Treatment of androgen deficiency in the aging male

Transcription

1 Treatment of androgen deficiency in the aging male The Practice Committee of the American Society for Reproductive Medicine Birmingham, Alabama Although guidelines for androgen replacement therapy for older men have been developed by several groups, the data to support treatment are based on the results of only a small number of clinical trials. It has not been definitively established that the decline in testosterone seen in most aging men results in an androgen deficient state with health-related outcomes that can be improved by androgen therapy. (Fertil Steril 2006;86(Suppl 4): S by American Society for Reproductive Medicine.) Serum testosterone levels decline as men age (1). 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 (2, 3), the data to support treatment are based on the results of only a small number of clinical trials. It has not been definitively established that the decline in testosterone seen in most aging men results in an androgen deficient state with health-related outcomes that can be improved by androgen therapy (4). INDICATIONS FOR TREATMENT Symptoms and Signs Symptoms associated with androgen deficiency in the aging male (ADAM) include low libido (with or without erectile dysfunction) (5); decreased strength, energy, or stamina (6); increased irritability or decreased enjoyment of life (7); and alterations in certain components of cognitive function (8). Physical findings that may be due to androgen deficiency include osteopenia/osteoporosis (9), loss of muscle mass (10), increased visceral adiposity (11), testicular atrophy, and gynecomastia. Age-related androgen deficiency may be worsened by significant abdominal obesity that leads to elevated levels of estrogens and sex hormone binding globulin (SHBG) (12), by liver disease or certain medications. Several published validated questionnaires allow assessment of the clinical manifestations of testosterone deficiency in older men (13 15). Laboratory Evaluations Measurement of one of the components of serum testosterone should be a part of the evaluation for androgen deficiency. Testosterone levels should be evaluated only for patients with signs or symptoms of androgen deficiency. Due Education Bulletin Under revision June Received January 12, 2004; revised and accepted January 12, No reprints will be available. Correspondence to: Practice Committee, American Society for Reproductive Medicine, 1209 Montgomery Highway, Birmingham, Alabama to the circadian variation and pulsatile nature of testosterone secretion, blood samples should be taken in the morning. Routine assessment of testosterone levels in all older men is not recommended because treatment of asymptomatic men has not documented benefits. Serum total testosterone is composed of free, albuminbound, and SHBG-bound components. The combination of free testosterone and albumin-bound testosterone is denoted as bioavailable testosterone, which, in epidemiological studies, is the component that best correlates with parameters such as bone mineral density (6), sexual function (16), and cognition (17). 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 result from its metabolites, such as estradiol in bone and dihydrotestosterone in the prostate. Since SHBG levels increase with age, the decline in serum bioavailable testosterone with normal aging is much greater than for total testosterone. The laboratory assay for serum total testosterone is widely available, but 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 (18), 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. Currently there is no universal consensus on the hormonal and clinical criteria that should be used to identify those older men who are candidates for androgen therapy. The current recommendations are therefore based on expert opinion, and there is an urgent need for additional studies to better elucidate which patients are likely to benefit from androgen therapy. Consensus recommendations from The Endocrine Society indicate that a total testosterone level below 200 ng/dl ( 6.9 nmol/l) indicates hypogonadism and warrants treatment unless contraindicated. Total testosterone levels of 200 to 400 ng/dl ( nmol/l) may suggest therapy could be beneficial, and total testosterone S236 Fertility and Sterility Vol. 86, Suppl 4, November /06/$32.00 Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 levels above 400 ng/dl are unlikely to reflect androgen deficiency (2). Measuring free or bioavailable testosterone or calculating the FTI may be useful in the evaluation of men who might benefit from androgen treatment. Values for bioavailable testosterone that are below the normal range for normal young adult men, or a FTI less than nmol/ nmol, (1) supports the diagnosis of androgen deficiency. A serum LH should be measured as part of the evaluation of an older man with androgen deficiency to detect secondary hypogonadism (of hypothalamic-pituitary 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 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 over age 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, physical examination before therapy begins should include the breasts, heart, lungs, and prostate to exclude preexisting gynecomastia, cardiovascular anomalies, or prostatic conditions that may be exacerbated by treatment. A pretreatment serum prostate specific antigen (PSA) and complete blood count also should be obtained. Prostate biopsy is recommended when the digital rectal examination or PSA 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 physiological findings that can be reasonably attributed to androgen deficiency. Such physiological 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 (19). The efficacy of testosterone therapy should be determined on an individual basis. There is no evidence that clinical response FERTILITY & STERILITY differs with the testosterone formulation employed; the benefits of treatment depend on the serum testosterone level that is achieved. Replacement of endogenous testosterone with equivalent levels of exogenous hormone has no measurable effect. 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. Table 1 lists the major testosterone delivery forms available in the United States that are considered safe for use in older men. 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 testosterone delivery form (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 ( mg/day) in older men, DHEA does not significantly increase serum testosterone levels (20), 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 two to three months after treatment begins, the older man receiving testosterone therapy should be seen to evaluate the clinical response and to identify possible adverse events. Assessment for weight gain, peripheral edema, gynecomastia, breast tenderness, symptoms of benign prostatic hyperplasia (BPH), problems with sleep, and a digital rectal examination of the prostate should be done. To assess effective administration of the testosterone, a single testosterone level should be measured (see Table 1 for recommended time to assess testosterone level for each replacement modality). Since therapy is empiric, the clinical response may be a better guide than the testosterone level. Some of the same questionnaires available for the initial ADAM evaluation can be used again to monitor relative treatment efficacy (15). Safety monitoring parameters should include a hemoglobin or hematocrit level and serum PSA determination. The PSA level is especially important, because a rapid rise ( 1.0 ng/ml) (27) within the first three to six months of therapy may reflect the presence of a preexisting cancer not previously detected, due to the fact that PSA production is androgen-dependent. Androgen therapy should be discontinued in men who have a significant increase in serum PSA until a complete prostate evaluation can be accomplished. Because there have been no reports of adverse effects on liver function or lipoprotein profiles in older men receiving androgen therapy, such monitoring during treatment is unnecessary for most men. If there are no obvious adverse treatment effects, the serum testosterone level is within the therapeutic range, and S237

3 S238 ASRM Practice Committee Androgen deficiency in the aging male Vol. 86, Suppl 4, November 2006 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 Testosterone enanthate ( mg every 2 wk or 2 3 d 1 wk Pain at injection site; mood swings mg/cc; 10 cc) 75 mg/wk Testosterone cypionate ( mg every 2 wk or 2 3 d 1 wk Elevated hematocrit mg/cc; 10 cc) 75 mg/wk Testosterone pellets 225 mg/4 6 mo 1 mo 3 4 mo Local site infection; extravasation of pellet; mood swings; elevated hematocrit Patches Scrotal (40 cm 2 ;60cm 2 ; Testoderm) 40 cm 2 ; 1 patch/d 3 5 h 12 h Local site irritation Nonscrotal (2.5 mg or 5 mg; 5 mg/d 6 10 h 12 h Skin irritation; urticaria Androderm, a Testoderm TTS) b Gel (2.5 g, 5 g packet; Testim, c Androgel) d 5 g/d Constant 2 4 wk Occasional mild skin irritation a Androderm (Watson Pharma, Morristown, NJ). b Testoderm TTS (Alza, Mountain View, CA). c Testim (Auxilium, East Norriton, PA). d Androgel (Solvay, Marietta, GA). ASRM Practice Committee. Androgen deficiency in the aging male. Fertil Steril 2006.

4 therapy is judged efficacious, evaluation should be repeated within three months, six months thereafter, and then at least annually. A CBC, serum PSA, and testosterone level should be obtained three and six months after treatment begins, and at least annually thereafter. If osteoporosis was an indication for androgen therapy, bone mineral density should be reevaluated approximately two years after the initiation 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 cardiovascular disease (CVD) risk. The fluid retention and gynecomastia are usually mild and occur infrequently for men with testosterone in the normal range. Although new or worsening sleep apnea during testosterone treatment has been observed (21), it appears to be infrequent (22). An increase in red blood cell mass leading to polycythemia also may occur during testosterone therapy in older men. The potential for treatment to aggravate CVD is theoretical and largely based on observations that CVD is more common in men than in age-matched women. However, epidemiological studies have observed that low testosterone levels are more predictive of male CVD than high levels, and other studies have shown that testosterone has arterial vasodilatory (23) and anti-ischemic effects (24). Androgen therapy in older men generally has been shown to improve, rather than worsen, atherosclerotic lipid profiles (2). Better definition of the effects of testosterone treatment on CVD risk awaits the results of large randomized clinical trials. Exacerbation of benign prostatic hyperplasia (BPH) or incident prostate cancer with testosterone treatment is another theoretical concern, although replacement studies performed todate have shown little to no change in PSA (25), no exacerbation of BPH symptoms, and no increased propensity for development of prostate cancer. Nevertheless, experience with androgen therapy in the older man is too limited to allow confident conclusions regarding the long-term prostate risks of treatment (4). Based on potential risks of treatment for androgen deficiency in older men, the absolute contraindications to such therapy are [1] clinical prostate cancer, [2] previous history or current evidence of breast cancer, [3] elevated hematocrit ( 55%), and [4] sensitivity to ingredients in androgen formulations. Relative contraindications to androgen therapy are [1] severe obstructive sleep apnea; [2] hematocrit 52%; [3] severe lower urinary tract symptoms due to benign prostatic hyperplasia (BPH); and [4] medical conditions wherein modest fluid retention may be harmful (example: congestive heart failure). Some evidence suggests that hypogonadal men are at increased risk for unsuspected prostate cancer because their PSA production is falsely suppressed by low androgen levels (26, 27). However, PSA levels in hypogonadal men with cancer are likely to increase rapidly during androgen treatment; therefore, androgen therapy may facilitate detection of prostate cancer with appropriate monitoring. FERTILITY & STERILITY SUMMARY 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. Testosterone replacement therapy may reverse these signs and symptoms. Only men with signs or symptoms of ADAM should have serum testosterone evaluation. For symptomatic men with low testosterone ( 200 ng/ dl), treatment should be considered. For symptomatic patients with borderline testosterone levels ( ng/dl), free or bioavailable testosterone levels or free testosterone index (FTI) should be evaluated. During treatment, testosterone, PSA, and hematocrit should be monitored, and routine digital rectal examination is recommended. Available data on the benefits and risks of testosterone replacement are limited and do not allow specific treatment recommendations. More randomized clinical trials are needed to evaluate the effects of androgen replacement in aging males. 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. While 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 in December 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: Swerdloff RS, chair. Proceedings of the Endocrine Society Andropause Consensus Conferences The Endocrine Society, Continuing Medical Education Series, Morales A, Lunenfeld B. 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