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Chapter 13/Androgens and Body Composition 243 13 Androgens and Body Composition Laurence Katznelson, MD CONTENTS INTRODUCTION TESTOSTERONE AND MALE HYPOGONADISM TESTOSTERONE ADMINISTRATION IN HYPOGONADAL MEN TESTOSTERONE ADMINISTRATION TO EUGONADAL MEN ARE THERE APPLICATIONS OF TESTOSTERONE IN CHRONIC ILLNESS? TESTOSTERONE AND WOMEN: ENDOGENOUS EFFECTS AND POTENTIAL USES CONCLUSIONS REFERENCES INTRODUCTION Ever since the clinical availability of androgens, it has been noted that androgens modulate body composition, leading to enhanced lean and diminished fat mass. Androgens have received particular attention with regard to improving body composition not only in normal populations but also in those with chronic illness with associated sarcopenia. For example, improvements in muscle mass following testosterone administration have been shown in sarcopenic states such as aging, cancer, and human immunodeficiency virus (HIV) wasting, although the implications of these changes with regard to function have not been well documented. The effects of androgens on fat mass have also generated much interest because of the potential effects of androgens in modulating cardiovascular risk. Additionally, there is excitement about the application of androgens to women because of the potential for beneficial effects on body composition in women with hypopituitarism and menopause. This chapter will provide an overview regarding both physiologic and supraphysiologic testosterone administration on body composition in eugonadal and hypogonadal individuals, including those with sarcopenia in the setting of chronic illness or aging. The potential applications of testosterone administration in these populations will be reviewed. TESTOSTERONE AND MALE HYPOGONADISM The rationale for investigating the effects of testosterone administration on body composition stems from cross-sectional studies that associate altered adipose deposition From: Contemporary Endocrinology: Androgens in Health and Disease Edited by: C. Bagatell and W. J. Bremner © Humana Press Inc., Totowa, NJ 243
244 Katznelson in men with testosterone deficiency. Hypogonadal adult men have greater deposition of central fat compared to age and body mass index (BMI)-matched eugonadal men (1). In a study utilizing computed tomography (CT) scans to quantify site-specific adiposity, we showed that hypogonadism was associated with more subcutaneous fat deposition, and there was a trend for more visceral fat compared to eugonadal men (1). In a study of 23 healthy men, serum testosterone and free-testosterone levels correlated negatively both with visceral fat deposition and insulin levels (2). These data indicate that lower testosterone levels correlate with increases in fat mass, with specific deposition in the central sites. In a cohort of 511 men aged 30–79 yr in 1972–1974, Khaw et al. (3) assessed the impact of androgens on central adiposity, estimated 12 yr later using the waist–hip circumference ratio. Levels of androstenedione, testosterone, and sex hormone-binding globulin (SHBG) measured at baseline were inversely related to accumulation of central adiposity. This suggests that lower testosterone levels have a contributory role in promoting central fat accumulation. Because central adiposity is associated with heightened cardiovascular risk, these data suggest that hypogonadism may have important implications with regard to health (4,5). There have been no studies clearly demonstrating a link between testosterone deficiency and cardiac events. TESTOSTERONE ADMINISTRATION IN HYPOGONADAL MEN Investigations into the effects of testosterone on body composition are based on prior evidence of the nitrogen-retaining properties of testosterone in castrate animals (6) and historical evidence for behavioral effects of testosterone substitution in animals (7). There are several models used to determine the effects of hypogonadism and testosterone administration in hypogonadism on body composition in men. One model utilizes biochemical castration to assess the effects of abrupt testosterone withdrawal on body composition. In a study by Mauras et al. (8), Lupron depot was administered to six healthy young men (mean age: 23 yr) for 10 wk. Using dual-energy X-ray analysis (DEXA), there was a 2.1-kg reduction in fat-free mass and a 1.1-kg increase in fat mass, without a significant change in weight. There was a significant decrease in whole-body proteolysis and whole-body protein synthesis, a trend for a reduction in lipid oxidation rates, and a reduction in skeletal muscle insulin-like growth factor (IGF)-1 mRNA expression. These data show that a reduction in serum testosterone to castrate levels in young men is associated with a change in body composition, including an increase in fat mass, a decrease in lean mass, and a decline in protein synthesis and growth factor production in skeletal muscle. There were no changes in serum growth hormone (GH) and IGF-1 values during this study, suggesting that the observed effects on body composition and metabolism were the result of changes in testosterone alone. These changes in adiposity and fat-free mass are similar to trends seen in men with modest to moderate hypogonadism (1). The effects of androgen administration on body composition in adult men with hypogonadism have been investigated in multiple, nonplacebo-controlled studies. Katznelson et al. (9) administered intramuscular testosterone enanthate for 18 mo to 29 adult men with acquired hypogonadism (median age: 57 yr) who had never previously received testosterone therapy. At baseline, there was more percent body fat, measured by bioelectrical impedance, in hypogonadal compared to control men. Percent body fat decreased by 14% following testosterone-replacement therapy. Comparison of CT scans in 13 men
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CONTEMPORARY ENDOCRINOLOGY Androgen
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CONTEMPORARY ENDOCRINOLOGY P. Micha
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© 2003 Humana Press Inc. 999 River
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vi Preface We hope Androgens in Hea
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viii Contents 13 Androgens and Body
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x Contributors RICHARD S. LEGRO, MD
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2 Winters and Clark
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4 Winters and Clark chorionic gonad
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6 Winters and Clark LH REGULATION O
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8 Winters and Clark These enzymes a
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10 Winters and Clark -subunit mRNA
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12 Winters and Clark Fig. 3. A sche
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14 Winters and Clark Table 1 Factor
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16 Winters and Clark Table 2 Tissue
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18 Winters and Clark 11. Thomas JL,
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20 Winters and Clark 61. Dufau ML,
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22 Winters and Clark 112. Raivio T,
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24 Brown Fig. 1. Mechanism for andr
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26 Brown increase in intracellular
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28 Brown Fig. 2. Structural and fun
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30 Brown Fig. 3. Amino acid sequenc
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32 Brown tions to shuttle the AR th
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34 Brown Fig. 4. Amino acid primary
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36 Brown part of an inactive chroma
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38 Brown the external genitalia is
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40 Brown tors, as well as the trans
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42 Brown 49. Williams SP, Sigler PB
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44 Brown 100. Gregory CW, He B, Joh
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46 Plymate Table 1 Classification o
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48 Plymate In addition to the direc
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50 Plymate LABORATORY FINDINGS In p
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52 Plymate those manifesting as phe
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54 Plymate result in some improveme
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56 Plymate If both testosterone and
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58 Plymate Persistent Müllerian Du
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60 Plymate INFERTILITY RESULTING FR
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62 Plymate unaffected, contralatera
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64 Plymate SECONDARY HYPOGONADISM H
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66 Plymate Other syndromes manifest
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68 Plymate period after the burn. I
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70 Plymate These findings suggest t
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72 Plymate 49. Goebelsmann U, Horto
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74 Plymate 104. Yoshimoto Y, Moride
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76 Plymate
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78 Sutton, Amory, and Clark levels
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80 Sutton, Amory, and Clark cebo in
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82 Sutton, Amory, and Clark Finaste
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84 Sutton, Amory, and Clark through
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86 Sutton, Amory, and Clark 40. The
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88 Sutton, Amory, and Clark 88. Rob
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90 Lindzey and Korach Fig. 1. Cellu
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92 Lindzey and Korach estrogen sign
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94 Lindzey and Korach TESTIS AND DU
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96 Lindzey and Korach sufficient to
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98 Lindzey and Korach Seminal Vesic
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100 Lindzey and Korach 17. Krege JH
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102 Lindzey and Korach 68. Chang WY
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104 McPhaul on the Y chromosome det
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106 106 McPhaul
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108 McPhaul number of alleles, dele
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110 McPhaul The first mutation of t
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112 McPhaul gene. In vitro studies
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114 McPhaul risk of impaired sperma
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116 McPhaul carrying a single mutan
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118 McPhaul REFERENCES 1. Koopman P
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120 McPhaul 45. Weidemann W, Peters
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122 McPhaul 92. Koivisto P, Kononen
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124 Legro Fig. 1. The spectrum of p
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126 Legro Virilization presents wit
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128 Legro Fig. 3. The paradox of an
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130 Legro small high-density athero
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132 Legro Table 2 Syndromes or Dise
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134 Legro Insulin-Sensitizing Agent
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136 Legro is undetermined according
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138 Legro 39. Lee O, Farquhar C, To
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140 Legro
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142 Wang and Swerdloff PHARMACOLOGY
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144 Wang and Swerdloff The 17α-alk
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146 Wang and Swerdloff Table 2 Dose
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148 Wang and Swerdloff The steroid
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150 Wang and Swerdloff The inabilit
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152 Wang and Swerdloff 15. De Lorim
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154 Wang and Swerdloff
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156 Marcelli et al.
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158 Marcelli et al. Differentiated
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160 Marcelli et al. These coactivat
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162 Marcelli et al. tigators have e
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164 Marcelli et al. AR in Prostate
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166 Marcelli et al. Table 1 Androge
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168 Marcelli et al. A molecular exp
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170 Marcelli et al. The above data
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172 Marcelli et al. up to 9 yr late
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174 Marcelli et al. Three major pha
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176 Marcelli et al. vitro model of
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178 Marcelli et al. yr, survival wa
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180 Marcelli et al. 26. McKenna NJ,
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182 Marcelli et al. 78. Isaacs J, C
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184 Marcelli et al. 126. Watanabe M
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186 Marcelli et al. 177. Kousteni S
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188 Marcelli et al. 231. Colombel M
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190 Marcelli et al.
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Page 215 and 216: 204 Wu and von Eckardstein THE HEMO
Page 217 and 218: 206 Wu and von Eckardstein In vivo
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Page 221 and 222: 210 Wu and von Eckardstein 4. Bhasi
Page 223 and 224: 212 Wu and von Eckardstein 57. Barr
Page 225 and 226: 214 Wu and von Eckardstein 107. Fra
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Page 229 and 230: 218 Wu and von Eckardstein 201. Cho
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Page 233 and 234: 222 Kenny and Raisz with a cartilag
Page 235 and 236: 224 Kenny and Raisz METABOLISM OF A
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Page 239 and 240: 228 Kenny and Raisz REFERENCES 1. G
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Page 243 and 244: 232 Kenny and Raisz 103. Snyder PJ,
Page 245 and 246: 234 Basaria and Dobs losses in wome
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Page 257 and 258: 246 Katznelson Fig. 1. Body weight,
Page 259 and 260: 248 Katznelson change during treatm
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Page 269 and 270: 258 Katznelson 71. Davis SR, McClou
Page 271 and 272: 260 Bancroft Androgen Deficiency an
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Page 277 and 278: 266 Bancroft much larger group of a
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Page 285 and 286: 274 Bancroft 4. Studies using place
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Page 291 and 292: 280 Bancroft Women with Endocrine A
Page 293 and 294: 282 Bancroft in response to the fil
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Page 303 and 304: 292 Cherrier and Craft Fig. 1. Path
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294 Cherrier and Craft ment of the
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296 Cherrier and Craft information
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298 Cherrier and Craft Fig. 3. Wech
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300 Cherrier and Craft gen excess r
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302 Cherrier and Craft occurring wi
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304 Cherrier and Craft gesting that
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306 Cherrier and Craft 39. Gouchie
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308 Cherrier and Craft 94. Kelso WM
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310 Cherrier and Craft
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312 Matsumoto
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314 Matsumoto long-term benefits an
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316 Matsumoto manifestations (7). F
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318 Formulation Usual adult dosage
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320 Matsumoto Fig. 1. Mean serum T
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322 Matsumoto dosage is increased g
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324 Matsumoto Androgel 5 g (50 mg o
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326 Matsumoto gen receptor and tiss
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328 Matsumoto such as hepatic cirrh
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330 Matsumoto occasionally, more se
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332 Matsumoto 27. Bhasin S, Bremner
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334 Matsumoto 77. Dobs AS, Meikle A
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336 Richmond and Rogol PHYSIOLOGY O
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338 Richmond and Rogol activity (28
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340 Richmond and Rogol increase lin
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342 Richmond and Rogol curve, the h
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344 Richmond and Rogol Permanent hy
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346 Richmond and Rogol 46. Stanhope
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348 Tenover In aging men, the combi
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350 Tenover Table 1 Changes in Andr
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352 Tenover studies in which eugona
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354 Tenover Table 3 Testosterone Th
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356 Tenover Table 5 ART in Older Me
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358 Tenover be overcome with either
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360 Tenover Laboratory tests should
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362 Tenover 40. Kohrt WM, Malley MT
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364 Tenover 95. Mooradian AD, Morle
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366 Davis Table 1 Proposed Androgen
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368 Davis transdermal testosterone
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370 Davis increase in circulating t
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372 Davis (93). Most recently, Zhou
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374 Davis Table 4 Androgen Replacem
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376 Davis 8. Vierhapper H, Nowotny
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378 Davis 60. Simberg N, Titinen A,
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380 Davis
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382 Bhasin, Woodhouse, and Storer h
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384 Table 2 Effects of Testosterone
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386 Bhasin, Woodhouse, and Storer e
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388 Bhasin, Woodhouse, and Storer F
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390 Bhasin, Woodhouse, and Storer t
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Table 3 Effects of Testosterone Sup
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Table 4 Effects of Testosterone Sup
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396 Bhasin, Woodhouse, and Storer c
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398 Bhasin, Woodhouse, and Storer C
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400 Bhasin, Woodhouse, and Storer w
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402 Bhasin, Woodhouse, and Storer 4
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404 Bhasin, Woodhouse, and Storer
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406 Amory Fig. 1. The endocrinology
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408 Amory pregnancies fathered by t
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410 Amory antagonists can suppress
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412 Amory 100-mg doses of weekly TE
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414 Amory FUTURE DIRECTIONS Given t
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416 Amory 22. Oral contraception. I
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418 Amory
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420 Anawalt inadequate androgen eff
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422 Anawalt few specialty commercia
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424 Anawalt Fig. 1. (C) Secondary h
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426 Anawalt Fig. 2. Evaluation and
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428 Anawalt All men with secondary
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430 Anawalt anemia (38). With the a
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432 Anawalt osterone levels achieve
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434 Anawalt SIDE EFFECTS OF ANDROGE
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436 Anawalt 7. Rosner W. Errors in
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438 Anawalt 59. Mackey MA, Conway A
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440 Index polycystic ovaries, 131 A
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442 Index lipoid congenital adrenal
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444 Index women, 254 dihydrotestost
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446 Index Pituitary adenoma, male h
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448 Index lipoid congenital adrenal
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