OF THE one thousand generations of humans that have

Transcription

1 X/98/$03.00/0 Vol. 83, No. 10 Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright 1998 by The Endocrine Society THERAPEUTIC PERSPECTIVE Issues in Testosterone Replacement in Older Men* SHALENDER BHASIN, C. J. BAGATELL, WILLIAM J. BREMNER, STEVEN R. PLYMATE, J. LISA TENOVER, STANLEY G. KORENMAN, AND EBERHARD NIESCHLAG All reprints must include the complete Therapeutic Perspective. I. Introduction Shalender Bhasin Charles R. Drew University of Medicine and Science and University of California Los Angeles School of Medicine Los Angeles, California OF THE one thousand generations of humans that have lived on this planet, only the men of the last two generations could have hoped to live past the age of 50! Since 1900, the number of Americans 65 yr of age or older has increased 11-fold, from 3.1 million to 33.9 million (1). By 2030, this number will have doubled again to 70 million. The older population is also getting older: while the age group is eight times larger now than it was in 1900, the 85 group is 31 times larger (1). Because of these powerful demographic trends brought about by increasing life expectancy, frailty, impaired sense of well-being, and sexual dysfunction have emerged as important quality-of-life issues for aging men. Ancient Indians, Greeks, and Egyptians were aware that extracts of animal testis could promote virility, potency, and vigor in men. In modern times, the castration and testistransplantation experiments in roosters, conducted initially by John Hunter (2) and later by Adolf Berthold (3), established the link between secretions of the testis and some of the sexually dimorphic features in the rooster. Brown- Sequard (4) recognized the association between changes in testicular function and the loss of vigor in older men; he claimed to have rejuvenated himself by injecting the extracts of guinea pig testis. In the 1930s, Butenandt (5) and Ruzicka shared the Nobel Prize for the chemical synthesis of testosterone. Although testosterone was the first hormone to be discovered and one of the first hormones to be chemically synthesized, it is ironic that we are just beginning to learn about its role in the aging process in men. There is agreement that testosterone levels decrease with advancing age in men; however, the significance of this decrease remains unclear. We do not know whether testosterone replacement therapy in older men would have beneficial effects on muscle function, sexual function, sense of well being, and quality of life, or whether this could be done safely. There is uncertainty about the longterm effects of testosterone administration on the prostate and on the cardiovascular system. Recognizing the relative paucity of definitive data, the increasing public interest, and the controversial nature of this issue, The Journal of Clinical Endocrinology & Metabolism invited several experts to present their opinions on unresolved questions related to androgen replacement in older men. Are older men hypogonadal? How should we define hypogonadism in older men? What testosterone assay has the best discriminating ability in older men? When should free testosterone levels be measured and by what method? Can testosterone supplementation produce clinically meaningful changes in body composition and muscle function in older men? Should testosterone be given to older men with sexual dysfunction and low normal testosterone levels? What are the long-term risks of testosterone replacement in older men? How should a clinician manage an older man presenting with low testosterone levels, or with sexual dysfunction and other symptoms of hypogonadism? How should testosterone replacement be administered and monitored in older men? What are the methodological and research design problems in the conduct and interpretation of studies of testosterone replacement in older men? It is well to remember that the debate over the relative risks and benefits of estrogen therapy in women has raged for 30 yr, and clarity has only recently begun to emerge in that field. In contrast, the debate over testosterone replacement in older men has just started; the ponderous issues of risks and benefits are unlikely to be resolved anytime soon. Accepted May 19, * Address all correspondence regarding these controversies and requests for reprints to: Shalender Bhasin, Chief, Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, and Professor of Medicine, University of California Los Angeles School of Medicine, Los Angeles, California Reprints of the Therapeutic Controversies will include all authors and all pages, as they appear in the journal. 1. Fowles DG A profile of older Americans: U.S. Department of Health and Human Services; Washington, DC: American Association of Retired Persons and the Administration on Aging. 2. Irvine W John Hunter s experiments: evidence of an eyewitness. Letter to Professor Thomas Hamilton, University of Glasgow, June 17, Lancet Berthold AA Transplantation der Hoden. Arch Anat Physiol Wiss Med

2 3436 THERAPEUTIC PERSPECTIVE JCE&M 1998 Vol 83 No Brown-Sequard CE Des effects produits chez Phomme par des injections souscutanées d un liquide retire des testicules frais de cobaye et de chien. CR Seanc Soc Biol. 1: Butenandt A Uber die chemische Unterschung der sexual hormones. Z. Angew Chem. 44: II. Changes in Reproductive Hormones During the Aging Process C. J. Bagatell and W. J. Bremner University of Washington and VA Puget Sound Health Care System (III) Seattle, Washington IN BOTH males and females, normal aging is accompanied by changes in reproductive function. Unlike the female, in whom reproductive aging culminates in menopause and the cessation of ovarian function, reproductive aging in the male is a gradual process. Many studies have assessed the changes in testosterone (T) and associated reproductive hormones that occur across the adult male life span. Serum T levels vary considerably depending on the overall health of the individual, smoking and alcohol use, obesity, and time of sampling. Although some earlier studies failed to show an age-related decline in serum T levels, it is now clear that there is a slow but continuous decline in average serum T after approximately age yr (1 3). Whereas younger men have higher serum T levels in the mornings than in the evenings, this circadian rhythm is often lost in older men (4). Also of interest, serum levels of sex hormone-binding globulin (SHBG) increase with aging, while levels of free T and non-shbg bound T decline, often to a greater extent that total T levels (3). Although all women undergo menopause, it is unknown whether every man experiences a decline in circulating androgens with aging. It has been estimated that approximately 50% of healthy men between the ages of 50 and 70 yr have levels of bioavailable T that are below the lower limit of normal for men aged 20 to 40 yr (5). However, there are currently few longitudinal studies of T levels in healthy men over a substantial portion of their life span, and it is unknown what percentage of men actually experience a reduction in serum T (or bioavailable T) over time. Assuming that T levels decrease in many men over time, on what basis should an older man be considered hypogonadal? If hypogonadism is defined strictly on the basis of serum T levels, a significant proportion of men over age 50 would meet the criteria for hypogonadism and could be considered candidates for T replacement. If the requirement of elevated gonadotropin levels is included, still a large number, perhaps 3 4% of all men in the yr age group (6), would be classed as hypogonadal. Should certain symptoms of T deficiency be required to diagnose hypogonadism in a man with a low T level? As described elsewhere in this symposium, T deficiency has wide-ranging manifestations. Because of concomitant medical conditions and medications, though, it is often difficult to know whether a particular complaint is the result of primarily androgen deficiency or of other factors. Thus, the diagnosis of hypogonadism in the older man is not always straight-forward. 1. Gray A, Beline JA, McKinlay JB, Longcope C An examination of research design effects on the association of testosterone and male aging: the results of a meta-analysis. J Clin Epidemiol. 44: Tenover, JS Androgen administration to aging men. Endo Metab Clin N Amer. 23: Tsitoura P, Bulat T The aging male reproductive system. Endo Metab Clin N Amer. 24: Bremner WJ, Vitiello MV, Prinz PN Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 56: Sih R, Morely JE, Kaiser FE, Perry HM, Patrick P, Ross C Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82: Feldman HA, McKinlay JB, Longcope C. Hypogonadism: correlates in a large random sample of Massachusetts men. Proceedings of the 79th Annual Meeting of The Endocrine Society, Minneapolis, MN, 1997, p (Abstract). III. Which Testosterone Assay Should Be Used In Older Men? 1 S. R. Plymate Veterans Affairs HCSPS and Geriatric Research Education and Clinical Center University of Washington School of Medicine Seattle, Washington IN WOMEN, the determination of age-associated gonadal failure is usually signaled as ovulation ceases with the cessation of the menstruation. A decrease in estrogen production after menopause is also evident by the onset of physical symptoms such as hot flushes, dry vagina, etc. that are easily discerned by the woman. However, measurement of estrogen levels during the follicular phase of the menstrual cycle preceding menopause and again after menopause does not necessarily reflect the magnitude of menopausal symptoms or marked increase in gonadotropins. The determination of age-associated hypogonadism (socalled andropause) is not as clear in men as it is in women. It is possible that andropause may not even occur in the majority of men, if it exists at all, as an independent entity outside of a disease-associated decline in plasma concentrations of testosterone. As men age, there is a decline in serum total testosterone levels that begins about the age of 40 yr. In cross-sectional studies the annual decline in total and free testosterone is 0.4% and 1.2%, respectively (1). However, it should be noted that these studies are cross-sectional, and although the serum testosterone level declines with age, the mean value for a group of disease-free men is rarely below the lower limits of the normal range for most laboratories, even into the ninth decade of life (2). The diagnosis of an andropause in an individual man is not necessarily further substantiated by the measurement of serum gonadotropins. In men, careful measurements of luteinizing hormone (LH) and FSH made in pooled blood samples reveals a small but significant increase in serum gonadotropin levels (3 5). However, unlike in women, the increase in blood gonadotropin levels in older, otherwise healthy men is not above the normal range for healthy adult men. Testosterone circulates in the blood 98% bound to protein. In men, approximately 40% of the binding is to the high 1 The author wishes to thank Dr. Sanjay Asthana for review of the manuscript.

3 THERAPEUTIC PERSPECTIVE 3437 affinity sex hormone binding globulin (SHBG), association constant (Ka) L/mol, and approximately 60% bound weakly to albumin (Ka L/mol) (6, 7). A number of measurements for testosterone are available from clinical laboratories, and it is important to understand the differences among them (7 11). The measurement of serum testosterone or total testosterone is usually performed by a radioimmunoassay and measures free plus protein bound testosterone. Free or dialyzable testosterone measurements are estimates of the fraction of testosterone in blood that is not bound to protein. These assays require determination of the percentage of unbound testosterone by a dialysis procedure, estimation of total testosterone, and the calculation of free testosterone. Free testosterone can also be calculated if total testosterone, SHBG, and albumin concentrations are known (8). Kits are available for determination of free testosterone without dialysis and are used to provide a free testosterone measurement by many laboratories. Unfortunately, these measurements are often inaccurate, especially when the testosterone levels are low and SHBG levels are elevated (9, 12). A third measurement of testosterone commonly made is that of bioavailable or non-shbg bound testosterone (10). This measurement determines the amount of testosterone not bound to SHBG and includes that which is nonprotein bound and weakly bound to albumin. It is this fraction that supposedly is bioavailable to tissues. This measurement takes into account that SHBG is precipitated by a lower concentration of ammonium sulfate, 50%, than albumin. Thus by precipitating a serum sample with 50% ammonium sulfate and measuring the testosterone value in the supernate, non- SHBG bound or bioavailable testosterone is measured. This fraction of testosterone can also be calculated if total testosterone, SHBG, and albumin levels are known. To evaluate the clinical utility of serum testosterone measurements, it is important to identify whether or not the normal laboratory range for testosterone is valid in the older man, or if there are changes in testosterone dynamics with age that may affect interpretation of testosterone levels. Serum testosterone levels begin to decline in normal healthy men on no medications, in the mid- to late-thirties. This decline is linear into the nineties, at a rate of 0.4%/year. If men with chronic medical illnesses are evaluated (illness defined as hypertension, heart disease, diabetes, but not a hospitalized patient), it appears that the same age-associated decline in serum testosterone occurs, but that at any age the level for a man with a chronic illness is 10 15% below that of healthy age-matched men. In addition to this decline with age in total testosterone, there is an associated increase in sex hormone binding globulin (SHBG), the circulating high affinity binding protein for testosterone (2, 5, 13). Therefore, as man ages, the total testosterone level decreases, but the serum binding of testosterone increases. This increase in testosterone binding results in a free or bioavailable testosterone level that decreases to a greater extent than total testosterone. As a result, the availability of the free active form of testosterone in the serum is further reduced compared with total testosterone. Clinically, free T is decreased with age to a greater extent than total T. However, it is unclear whether free T is the only bioavailable fraction of testosterone for most of the tissues. Using various model systems and depending on the tissue and rate of blood flow through the tissue, the total concentration of circulating testosterone available to the organs can be calculated (6). The problem arises when studies attempt to determine whether certain age- and gender-associated problems, such as impotence, are better correlated with measurements of free or bioavailable testosterone than total testosterone (10). However, when men with impotence and low levels of bioavailable testosterone receive testosterone replacement therapy, there is no greater improvement in their impotence compared with similarly treated impotent men with normal levels of testosterone (14). Thus, although bioavailable and free testosterone measurements are lower in men with possible androgen related symptoms, they apparently do not respond to androgen replacement. These data point to two problems, 1) symptoms that we may feel are androgen related are probably multifactorial and not reliable measures of androgen action. Secondly, the measurement of testosterone that relies on an assessment of protein-bound T may not be a reflection of a deficiency of T, but may be the result of a change in the binding protein by a problem independent of the androgen state of the man. For example, a decrease in SHBG may occur in type II diabetes mellitus as a result of an increase in insulin or insulin-like growth factor I levels (15, 16). This reduction in SHBG level, unrelated to androgen deficiency and associated with decreased total androgen in diabetic patients, may be coincidentally related to impotence, when in fact, the impotence is due to diabetes mellitus. Clinical situations such as these, point out the difficulty in assessing androgen status when there is no good independent marker of androgen action that can be used in vivo. In addition, there are no well designed clinical trials that have indicated that one method of testosterone measurement is better than any another at defining a group of men who are androgen deficient and will respond to testosterone replacement therapy. Therefore, either until appropriate clinical studies are published or until a good marker of testosterone action becomes available, a total serum testosterone is as good a measurement, and less expensive, than a more complex and labor intensive measure of free or bioavailable testosterone. In addition, one must be aware that assays that purport to measure free testosterone without using a dialysis method or without calculating free testosterone levels based on separate measurements of testosterone and SHBG, can markedly underestimate by as much as 100% the true free hormone level (9). This sort of assay error can result in an incorrect overestimation of the degree or prevalence of androgen deficiency. An additional factor that needs to be taken into account when looking at the differences in testosterone levels between young and elderly men, is the difference in circadian variation. Young men clearly have a circadian rhythm of testosterone, with the zenith in the morning between 0600 h and 0800 h and the nadir in the late afternoon between 1700 h and 1800 h (5, 17). In elderly men, the circadian rhythm, if detected, is much flatter and tends not to be consistent between individuals. Clinically, this means that the difference in blood testosterone levels between young and elderly men can be readily detected when measurements are made in the morning during the zenith of the testosterone rhythm, but

4 3438 THERAPEUTIC PERSPECTIVE JCE&M 1998 Vol 83 No 10 the difference may be lost if samples are collected in the late afternoon. However, even though the difference in testosterone secretory patterns is clearly altered between young and elderly men, the clinical significance of this altered secretory pattern has not yet been determined. With the development of testosterone delivery systems that can mimic the circadian variation in testosterone secretion, clinical studies may be designed that can address the biological significance of the circadian variation in testosterone. In summary, based on the data currently available, the measurement of total blood testosterone is the most appropriate test to determine whether an older individual is hypogonadal or not. If the total testosterone level is less than 7.0 nm/l (2 ng/ml), the individual should be considered hypogonadal and, regardless of age, further evaluation should be the same as for any other hypogonadal individual. The question that cannot be answered with our present data base, however, is whether or not otherwise healthy men or those with chronic illnesses with testosterone levels of less than 10.5 nm/l (3 ng/ml) but greater than 7.0 nm/l (2 ng/ml) are hypogonadal, and whether these hypogonadal men would benefit from replacement, especially if their gonadotropin levels are normal. Even though older men have reduced muscle mass, decrease in body hair, and decrease in bone mass, there have been no conclusive data demonstrating that these findings are the result of age-associated reduction in testosterone levels. In fact, the argument can just as well be made that even if an elderly man has a testosterone level in what would be considered the normal range, his current level is below what it would have been when he was younger and, therefore, he is hypogonadal. This concept is supported by the evidence of a steady decline in testosterone levels, which reportedly start to fall by the beginning at the fourth decade of life. Measurements of free or bioavailable testosterone should be considered experimental, until they are clearly shown to be a better marker of hypogonadism in the elderly than total testosterone levels. Therefore, measurement of free or bioavailable testosterone is not currently justified. When a testosterone level is found to be below 7.0 nm/l (2 ng/ml), evaluation should proceed with measurement of gonadotropins, prolactin, etc., regardless of age. However, the issue that is not clear is what should be done for the healthy individual who does present with a testosterone level between 7.0 and 10.5 nm/l (2 3 ng/ml). Should these individuals have gonadotropin and prolactin levels measured? This decision should be made based on the primary purpose for which the testosterone measurement was initially made. If the testosterone level was obtained because of the clinical suspicion of hypogonadism and the value obtained was below the lower limits of normal for the reference laboratory, then gonadotropin levels should be determined. If the gonadotropin levels obtained are elevated, then appropriate evaluation and treatment for primary testicular failure should be performed. If the gonadotropin levels are low, evaluation for secondary hypogonadism should be considered, including measurement of prolactin and consideration of a pituitary imaging procedure. In these men with borderline low levels of testosterone, if prolactin and gonadotropin measurements do not provide an indication of the reason for the marginal testosterone levels, consideration can be given to some measurement of free or bioavailable testosterone. For the reasons discussed earlier in this section, a free testosterone level measured by a kit should be used cautiously. A more appropriate choice would be bioavailable testosterone measured by ammonium sulphate precipitation, free testosterone by a dialysis method, or separate measurements of SHBG and testosterone with calculation of free testosterone. If the free or bioavailable measurement is decreased and the man is clinically hypogonadal but the cause is not clear, consideration to testosterone replacement could be given, although the clinical response measurements have not yet been defined. Note that the reason for the testosterone measurement in these cases was a clinical suspicion of hypogonadism. Until the results of appropriate clinical studies (several NIH-sponsored studies addressing this issue are nearing completion) become available, measurement of testosterone in older men without a clinical suspicion of hypogonadism is inappropriate. 1. Gray A, Feldman HA, McKinley JB, Longcope C Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 73: Vermeulen A, Deslypere J Testicular endocrine function in the ageing male. Maturitas. 7: Tenover J, Dahl K, Hsueh A, Lim P, Matsumoto A, Bremner W Serum bioactive and immunoreactive follicle-stimulating hormone levels and the response to clomiphene in healthy young and elderly men. J Clin Endocrinol Metabol. 64: Tenover J, Matsumoto A, Clifton D, Bremner W Age-related alterations in the circadian rhythms of pulsatile luteinizing hormone and testosterone secretion in healthy men. J Gerontol. 43: Plymate SR, Tenover JS, Bremner WJ Circadian variation in testosterone, sex hormone binding globulin, and calculated non-sex hormone binding globulin bound testosterone in healthy young and elderly men. J Androl. 10: Pardridge W Selective delivery of sex steroid hormones to tissues in vivo by albumin and by sex hormone-binding globulin. Ann NY Acad Sci. 538: Hammond G, Nisker J, Jones L, Siiteri P Estimation of the percentage of free steroid in undiluted serum by centrifugal ultrafiltration dialysis. J Biol Chem. 255: Sødergard R, Backström T, Shanbhag V, Carstensen H Calculation of free and bound fractions of testosterone and estradiol-17 to human plasma proteins at body temperature. J Steroid Biochem. 16: Rosner W Errors in measurement of plasma free testosterone. J Clin Endocrinol Metabol. 82: Nankin H, Calkins J Decreased bioavailable testosterone in aging normal and impotent men. J Clin Endocrinol Metab. 63: Umstot E, Baxter J, Anderson R A theoretically sound and practicable equilibrium dialysis method for measuring percentage of free testosterone. J Steroid Biochem. 22: Giraudi G, Cenderelli G, Migliardi M Effect of tracer binding to serum proteins on the reliability of a direct free testosterone assay. Steroids. 52: Tenover J, Matsumoto A, Plymate S, Bremner W The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: Response to clomiphene citrate. J Clin Endocrinol Metab. 65: Morley J, Perry H, Kaiser F, et al Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc. 41: Peiris A, Stagner J, Plymate S, Vogel R, Heck M, Samols E Sex hormone binding globulin levels in normal men: role of pulsatile insulin secretion. J Clin Endocrinol Metab. 76: Plymate S, Matej L, Jones R, Friedl K Inhibition of sex hormone binding globulin (SHBG) production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab. 67: Bremner W, Vitiello M, Prinz P Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 56:

5 THERAPEUTIC PERSPECTIVE 3439 IV. Can Replacement Doses of Testosterone Produce Clinically Meaningful Changes in Body Composition in Older Men? J. Lisa Tenover Emory University, School of Medicine Atlanta, Georgia AS MEN get older, a decline in their lean body mass and appendicular skeletal muscle occurs, while their percentage of body fat increases (1). Cross-sectional studies have shown that body fat in men increases from 18% to 36% between the ages of 18 and 85 yr, with the largest increases occurring in intra-abdominal fat. Additionally, by age 70 yr, the average man has 12 kg less lean body mass than he had at age 25 yr. The main component of lean body mass is muscle, and the decline in muscle mass with age is secondary to a decline in both muscle cell mass and fiber number, especially fast twitch (type 2) fibers. Type 2 muscle fibers represent approximately 60% of the skeletal muscle of young sedentary men and less than 30% of the same muscle in 80 yr old men. Age-associated alterations in body composition can have effects on metabolism, but the impact of these changes on overall health and function in older men is not clear. For example, aging is associated with a decline in glucose tolerance, but the contribution of increasing abdominal fat stores to glucose intolerance in this age group is unknown. Similarly, the exact relationship between muscle mass and muscle strength in older adults is not straightforward. Like muscle mass, muscle strength declines with aging in both sedentary and endurance trained individuals. Muscle strength, especially maximal strength, correlates with muscle mass at any age (correlation coefficient of 0.79 in one study of subjects older than 65 yr; 2), but decreases more profoundly with advanced age than does muscle mass. Significant declines with age in muscle mass and strength are strong predictors of functional problems. The clinical correlates of sarcopenia, the age-related loss in skeletal muscle, include falls, fractures, loss of mobility, and development of dependence in basic activities of daily living. Not just muscle strength, but also endurance, power, and taskspecific performance are important in maintaining function. Age-related sarcopenia not only affects muscle strength but may also have metabolic consequences. Although yet unproved, these may include a lower basal metabolic rate, abnormal thermoregulation, impaired glucose metabolism, and worsening of osteopenia. The nitrogen retaining effects of androgens were first described in 1935 in experiments in castrated dogs. Since that time, androgen therapy has been shown repeatedly to increase muscle mass in castrated males from a number of animal species. In humans, testosterone given in replacement doses to hypogonadal young adult men has been shown to increase lean body mass, increase the synthesis of skeletal muscle, increase muscle size, and improve muscle strength. Some studies also have reported a decline in fat mass with testosterone therapy in these young men. Additionally, supraphysiological replacement of testosterone in healthy eugonadal young men has been shown to increase lean body mass, muscle size, and strength, even in the absence of exercise. For the older man, the questions in regard to testosterone replacement therapy and body composition are multiple. First, with physiological replacement therapy, can clinically meaningful increases in muscle mass and strength be achieved? Second, do older men have the same anabolic and compositional responses to testosterone as do younger men, or are they some how more insensitive to testosterone s anabolic properties? Third, are there changes in body fat mass that occur with physiological testosterone replacement in older men and, if so, are these of such magnitude that metabolic consequences result (such as decreased insulin resistance). In regard to the first question as to whether clinically meaningful changes in muscle mass and strength occur with testosterone therapy, the goal is NOT to produce an older version of Mr. Universe or an olympic athlete, but rather to have the older man maintain or improve strength so that his functional capacity can be maximized. These are not easy endpoints to demonstrate, and an increase in muscle mass with therapy may not necessarily lead to a meaningful increase in muscle strength, and an increase in muscle strength may not directly translate into a significant improvement in functional status. To date, there have been no studies on the effects of testosterone replacement therapy in chronically diseased or frail older men, and studies involving physiological replacement dosing of testosterone in healthy older ( 50 yr) men are limited; the total number of older men treated in all published studies combined is somewhat less than 75, and the length of therapy has varied from 1 to 18 months. The results from these testosterone replacement studies in older men, however, have been consistent; reported are treatmentrelated declines in body fat mass ranging from 6.4% to 14%, and increases in lean mass ranging from 3.2% to 5.0% (3). One additional study, involving testosterone therapy in older, abdominally obese men, noted a mean 9.1% decline in visceral fat mass with a concomitant decline in fasting blood glucose concentrations (4). There are several completed but as yet unpublished studies involving 3 years of testosterone replacement in older men. Preliminary data from one of these studies suggests that lean body mass may increase as much as 8%, while body fat decreases 17%, in men on testosterone therapy (Tenover JL, unpublished results). When comparing the scope of body compositional effects of testosterone therapy in the older men with those noted in replacement therapy in hypogonadal young men, the magnitude of the fat mass changes appear similar, while the lean body mass changes are less dramatic in the older men. This issue, however, has not been fully explored, and more data, especially as regards the dose-response of muscle to the anabolic actions of androgens with age, are needed. In terms of strength changes, six out of seven studies that have evaluated strength in older men on testosterone replacement have demonstrated a statistically significant increase in strength with therapy (3, 5). Most of these studies have been blinded and placebo-controlled, but most also have used grip strength as the primary strength measure;

6 3440 THERAPEUTIC PERSPECTIVE JCE&M 1998 Vol 83 No 10 only two studies, involving fewer than 15 men in all, have evaluated lower extremity strength. No published studies have yet evaluated functional performance in response to testosterone therapy. Overall, although the data on the body compositional changes, strength improvements, and metabolic consequences of testosterone replacement therapy in older men are limited, testosterone therapy appears to hold some promise for beneficial effects for this age group. More study needs to be done to address the many unknowns in this arena. 1. Steen B Body composition and aging. Nutr Rev. 46: Reed RL, Pearlmutter L, Yochum K, et al The relationship between muscle mass and muscle strength in the elderly. J Am Geriatr Soc. 39: Tenover JL Effects of androgen supplementation in the aging male. In: Oddens BJ, Vermeulen A, eds. Androgens and the aging male. New York: Parthenon Publishing Group; Marin P, Holmang S, Gustafsson C, et al Androgen treatment of abdominally obese men. Obes Res. 1: Sih R, Morley JE, Kaiser FE, et al Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82: V. The Effects of Aging and Testosterone on Lipids and Cardiovascular Risk C. J. Bagatell and W. J. Bremner University of Washington and VA Puget Sound Health Care System (III) Seattle, Washington Aging and plasma lipids and lipoproteins IN prepubertal children plasma levels of lipoproteins and triglycerides show no gender difference. During puberty plasma levels of HDL decline in boys, while plasma triglycerides and LDL increase slightly. The adult male generally has lower levels of HDL cholesterol and higher levels of LDL and triglycerides than does the premenopausal woman (1). After menopause HDL levels in females tend to remain approximately the same, but plasma LDL levels increase considerably (1), contributing to the greater incidence of coronary artery disease in postmenopausal women. In contrast, large epidemiological studies show that plasma HDL levels in elderly men are actually slightly higher than in middle-aged men (2). One explanation for this phenomenon is that individuals with lower HDL levels succumb to atherosclerotic disease earlier in life so that, by a process of elimination, men with higher levels of HDL cholesterol tend to survive to older age. Alternatively, higher HDL levels in older men could be associated with the age-related decline in circulating androgens. Again, in contrast to the pattern seen in women, LDL levels in men increase slowly but progressively from the late teenage years to the mid 50 s, at which point they become relatively constant. In the Lipid Research Prevalence study (2), mean LDL levels in women over the age of 60 were in fact slightly higher than mean levels seen in men of the same age. Effects of T on plasma lipids and cardiovascular risk The majority of cross-sectional studies of androgens and plasma HDL levels show a positive relationship between serum T levels and corresponding levels of HDL cholesterol (reviewed in 1). In contrast, most studies of T administration in young, hypogonadal or eugonadal men demonstrate a decrease in HDL cholesterol of 5 15% as T levels are raised (1); the magnitude of decrease has tended to be greater in subjects with higher baseline levels of HDL. In general, plasma LDL and triglyceride levels have remained unchanged in these experimental paradigms. Recent data suggest that in young men, supraphysiological levels of T may also suppress levels of lipoprotein (a) [Lp(a)], which is generally acknowledged as an independent risk factor for coronary artery disease. As with HDL, this effect is most noticeable in subjects with high baseline levels (3). Thus, the net effects of T on plasma lipids are complex and may vary from individual to individual, depending in part on that person s baseline lipoprotein profile. Clearly there is a discrepancy between the results of the cross-sectional and interventional studies of the association between androgens and lipids. However, both HDL cholesterol and testosterone may be influenced by multiple factors including disease states, lifestyle (for example smoking, exercise), and factors such as body mass index, fat distribution, and waist-to-hip ratio. In general, factors that decrease HDL cholesterol also decrease testosterone levels. It is therefore possible that such factors could explain the population findings that men with higher T levels also have higher levels of HDL cholesterol and lower levels of triglycerides. It should be noted that the aforementioned changes in plasma lipids are in response to administration of aromatizable androgens such as T enanthate or T cypionate. When nonaromatizable, particularly oral, androgens such as stanozolol or methyltestosterone are administered, HDL levels decrease profoundly whereas LDL levels increase significantly (1). There are several case reports of stroke and myocardial infarction in young users of high doses of nonaromatizable androgens (4). In addition to their effects on lipids, androgens may serve as regulators of other factors contributing to cardiac risk. In animals, androgens act as vasodilators (5), but in the human male, plasma levels of the vasoconstrictor endothelin are higher than in the female (6). Visceral fat accumulation is generally believed to increase risk for atherosclerotic disease. A few recent studies have shown that, in both young and middle-aged men, androgen administration is associated with a reduction in visceral fat accumulation in the abdomen (7, 8). In one very recent report, lower T levels were predictive of increases in abdominal fat in normal men assessed prospectively over 7.5 yr (9). T administration and cardiovascular risk in older men There are relatively few data regarding T effects on cardiovascular risk factors in older men. In one long-term study of a very low dose of T cypionate (25 mg im, weekly for 4 yr) HDL cholesterol levels did not change during treatment, and total and LDL cholesterol levels decreased significantly (10). Studies of higher doses of T, used for shorter periods of time, have also demonstrated significant decreases in total and LDL cholesterol levels (11 13). In these studies, HDL cholesterol levels were either unchanged or showed a nonsignificant decrease in response to the higher ambient T levels.

7 THERAPEUTIC PERSPECTIVE 3441 It is presently unknown whether androgens have a different mechanism of action on plasma lipids in older men than in younger men. Also unknown at this time is the effect of T on abdominal fat depots in older men. T administration is associated with a modest decrease in total body fat (11), but more specific studies are needed to determine whether the visceral abdominal fat depots associated with increased risk of coronary artery disease are also reduced. Cardiovascular disease is a major cause of morbidity and mortality in older men. Before androgen replacement can be considered truly safe for this population, it will be important to examine the long-term effects of T replacement on plasma lipids, lipoproteins such as Lp(a), and body fat distribution, specifically in older men. It will also be important to analyze the incidence of cardiovascular events in men who receive androgens for extended periods. The available data suggest, however, that from the cardiovascular perspective, judicious administration of aromatizable forms of T is likely to be safe for the majority of older hypogonadal men. 1. Bagatell CJ, Bremner WJ Androgen and progestagen effects on plasma lipids. Progress in Cardiovascular Disease. 38: Lipid Research Clinics Population Studies Data Book Vol 1: The Prevalence Study. Department of Health and Human Services. 3. Marcovina SM, Lippi G, Bagatell CJ, Bremner WJ Testosterone induced suppression on lipoprotein (a) in normal men; relation to basal lipoprotein (a) level. Atherosclerosis. 132: Bagatell CJ, Bremner WJ Androgens in men: uses and abuses. N Eng J Med. 334: Adams MR, Williams JK, Kaplan JR Effects of androgens on coronary artery atherosclerosis and atherosclerosis-related impairment of vascular responsiveness. Aterioscler Thromb Vasc Biol. 15: Polderman HK, Stehouwer CDA, van Kamp GJ, Dekker GA, Verheugt WA, Gooren LJG Influence of sex hormones on plasma endothelin levels. Ann Intern Med. 118: Marin P, Holman S, Fustafsson C, et al Androgen treatment of abdominally obese men. Obes Res. 1: Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab. 81: Tsai EC, Boyko EJ, Newell-Lewis L, Leonetti DL, Fujimoto WY Decreased testosterone is a predictor of increased intra-abdomenal fat in secondgeneration Japanese-American men. Diabetologia. 40:[Suppl 1]:A Ellvin FM, Plunkett-Reid K, Rumilla AE The long-term beneficial effect of low-dose testosterone in the aging male. Proceedings of the 79th Annual Meeting of the Endocrine Society, Minneapolis, MN, p. 236 (Abstract). 11. Tenover JS Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 75: Morley JE, Perry M, Kaiser FE, et al Effects of testosterone replacement therapy in older hypogonadal males: a preliminary study. J Am Geriatr Soc. 41L: Zgliczynski S, Ossowski M, Slowinska-Srzednicha J, et al Effect of testosterone replacement on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis. 121: VI. A Pragmatic Approach to Androgen Replacement in Older Men: Risks vs. Benefits Stanley G. Korenman University of California Los Angeles, School of Medicine Los Angeles, California MY ROLE in this debate is to consider the costs vs. benefits of androgen treatment of older men with normal total T levels. Underlying that decision are three questions: 1. How do we define hypogonadism in an older man? 2. What are the problems with testosterone treatment? 3. Is it appropriate to treat men who are not hypogonadal? Men over fifty present to me either because of sexual dysfunction, (usually erectile failure), loss of sexual interest, or loss of energy and well-being. In one study, measurement of their serum total and bioavailable testosterone (BT) demonstrated a much higher proportion of men with a BT two sd or more below the mean for young men than of abnormally low T levels (1). The mean BT falls from ages forty to seventy by three times the fall of T (2). The LH level does not exceed the range of normal in most of these men, so we must diagnose hypogonadism on the basis of the steroid hormone level alone. We believe that there is no reason to think that the tissues of older men require less BT than those of younger men, thus we define hypogonadism as a fasting, morning BT below 67 ng/dl (2.3 nm). To rule out a pituitary tumor we measure LH, FSH, and prolactin in all hypogonadal men. We limit pituitary magnetic resonance imaging to men under 50, to those with visual changes or recent onset headaches, to those with hyperprolactinemia unassociated with antidopaminergic drugs, to those with very low gonadotropins (below the limit of normal for the assay), and to those with a very low BT ( 20 ng/dl). Other circumstances may precipitate a pituitary magnetic resonance imaging examination, but it is important to remember that hypogonadism is very common, and clinically significant pituitary tumors are rare in older men. Should we treat symptomatic men meeting the criterion of hypogonadism, or alternatively all symptomatic men with androgens? That depends on the negative consequences of replacement doses of androgen therapy. Most likely, the putative long-term adverse effects of androgens inhibit physicians from utilizing replacement doses and encourage them to withdraw therapy at the first sign of a possible problem. The principal issues surrounding androgen administration include an increased risk of clinically progressive prostate carcinoma, precipitation or exacerbation of benign prostatic hyperplasia (BPH), an increased hematocrit due to persistent erythropoietic stimulation, occasional exacerbation of sleep-apnea syndrome, a tendency toward thrombosis, and a reduction of total and high density lipoprotein (HDL)-cholesterol. There are also the occasional development of pedal edema, a physiologic increase of appetite, and an increase of blood volume that may increase mean blood pressure. The scientific basis for these concerns needs to be addressed. There is no evidence that exogenous T at any dose will stimulate the development of clinically significant prostate carcinoma. Because androgen withdrawal inhibits the progression of existing prostate carcinomas, a carcinogenic effect of T has been suspected. Data are inconsistent regarding a relation between endogenous T and prostate carcinoma. Two studies (3, 4) failed to show a relationship between endogenous T and subsequent development of prostate carcinoma, while one study demonstrated that the calculated BT [T corrected for sex hormone-binding globulin (SHBG)] resulted in a linear increase of risk ratio for prostate carcinoma (5). However, in this study SHBG

8 3442 THERAPEUTIC PERSPECTIVE JCE&M 1998 Vol 83 No 10 was highly correlated with T (meaning that most men with higher T levels are protected), and estradiol levels were inversely correlated with risk as well, making it very difficult to determine risk in an individual. Prostate specific antigen (PSA) levels did not correlate with T levels. I routinely follow the digital rectal exam and the PSA in men receiving T. Those few who demonstrate increases of PSA to above normal are followed up with prostate biopsies under ultrasound control to discover small, and we hope resectable, tumors. There has been no relationship established between endogenous T and BPH (6). With regard to administered T, the only relevant study we found indicated that T, either as the enanthate or as the nonscrotal patch, increased prostate volume modestly and not progressively, but did not cause any clinical symptoms or increased AUA screening scores (7). In my practice, I have not observed treatment with physiologic doses of T to increase the symptoms of clinical BPH by the criteria of frequency, hesitancy, dysuria, or nocturia. T routinely increases the hematocrit within the normal range. When it reaches 51%, we suggest that the patient donate blood regularly or reduce the T dose or frequency; and if it reaches 54%, we stop therapy. This is not a rare occurrence in older men (8). Daily administration of T patches, yielding more physiologic peak levels of T, may produce less erythropoietic stimulation than injection of long-acting T esters. T therapy at hyperphysiologic dosage reduces total and HDL-cholesterol levels (9). However, physiological doses of androgens in hypogonadal or elderly men actually reduced total and LDL cholesterol and had no effect on HDL, HDL 2,orHDL 3 cholesterol (10). Whether these changes make any difference in cardiovascular risk is unknown. Because T also increases energy and exercise tolerance, and because patients can be given low fat diets, exercise, aspirin and, when indicated, a cholesterol-lowering agent, this limitation seems minimal. T does not seem to have an adverse effect on clotting (11). T also sensitizes to coumarin anticoagulants, requiring a reduction in dose in patients taking these agents. A role for T in the sleep-apnea syndrome has been reported in very few cases. The possible incidence of this syndrome in men taking physiological amounts of T is not known. A possible effect of T on respiratory function may be most relevant to substantially overweight individuals and to those with chronic lung disease. One should question patients receiving T as to their snoring and the quality of their sleep. We routinely treat any hypogonadal older man, (with a BT below 2.3 nm) with a 3-month trial of testosterone in one of its available therapeutic forms, after verifying that the subject is unlikely to have a pituitary tumor. A therapeutic trial should have a defined end-point, but unfortunately, the endpoints for androgen therapy are largely subjective both for the patient and for the physician. This is especially true in the milder cases of hypogonadism seen in association with the aging process. Although many patients with hypogonadism and erectile dysfunction (ED) report an improvement in erectile function, we do not expect restoration of erectile function to be a consequence of T therapy (1, 12). Hypogonadism is the sole cause of ED in 10% or less of cases. The vast majority have other risk factors, including intrinsic penile disease, atherosclerotic vascular disease, pelvic surgery, autonomic neuropathies, depression, as well as drugs for central nervous system, cardiovascular (including hypertension), and endocrine disorders (including diabetes) (13). When we treat with T we follow sense of well-being, including strength, energy, mood, and self-esteem, as well as libido, which is the only response directly increased by androgens. T therapy increases bone density in men with osteoporosis, which can be followed radiographically(14). In this era of evidence-based medicine the following may be suspect, but I have found that men who respond to T enter the examining room with more vigor, communicate with greater assurance, and are viewed by their partners as more vigorous and energetic and more interested in sex. Those who don t respond, show no improvement and usually have no interest in remaining on androgen therapy. I do not believe that there is much of a placebo effect from T therapy. How do we approach the question of treating men with loss of sexual interest and/or loss of energy and feeling of well-being who have a normal T and BT? Are we justified in giving them a trial of T therapy? I would not treat a patient whose main complaint is erectile dysfunction with T because it is not likely to be effective and because other forms of therapy are available. For men who are not obviously depressed, but who complain of loss of energy and/or libido, one might argue that a 3-month trial with a physiological dose of androgen is not likely to cause any adverse effects and may provide symptomatic relief. If so, continuation of therapy may be warranted with due attention to the possible complications noted above and a realization that many of the fears of T therapy are unfounded. 1. Korenman SG, Morley JE, Mooradian AD, et al Secondary hypogonadism in older men: its relation to impotence. J Clin Endocrinol Metab. 71: Gray A, Feldman HA, McKinlay JB, Longcope C Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 73: Gustafsson O, Norming U, Gustafsson S, Eneroth P, Astrom G, Nyman CR Dihydrotestosterone, and testosterone levels in men screened for prostate cancer: a study of a randomized population. Br J Urol. 77: Carter HB, Pearson JD, Metter EJ, et al Longitudinal evaluation of serum androgen levels in men with and without prostate cancer. Prostate. 27: Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ Prospective study of sex hormone levels and risk of prostate carcinoma. J Natl Cancer Inst. 88: Gann PH, Hennekens CH, Longcope C, Verhoek-Oftedahl W, Grodstein F, Stampfer MJ A prospective study of plasma hormone levels, nonhormonal factors, and development of benign prostatic hyperplasia. Prostate. 26: Meikle AW, Dobs AS, Adolfsson J, et al Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology. 49: Sih R, Morley JE, Kaiser FE, Perry III HM, Patrick P, Ross C Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82: Meriggiola MC, Marcovina S, Paulsen CA, Bremner WJ Testosterone enanthate at a dose of 200 mg/week decreases HDL-cholesterol levels in healthy men. Int J Androl. 18: Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, et al Effect of testosterone replacement on lipids, and lipoproteins in hypogonadal and elderly men. Atherosclerosis. 121: Winkler UH Effects of androgens on haemostasis. Maturitas. 24: Guay AT, Bansal S, Heatley GJ Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-