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Chapter 6/Mutations of the AR 119 24. Ris-Stalpers C, Kuiper GG, Faber PW, et al. Aberrant splicing of androgen receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity. Proc Natl Acad Sci USA 1990;87:7866–8670. 25. Ris-Stalpers C, Verleun-Mooijman MC, de Blaeij TJ, et al. Differential splicing of human androgen receptor pre-mRNA in X-linked Reifenstein syndrome, because of a deletion involving a putative branch site. Am J Hum Genet 1994;54:609–617. 26. McPhaul MJ, Marcelli M, Zoppi S, et al. Mutations in the ligand-binding domain of the androgen receptor gene cluster in two regions of the gene. J Clin Invest 1992;90:2097–2101. 27. Marcelli M, Zoppi S, Wilson CM, et al. Amino acid substitutions in the hormone-binding domain of the human androgen receptor alter the stability of the hormone receptor complex. J Clin Invest 1994;94:1642–1650. 28. Marcelli M, Tilley WD, Zoppi S, et al. Androgen resistance associated with a mutation of the androgen receptor at amino acid 772 (ArggCys) results from a combination of decreased messenger ribonucleic acid levels and impairment of receptor function. J Clin Endocrinol Metab 1991;73:318–325. 29. Wilson CM, Griffin JE, Wilson JD, et al. Immunoreactive androgen receptor expression in patients with androgen resistance. J Clin Endocrinol Metab 1992;75:1474–1478. 30. Lubahn DB, Brown TR, Simental JA, et al. Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci USA 1989;86:9534–9538. 31. Brown TR, Lubahn DB, Wilson EM, et al. Functional characterization of naturally occurring mutant androgen receptors from subjects with complete androgen insensitivity. Mol Endocrinol 1990;4:1759–1772. 32. Grino PB, Isidro-Gutierrez RF, Griffin JE, Wilson JD. Androgen resistance associated with a qualitative abnormality of the androgen receptor and responsive to high dose androgen therapy. J Clin Endo Metab 1989;68:578–584. 33. McPhaul MJ, Marcelli M, Tilley WD, et al. Molecular basis of androgen resistance in a family with a qualitative abnormality of the androgen receptor and responsive to high-dose androgen therapy. J Clin Invest 1991;87:1413–1421. 34. Langley E, Zhou ZX, Wilson EM. Evidence for an anti-parallel orientation of the ligand-activated human androgen receptor dimmer. J Biol Chem 1995;270:29983–29990. 35. Doesburg P, Kuil CW, Berrevoets CA, et al. Functional in vivo interaction between the aminoterminal, transactivation domain and the ligand binding domain of the androgen receptor. Biochemistry 1997;36:1052–1064. 36. Prior L, Bordet S, MA Trifiro, et al. Replacement of arginine 773 by cysteine or histidine in the human androgen receptor causes complete androgen insensitivity with different receptor phenotypes. Am J Hum Genet 1992;51:143–155. 37. Beitel LK, Kazemi-Esfarjani P, Kaufman M, et al. Substitution of arginine-839 by cysteine or histidine in the androgen receptor causes different receptor phenotypes in cultured cells and coordinate degrees of clinical androgen resistance. J Clin Invest 1994;94:546–554. 38. P Kazemi-Esfarjani, Beitel LK, Trifiro M, et al. Substitution of valine-865 by methionine or leucine in the human androgen receptor causes complete or partial androgen insensitivity, respectively with distinct androgen receptor phenotypes. Mol Endocrinol 1993;7:37–46. 39. Ris-Stalpers C, Trifiro MA, Kuiper GG, et al. Substitution of aspartic acid-686 by histidine or asparagine in the human androgen receptor leads to a functionally inactive protein with altered hormonebinding characteristics. Mol Endocrinol 1991;5:1562–1569. 40. Tincello DG, Saunders PT, Hodgins MB, et al. Correlation of clinical, endocrine and molecular abnormalities with in vivo responses to high-dose testosterone in patients with partial androgen insensitivity syndrome. Clin Endocrinology 1997;46:497–506. 41. Yong EL, Ng SC, Roy AC, et al. Pregnancy after hormonal correction of severe spermatogenic defect due to mutation in androgen receptor gene Lancet 1994;344:826–827. 42. Ong YC, Wong HB, Adaikan G, Yong EL. Directed pharmacological therapy of ambiguous genitalia due to an androgen receptor gene mutation Lancet 1999;354:1444–1445. 43. Tincello DG, Saunders PT, Hodgins MB, et al. Correlation of clinical, endocrine and molecular abnormalities with in vivo responses to high-dose testosterone in patients with partial androgen insensitivity syndrome. Clin Endocrinol 1997;46:497–506. 44. Radmayr C, Culig Z., Hobisch A, et al. Analysis of a mutant androgen receptor offers a treatment modality in a patient with partial androgen insensitivity syndrome. Eur Urol 1998;33:222–226.
120 McPhaul 45. Weidemann W, Peters B, Romalo G, et al. Response to androgen treatment in a patient with partial androgen insensitivity and a mutation in the deoxyribonucleic acid-binding domain of the androgen receptor. J Clin Endocrinol Metab 1998;83:1173–1176. 46. Zoppi S, Marcelli M, Deslypere JP, et al. Amino acid substitutions in the DNA-binding domain of the human androgen receptor are a frequent cause of receptor-binding positive androgen resistance. Mol Endocrinol 1992;6:409–415. 47. Beitel LK, Prior L, Vasiliou DM, et al. Complete androgen insensitivity due to mutations in the probable alpha-helical segments of the DNA-binding domain in the human androgen receptor. Hum Mol Genet 1994;3:21–27. 48. De Bellis A, Quigley CA, Marschke KB, et al. Characterization of mutant androgen receptors causing partial androgen insensitivity syndrome. J Clin Endocrinol Metab 1994;78:513–522. 49. Sultan C, Lumbroso S, Poujol N, et al. Mutations of androgen receptor gene in androgen insensitivity syndromes. J Steroid Biochem Mol Biol 1993;46:519–530. 50. Lumbroso S, Lobaccaro JM, Belon C, et al. A new mutation within the deoxyribonucleic acid-binding domain of the androgen receptor gene in a family with complete androgen insensitivity syndrome. Fertil Steril 1993;60:814–819. 51. Mowszowicz I, Lee HJ, Chen HT, et al. A point mutation in the second zinc finger of the DNA-binding domain of the androgen receptor gene causes complete androgen insensitivity in two siblings with receptor-positive androgen resistance. Mol Endo 1993;7:861–869. 52. Quigley CA, Evans BAJ, Simental JA. Complete androgen insensitivity due to deletion of exon C of the androgen receptor gene highlights the functional importance of the second zinc-finger of the androgen receptor in vivo. Mol Endocrinol 1992;6:1103–1112. 53. Wooster R, Mangion J, Eeles R, et al. A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nat Genet 1992;2:132–134. 54. Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988;240:889–895. 55. Lobaccaro JM, Lumbroso S, Belon C, et al. Androgen receptor gene mutation in male breast cancer. Hum Mol Genet 1993;2:1799–1802. 56. Poujol N, Lobaccaro JM, Chiche L, et al. Functional and structural analysis of R607Q and R608K androgen receptor substitutions associated with male breast cancer. Mol Cell Endocrinology 1997;130:43–51. 57. Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are present in human genital skin fibroblasts. Proc Natl Acad Sci USA 1994;91:1234–1238. 58. Gao TS, McPhaul MJ. Functional activities of the A- and B- forms of the human androgen receptor in response to androgen receptor agonists and antagonists. Mol Endo 1998;12:654–663. 59. Choong CS, Quigley CA, French FS, Wilson EM. A novel missense mutation in the amino-terminal domain of the human androgen receptor gene in a family with partial androgen insensitivity syndrome causes reduced efficiency of protein translation. J Clin Invest 1996;98:1423–1431. 60. Tsukada T, Inoue M, Tachibana S, et al. An androgen receptor mutation causing androgen resistance in undervirilized male syndrome. J Clin Endocrinol Metab 1994;79:1202–1207. 61. Wang Q, Ghadessy FJ, Trounson A, et al. Azoospermia associated with a mutation in the ligandbinding domain of an androgen receptor displaying normal ligand binding, but defective transactivation. J Clin Endocrinol Metab 1998;83:4303–4309. 62. Lim J, Ghadessy FJ, Abdullah AAR, et al. Human androgen receptor mutation disrupts ternary interactions between ligand, receptor domains, and the coactivator TIF2 (transcription intermediary factor 2). Mol Endocrinol 2000;14:1187–1197. 63. Ghadessy FJ, Lim J, Abdullah AAR, et al. Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions. J Clin Invest 1999;103:1517–1525. 64. Patrizio P, Leonard DGB, Chen KL, et al. Larger trinucleotide repeat size in the androgen receptor gene of infertile men with extremely severe oligozoospermia. J Androl 2001;22:444–448. 65. Mifsud A, Sim CKS, Boettger-Tong H, et al. Trinucleotide (CAG) repeat polymorphisms in the androgen receptor gene: molecular markers of risk for male infertility. Fertility Sterility 2001;75:275–281. 66. Tut TG, Ghadessy FJ, Trifiro MA, et al. Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab 1997;82:3777–3782. 67. Yong EL, Lim LSE, Wang Q, et al. Androgen receptor polymorphisms and mutations in male infertility. J Endocrinol Invest 2000;23:573–577.
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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
Page 79 and 80: 68 Plymate period after the burn. I
Page 81 and 82: 70 Plymate These findings suggest t
Page 83 and 84: 72 Plymate 49. Goebelsmann U, Horto
Page 85 and 86: 74 Plymate 104. Yoshimoto Y, Moride
Page 87 and 88: 76 Plymate
Page 89 and 90: 78 Sutton, Amory, and Clark levels
Page 91 and 92: 80 Sutton, Amory, and Clark cebo in
Page 93 and 94: 82 Sutton, Amory, and Clark Finaste
Page 95 and 96: 84 Sutton, Amory, and Clark through
Page 97 and 98: 86 Sutton, Amory, and Clark 40. The
Page 99 and 100: 88 Sutton, Amory, and Clark 88. Rob
Page 101 and 102: 90 Lindzey and Korach Fig. 1. Cellu
Page 103 and 104: 92 Lindzey and Korach estrogen sign
Page 105 and 106: 94 Lindzey and Korach TESTIS AND DU
Page 107 and 108: 96 Lindzey and Korach sufficient to
Page 109 and 110: 98 Lindzey and Korach Seminal Vesic
Page 111 and 112: 100 Lindzey and Korach 17. Krege JH
Page 113 and 114: 102 Lindzey and Korach 68. Chang WY
Page 115 and 116: 104 McPhaul on the Y chromosome det
Page 117 and 118: 106 106 McPhaul
Page 119 and 120: 108 McPhaul number of alleles, dele
Page 121 and 122: 110 McPhaul The first mutation of t
Page 123 and 124: 112 McPhaul gene. In vitro studies
Page 125 and 126: 114 McPhaul risk of impaired sperma
Page 127 and 128: 116 McPhaul carrying a single mutan
Page 129: 118 McPhaul REFERENCES 1. Koopman P
Page 133 and 134: 122 McPhaul 92. Koivisto P, Kononen
Page 135 and 136: 124 Legro Fig. 1. The spectrum of p
Page 137 and 138: 126 Legro Virilization presents wit
Page 139 and 140: 128 Legro Fig. 3. The paradox of an
Page 141 and 142: 130 Legro small high-density athero
Page 143 and 144: 132 Legro Table 2 Syndromes or Dise
Page 145 and 146: 134 Legro Insulin-Sensitizing Agent
Page 147 and 148: 136 Legro is undetermined according
Page 149 and 150: 138 Legro 39. Lee O, Farquhar C, To
Page 151 and 152: 140 Legro
Page 153 and 154: 142 Wang and Swerdloff PHARMACOLOGY
Page 155 and 156: 144 Wang and Swerdloff The 17α-alk
Page 157 and 158: 146 Wang and Swerdloff Table 2 Dose
Page 159 and 160: 148 Wang and Swerdloff The steroid
Page 161 and 162: 150 Wang and Swerdloff The inabilit
Page 163 and 164: 152 Wang and Swerdloff 15. De Lorim
Page 165 and 166: 154 Wang and Swerdloff
Page 167 and 168: 156 Marcelli et al.
Page 169 and 170: 158 Marcelli et al. Differentiated
Page 171 and 172: 160 Marcelli et al. These coactivat
Page 173 and 174: 162 Marcelli et al. tigators have e
Page 175 and 176: 164 Marcelli et al. AR in Prostate
Page 177 and 178: 166 Marcelli et al. Table 1 Androge
Page 179 and 180: 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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192 Wu and von Eckardstein contrace
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194 Wu and von Eckardstein beam com
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196 Wu and von Eckardstein excess o
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198 Wu and von Eckardstein Endogeno
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Table 3 Change in Lipids in Hypogon
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Table 3 (continued) ∆LDL ∆HDL
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204 Wu and von Eckardstein THE HEMO
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206 Wu and von Eckardstein In vivo
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208 Wu and von Eckardstein (uptake
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210 Wu and von Eckardstein 4. Bhasi
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212 Wu and von Eckardstein 57. Barr
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214 Wu and von Eckardstein 107. Fra
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216 Wu and von Eckardstein 152. Zmu
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218 Wu and von Eckardstein 201. Cho
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220 Wu and von Eckardstein 250. Eic
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222 Kenny and Raisz with a cartilag
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224 Kenny and Raisz METABOLISM OF A
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226 Kenny and Raisz The level of th
Page 239 and 240:
228 Kenny and Raisz REFERENCES 1. G
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230 Kenny and Raisz 51. Morishima A
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232 Kenny and Raisz 103. Snyder PJ,
Page 245 and 246:
234 Basaria and Dobs losses in wome
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236 Basaria and Dobs 15 dialysis pa
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238 Basaria and Dobs duced remissio
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240 Basaria and Dobs hematocrit lev
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242 Basaria and Dobs 40. Sanchez-Me
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244 Katznelson in men with testoste
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246 Katznelson Fig. 1. Body weight,
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248 Katznelson change during treatm
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250 Katznelson testosterone or free
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252 Katznelson disproportionate dec
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254 Katznelson have been additional
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256 Katznelson 18. Marin P, Lonn L,
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258 Katznelson 71. Davis SR, McClou
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260 Bancroft Androgen Deficiency an
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262 Bancroft studies had presented
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264 Bancroft Bagatell et al. (36) g
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266 Bancroft much larger group of a
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268 Bancroft In a report of a serie
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270 Bancroft onset was related to a
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272 Bancroft Particularly confusing
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274 Bancroft 4. Studies using place
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276 Bancroft either E and T or plac
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278 Bancroft cytotoxic therapy supp
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280 Bancroft Women with Endocrine A
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282 Bancroft in response to the fil
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284 Bancroft Men are much more awar
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286 Bancroft 22. Morales A, Johnsto
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288 Bancroft 78. Hyde JS, DeLamater
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290 Bancroft 129. Appelt H, Strauss
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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
Page 359 and 360:
348 Tenover In aging men, the combi
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350 Tenover Table 1 Changes in Andr
Page 363 and 364:
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
Page 371 and 372:
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
Page 379 and 380:
368 Davis transdermal testosterone
Page 381 and 382:
370 Davis increase in circulating t
Page 383 and 384:
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
Page 389 and 390:
378 Davis 60. Simberg N, Titinen A,
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380 Davis
Page 393 and 394:
382 Bhasin, Woodhouse, and Storer h
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384 Table 2 Effects of Testosterone
Page 397 and 398:
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
Page 419 and 420:
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
Page 431 and 432:
420 Anawalt inadequate androgen eff
Page 433 and 434:
422 Anawalt few specialty commercia
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424 Anawalt Fig. 1. (C) Secondary h
Page 437 and 438:
426 Anawalt Fig. 2. Evaluation and
Page 439 and 440:
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
Page 445 and 446:
434 Anawalt SIDE EFFECTS OF ANDROGE
Page 447 and 448:
436 Anawalt 7. Rosner W. Errors in
Page 449 and 450:
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
Page 455 and 456:
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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