parameter Schedule Comments Testosterone level After 3-6 mo TRT should aim to raise serum testosterone to mid-normal range Hematocrit Baseline, after If hematocrit is >54%, discontinue TRT until hematocrit 3-6 mo, then annually decreases to safe level; exclude hypoxia or sleep apnea; resume TRT with a reduced dose BMD After 1-2 y Measure in hypogonadal men with osteoporosis or low trauma fracture PSA and DRE Baseline, after 3-6 mo, then Measure in men aged 40 y with baseline PSA >0.6 ng/ml in accordance with standard screening guidelines Adverse events Every office visit Monitor for formula-specific adverse events, such as skin reactions (patch) or changes in taste (buccal tablets) BMD: bone mineral density; DRE: digital rectal examination; PSA: prostate-specific antigen; TRT: testosterone replacement therapy. Source: Reference 1. 13

16 testosterone should be measured in a nonfasting blood sample taken between 7:00 am and 11:00 am, or within a few hours of waking in nightshift workers and others with nontraditional sleep/wake schedules. 1 Other Monitoring Recommendations Patients should receive ongoing assessments of response and adherence to treatment with TRT (TABLE 5). This includes an evaluation of formulation-specific adverse effects at every office visit. 1 The patient s hematocrit should be measured at 3 to 6 months after treatment initiation and then annually, and TRT should be stopped if hematocrit exceeds 54%. 1 If the hematocrit later decreases to normal levels and evaluation reveals no contraindication such as hypoxia or sleep apnea, TRT may be resumed at a reduced dose. 1 In men with osteoporosis or a history of low-trauma fracture, BMD should be measured at the lumbar spine, femoral neck, and hip 1 to 2 years after TRT initiation. 1 Prostatespecific antigen (PSA) test and digital rectal exam (DRE) should be assessed at baseline, after 3 to 6 months, and then in accordance with standard prostate cancer screening guidelines. 1 Treatment Modification For the patient who does not achieve an adequate response to TRT within 3 to 6 months of starting therapy, an additional workup may be required to identify other factors contributing to the clinical presentation. This may include a shift in the relative contribution of primary and secondary hypogonadism that warrants a change in treatment plan. Treatment adherence also should be assessed. For patients with poor adherence to TRT, a change in formulation may improve treatment success. Changes in dosing also may be needed, keeping in mind that serum testosterone levels should not exceed the normal physiologic range. Need for Referral In collaborative care settings, multidisciplinary healthcare providers work together to select appropriate therapy and assess therapeutic outcomes. Collaborative-care models that include pharmacists have improved outcomes in a range of complex chronic conditions, including mental health disorders and chronic kidney disease. 66,67 As central members of the care team, pharmacists provide guidance on initiating, modifying, and discontinuing drug therapy; provide patient counseling and education; and identify and resolve potential and actual drug-related problems. Pharmacists can refer patients to other healthcare providers as warranted. Patients who fail to respond to treatment, lose response after an initial benefit, or have adverse events may need to be re-evaluated for a change in underlying disease status. In particular, patients in whom new prostate or urinary symptoms develop should be assessed by a urologist. 1 CONCLUSIONS Testosterone deficiency is a highly prevalent condition among aging men, particularly among men who are obese and in those with metabolic syndrome, T2DM, and other chronic conditions. Increasingly recognized as more than a marker of sexual function, testosterone is now understood to be an integral component of many metabolic pathways associated with body composition, cardiometabolic risk profile, and general well-being. New and emerging options for TRT may improve tolerability and treatment adherence, allowing patients to replace testosterone at near-normal physiologic levels with a low risk of adverse events. Successful treatment depends on matching the patient s needs, lifestyle, and preferences with specific formulations. Pharmacists play an essential role in educating patients about the value of TRT, explaining potential complications associated with its use, and setting treatment expectations to improve adherence and satisfaction with therapy. How to Receive Credit Participants wishing to earn CPE credit must: Read the supplement. Relate the content material to the learning objectives. Complete the self-assessment questions and evaluation form online at: After login, please enter the code: CAE76711 Successful completion of the self-assessment is required to earn CPE credit. Successful completion is defined as a cumulative score of at least 70%. A certificate of credit will be automatically generated upon successful completion of the activity. 14

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19 NOTES

20 This Continuing Education article is supported by an educational grant from Abbott Laboratories and Lilly USA, LLC.