AS our population ages, concerns about frailty and

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1 Journal of Gerontology: MEDICAL SCIENCES 2004, Vol. 59A, No. 5, Copyright 2004 by The Gerontological Society of America Special Article Masculine Vitality: Pros and Cons of Testosterone in Treating the Andropause Sanjay Asthana, 1 Shalendar Bhasin, 2 Robert N. Butler, 3 Howard Fillit, 4 Joel Finkelstein, 5 S. Mitchell Harman, 6 Lana Holstein, 7 Stanley G. Korenman, 8 Alvin M. Matsumoto, 9 John E. Morley, 10 Panayiotis Tsitouras, 6 and Randall Urban 11 1 University of Wisconsin Medical School, Madison. 2 Charles R. Drew University of Medicine and Science, Los Angeles, California. 3 International Longevity Center-USA, Alliance for Health & the Future, New York. 4 Institute for the Study of Aging, New York. 5 Harvard Medical School, Cambridge, Massacusetts. 6 Kronos Longevity Research Institute, Phoenix, Arizona. 7 Miraval Life in Balance Resort, Tucson, Arizona. 8 UCLA School of Medicine, Los Angeles, California. 9 VA Puget Sound Health Care System, Seattle, Washington. 10 Saint Louis University School of Medicine, St. Louis, Missouri. 11 University of Texas Medical Branch in Galveston. AS our population ages, concerns about frailty and disability, as well as the all-too-human desire to remain young for as long as possible, have led increasing numbers of women and men to the questionable practice of restoring diminishing hormone levels. Recent research findings have highlighted the health risks of oral estrogen progestin combination therapy in older women. To date, however, no serious long-term randomized trials of sufficient size to examine the effects of testosterone replacement on men have been conducted, nor is it clear what role the observed decline in total and bioavailable testosterone plays in male aging. Currently, the long-term clinical beneficial effects of testosterone replacement in older men are poorly defined, and the magnitude of risks for prostate and heart disease remain largely unknown. Because of these uncertainties, the academic community is in agreement that large-scale definitive studies are needed. In contrast, the media and the public at large appear to have moved beyond science in this field. A recent market analysis indicates that testosterone sales were expected to reach $400 million in 2002 (1). Upward trends in the sales of testosterone products are likely to persist and even grow in the foreseeable future. Thus, it is extremely important for the scientific community to develop a consensus about the health benefits and safety of these products. The purposes of this special article are to: 1) summarize what we already know about the andropause and the effects of testosterone replacement therapy; 2) propose a research agenda for future work; and 3) identify other steps that might be taken in the realm of public information and policy. For a more detailed treatment of these issues, see the International Longevity Center Workshop Report, which is available at BIOCHEMISTRY AND METABOLISM OF TESTOSTERONE Little proof exists to support the hypothesis of andropause the so-called male menopause. Unlike women, whose estrogen levels precipitously decline beginning in their fourth decade, men exhibit a wide range of testosterone levels throughout life. Serum levels of total and free testosterone increase during puberty, reaching a maximum in the twenties and thirties, then generally decline steadily at approximately 1% per year with increasing age. A critical factor in evaluating the biologic effectiveness of testosterone is the circulating concentration of bioavailable testosterone. This factor, the fraction of circulating testosterone that is not tightly bound to sex hormone-binding globulin, is considered to be the biologically active component that actually enters cells, interacts with intracellular androgen receptors, and, in that manner, regulates gene expression and cellular function. Testosterone is actively metabolized to estradiol, a potent estrogen, and to dihydrotestosterone, an androgen more potent than testosterone. The role of each in mediating the effects of circulating testosterone on target tissues and biological function, especially as a function of aging, is not well understood (2). AGE-RELATED CHANGES IN TESTOSTERONE FUNCTION By the seventh to eighth decade of life, a significant number of otherwise healthy men have levels of free or bioavailable testosterone that, if observed in men under the age of 45, would undoubtedly lead to their classification as hypogonadal. The extent to which this observed reduction in testosterone levels contributes to loss of bone, lean body/skeletal muscle mass, gain in body fat, and frailty remains to be determined. Preliminary evidence suggests 461

2 462 ASTHANA ET AL. that testosterone replacement has some potential to reduce these concomitants of aging in men, but the interactions of testosterone with diet, exercise, and other hormone deficiencies or excesses characteristic of aging are largely unexplored. DEFINITION OF HYPOGONADISM Men with total and/or bioavailable testosterone levels below the normal range (defined statistically based on measurements in large numbers of young men) are currently classified as hypogonadal. The Endocrine Society s Second Annual Andropause 2001 meeting reports: Total testosterone levels, 200 ng/dl clearly indicate hypogonadism, and in most instances indicate that benefits may be derived from testosterone replacement therapy...if a healthy man has a serum testosterone level. 400 ng/dl, it is unlikely he is testosterone deficient. [Note that recent data suggesting an upper value of 500 ng/dl may be more appropriate (3).] As a corollary, values between 200 and 500 ng/dl may be considered questionable for hypogonadism and suggest a need for further evaluation in men with symptoms of testosterone deficiency. Members of the Endocrine Society can access the full report at www. endosociety.org/membersonly.cfm To properly define hypogonadism, however, functional as well as biochemical criteria should be used rather than this type of statistical construct. Appropriate criteria would include low serum levels of bioavailable testosterone as well as subjective physiological changes consistent with androgen deficiency, such as reduced muscle mass or strength, reduced bone mass, and reduced libido. It is quite possible that the relationship between circulating testosterone levels and various physiological endpoints differs for each system. Thus, a level of testosterone that is sufficient to support libido may be inadequate to maintain bone mineral density or muscle mass. Unfortunately, at the time of this report, insufficient data exist to rigorously identify levels of total bioavailable testosterone that define physiological or functional hypogonadism for most target organs and tissues or for men of different ages. Research to address this problem and the related problem of accuracy and reliability of assays for total and bioavailable testosterone should be a high priority. TESTOSTERONE REGULATION OF SKELETAL MUSCLE A common finding of studies of hypogonadal young men, as well as older men with age-related declines in testosterone, is reduced lean body mass. The observation that testosterone supplementation in both young and older men increases muscle mass suggests that testosterone may play an important role in the preservation of muscle mass (4 8). Testosterone effects on the muscle are highly correlated with the administered dose of testosterone and the resulting testosterone concentrations (9). Previous studies in older men used relatively small doses of testosterone (6,8,10); these studies demonstrated modest gains in fat-free mass, a significant decrease in fat mass, but inconsistent changes in muscle strength. Testosterone supplementation is associated with hypertrophy of both type I and type II muscle fibers, and a dose-dependent increase in the number of myonuclei and satellite cells (11). Androgens increase muscle mass by promoting the commitment of mesenchymal pluripotent cells into the myogenic lineage and inhibiting the differentiation of these cells into the adipogenic lineage (12). In addition, testosterone stimulates muscle protein synthesis and improves the reutilization of amino acids by the skeletal muscle (13). The molecular mechanisms that mediate the anabolic effects of androgens are poorly understood. Further studies are needed to determine whether testosterone supplementation improves physical function and health-related outcomes in individuals at risk for disability. EFFECT OF TESTOSTERONE ON BONE DENSITY As men age, their bone mineral density declines and they become vulnerable to fractures (14 16). It is unclear the extent to which this decline is related to the age-related changes in testosterone versus other bone-regulating factors (e.g., parathyroid hormone, vitamin D, growth hormone) (17 20). One study conducted to determine testosterone s role in increasing spinal bone density suggested that testosterone increased bone mineral density only in men whose serum testosterone levels were particularly low before treatment (21). Although research suggests that testosterone replacement may benefit some older men, further studies are needed. TESTOSTERONE, BRAIN FUNCTION, AND COGNITION Testosterone, which crosses the blood brain barrier easily, affects brain function via androgen receptors selectively distributed throughout the brain (22). Additionally, androgens are probably synthesized in the brain and play an important role in its development, growth, maturation, and differentiation (23). The results of basic science investigations corroborate those of clinical trials and epidemiological studies. Although not universally confirmed, administration of testosterone to men with low testosterone levels has been shown to enhance specific areas of cognitive function in the majority of studies. Administration of testosterone, either by weekly injection or daily scrotal patch, significantly enhanced spatial memory, working memory, and verbal fluency of healthy older men (24 28). These results must be considered preliminary. TESTOSTERONE AND PROSTATE Among the greatest fears related to testosterone replacement for older men are increased risks for benign prostatic hyperplasia and prostate cancer (29,30). Dozens of reports from testosterone replacement studies over the last 20 years have shown no increase in prostate cancer. However, definitive conclusions await a study of sufficient duration to answer that important question (31 36). TESTOSTERONE AND ERECTILE FUNCTION Male-type libido appears to require male levels of serum testosterone (37), and testosterone clearly improves libido when administered to older men (38). Erectile dysfunction, on the other hand, appears to be influenced by many factors, including depression, vascular and intrinsic penile disease, and autonomic neuropathy, in addition to hypogonadism.

3 ANDROPAUSE 463 Thus, although no direct relationship between hypogonadism and human erectile dysfunction has been established, they are both common manifestations of aging (39). TESTOSTERONE, INSULIN SENSITIVITY, AND THE CARDIOVASCULAR SYSTEM The effects of testosterone supplementation on a wide variety of physiological systems in older men have recently been reviewed and summarized by Morley (40). It is noteworthy that testosterone and dihydrotestosterone generally raise insulin-like growth factor levels and lean body mass while decreasing fat mass. They also lower serum total cholesterol and low-density lipoprotein, but also diminish high-density lipoprotein. Coronary artery disease has been associated with low testosterone levels in men (41), although cause and effect have not been established. Adequately powered long-term studies are needed to determine the deleterious and beneficial effects of testosterone treatment on the cardiovascular system. THE NEED FOR A LARGE CLINICAL STUDY Given the increasing use of testosterone by the public, it is crucial to establish the risk/benefit ratio of testosterone replacement therapy so that patients and doctors can make informed choices. No studies to date have included a sufficient number of participants to adequately make these assessments. A large-scale prospective randomized, placebo-controlled trial with approximately 6000 participants (3000 taking testosterone, with an equal number taking placebo) has been proposed by a consortium of academic andrologists to ascertain changes in the incidence of prostate cancer and coronary events. This number of participants, based on the need to define possible risks, should be enough to firmly establish the possible benefits of testosterone replacement therapy. The need to conduct a large-scale clinical trial is underscored by the history of hormone replacement therapy (estrogen plus progesterone) in women. Decades of epidemiologic research led to widespread use of this treatment for postmenopausal women. Only recently, as a result of randomized, placebo-controlled, large-scale clinical trials, have we come to conclude that the prior interpretation based on limited epidemiologic data may have been misleading. In a population of women, most of whom were well past the menopause, total morbidity attendant to treatment with hormone replacement therapy has been found to increase, not decrease, with greater likelihood of cardiovascular events and development of breast cancer (42). Based on these data, which could only be attained from a largescale clinical trial, millions of older women and their physicians are reassessing the wisdom of beginning or continuing on hormone replacement therapy. Similarly, a large-scale clinical trial of testosterone replacement therapy for older men is required to inform the public and physicians about the risks and benefits of treatment with testosterone. The study should focus on the response of older hypogonadal men to an extended period of testosterone replacement therapy (5 to 6 years), with measurable endpoints to include muscle mass and strength; physical functioning; bone mineral density and incidence of bone fractures; body composition; insulin sensitivity, glucose tolerance, and incidence of diabetes mellitus; cognitive function and incidence of dementia; sense of well-being and incidence of dysthymia; erythremia; sleep apnea; progression of atherosclerosis; and, most important, the incidence of cardiovascular events, e.g., myocardial infarction, stroke, and cardiac death. It would also evaluate effects on erectile function; the development of benign prostatic hypertrophy requiring invasive therapy; and the development of clinical prostate cancer. Major questions about how to conduct such a trial have been addressed in some detail (43). RESEARCH AGENDA Beyond the need for a large clinical study, additional questions need to be addressed. Assays for Testosterone Better technology is needed for assaying circulating levels of testosterone, particularly for clinical laboratories. In the absence of reliable, well-standardized methodologies for determining blood levels of testosterone and bioavailable testosterone, little progress can be made in defining agerelated hypogonadism chemically and functionally. If we cannot accurately determine which men have low biological action of testosterone based on serum measurements, then we cannot select appropriate populations to study for risk/ benefit ratios of testosterone replacement in older men. Baseline testosterone will undoubtedly be a major determinant of individuals who are likely to benefit. Screening Tests for Hypogonadism Accurate diagnostic testing must be developed. Although at least three screening questionnaires are currently in use to determine whether men are functionally hypogonadal (44 46), independent epidemiological validation of these questionnaires is lacking. A screening questionnaire based more on quantifiable symptoms of hypogonadism is needed. Clinical Trials Many earlier clinical trials have suffered from methodological shortcomings, including insufficient numbers of participants; short duration of follow-up; lack of adequate control for effects of age, race, ethnicity, medication use, and illness; and lack of standardized methods of reporting. Care must be taken to address all of these issues in any new clinical trials undertaken. The source of the androgen also requires careful consideration. Use of a testosterone gel rather than an injection has been recommended both to avoid large swings in testosterone levels leading to nonphysiological levels, and because a gel is the form most likely to be used by the public if a trial indicates safety and efficacy. Biological Studies Additional research is needed to: Identify levels of testosterone that better define physiological or functional hypogonadism for target tissues and organs Better understand the relative roles of testosterone, di-

4 464 ASTHANA ET AL. hydrotestosterone, and E2 in mediating the effects of bioavailable testosterone on these target tissues and organs Determine the number and location of androgen receptors in target tissues and organs, and learn whether these change with age Improve our knowledge of age-related changes in tissuespecific sensitivity and dose response to testosterone at both the molecular and clinical level Research is needed to better understand the molecular mechanisms for the effects of testosterone in many areas: bone mineral density, regional fat distribution and metabolism, muscle mass and strength, physical performance and function, cognitive function and mood, libido and sexual activity, cardiovascular performance, and immune function, if any. Studies in the frail elderly population are particularly needed. PUBLIC POLICY ISSUES In 2002, the Department of Veterans Affairs and the National Institute on Aging announced they would not go ahead with a planned 6000-man clinical trial to study testosterone replacement therapy in aging men. This was apparently due to concerns about whether a clinical trial could be designed that would protect the study s participants from potential health risks such as prostate cancer, heart attacks, and strokes. Such concerns are consistent with the recent report that estrogen plus progesterone replacement therapy may not be as safe as originally had been assumed (42). After evaluating the pros and cons of conducting a largescale clinical trial of testosterone therapy, an expert panel of the Institute of Medicine of the National Academies recommended going forward only with small-to-mediumsized trials to explore whether testosterone produces significant clinical benefits in older men (47). 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