Androgen deficiency in the aging male

Androgen deficiency in the aging male Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology The American Society for Reproductive Medicine, Birmingham, Alabama The purpose of this Educational Bulletin is to review current methods of evaluation, the indications for treatment, and to provide recommendations for treatment of androgen deficiency in the aging male (ADAM). (Fertil Steril Ò 2008;90:S83 7. Ó2008 by American Society for Reproductive Medicine.) Serum testosterone levels decline as men age (1, 2). In a portion of older men (over 50 years), this decline may result in clinical symptoms and signs of androgen deficiency, or andropause. Although guidelines for androgen replacement therapy for older men have been developed by several groups (3 5), the data to support treatment are based on the results of only a small number of clinical trials (6). It has not been established definitively that the decline in testosterone observed in most aging men results in an androgendeficient state having health implications that can be avoided or ameliorated by androgen therapy (7 10). The purpose of this document is to review current methods of evaluation, the indications for treatment, and to provide recommendations for treatment of androgen deficiency in the aging male (ADAM). INDICATIONS FOR TREATMENT Symptoms and Signs Symptoms associated with low testosterone levels in the aging male include low libido (with or without erectile dysfunction) (11); decreased strength, energy, or stamina (12); increased irritability or decreased enjoyment of life (13); and alterations in certain components of cognitive function (14). Physical findings that may be due to androgen deficiency include osteopenia/osteoporosis (15), loss of muscle mass (16), increased visceral adipose (17), testicular atrophy, and gynecomastia. Age-related androgen deficiency may be worsened by significant abdominal obesity leading to elevated levels of estrogens and sex hormone binding globulin (SHBG) (18), by liver disease, or by certain medications. Several published validated questionnaires provide the means for assessing the clinical manifestations of testosterone deficiency in older men (19 21). However, scores derived from such questionnaires do not predict or correlate well with measured free and total testosterone levels (22) and thus lack specificity for the clinical diagnosis of ADAM (23 25). Educational Bulletin Revised August 2008. No reprints will be available. Laboratory Evaluations Serum testosterone should be evaluated only in men with signs or symptoms of androgen deficiency. Serum total testosterone is composed of free, albumin-bound, and SHBGbound components. The combination of free testosterone and albumin-bound testosterone is denoted as bioavailable testosterone which, in epidemiologic studies, is the component that best correlates with parameters such as bone mineral density (12), sexual function (26), and cognition (27). However, it is by no means established that bioavailable testosterone represents the effective and clinically relevant fraction of total testosterone for every androgen target organ. Some effects of testosterone may reflect the actions of its metabolites, such as estradiol in bone and dihydrotestosterone in the prostate. Because SHBG levels increase with age, the agerelated decline in serum bioavailable testosterone is much greater than for total testosterone (28). The laboratory assay for serum total testosterone is widely available, but it may lead to misclassification of some men who would be considered androgen deficient on the basis of bioavailable or free testosterone levels. However, the accuracy of some methods for the measurement of free testosterone levels has been challenged (29), and bioavailable testosterone assays are not widely available. A recent trend toward measurement of total testosterone and SHBG has emerged, allowing calculation of a free testosterone index (FTI: total testosterone/shbg) as an indication of the amount of bioavailable testosterone. Regardless of which component of serum testosterone is measured, blood samples should be obtained in the morning because of the circadian variation and pulsatile nature of testosterone secretion. Currently there is no established consensus on the hormonal and clinical criteria for identifying older men who are candidates for androgen therapy. Therefore, current recommendations are based on expert opinion, and there is an urgent need for additional studies to better define which patients are likely to benefit from androgen therapy. Consensus recommendations issued by the Endocrine Society have proposed that total testosterone levels below 200 ng/dl (<6.9 nmol/l) identify hypogonadism that warrants treatment, unless contraindicated (as discussed later). The recommendations further suggest that men with levels between 200 and 400 ng/dl (6.9 13.9 nmol/l) may benefit from therapy, and that androgen deficiency is unlikely in men with total testosterone concentrations above 400 ng/dl (3). Measuring free or bioavailable testosterone or calculating the FTI may be useful in the evaluation of men who might benefit from 0015-0282/08/$34.00 Fertility and Sterility â Vol. 90, Suppl 3, November 2008 S83 doi:10.1016/j.fertnstert.2008.08.094 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.

androgen treatment. Values for bioavailable testosterone that are below the normal range for normal young adult men, or a FTI less than 0.153 nmol/nmol (1), support the diagnosis of androgen deficiency. The serum luteinizing hormone (LH) should be measured as part of the evaluation of an older man with androgen deficiency to detect secondary hypogonadism (of hypothalamicpituitary origin.) Serum gonadotropin levels rise modestly with age, but few older men have values outside the normal range for young adult men. Further evaluation with serum prolactin and pituitary magnetic resonance imaging (MRI) is warranted when the total testosterone level is very low (<150 ng/ dl, <5.2 nmol/l) and the serum LH is normal or low. DECISION TO TREAT Men aged over 50 years should be considered candidates for androgen therapy if they have [1] clinical manifestations indicative of ADAM (osteopenia, decreased muscle mass and strength, decline in stamina and energy, low libido, loss of erectile quality, irritability, impaired cognition, or other mood changes); [2] a low serum testosterone, bioavailable testosterone, or FTI; and [3] no contraindications to treatment. Because the long-term health risks and benefits of androgen therapy for androgen deficiency in the older man have not been defined, it is important to monitor treated patients for both efficacy and safety. At a minimum, the physical examination before therapy begins should include the breasts, heart, lungs, and prostate to exclude preexisting gynecomastia, cardiovascular abnormalities, or prostatic conditions that may be exacerbated by treatment. A pretreatment serum prostate specific antigen (PSA) test and complete blood count also should be obtained. Prostate biopsy is recommended when the digital rectal examination or PSA result is abnormal. It is premature to recommend preventive androgen therapy in older men with androgen deficiency. Most older men are relatively hypogonadal and should be considered as candidates for androgen therapy only when they have symptoms or physiologic findings that reasonably can be attributed to androgen deficiency. Such physiologic findings and symptoms have a complicated pathogenesis and could be affected by a variety of factors. THERAPEUTIC AGENTS AND MONITORING DURING TREATMENT Therapeutic Agents All commercial androgen formulations currently available in the United States are preparations of testosterone, an androgen that can be converted to estradiol. Estradiol may be the major sex steroid affecting male bone density (30). The efficacy of testosterone therapy should be determined on an individual basis. There is no evidence that clinical response differs with the testosterone formulation employed; the benefits of treatment depend on the serum testosterone level that is achieved. The goal of androgen therapy is to raise testosterone levels over pretreatment values without exceeding the normal range for young adult males. No dose-effect of androgen therapy has been demonstrated. However, dose escalation to increase efficacy may lead to an increase in side effects (31). The major forms of testosterone delivery available in the United States and considered safe for use in older men are listed in Table 1. The oral methylated testosterones are not listed and should not be used because of their potential for liver toxicity. Selection is based on patient preference, the serum testosterone levels that can be obtained, and the potential side effects unique to the mode of testosterone delivery (see Table 1). Dehydroepiandrosterone (DHEA), a progenitor of testosterone and other sex steroids, is commercially available in oral form as an unregulated health supplement. When used in standard replacement doses (50 100 mg/day) in older men, DHEA does not significantly increase serum testosterone levels (32), although higher doses may. No data relating to the efficacy of DHEA for the treatment of androgen deficiency in older men are available. Monitoring During Treatment Within the first 2 to 3 months after treatment begins, older men receiving testosterone therapy should be seen to evaluate the clinical response and to identify possible adverse effects of treatment, including weight gain, peripheral edema, gynecomastia, breast tenderness, symptoms of benign prostatic hyperplasia, or problems with sleep; a digital rectal examination of the prostate also should be performed. The testosterone level should be measured to determine whether the treatment regimen is achieving its intended goals. The optimal time to measure the testosterone level varies with the mode of treatment (see Table 1). Because therapy is empiric, the clinical response may help to guide therapy more than the testosterone level. The questionnaires used for the initial evaluation of ADAM also can be used to monitor the efficacy of treatment (15). Safety monitoring parameters should include measurements of hemoglobin or hematocrit and serum PSA. The PSA level is especially important because PSA production is androgen dependent and a rapid rise (>1.0 ng/ml) within the first 3 to 6 months of therapy may reflect the presence of a preexisting unrecognized cancer (33). In men who exhibit a significant increase in serum PSA, androgen therapy should be discontinued until a thorough prostate evaluation can be accomplished. There is no evidence that androgen therapy has adverse effects on liver function or lipoprotein levels in older men; consequently, such monitoring during treatment is unnecessary for most men. When there is no evidence of adverse effects, the serum testosterone level is within the therapeutic range, and therapy is judged efficacious, evaluation should be repeated within 3 months, again 6 months later, and then at least annually S84 ASRM Practice Committee Androgen Deficiency in the Aging Male Vol. 90, Suppl 3, November 2008

TABLE 1 Testosterone delivery systems available in the United States. Preparation Initial treatment dose for older men Time to peak testosterone Timing of testosterone testing during treatment Possible specific side effects Injectable esters Pain at injection Testosterone 150 200 mg 2 3 days 1 week site, mood swings, enanthate (100 200 mg/ml; 10 ml) every 2 weeks or 75 100 mg/week elevated hematocrit Testosterone 150 200 mg every 2 3 days 1 week cypionate (100 200 mg/ml; 10 ml) 2 weeks or 75 100 mg/week Testosterone pellets 225 mg/4 6 months 1 month 3 4 months Local site infection, extravasation of pellet, mood swings, elevated hematocrit Patches Scrotal (Testoderm: 40 cm 2 ; 1 patch/day 3 5 hour 12 hours Local site irritation 40 cm 2 or 60 cm 2 ) Nonscrotal (Androderm: 2.5 mg or 5.0 mg) 5 mg/day 6 10 hours 12 hours Skin irritation, urticaria Gel (Testim, Androgel: 2.5-g, 5.0-g packet) 5 g/day Constant 2 4 week Occasional mild skin irritation Notes: Androderm, Watson Pharma, Morristown, NJ. Androgel, Solvay, Marietta, GA. Testim, Auxilium, East Norriton, PA. ASRM Practice Committee. Androgen Deficiency in the Aging Male. Fertil Steril 2008. thereafter. A complete blood count, serum PSA, and testosterone level should be obtained 3 and 6 months after treatment begins and at least annually afterward. If osteoporosis was an indication for androgen therapy, bone mineral density should be reevaluated after approximately 2 years of treatment. Risks of Treatment The potential risks of androgen therapy in older men include fluid retention, gynecomastia, excessively elevated red blood cell mass, exacerbation of sleep apnea or benign or malignant prostate disease, and an increase in risk for cardiovascular disease (CVD). The fluid retention and gynecomastia are usually mild and occur infrequently in men with testosterone levels in the normal range. Although new or worsening sleep apnea during testosterone treatment has been observed (34), it appears to be infrequent. An increase in red blood cell mass leading to polycythemia also may occur during testosterone therapy in older men. Fertility and Sterility â Concerns that treatment may aggravate CVD are theoretical and based largely on observations that CVD is more common in men than in age-matched women. However, in epidemiologic studies, low testosterone levels are more predictive of CVD than high levels in men; low testosterone levels have been associated with an increased risk for development of atherosclerosis (35) and the metabolic syndrome, which is a precursor of CVD (36). Other studies have demonstrated that testosterone has arterial vasodilatory (37) and anti-ischemic effects (38). Androgen therapy in older men generally has been observed to improve, rather than worsen, atherosclerotic lipid profiles (3). The inverse relationship between testosterone levels and the risk for CVD has been well documented (39, 40) and suggests that testosterone therapy may be offered without serious concerns about potential adverse cardiovascular effects (40). Large randomized clinical trials are required to better define the effects of testosterone treatment on CVD risk. Another theoretical concern is that testosterone treatment may exacerbate benign prostatic hyperplasia or incident prostate cancer, although studies of the effects of testosterone therapy undertaken thus far have observed little or no change in PSA (41), no increase in symptoms of benign prostatic hyperplasia, and no increased propensity for development of prostate cancer. Nevertheless, experience with androgen therapy in older men still is too limited to allow confident conclusions regarding any associated long-term risks of prostatic disease (7). Although rarely of clinical importance in S85

older men, exogenous androgen supplementation may decrease sperm production significantly. The absolute contraindications to androgen therapy in older men are [1] clinical prostate cancer, [2] a previous history or current evidence of breast cancer, [3] an elevated hematocrit (>55%), and [4] sensitivity to any of the ingredients in androgen formulations. Relative contraindications to androgen therapy include [1] severe obstructive sleep apnea, [2] a hematocrit between 52% and 55%, [3] severe symptoms in the lower urinary tract related to benign prostatic hyperplasia, and [4] medical conditions wherein modest fluid retention may be harmful (e.g., congestive heart failure). There is some evidence to suggest that hypogonadal men may be at increased risk for unsuspected prostate cancer because PSA production is falsely low due to low circulating androgen levels (33, 42). However, because PSA levels in hypogonadal men with prostate cancer are likely to increase rapidly during androgen treatment, therapy actually may facilitate detection of prostate cancer when monitored appropriately. SUMMARY AND RECOMMENDATIONS Androgen deficiency in the aging male may be associated with changes in mood, body composition, stamina, energy, and decreased sexual and cognitive function as well as loss of bone mineral density. Such signs and symptoms may be relieved or eliminated with testosterone replacement therapy. Serum testosterone should be evaluated only in men with signs or symptoms of androgen deficiency. Androgen therapy should be considered for men who have symptoms of androgen deficiency and a low serum total testosterone concentration (<200 ng/dl). Free or bioavailable testosterone levels or the free testosterone index should be evaluated in men who have symptoms of androgen deficiency and a borderline total serum testosterone concentration between 200 ng/dl and 400 ng/dl. During androgen therapy, serum testosterone, PSA, and hematocrit should be monitored, and periodic digital rectal examination is recommended. Limited data regarding the benefits and risks of testosterone replacement therapy do not permit specific treatment recommendations at this time. Further randomized clinical trials are required to better define the effects of androgen replacement therapy in aging men. Acknowledgments: This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine as a service to their members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. This report was approved by the Board of Directors of the American Society for Reproductive Medicine. REFERENCES 1. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone in healthy men. J Clin Endocrinol Metab 2001;86:724 31. 2. Arujo AB, O Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM, McKinlay JB. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2004;89:5920 6. 3. Swerdloff RS, Chair. 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