REVIEW ARTICLE

Drugs Aging 2002; 19 (11): 865-877 1170-229X/02/0011-0865/$25.00/0 © Adis International Limited. All rights reserved.

Role of Hormones in the Pathogenesis and Management of Sarcopenia Hosam K. Kamel,1 Diana Maas2 and Edmund H. Duthie Jr1 1 2

Division of Geriatrics, Department of Medicine, Medical College of Wisconsin, and the Clement J. Zablocki VAMC, Milwaukee, Wisconsin, USA Division of Endocrinology, Department of Medicine, Medical College of Wisconsin, and the Clement J. Zablocki VAMC, Milwaukee, Wisconsin, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Sarcopenia: a Novel Epidemic . . . . . . . . . . . . . . . . . . . . . 2.1 Prevalence of Sarcopenia . . . . . . . . . . . . . . . . . . . . 3. Endogenous and Exogenous Hormones in the Development and Management of Sarcopenia . . . . . . . . . . 3.1 Growth Hormone . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1 Growth Hormone Supplementation . . . . . . . . . . . . 3.1.2 Growth Hormone-Releasing Hormone Supplementation 3.1.3 Insulin-like Growth Factor-1 Manipulation . . . . . . . . . 3.2 Testosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Dehydroepiandrosterone . . . . . . . . . . . . . . . . . . . . . 3.4 Estrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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There is growing evidence to indicate that age-related declines in growth hormone (GH), insulin-like growth factor (IGF)-1, and androgen and estrogen production play a role in the pathogenesis of sarcopenia (an age-related decline in muscle mass and quality). Although GH supplementation has been reported to increase lean body mass in elderly individuals, the high incidence of adverse effects combined with a very high cost has limited the applicability of this form of therapy. The assessment of an alternative approach to enhance the GH/IGF-1 axis in the elderly by using GH-releasing hormone and other secretagogues is currently under way and is showing some promise. Testosterone replacement therapy may increase muscle mass and strength and decrease body fat in hypogonadal elderly men. Long-term randomised, controlled trials are needed, however, to better define the risk-benefit ratio of this form of therapy before it can be recommended. Available data are currently insufficient to decide what role estrogen replacement therapy may play in the management of sarcopenia. Therefore, although the evidence linking age-related hormonal changes to the development of sarcopenia is rapidly growing, it is still too early to determine the clinical utility of hormonal supplementation in the management of sarcopenia.

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1. Background Advancing age is associated with profound changes in body composition.[1] A change that is increasingly being recognised to have important consequences in old age is the loss of muscle mass and deterioration in muscle quality. This phenomenon was called sarcopenia by Rosenberg (in 1989), who coined the term from the Greek for ‘poverty of flesh’.[2] Sarcopenia should be differentiated from cachexia and wasting. Cachexia refers to a condition of accelerated loss of muscle mass in the context of chronic inflammation,[3] and wasting refers to unintentional weight loss that is largely driven by inadequate dietary intake.[4] Sarcopenia has been linked to several physical and functional limitations that may impair the quality of life and increase healthcare costs of affected individuals (figure 1).[5-11] This, combined with growing evidence indicating a high prevalence of clinically significant degrees of sarcopenia in the elderly,[12,13] makes sarcopenia an important public health problem. Sarcopenia is probably the result of multiple interacting factors (figure 1). Possible candidate mechanisms include increased oxidative stress, dysregulation of catabolic cytokines, age-related alteration in excitation-contraction coupling and calcium homeostasis, loss of endogenous growth hormone (GH) production, loss of estrogen and androgen production, inadequate protein intake and reduced physical activity.[4,14] In the last decade, major advances in our understanding of the pathogenesis of sarcopenia have occurred. These have been accompanied by a growing interest in exploring different interventions to prevent or reverse the condition. This article reviews the evidence linking age-related hormonal changes to the development of sarcopenia and the clinical utility of hormonal supplementation in its management. The hormones discussed are GH, testosterone, dehydroepiandrosterone (DHEA) and estrogen. Androstenedione, nandrolone and oxandrolone have not been tested in older individuals and thus are not discussed. © Adis International Limited. All rights reserved.

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2. Sarcopenia: a Novel Epidemic Several changes have been reported in the aging muscle (table I). Among these, loss of muscle mass was the earliest to be described. In 1960, Allen et al.[15] published one of the earliest studies that demonstrated, by measuring total body potassium levels, loss of muscle mass with increasing age. Later, excretion of creatinine was used to measure muscle mass in 959 healthy individuals who were between the ages of 20 and 97 years, and a reduction with age amounting to approximately onethird was found.[16] With the introduction of modern radiological imaging techniques, muscle mass and muscle cross-sectional area could be estimated more directly. Using ultrasonography, investigators reported a 25–35% reduction in the cross-sectional area of the quadriceps muscle in older men[17] and women[18] compared with their younger counterparts. In addition, computed tomography scanning demonstrated age-related reduction in cross-sectional area of the psoas major and sacrospinalis muscles,[19] as well as the quadriceps muscle[20,21] and plantar flexors.[22] At the tissue level, there is an increase in the amount of fat and connective tissue in muscle with advancing age.[19,22] In addition, the size of type 2 (fast-twitch) fibres decreases with advancing age, while the size of type 1 (slow-twitch) fibres remains unaffected.[23,24] Most of the reduction in fibre size can be attributed to age-related reduction in myofibrillar proteins, especially myosin heavy chains.[14,25] The total number of muscle fibres declines with increasing age.[26] Table I lists other age-related morphological changes observed in muscle tissue.[23,27] Studies using quantitative electromyography demonstrated a reduction in the number of functioning motor units in aging human muscles.[28] This loss has also been reported in rodents and nonhuman primates.[29,30] The loss was greatest among the largest and fastest motor units, i.e. type 2 motor fibres.[31] Morphological studies have shown that the number of motor neurons in the lumbosacral cord is reduced after the age of 60 years, with some cases exhibiting counts of only 50% of those in Drugs Aging 2002; 19 (11)

Hormones in Pathogenesis and Management of Sarcopenia

Malnutrition

↑ Dysregulation of cytokines

↓ GH and IGF-1

↓ Testosterone and estrogen

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↓ Physical activity

↑ Oxidative stress

Alteration in excitation-contraction coupling and calcium homeostasis

SARCOPENIA

Falls

Impaired ADLS

↓ BMR

Osteoporosis

↓ Maximal aerobic capacity

Impaired thermoregulation

↓ Walking speed

Malnutrition

Impaired balance

FRAILITY

Fig. 1. Pathogenesis and functional and metabolic consequences of sarcopenia. ADLS = activities of daily living score; BMR = basal metabolic rate; GH = growth hormone; IGF-1 = insulin-like growth factor-1.

younger individuals. The loss of motor neurons in the lumbar spinal cord is accompanied by a reduction in the numbers of large and intermediate ventral root fibres.[31] Researchers have also demonstrated a progressive decline in the rate of muscle protein synthesis with age.[32] The decline in the synthesis of one of these proteins, the myosin heavy chain, is thought to contribute to the reduction in the contractile function of the aging muscle.[33,34] There is also evidence that muscle strength declines with increasing age. Data from both crosssectional[35-46] and longitudinal studies[47-50] indicate that muscle strength tends to peak by the age of 30 years and remains the same until the age of 50 years in men. Losses of strength then begin to occur at a rate of approximately 12–15% per decade until the eighth decade. In women, this decline generally begins sooner and proceeds at a slower rate. However, Tanaka and Seals[51] performed a 5-year retrospective analysis of top freestyle performance times from the US Masters Swimming Championships and showed that physiological functional capacity (as assessed by swimming performance) peaks at age 35–40 years and © Adis International Limited. All rights reserved.

decreases linearly thereafter until age 70–80 years, whereupon the decline becomes exponential. In this study, the rate and magnitude of the decline with age were significantly greater in women than in men. Other investigators[52,53] reported similar findings in relation to endurance running capacity. These findings may be related to the decline in oxidative capacity that was reported in the aging muscle.[54,55] All in all, published evidence indicates that sarcopenia is probably a universal phenomenon. Sarcopenia has been linked to physical frailty, falls, functional decline and impaired mobility in older adults (figure 1).[56-58] Whether these morbid outcomes become clinically evident during life depends to a great extent on the starting level of muscle mass and the rate of its decline.[59] Unlike the situation with age-related changes in bone density, a quantitative relationship between pathology and morbidity is largely undetermined in the case of sarcopenia. If unchecked, sarcopenia may transform from an age-related physiological change to a pathological condition that may impair function and quality of life of affected individuals. At present, there are insufficient data to form a consensus Drugs Aging 2002; 19 (11)

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on when such a transition occurs, and consequently on the prevalence of clinically significant (pathological) sarcopenia. 2.1 Prevalence of Sarcopenia

Baumgartner and colleagues[12] measured appendicular muscle mass using dual-energy x-ray absorptiometry in 883 randomly selected elderly Hispanic and White men and women from the New Mexico Elder Health Study. They arbitrarily defined clinically significant sarcopenia as a muscle mass of less than two standard deviations below the mean of a young reference group. The prevalence of sarcopenia by this definition increased from 13–24% in persons aged 65–70 years to over 50% of those older than 80 years. Although the prevalence increased in both men and women in relation to age, the actual prevalence was higher in men than in women. The presence of this degree of sarcopenia was associated with a 3- to 4-fold increase in the likelihood of disability in older individuals, independent of age, sex, obesity, ethnicity, socioeconomic status, chronic morbidity and health behaviours. Melton et al.,[13] using a similar definition, studied the prevalence of sarcopenia in 699 randomly Table I. Anatomical and biochemical changes in the aging muscle Anatomical changes Decreased muscle mass and cross-sectional area Infiltration of fat and connective tissue Decrease in type 2 fibre size with no change in type 1 fibre size Decrease in types 1 and 2 fibre number Accumulation of internal nuclei, ring fibres and ragged fibres Disarrangement of myofilaments and Z-lines Proliferation of the sarcoplasmic reticulum and t-tubular system Accumulation of lipofuscin and nemaline rod structures Decrease in number of motor neurons Decreased blood flow Biochemical changes Decline in mixed muscle protein synthesis Decline in synthesis of myosin heavy chain Decline in concentration of mitochondrial proteins and enzyme activity Alteration in muscle protein expression Increased mitochondrial DNA and oxidative stress

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selected community-dwelling individuals in Rochester, Minnesota, USA. In this study, the age- and sex-adjusted prevalence of sarcopenia varied from 6–15% among individuals who were aged ≥65 years. Those diagnosed to have sarcopenia by this definition had multiple physical and functional limitations. Although the validity of this definition of clinically significant sarcopenia remains to be determined, both studies provide enough evidence to characterise sarcopenia as an important public health problem. 3. Endogenous and Exogenous Hormones in the Development and Management of Sarcopenia 3.1 Growth Hormone 3.1.1 Growth Hormone Supplementation

There is evidence to support the contention that age-related decline in GH and insulin-like growth factor-1 (IGF-1) may contribute to the development of sarcopenia.[60-64] Studies of body composition in GH-deficient adults have noted important similarities to the changes frequently observed in aging.[62-64] Adults deficient in GH have more adipose tissue and less fat-free mass than agematched controls.[63] In addition, GH-deficient adults have more central distribution of adiposity. The decline in GH and IGF-1 levels with aging is largely attributed to changes in the effect of the hypothalamic factors somatostatin and GH-releasing hormone (GHRH) on the pituitary gland.[61] With aging, there is a reduction in GH response to GHRH and a simultaneous increase in the inhibitory effect of somatostatin.[61] These observations have resulted in several attempts to replace the GH axis in elderly individuals to prevent or reverse sarcopenia. The landmark study in this regard was published by Rudman and colleagues in 1990.[65] In this randomised, controlled trial, the authors assessed changes in parameters of body composition and bone mass in relation to GH supplementation over a 6-month period in 21 healthy men (aged 61–81 Drugs Aging 2002; 19 (11)

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years) who were found to have low IGF-1 serum levels (<0.24 U/ml). Participants were randomised to receive either recombinant human GH (somatropin; 0.03 mg/kg three times a week) or placebo subcutaneously for 6 months. The somatropintreated group (n = 12) had a 2.5- to 3-fold rise in serum IGF-1 levels, bringing levels to the midnormal range for young healthy males, at the end of the study. Somatropin treatment was associated with an 8.8% increase in lean body mass (p < 0.02). The effect of somatropin on muscle strength was not tested in this study. There was a 7% increase in serum glucose levels, as well as in systolic blood pressure, but none of the individuals developed diabetes mellitus or hypertension. This initial study raised expectations that somatropin may play a significant role in the management of sarcopenia. Subsequently, the same group of investigators, using a similar design, carried out a larger-scale study for a total of 12 months of intervention.[66] The study involved 83 overtly healthy elderly men with plasma IGF-1 levels <0.35 U/ml. Plasma IGF1 levels were measured monthly and lean body mass and adipose mass were measured every 6 months. Muscle strength was not assessed in this study. Somatropin treatment increased IGF-1 levels from the range of 0.10–0.36 U/ml into the range of 0.5–2.2 U/ml, increased lean body mass to 106% of the initial baseline level, and decreased adipose mass to 84% of that at baseline. The frequency of adverse effects and dropout rates among the intervention group were, however, substantial; 44% of the somatropin-treated group had dropped out by month 6 compared with 10% of the placebo group. After 12 months, of the remaining 35 somatropintreated individuals, 29% developed carpal tunnel syndrome, 11% developed gynaecomastia and 9% developed hyperglycaemia. Papadakis et al.[67] randomised 53 men (age range 75–85 years) with low IGF-1 levels to receive somatropin (0.03 mg/kg bodyweight subcutaneously three times a week) or placebo for a period of 6 months. Although somatropin administration resulted in increased lean body mass and © Adis International Limited. All rights reserved.

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decreased fat mass, it had no effect on knee or handgrip strength or on systemic endurance. The incidence of adverse events was significantly greater in the somatropin group than in the placebo group. Kaiser and co-workers,[68] using a randomised placebo-controlled design, administered 100 μg/kg once a day somatropin intramuscularly to ten elderly frail, malnourished men. Over the 3-week study period, somatropin treatment resulted in an increase in mid-arm muscle circumference and in positive nitrogen balance. No adverse events were reported in this study. More recently, Chu et al.[69] randomised 19 malnourished elderly individuals to receive lowdose somatropin (0.03 mg/kg subcutaneously three times a week) or placebo for a period of 4 weeks. In addition, both groups also received dietary interventions. The somatropin-treated group demonstrated faster gain in bodyweight and lean body mass as well as a greater rise in haemoglobin and serum albumin levels. These changes were associated with a greater increase in walking speed when compared with the placebo group. No adverse effects were reported. On the other hand, the use of somatropin to treat critically ill patients with severe malnutrition resulted in increased mortality.[70] Findings from these studies (as well as from other similar studies[71,72] ) indicate that, although somatropin therapy increased lean body mass, functional ability and strength did not improve in the majority of studies. They also show that longterm somatropin treatment was associated with a high incidence of adverse effects. This, combined with a very high cost, greatly limited the clinical utility of GH replacement in otherwise healthy elderly individuals. The short-term usage of GH supplementation in frail elderly, however, deserves further study. 3.1.2 Growth Hormone-Releasing Hormone Supplementation

Several investigators have recently begun to assess a different approach to enhance the GH/IGF-1 axis in the elderly. Iovino and colleagues[73] demonDrugs Aging 2002; 19 (11)

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strated that repetitive intravenous administration of GHRH (somatorelin) to older individuals could restore the suppressed GH response to GHRH usually noted with aging. Similarly, Corpas and colleagues[74] noted that twice-daily subcutaneous administration of somatorelin for 14 days increased GH and IGF-1 levels in older men. Chapman et al.,[75] using a randomised, double-blind, placebocontrolled trial, tested the effect of ibutamoren (MK 677), an orally administered GH-releasing peptide mimetic, on GH/IGF-1 axis in 32 healthy individuals (15 women and 17 men aged 64–81 years). In this study, once-daily administration of oral ibutamoren 25 mg/day for up to 4 weeks enhanced pulsatile GH release and restored IGF-1 levels to those of younger persons. The potential advantage of using GHRH or GHRH-mimetics is the maintenance of the major counter-regulatory mechanisms, which could modulate the adverse effects of treatment.[76] At present, published data are insufficient to decide about the clinical utility of this approach. 3.1.3 Insulin-like Growth Factor-1 Manipulation

Circulating IGF-1 levels increase at puberty and, thereafter, progressively decline with increasing age.[77] Levels in the elderly may overlap with levels recorded in patients with GH deficiency.[78] Large population studies of elderly patients, however, showed that 50% of elderly patients have circulating IGF-1 levels within the adult range.[79] Although the age-related reduction in IGF-1 levels largely parallels the decrease in GH secretion,[80] there is evidence to suggest that IGF-1 synthesis, release and activity are affected by nutritional status,[81] insulin,[82] gonadal steroids[83] and IGFbinding proteins.[84] Veldhuis et al.[85] examined the feedback role of systemic IGF-1 on GH secretion by administering pegvisomant (an oligopegylated recombinant human GH peptide that is mutated to antagonise GH receptor-dependent signalling) to eight men aged 19–46 years and four women aged 19–39 years. The administration of pegvisomant resulted in short-term depletion of IGF-1 levels and stimulation of GH secretion. The increment in GH secre© Adis International Limited. All rights reserved.

Kamel et al.

tory activity was proportionate to the fall in plasma IGF-1 levels. Quinn and Haugk,[86] using bovine myogenic culture, showed that overexpression of IGF-1 receptor can enhance IGF sensitivity and modify the proliferation and differentiation behaviour of untransformed low passage myoblasts. The clinical utility of such manipulation is yet to be determined. 3.2 Testosterone

A link between serum testosterone levels and muscle mass and strength has been demonstrated in both animals[87] and humans.[87-89] Baumgartner and colleagues[88] studied 121 male participants in the New Mexico Elder Health Study and found that free testosterone index, IGF-1 levels and physical activity were strong predictors of muscle mass and strength. Perry et al.[89] studied 65 older African American men (aged 70–102 years) from the Saint Louis University Inner City Aging Project and demonstrated an age-related decline in testosterone levels in this cohort. Additionally, testosterone levels correlated with upper and lower limb strength and functional status. The mechanisms by which testosterone affects muscle have been reported to be increased protein synthesis, increased intramuscular mRNA concentrations of IGF-1 and decreased concentrations of the inhibitory IGFbinding protein 4. All of this indicates a stimulation of the intramuscular IGF-1 system during testosterone administration.[90-92] Furthermore, Gentili et al.[93] have proposed that intramuscular administration of testosterone 200mg to older men affected the GH/IGF-1 axis, resulting in increased burst mass, basal secretion and 24-hour rhythmicity of GH production, as well as increased IGF-1 serum levels. Cross-sectional[94] and longitudinal studies[95] provide evidence that serum testosterone levels decline with aging. It is estimated that half of the healthy men aged between 50 and 70 years have levels of bioavailable testosterone (the fraction not bound to sex hormone-binding globulin) that are below the lowest levels seen in healthy men aged 20–40 years (i.e. are hypogonadal).[96] The vast Drugs Aging 2002; 19 (11)

Hormones in Pathogenesis and Management of Sarcopenia

majority of older men with low testosterone levels have normal gonadotropin values. Their failure to mount a gonadotropin response is probably the result of a combination of hypothalamic-pituitary and testicular failure.[97] Several published studies have assessed the effects of testosterone supplementation on muscle mass and strength.[92,96,98-105] The first report was published by Tenover in 1992.[96] In this randomised, crossover study, 13 healthy elderly men with low or borderline serum testosterone levels (i.e. a mixture of eugonadal and hypogonadal individuals) received weekly intramuscular injections of testosterone enanthate 100mg or placebo for a period of 3 months. Testosterone therapy resulted in a 3% increase in lean body mass. There were no changes in grip strength, body fat or fat distribution in relation to testosterone administration. Both haematocrit and prostate specific antigen levels increased, while plasma lipid levels remained unchanged except for a 12% decline in total serum cholesterol levels. In another study, Morley and colleagues[92] administered testosterone enanthate 200mg intramuscularly every 2 weeks to eight elderly hypogonadal men (mean age 78 years, bioavailable testosterone level <70 ng/dl) and placebo to six controls (mean age 76 years) for a period of 3 months; they found that testosterone therapy increased right-hand-grip strength and haematocrit, and caused a small decline in low-density lipoprotein cholesterol levels. There were no significant changes in bodyweight, body fat or lean body mass. In another study,[98] using a prospective, placebo-controlled design, the same group of investigators administered testosterone cipionate 200mg intramuscularly every 2 weeks to 15 hypogonadal healthy community-dwelling men (bioavailable testosterone level <60 ng/dl, mean age 68 years) and placebo to 17 hypogonadal men (mean age 65 years) for 12 months. An increase in bilateral hand-grip strength in the intervention group was demonstrated. No measures of body composition were performed in this study. © Adis International Limited. All rights reserved.

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Snyder et al.[99] randomised 108 older men with serum testosterone levels of one standard deviation or more below the mean for normal young men (i.e. mixture of eugonadal and hypogonadal individuals) to wear either a testosterone patch delivering 6 mg/day or a placebo patch for 36 months. They measured body composition using dual-energy x-ray absorptiometry and lower body muscle strength by dynamometer before and during treatment. The intervention group showed a significant decrease in fat mass and an increase in lean body mass compared with the control group. Testosterone therapy did not result in a significant change in lower body muscle strength. Wang and colleagues[100] reported the effects of 180 days of treatment with 1% testosterone gel preparation (50 or 100 mg/day) compared with those of a permeation-enhanced testosterone patch (5 mg/day) on muscle mass and strength in 227 hypogonadal men aged 16–68 years. In this study, body composition was determined by dual-energy x-ray absorptiometry, and muscle strength was measured by the repetitive maximum technique on bench and leg press exercises. Mean muscle strength in the leg press exercise increased by 11–13kg in all treatment groups by 90 days and did not improve further at 180 days of treatment. Moderate increases were also observed in arm/ chest muscle strength. At day 90, lean body mass had increased more in the testosterone gel 100 mg/ day group (+2.74 ± 0.28kg, p < 0.01) than in the testosterone gel 50 mg/day group (+1.28 ± 0.32kg) or the testosterone patch group (+1.2 ± 0.26kg). Fat mass and percentage body fat were not significantly affected in the testosterone patch group, but decreased in the testosterone gel groups (50 mg/ day, –0.90 ± 0.32kg; 100 mg/day, –1.05 ± 0.22kg). Both the increase in lean body mass and the decrease in fat mass were correlated with the changes in average serum testosterone levels attained after transdermal testosterone replacement. Brodsky and colleagues[101] showed that testosterone replacement therapy in hypogonadal men enhanced skeletal muscle mass by stimulating muscle protein synthesis. They administered intraDrugs Aging 2002; 19 (11)

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muscular testosterone cipionate 3 mg/kg twice a week for 6 months to five hypogonadal men aged 33–57 years. Testosterone therapy increased fatfree mass by 15% (p < 0.05), decreased fat mass by 11% (p < 0.05) and increased muscle mass by 20% (p < 0.05) from baseline. The increase in muscle mass was associated with a 56% (p < 0.05) increase in the fractional synthesis rate of mixed skeletal muscle proteins and a trend toward an increase in the fractional synthesis rate of myosin heavy chain (46%, p = 0.098). More recently, Bakhshi et al.[103] randomised a group of 15 frail elderly men admitted to a Geriatrics Evaluation and Management unit to receive weekly injections of testosterone enanthate 100mg or placebo. At the time of discharge, there was a significant increase in task-specific performance (assessed using the Functional Independence Measure) and grip strength in the group that received testosterone supplementation compared with the group that received placebo. Ly et al.[104] randomised 37 hypogonadal community-dwelling men (aged ≥60 years) to undergo daily dermal application of androstanolone (dihydrotestosterone) gel 70mg or placebo for a period of 3 months. Androstanolone decreased skin-fold thickness and fat mass but did not affect lean body mass or waist-to-hip ratio. Apart from an increase in strength of flexor muscles of the dominant knee, there were no changes in the strength of extensor muscles of the dominant knee or in shoulder contractions, or in gait, balance, mobility tests, cognitive function or quality-of-life measures. Overall, these studies indicate that physiological testosterone replacement in older men with low testosterone levels may increase muscle mass, strength and function and decrease body fat. In eugonadal individuals, on the other hand, although physiological dosages of testosterone therapy increased lean body mass, they had no effect on muscle strength. Testosterone therapy is not without complications, however. Potential adverse effects include increased haematocrit levels, stimulation of benign prostatic hypertrophy, prostate carcinoma and provocation of aggressive behaviour. © Adis International Limited. All rights reserved.

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3.3 Dehydroepiandrosterone

DHEA and DHEA sulphate (DHEAS) are both precursors of adrenal sex steroids, and their levels decrease dramatically with advancing age.[105] DHEA (prasterone) is widely available in healthfood stores and is being marketed as a ‘nutritional supplement’. In a study of 144 men and 118 women (independent, community-dwelling elderly), DHEAS serum levels were significantly correlated to percentage body fat (r = –0.3) and percentage lean body mass (r = 0.3) in men but not in women.[106] Morales and colleagues,[107] using a randomised, controlled design, administered oral prasterone (DHEA) 100mg to nine men aged 50–65 years and ten women aged 50–65 years for a period of 6 months. They demonstrated significant increases in IGF-1 serum levels in both men (+16 ± 6%, p < 0.05) and women (+31 ± 12%, p < 0.02). In addition, body fat decreased (–6.1 ± 2.6%, p < 0.05) and knee and lumbar muscle strength significantly increased in men (+15 ± 3.3% and +13.9 ± 5.4%, respectively) but not in women. No significant adverse effects were observed. In a double-blind, placebo-controlled trial, Baulieu et al.[108] randomised 280 healthy older men and women (aged 60–79 years) to receive oral prasterone 50mg or placebo daily for a year. Supplementation of DHEA with prasterone increased serum DHEAS levels to those of younger individuals. In addition, there was a small increase in serum levels of testosterone and estradiol, particularly in women. Bone density, as assessed by dual-energy x-ray absorptiometry, increased selectively in women who were older than 70 years. This group of women also showed a significant increase in most libido parameters. Significant improvement was also noted in skin status, particularly in women. The administration of this dose of prasterone for a year did not result in significant adverse effects. Preliminary analysis of the study by Flynn et al.,[109] on the other hand, found no change in body composition after the administration of prasterone 100mg daily for a period of 6 months. Drugs Aging 2002; 19 (11)

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Larger-scale and longer randomised, controlled trials are needed before reaching valid conclusions as to the clinical utility of DHEA supplementation in the management of sarcopenia. The direct biological activity of adrenal androgens (androstenedione, DHEA and DHEAS) is minimal as they function primarily as precursors for peripheral conversion to the active androgenic hormones testosterone and dihydrotestosterone. With the exception of DHEA and DHEAS, anabolic hormones such as androstenedione and nandrolone deconate have not been studied in elderly individuals. 3.4 Estrogen

Normal menopausal transition is associated with changes in body composition and muscle strength. Poehlman et al.[110] examined longitudinal changes in resting energy expenditure and body composition in a cohort of 35 women who experienced menopause compared with an agematched group of women who remained premenopausal. The study demonstrated a 3kg loss of fatfree mass, a 2.5kg increase in fat mass, a 100 kcal/day decline in resting metabolic rate and an increase in waist-to-hip ratio over 6 years. Although, estrogen has a direct anabolic action on muscle, its effects may also be mediated through conversion to testosterone.[111] Both estrogen and testosterone inhibit the production of catabolic cytokines such as interleukin (IL)-1 and IL-6, suggesting that loss of these gonadal hormones with age could have both direct and indirect catabolic effects on muscle tissue.[112,113] The effect of estrogen on muscle may also be mediated through its modulatory effect on the GH/IGF-1 axis. Estrogen has a positive modulatory effect on GH secretion.[114] Whether the effect of menopausal transition on muscle is due to hormonal changes and/or lifestyle modifications is yet to be determined. There is little information documenting the effects of estrogen replacement therapy on muscle mass and strength in postmenopausal women. Baumgartner et al.,[88] using a cross-sectional design, compared a group of elderly women who © Adis International Limited. All rights reserved.

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were receiving estrogen replacement therapy (n = 132) and an age-matched control group who were not receiving estrogen (n = 48) and found no association between estrogen replacement therapy and either muscle mass or strength. Similarly, the results from a 2-year, prospective, randomised, placebo-controlled trial of 62 early postmenopausal women showed no effect of estrogen replacement therapy on lean body mass. Estrogen replacement therapy, however, prevented postmenopausal accumulation of central fat.[115] A cross-sectional study of 70 postmenopausal women aged 45–55 years showed that estrogen use resulted in higher serum levels of sex hormonebinding globulin and lower concentrations of free testosterone.[116] Total testosterone concentrations were not affected by estrogen use. In this study, total lean body mass and leg lean mass but not arm lean mass were related to free testosterone levels. Sorensen and colleagues,[117] using a placebocontrolled, crossover design, randomised 16 postmenopausal women (mean age 55 years) to receive estradiol (17β-estradiol) plus cyclical norethisterone acetate or placebo in two 12-week periods separated by a 3-month washout period. The study showed that hormone replacement therapy was associated with a significant increase in lean body mass and decrease in total fat mass. Dionne and colleagues[118] conducted an extensive review of published studies investigating the effect of estrogen replacement therapy on muscle mass and function in postmenopausal women and found that, although the limited clinical trials failed to demonstrate any effect of estrogen replacement therapy on muscle mass, crosssectional and longitudinal studies linked hormone replacement therapy to increased muscle strength and function. 4. Conclusion Sarcopenia is a recently recognised epidemic that constitutes a great threat to the functional independence and quality of life of older individuals. There is growing evidence linking the occurrence of sarcopenia to age-related decline in the producDrugs Aging 2002; 19 (11)

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tion of testosterone, GH, DHEA and estrogen. Testosterone replacement therapy may have salutary effects on muscle in hypogonadal men with sarcopenia. Long-term trials are needed, however, to better define the risk-benefit ratio of such therapy before it can be recommended. The treatment of sarcopenia is still in its infancy, as the mechanisms involved in the development and progression of sarcopenia are poorly understood. Acknowledgements The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.

References 1. Baumgartner RN, Stauber PM, McHugh D, et al. Crosssectional age differences in body composition in persons 60+ years of age. J Gerontol A Biol Sci Med Sci 1995; 50: M307-16 2. Rosenberg IH. Sarcopenia: origins and clinical relevance. J Nutr 1997; 127: 990S-1S 3. Kotler DP. Cachexia. Ann Intern Med 2000; 133: 622-34 4. Roubenoff R. The pathophysiology of wasting in the elderly. J Nutr 1999; 129: 256S-9S 5. Alexander NB, Schultz A, Warwick DN. Rising from a chair: effects of age and functional ability on performance biomechanics. J Gerontol 1991; 46: M91-8 6. Hubert HB, Bloch DA, Fries JF. Risk factors for physical disability in an aging cohort: the NHANES 1 epidemiologic follow-up study. J Rheumatol 1993; 20: 480-8 7. Guralink JM, Simonsick EM, Ferrucci L, et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol 1994; 49: M85-94 8. Kritz-Silverstein D, Barrett-Conner E. Grip strength and bone mineral density in older women. J Bone Miner Res 1994; 9: 45-52 9. Toner MM, Sawka MN, Foley ME, et al. Effects of body mass and morphology on thermal responses in water. J Appl Physiol 1986; 60: 521-5 10. Kohert WM, Kirwan JP, Staten MA, et al. Insulin resistance in aging is related to abdominal obesity. Diabetes 1993; 42: 273-81 11. Dutta C, Hadley E. The significance of sarcopenia in old age. J Gerontol 1995; 50 (A): 1-4 12. Baumgartner RN, Koehler KM, Gallagher D, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol 1998; 147: 755-63 13. Melton J, Khosla S, Crowson C, et al. Epidemiology of sarcopenia. J Am Geriatr Soc 2000; 48: 625-30 14. Navarro A, Lopez-Cepero JM, Sanchez del Pino MJ. Skeletal muscle and aging. Front Biosci 2001; 6: d26-44 15. Allen TH, Anderson EC, Langham WH. Total body potassium and gross body composition in relationship to age. J Gerontol 1960; 15: 348-57

© Adis International Limited. All rights reserved.

16. Tzankoff SP, Norris AH. Effect of muscle mass decrease on age-related BMR changes. J Appl Physiol 1977; 43: 1001-6 17. Young A, Stokes M, Crowe M. Size and strength of the quadriceps muscles of old and young men. Clin Physiol 1985; 5: 145-54 18. Young A, Stokes M, Crowe M. Size and strength of the quadriceps muscles of old and young women. Eur J Clin Invest 1984; 14: 282-7 19. Imamura K, Ashida H, Ishikawa T, et al. Human major psoas muscle and sacrospinalis muscle in relation to age: a study by computed tomography. J Gerontol 1983; 38: 678-81 20. Kligaard H, Mantoni M, Schianffino S, et al. Function, morphology and protein expression of aging skeletal muscle: a cross-sectional study of elderly men with different training backgrounds. Acta Physiol Scand 1990; 140: 119-39 21. Overend TJ, Cunningham DA, Paterson DH, et al. Thigh composition in young and elderly men determined by computed tomography. Clin Physiol 1992; 12: 629-40 22. Rice CL, Cunningham DA, Paterson DH, et al. Arm and leg composition determined by computed tomography in young and elderly men. Clin Physiol 1989; 9: 207-20 23. Tomonaga M. Histochemical and ultrastructural changes in senile human skeletal muscle. J Am Geriatr Soc 1977; 25: 125-31 24. Jennekens FG, Tolinson BE, Walton J. Histochemical aspects of five limb muscles in old age: an autopsy study. J Neurol Sci 1971; 14: 259-76 25. Balagopal P, Rooyackers OE, Adey DB, et al. Effects of aging on in vivo synthesis of skeletal muscle myosin heavy-chain and sarcoplasmic protein in humans. Am J Physiol 1997; 273: E790-800 26. Lexell J, Henriksson-Larsen K, Winblad B, et al. Distribution of different fiber types in human skeletal muscle: effects of aging studied in whole muscle-cross sections. J Appl Physiol 1985; 59: 1228-36 27. Jakobson F, Borg K, Edstrom L. Fiber-type composition, structure and cytoskeletal protein location of fibers in anterior tibial muscle: comparison between young adults and physically active aged humans. Acta Neuropathol 1990; 80: 459-69 28. Doherty TJ, Brown WF. The estimated number and relative size of thenar motor units as selected by multiple point stimulation in young and older adults. Muscle Nerve 1993; 74: 868-74 29. Wanagat J, Cao Z, Pathare P, et al. Mitochondrial DNA deletion mutations co localize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. FASEB J 2001; 15 (2): 322-32 30. Weindruch R. Interventions based on the possibility that oxidative stress contributes to sarcopenia. J Gerontol A Biol Sci Med Sci 1995; 50: 157-61 31. Doherty TJ, Vandervoort AA, Taylor AW, et al. Effects of aging on the motor unit: a brief review. Can J Appl Physiol 1992; 18: 331-58 32. Tomlinson BE, Irving D. The numbers of limb motor neurons in the human lumbosacral cord throughout life. J Neurol Sci 1977; 34: 213-9 33. Welle S, Thornton T, Jozefowicz R, et al. Myofibrillar protein synthesis in young and old men. Am J Physiol 1993; 26: E693-8 34. Balagopal P, Rooyackers OE, Adey DB, et al. Effects of aging on in vivo synthesis of skeletal muscle myosine heavy-chain and sarcoplasmic protein in humans. Am J Physiol 1997; 273: E790-800

Drugs Aging 2002; 19 (11)

Hormones in Pathogenesis and Management of Sarcopenia

35. Clement FJ. Longitudinal and cross-sectional assessments of age changes in physical strength as related to sex, social class, and mental ability. J Gerontol 1974; 29: 423-9 36. Larsson L, Grimby G, Karlsson J. Muscle strength and speed of movement in relation to age and muscle morphology. J Appl Physiol 1979; 46: 451-6 37. Murray MP, Gardner GM, Mollinger LA, et al. Strength of isometric and isokinetic contractions. Phys Ther 1980; 60: 412-9 38. Johnson T. Age-related differences in isometric and dynamic strength and endurance. Phys Ther 1982; 62: 985-9 39. Viitasalo JT, Era P, Leskinen AL, et al. Muscular strength profiles and anthopometry in random samples of men aged 3135, 5155, and 71-75 years. Ergonomics 1985; 28: 1563-74 40. Frontera WR, Hughes VA, Lutz KJ, et al. A cross-sectional study of muscle strength and mass in 45-78-year-old men and women. J Appl Physiol 1991; 71: 644-50 41. Era P, Lyyra AL, Viitasalo JT, et al. Determinants of isometric muscle strength in men of different ages. Eur J Appl Physiol 1992; 64: 84-91 42. Asmussen E, Heeboll-Nielsen K. Isometric muscle strength in relation to age in men and women. Ergonomics 1962; 5: 167-9 43. Harries UJ, Bassey EJ. Torque-velocity relationships for the knee extensors in women in their 3rd and 7th decades. Eur J Appl Physiol 1990; 60: 187-90 44. Maurray MP, Duthie Jr EH, Gambert SR, et al. Age-related differences in knee muscle strength in nominal women. J Gerontol 1985; 40: 275-80 45. Young A, Stokes M, Crowe M. Size and strength of the quadriceps muscles of old and young women. Eur J Clin Invest 1984; 14: 282-7 46. Stalberg E, Borges O, Ericsson M, et al. The quadriceps femoris muscle in 20-70-year-old subjects: relationships between knee extension torque electrophysiological parameters, and muscle fiber characteristics. Muscle Nerve 1989; 12: 382-9 47. Aniansson A, Sperling L, Rundgren A, et al. Muscle function in 75-year-old men and women: a longitudinal study. Scand J Rehabil Med Suppl 1983; 9: 92-102 48. Aniansson A, Hedberg M, Henning GB, et al. Muscle morphology, enzymatic activity, and muscle strength in elderly men: a follow-up study. Muscle Nerve 1986; 9: 585-91 49. Aniansson A, Grimby G, Hedberg N. Compensatory muscle fiber hypertrophy in elderly men. J Appl Physiol 1992; 73: 812-6 50. Bassey EJ, Harries UJ. Normal values for hand grip strength in 920 men and women aged over 65 years, and longitudinal changes over 4 years in 620 survivors. Clin Sci 1993; 84: 331-7 51. Tanaka H, Seals DR. Age and gender interactions in physiological functional capacity: insight form swimming performance. J Appl Physiol 1997; 82 (3): 846-51 52. Dempsey JA, Seals DR. Aging, exercise and cardiopulmonary function. In: Lamb DR, Gisolfi CV, Nadel E, editors. Perspectives in exercise science and sports medicine: exercise in older adults. Carmel (IN): Cooper, 1995: 237-304 53. Joyner MJ. Physiological limiting factors and distance running: influence of gender and age on record performances. In: Holloszy JO, editor. Exercise and sport science reviews. Baltimore (MD): Williams & Wilkins, 1993: 103-33 54. Conley KE, Kemper WF, Crowther GJ. Limits to sustainable muscle performance: interaction between glycolysis and

© Adis International Limited. All rights reserved.

875

55.

56.

57. 58.

59. 60. 61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72. 73.

74.

oxidative phosphorylation. J Exp Biol 2001; 204 (Pt 18): 3189-94 Conely KE, Esselman PC, Jubrias SA, et al. Ageing, muscle properties and maximal O(2) uptake rate in humans. J Physiol 2000; 526 Pt 1: 211-7 Fiatarone MA, O’Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 1994; 330: 1769-75 Bendall MJ, Bassey EJ, Pearson MB. Factors affecting walking speed of elderly people. Age Ageing 1989; 18: 327-32 Vellas B, Baumgartner RN, Wayne SJ, et al. Relationship between malnutrition and falls in the elderly. Nutrition 1992; 8: 105-8 Roubenoff R, Hughes VA. Sarcopenia: current concepts. J Gerontol 2000; 55A (12): M716-24 Rudman D. Growth hormone, body composition, and aging. J Am Geriatr Soc 1985; 33: 800-1 Kelijman M. Age-related alterations of growth hormone/ insulin-like-growth-factor I axis. J Am Geriatr Soc 1991; 39: 295-307 Jorgensen JO, Pedersen SA, Thuesen L, et al. Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 1989; I: 1221-5 Binnerts A, Deurenberg P, Swat GR, et al. Body composition in growth hormone-deficient adults. Am J Clin Nutr 1992; 55: 918-23 Debore H, Block GJ, Voerman HJ, et al. Body composition in adult growth hormone-deficient men, assessed by anthropometry and bioimpedance. J Clin Endocrinol Metab 1986; 75: 833-7 Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990; 323: 1-6 Cohen L, Feller AG, Draper MW, et al. Carpal tunnel syndrome and gynaecomastia during growth hormone treatment of elderly men with low circulating IGF-1 concentrations. Clin Endocrinol 1993; 39: 417-25 Papadakis MA, Grady B, Black D, et al. Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Intern Med 1996; 124: 708-16 Kaiser FE, Silver AJ, Morley JE. The effect of recombinant human growth hormone on malnourished older individuals. J Am Geriatr Soc 1991; 39: 235-40 Chu LW, Lam KS, Tam SC, et al. A randomized controlled trial of low-dose recombinant human growth hormone in the treatment of malnourished elderly medical patients. J Clin Endocrinol Metab 2001; 86 (5): 1913-20 Takala J, Ruokonen E, Webster NR, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999; 341: 785-92 Bengtsson B, Eden S, Lonn L, et al. Treatment of adults with growth hormone deficiency with recombinant human GH. J Clin Endocrinol Metab 1993; 76 (2): 309-31 Lissett CA, Shalet SM. Effects of growth hormone on bone and muscle. Growth Horm IGF Res 2000; 10 Suppl. B: S95-101 Iovino M, Monteleone P, Steardo L. Repetitive growth hormone-releasing hormone administration restores the attenuated growth hormone (GH) response to GH-releasing hormone testing in normal aging. J Clin Endocrinol Metab 1989; 69: 910-3 Corpas E, Harman SM, Pineyro MA, et al. Growth hormone (GH)-releasing hormone-(1-29) twice daily reverses the de-

Drugs Aging 2002; 19 (11)

876

75.

76. 77.

78. 79. 80. 81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

Kamel et al.

creased GH and insulin like growth factor-1 levels in old men. J Clin Endocrinol Metab 1992; 75: 530-5 Chapman IM, Bach MA, Van Cauter E, et al. Stimulation of the growth hormone (GH)-insulin-like growth facto I axis by daily oral administration of a GH secretagogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab 1996; 81 (12): 4249-57 Mooradian AD, Morley JE, Korenman SG. Biological actions of androgens. Endocr Rev 1987; 8: 1-18 Juul A, Bang P, Hertel NT, et al. Serum insulin-like growth factor-1 in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. J Clin Endocrinol Metab 1994; 78 (3): 744-52 Hammerman MR. Insulin-like growth factors and aging. Endocrinol Metab Clin North Am 1987; 16 (4): 995-1011 Arvat E, Broglio F, Ghigo E. Insulin-like growth factor 1. Drugs Aging 2000; 16 (1): 29-40 Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev 1993; 14 (1): 20-39 Thissen J, Keteslegers JM, Underwood LE. Nutritional regulation of the insulin-like growth factors. Endocr Rev 1994; 15: 80-101 Johnson TR, Blossey BK, Denko CW, et al. Expression of insulin-like growth factor-1 in cultural rat hepatocytes: effects of insulin and growth hormone. Mol Endocrinol 1989; 3: 580-7 Rutanen EM, Karkkainen T, Stenman UH, et al. Aging is associated with decreased suppression of insulin-like growth factor binding proteins and insulin sensitivity. J Clin Endocrinol Metab 1997; 82: 2177-81 Benbassat CA, Maki KC, Unterman TG. Circulating levels of insulin-like growth factor (IGF) binding protein-1 and -3 in aging men: relationships to insulin, glucose, IGF, and dehydroepiandrosterone sulfate levels and anthropometric measures. J Clin Endocrinol Metab 1997; 82 (5): 1484-91 Veldhuis JD, Bidlingmaier S, Anderson SM, et al. Lowering total plasma insulin-like growth factor 1 concentrations by way of a novel, potent, and selective growth hormone (GH) receptor antagonist, pegvisomant (B2036-Peg), augments the amplitude of GH secretary bursts and elevates basal/nonpulsatile GH release in healthy women and men. J Clin Endocrinol Metab 2001; 86 (7): 3304-10 Quinn LS, Haugk KL. Over expression of the type-1 insulin-like growth factor receptor increases ligand-dependent proliferation and differentiation in bovine skeletal myogenic cultures. J Cell Physiol 1996; 168 (1): 34-41 Schwartz RS. Trophic factor supplementation: effect on the age-associated changes in body composition. J Gerontol Series A 1995; 50A: 151-6 Baumgartner R, Waters D, Gallgher D, et al. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999; 107: 123-36 Perry HM, Miller DK, Patrick P, et al. Testosterone and leptin in older African-American men: relationship to age, strength, function, and season. Metabolism 2000; 49 (8): 1085-91 Ashton WS, Degnan BM, Daniel A, et al. Testosterone increases insulin-like growth factor-1 and insulin-like growth factor-binding protein. Ann Clin Lab Sci 1995; 24: 381-8 Urban RJ, Bodenburg YH, Gilkison C, et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol 1995; 269 (5 Pt 1): E820-6

© Adis International Limited. All rights reserved.

92. Morley JE, Perry III M, Kaiser FE, et al. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 1993; 41: 149-52 93. Gentili A, Mulligan T, Godschalk M, et al. Unequal impact of short-term testosterone repletion on the somatotrophic axis of young and older men. J Clin Endocrinol Metab 2002; 87 (2): 825-34 94. Gray A, Feldman HA, Mckinlay J, et al. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 1991; 73: 1016-25 95. Morley JE, Kaiser FE, Perry HM, et al. Longitudinal changes in testosterone, luteinizing hormone and follicle stimulating hormone in healthy older males. Metabolism 1997; 46: 410-4 96. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrin Metab 1992; 75: 1092-8 97. Korenman SG, Morley JE, Mooradian AD, et al. Secondary hypogonadism in older men: its relationship to impotence. J Clin Endocrinol Metab 1990; 71: 963-9 98. Sih R, Morley JE, Kaiser FE, et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997; 82 (6): 1661-7 99. Snyder PJ, Peachey H, Hannoush P, et al. Effects of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999; 84 (8): 2647-53 100. Wang C, Swedloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone Gel Study Group. J Clin Endocrinol Metab 2000; 85 (8): 2839-53 101. Brodsky IG, Balagopal P, Nair KS. Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men: a clinical research center study. J Clin Endocrinol Metab 1996; 81 (10): 3469-75 102. Katznelson L, Finkelstein JS, Scheoenfeld DA, et al. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 1996; 81 (12): 4358-65 103. Bakhshi V, Elliot M, Gentili M, et al. Testosterone improves rehabilitation outcomes in ill older men. J Am Geriatr Soc 2001; 48 (5): 550-3 104. Ly LP, Jimernes M, Zhuang TN, et al. A double-blind, placebocontrolled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. J Clin Endocrinol Metab 2001; 86 (9): 4078-88 105. Morley JE, Kaiser FE, Raum WJ, et al. Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decrease in bioavailable testosterone, and dehydroepiandrosterone sulfate. Proc Natl Acad Sci U S A 1997; 94: 7537-42 106. Abbasi A, Duthie EH, Sheldahl L, et al. Association of dehydroepiandrosterone sulfate, body composition, and physical fitness in independent community-dwelling older men and women. J Am Geriatr Soc 1998; 46: 263-73 107. Morales AJ, Haubrich RH, Hwang JY, et al. The effect of six months treatment with a 100mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol 1998; 49: 421-32 108. Baulieu E, Thomas G, Legarain S, et al. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of

Drugs Aging 2002; 19 (11)

Hormones in Pathogenesis and Management of Sarcopenia

109.

110.

111.

112.

113.

114.

the DHEAge study to a sociomedical issue. Proc Natl Acad Sci U S A 2000; 97 (8): 4279-84 Flynn MA, Weaver-Osterholtz D, Sharpe-Timms KL, et al. Dehydroepiandrosterone replacement in aging humans. J Clin Endocrinol Metab 1999; 84: 1527-33 Poehlman ET, Toth MJ, Gardner AW. Changes in energy balance and body composition at menopause: a controlled longitudinal study. Ann Intern Med 1995; 123 (9): 673-5 Grinspoon S, Corcoran C, Miller K, et al. Body composition and endocrine function in women with acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1997; 82: 1332-7 Pottratz ST, Bellido T, Mocharla H, et al. 17 alpha estradiol inhibits expression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism. J Clin Invest 1994; 93: 944-50 Ralston SH. Analysis of gene expression in human bone biopsies by polymerase chain reaction: evidence for enhanced cytokine expression in postmenopausal osteoporosis. J Bone Miner Res 1994; 9: 883-90 Veldhuis JD, Evans WS, Bowers CY, et al. Interactive regulation of postmenopausal growth hormone insulin-like growth

© Adis International Limited. All rights reserved.

877

115.

116.

117.

118.

factor axis by estrogen and growth hormone-releasing peptide-2. Endocrine 2001; 14 (1): 45-62 Haarbo J, Marslew U, Gotfrdsen A, et al. Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause. Metabolism 1991; 40: 1323-6 Gower BA, Nyman L. Association among oral estrogen use, free testosterone concentrations, and lean body mass among postmenopausal women. J Clin Endocrinol Metab 2000; 85: 4476-80 Sorensen MB, Rosenfalck AM, Hojgaard L, et al. Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy. Obes Res 2001; 9 (10): 622-6 Dionne JI, Kinaman KA, Poehlman ET. Sarcopenia and muscle function during menopause and hormone-replacement therapy. J Nutr Health Aging 2000; 4 (3): 156-61

Correspondence and offprints: Dr Hosam K. Kamel, Division of Geriatrics/Gerontology, Clement J. Zablocki VAMC, 5000 West National Ave (CC-G), Milwaukee, WI 53295, USA. E-mail: [email protected]

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