Testosterone : action, deficiency, substitution

Cover......Page 1
Half-title......Page 3
Title......Page 5
Copyright......Page 6
Contents......Page 7
Contributors......Page 10
Preface......Page 15
1.1 Introduction......Page 17
1.2.1 General......Page 18
1.2.3 Regulation of cholesterol side chain cleavage activity......Page 21
1.2.4 Regulation of pregnenolone metabolism......Page 23
1.3.1 General......Page 25
1.3.2 Stimulatory actions of LH......Page 26
1.3.3 Adaptation of Leydig cells......Page 29
1.4.1 Locally produced factors......Page 31
1.4.2 Other influences......Page 35
1.5.1 Trafficking inside cells......Page 36
1.5.3 Transport of androgens in the body......Page 37
1.6 Metabolism of testosterone......Page 39
1.7 Non-genomic effects of androgens......Page 42
1.8 Key messages......Page 44
1.9 REFERENCES......Page 45
2 The androgen receptor: molecular biology......Page 55
2.1 Introduction......Page 56
2.2.2 Structure of the androgen receptor gene and its mRNA......Page 57
2.2.3 Evolution of the androgen receptor......Page 59
2.3.1 Amino terminal domain......Page 60
2.3.2 DNA binding domain......Page 61
2.3.3 Nuclear localization and hinge region......Page 62
2.3.5 Amino- and carboxyl-terminal interaction......Page 63
2.4.1 Chaperones and co-chaperones in androgen receptor action......Page 64
2.4.2 Androgen response elements......Page 66
2.4.3 Co-activators and co-repressors......Page 68
2.5.1 Rapid non-transcriptional action of the androgen receptor......Page 69
2.5.2 Ligand independent activation of the androgen receptor......Page 71
2.6.1 Prostate development......Page 73
2.6.3 Androgen ablation therapy of prostate cancer......Page 74
2.6.4 Androgen receptor involvement in failure of androgen ablation therapy......Page 76
2.6.5 Androgen receptor as a therapy target in hormone-resistant prostate cancer......Page 79
2.7 Pathogenicity of CAG repeat amplification in the androgen receptor......Page 81
2.7.1 Kennedy syndrome (spinobulbar muscular atrophy – SBMA)......Page 82
2.7.2 Characteristic features of the androgen receptor in SBMA......Page 83
2.7.3 Animal models for SBMA......Page 84
2.8 Key messages......Page 86
2.9 REFERENCES......Page 87
3.1 Introduction......Page 109
3.2.1 In foetal sexual differentiation......Page 111
3.2.2 In puberty and adulthood......Page 114
3.3 Generalized androgen insensitivity in humans......Page 115
3.3.1.1 Pituitary-testicular axis......Page 116
3.3.1.2 SHBG androgen sensitivity test......Page 117
3.3.2 Genetic aspects of the androgen receptor in human androgen insensitivity......Page 118
3.4.2 Ethnic differences......Page 120
3.4.3 Prostate development and malignancy......Page 121
3.4.4 Reproductive functions......Page 122
3.4.5 Bone tissue......Page 123
3.4.6 Cardiovascular risk factors......Page 124
3.4.7 Psychological implications......Page 125
3.4.9 Pharmacogenetic aspects of testosterone therapy......Page 126
3.4.10 A hypothetical model of androgen action......Page 127
3.5 Treatment options in androgen insensitivity syndromes......Page 128
3.6 Outlook......Page 129
3.7 Key messages......Page 130
3.8 REFERENCES......Page 131
4.1 Introduction......Page 141
4.2.1 Influence of testosterone on sexual behaviour in men......Page 143
4.2.2 Influence of testosterone on sexual behaviour in women......Page 146
4.2.3 Influence of sexual behaviour on testosterone......Page 147
4.3 Stress......Page 148
4.4 Physical exercise......Page 149
4.5 Aggression......Page 150
4.5.1 Prenatal hormones and aggression......Page 151
4.5.2.1 Aggressive behaviour......Page 152
4.5.2.2 Sexual aggression......Page 154
4.5.2.3 Self-ratings of aggression......Page 155
4.5.3 Testosterone administration......Page 156
4.6 Mood......Page 158
4.7 Cognitive function......Page 162
4.7.1 Clinical studies and testosterone substitution......Page 163
4.7.2 Endogenous testosterone levels......Page 166
4.8 Key messages......Page 169
4.9 REFERENCES......Page 170
5.1 Rationale......Page 189
5.2.1 Basic and common features......Page 190
5.2.2 Species-specific features......Page 192
5.3 The hypothalamo-hypophyseal-testicular circuit......Page 195
5.4.2 Pubertal initiation of spermatogenesis......Page 197
5.4.3 Adult spermatogenesis: maintenance and reinitiation......Page 199
5.5.1 Testicular androgen production, metabolism and transport......Page 201
5.5.2 Testicular androgen concentrations and spermatogenesis......Page 202
5.5.3 Testicular androgen receptor and sites of androgen action......Page 204
5.6.1 FSH receptor and sites of FSH action......Page 205
5.6.2 FSH dependence of spermatogenesis......Page 206
5.7.1 Synergistic and differential action of androgens and FSH on testicular functions......Page 207
5.9 Clinical relevance of animal models for the study of androgen actions......Page 210
5.11 REFERENCES......Page 212
6.1 Introduction......Page 223
6.2.1 The roles of human hair......Page 224
6.2.3 The hair follicle growth cycle......Page 225
6.3.1 Human hair growth before and after puberty......Page 227
6.3.2 Evidence for the role of androgens......Page 231
6.3.3.1 Androgenetic alopecia......Page 232
6.4.1 Hair growth in androgen insufficiency syndromes......Page 234
6.4.2.1 The role of the dermal papilla......Page 235
6.4.2.2 Paracrine factors implicated in mesenchyme-epithelial interactions in the hair follicle......Page 237
6.5.1 Androgenetic alopecia......Page 238
6.5.2 Hirsutism......Page 239
6.6 Key messages......Page 240
6.7 REFERENCES......Page 241
7.1 Introduction......Page 249
7.2.1 In vitro studies......Page 250
7.2.2 Animal studies......Page 251
7.2.3 Androgens and their relation to calcium regulatory hormones and IGF-1......Page 253
7.2.4 Androgens and bone turnover in men......Page 254
7.2.5 The role of estradiol as testosterone metabolite in bone metabolism......Page 256
7.2.6 Relation of androgens to bone tissue in healthy men......Page 257
7.3.1 Bone density in men with disorders of androgen action......Page 259
7.3.2 Effects of androgen substitution on bone tissue......Page 260
7.3.3 Additional modalities for therapy of androgen-related bone loss......Page 262
7.6 REFERENCES......Page 263
8.1 Historical aspects of the anabolic steroid controversy......Page 271
8.2.2 The effects of lowering endogenous testosterone concentrations on body composition......Page 273
8.2.4 The effect of supraphysiologic doses of testosterone on body composition and muscle strength......Page 274
8.3 Testosterone dose-response relationships in men......Page 275
8.4 Testosterone effects on muscle performance......Page 278
8.5.1 Testosterone effects on muscle histomorphometry......Page 279
8.5.2 Muscle protein synthesis as the target of androgen action......Page 281
8.5.3 Pluripotent stem cells as the target of androgen action......Page 282
8.5.4 The role of 5alpha-reduction and aromatization of testosterone in the muscle......Page 285
8.6.2 Why have previous studies of testosterone replacement in older men failed to demonstrate significant improvements in physical function?......Page 287
8.6.3 Effects of androgen replacement on body composition and muscle function in sarcopenia associated with chronic illnesses......Page 288
8.8 Key messages......Page 291
8.9 REFERENCES......Page 292
9.1 Introduction......Page 299
9.2.1 Stimulation of erythropoietin (EPO)......Page 300
9.2.3 Iron incorporation......Page 301
9.2.6 Red cell 2,3-diphosphoglycerate......Page 302
9.3 Androgen treatment in hypogonadism and effects on erythropoiesis......Page 303
9.4 Hematocrit and ischemic disease......Page 306
9.6 REFERENCES......Page 308
10 Testosterone and cardiovascular diseases......Page 313
10.2 Relationships between serum levels of testosterone and cardiovascular disease – observational studies......Page 314
10.2.1 Testosterone and cardiovascular disease in men......Page 315
10.2.2 Testosterone and cardiovascular disease in women......Page 316
10.3.1 Endogenous androgen deprivation......Page 317
10.3.3 Exogenous testosterone treatment in men with cardiovascular disease......Page 318
10.3.4 Exogenous androgen treatment in women......Page 319
10.4.1 Atherosclerosis......Page 320
10.5 Effects of testosterone on cardiovascular risk factors......Page 321
10.5.1 Associations of endogenous testosterone with cardiovascular risk factors......Page 322
10.5.3.1 Lipoproteins......Page 323
10.5.3.3 Inflammation......Page 325
10.5.3.4 Obesity and insulin sensitivity......Page 326
10.6.1 Vascular and cardiac expression of sex hormone receptors and testosterone converting enzymes: implications for genomic and non-genomic effects......Page 327
10.6.2 Effects of testosterone on vascular reactivity......Page 328
10.6.3 Effects of testosterone on endothelial cells......Page 330
10.6.5 Effects of testosterone on macrophage functions......Page 331
10.7 Lessons from genetic studies on the role of testosterone in atherosclerosis......Page 333
10.7.2 Variation in the estrogen receptor......Page 334
10.8 Clinical implications......Page 335
10.10 REFERENCES......Page 337
11.1 Introduction......Page 349
11.3 Direct effects of testosterone on erection......Page 350
11.5 Testosterone and erection in normal men......Page 352
11.6 Prevalence of testosterone deficiency in patients with erectile dysfunction......Page 354
11.7 Combined therapy with testosterone and phosphodiesterase type 5 inhibitors in patients with erectile dysfunction......Page 355
11.8 Effects of treatment of erectile dysfunction on testosterone......Page 357
11.10 Key messages......Page 358
11.11 REFERENCES......Page 359
12.1 Introduction......Page 363
12.2 Role of testosterone in the development and maintenance of the prostate......Page 366
12.3 Zonal and cellular organization of the prostate......Page 368
12.4 Testosterone metabolism in the prostate......Page 371
12.5 Paracrine androgen axis in the normal prostate......Page 374
12.6 Androgen in benign prostatic hyperplasia......Page 376
12.7 Conversion of paracrine to autocrine mechanism of androgen action during prostatic carcinogenesis......Page 378
12.8 Role of androgen in prostate cancer......Page 380
12.9 Side effects of androgen replacement/ablation in the aging male......Page 381
12.10 Key messages......Page 382
12.11 REFERENCES......Page 383
13.1 Use of testosterone in male hypogonadism......Page 391
13.1.1 Classification and symptoms of hypogonadism......Page 394
13.1.2 Initiation of substitution therapy and choice of preparation......Page 395
13.1.3.2 Sexuality......Page 398
13.1.3.3 Phenotype......Page 399
13.1.3.4 Blood pressure......Page 400
13.1.3.5 Serum testosterone......Page 401
13.1.3.8 Gonadotropins......Page 402
13.1.3.10 Liver function......Page 403
13.1.3.12 Prostate and seminal vesicles......Page 404
13.1.3.13 Bone mass......Page 405
13.2 Treatment of delayed puberty in boys......Page 407
13.3 Overtall stature......Page 408
13.5 Ineffective use of testosterone in male infertility......Page 409
13.7 Overall effect of testosterone......Page 410
13.8 Key messages......Page 412
13.9 REFERENCES......Page 413
14.1 Historical development of testosterone therapy......Page 421
14.2 General considerations......Page 422
14.3 Pharmacology of testosterone preparations......Page 424
14.3.1.1 Unmodified testosterone......Page 425
14.3.1.2 17alpha-methyltestosterone......Page 426
14.3.1.5 Testosterone undecanoate......Page 427
14.3.2 Sublingual application......Page 429
14.3.3 Buccal application......Page 430
14.3.6 Intramuscular application......Page 431
14.3.6.1 Testosterone propionate......Page 433
14.3.6.2 Testosterone enanthate......Page 434
14.3.6.3 Testosterone cypionate and testosterone cyclohexanecarboxylate......Page 437
14.3.6.4 Testosterone ester combinations......Page 438
14.3.6.5 Testosterone buciclate......Page 440
14.3.6.6 Testosterone undecanoate......Page 442
14.3.6.7 Testosterone decanoate......Page 444
14.3.6.8 Testosterone microspheres......Page 445
14.3.7.1 Testosterone pellets......Page 446
14.3.7.2 Testosterone microcapsules......Page 447
14.3.8 Transdermal application......Page 448
14.5 REFERENCES......Page 452
15 Androgen therapy in non-gonadal disease......Page 461
15.1 Introduction......Page 462
15.2.1 Cirrhosis......Page 463
15.2.2 Hepatitis......Page 464
15.3.1 Erythropoiesis and marrow stimulation......Page 465
15.3.2 Anemia due to marrow failure......Page 466
15.3.4 Thrombocytopenia......Page 468
15.4.1 Effect of androgens on renal function......Page 469
15.4.2 Anemia of end-stage renal failure......Page 470
15.4.3 Growth......Page 472
15.5.1 Muscular dystrophies......Page 473
15.6.1 Hereditary angioedema......Page 474
15.6.2 Rheumatoid arthritis (RA)......Page 475
15.6.3 Other rheumatological disorders (SLE, Raynauds, systemic sclerosis, and Sjogrens disease, chronic urticaria)......Page 476
15.7 Bone disease......Page 478
15.8.1 Muscle mass......Page 479
15.8.3 Rehabilitation......Page 481
15.9.1 AIDS/HIV wasting......Page 482
15.10.1 Effects on morbidity and mortality......Page 484
15.10.2 Cytoprotection......Page 487
15.11.1 Chronic obstructive lung disease......Page 488
15.11.2 Obstructive sleep apnea......Page 489
15.12.1 Headache......Page 491
15.12.2 Depression......Page 492
15.13.2 Venous disease......Page 493
15.14.2 Obesity......Page 494
15.15 Dermatological disease......Page 495
15.16 Key messages......Page 496
15.17 REFERENCES......Page 497
16.1 Introduction......Page 513
16.2.1 Testosterone production and serum levels......Page 514
16.2.2 Sex hormone binding globulin and free testosterone serum levels......Page 516
16.2.3 Tissue levels and metabolism of androgens......Page 517
16.2.4.1 Influence of physiological factors and lifestyle......Page 518
16.2.4.2 Testosterone serum levels in disease......Page 521
16.3.1 Primary testicular changes......Page 522
16.3.2 Altered neuroendocrine regulation......Page 523
16.4.1 General background......Page 525
16.4.2 Hypoandrogenism of senescence and sexual activity......Page 526
16.4.3 Body composition and sarcopenia......Page 527
16.4.4 Senile osteoporosis......Page 529
16.4.5 Additional clinical variables......Page 532
16.5.1 Who should be considered for treatment?......Page 533
16.5.2 Potential benefits......Page 536
16.5.3 Potential risks......Page 537
16.6 Key messages......Page 539
16.7 REFERENCES......Page 540
17.1 Androgen dynamics in women......Page 559
17.2 Androgen deficiency states in women......Page 563
17.3 Do androgens have physiologic relevance in women?......Page 569
17.4 Possible benefits of androgen replacement in women......Page 570
17.4.1 Testosterone replacement and sexual function......Page 571
17.4.2 Testosterone and insulin sensitivity in women......Page 573
17.4.4 Testosterone replacement and body morphology in women......Page 574
17.4.5 Testosterone replacement and bone mass in women......Page 576
17.5 Androgen replacement in women: the present state of the art......Page 577
17.6 Summary and future directions......Page 580
17.7 Key messages......Page 581
17.8 REFERENCES......Page 582
18 Clinical use of 5alpha-reductase inhibitors......Page 587
18.1.2 Evidence for role of 5alpha-reductase in pathophysiology of androgen disorders......Page 588
18.1.2.1 Genetic 5alpha-reductase deficiency......Page 589
18.2 Rationale for and development of 5alpha-reductase inhibitors......Page 591
18.3.1 Effects on serum androgens and gonadotropins......Page 592
18.4.1 Efficacy based on prostate volume and symptoms......Page 593
18.4.2 Long-term effects on disease progression......Page 594
18.4.3 Safety......Page 595
18.5.1 Efficacy based on hair count, hair weight, clinical photography, patient assessment......Page 596
18.5.3 Long-term follow-up......Page 597
18.6.2 Effects on semen......Page 599
18.7.1 Study in postmenopausal women with androgenetic alopecia......Page 600
18.8.1 Effects on serum and sebum DHT......Page 601
18.8.1.1 Effects in combination with finasteride......Page 602
18.9.1 Long-term study of finasteride in chemoprevention of prostate cancer......Page 603
18.10 Key messages......Page 604
18.11 REFERENCES......Page 605
19.1 Introduction......Page 613
19.2 DHEA secretion and age......Page 614
19.3 Epidemiology......Page 615
19.4.1 DHEA......Page 616
19.4.2 Androstenedione......Page 618
19.5.1 Patients with adrenal insufficiency......Page 619
19.5.2 Elderly subjects......Page 623
19.5.4 Patients with immunological disorders......Page 624
19.7.1 Effects on the central nervous system......Page 625
19.7.2 Metabolism and body composition......Page 626
19.7.3 Skeletal system......Page 627
19.7.5 Immune system......Page 628
19.8 Practical approach to the patient with DHEA deficiency......Page 629
19.9 Future perspectives......Page 630
19.11 REFERENCES......Page 631
20.1 Introduction......Page 639
20.2.1 Metabolism of androgens in different tissues......Page 642
20.2.3 Protein/protein interaction of the AR......Page 643
20.2.4 Tissue distribution of AR and AR-specific comodulators......Page 645
20.2.5 Other approaches for selective actions......Page 646
20.3.2 Promoter specific regulation......Page 648
20.3.4 The ideal tissue-selective androgen......Page 649
20.4.1 General......Page 650
20.4.2 Role of 5alpha-reduction......Page 651
20.6 REFERENCES......Page 652
21.1 Introduction......Page 657
21.2 Testosterone in blood......Page 658
21.3 Principles of immunological testosterone assays......Page 660
21.4.2 Radioimmunoassay......Page 664
21.4.3 Other immunoassays......Page 665
21.4.4 Assessment of free testosterone......Page 666
21.4.4.2 Ultrafiltration......Page 667
21.4.4.3 Direct free testosterone RIA......Page 668
21.4.4.4 Salivary testosterone......Page 669
21.4.4.6 Calculated free testosterone......Page 670
21.5 Measurement of DHT......Page 671
21.6.1 Choice of the kit and assay validation......Page 673
21.6.3 External quality assessment......Page 674
21.7 Key messages......Page 677
21.8 REFERENCES......Page 678
22.1 Introduction......Page 681
22.2 Synthesis of nandrolone derivatives and reference steroids......Page 682
22.2.2 Preparation of nandrolone derivatives......Page 683
22.3.1 Androgen receptor transactivation and binding......Page 685
22.3.2 Determination of metabolic stability with human hepatocytes......Page 687
22.3.4 Effects on bone, LH/FSH, ventral prostate and muscle in castrated male rats......Page 688
22.4.1 Androgen receptor binding and transactivation......Page 689
22.4.2 Metabolic stability in human hepatocytes......Page 690
22.4.3 Susceptibility for human aromatase......Page 691
22.4.4 Efficacy in castrated rats: effects on bone, LH/FSH, ventral prostate and muscle......Page 692
22.4.5 Efficacy in intact monkeys: effects on serum testosterone......Page 693
22.4.6 Pharmacokinetic evaluation in different species......Page 696
22.5 Interpretation of results......Page 697
22.7 REFERENCES......Page 698
23 Hormonal male contraception: the essential role of testosterone......Page 701
23.1.2 Existing methods......Page 702
23.1.3 New approaches to male contraception......Page 703
23.2 Principle of hormonal male contraception......Page 704
23.3.1 Testosterone enanthate......Page 707
23.3.3 Testosterone undecanoate......Page 708
23.3.6 7alpha-Methyl-19-nortestosterone (MENT)......Page 709
23.4.1 Testosterone or 19-nortestosterone plus DMPA......Page 710
23.4.2 Testosterone plus levonorgestrel......Page 716
23.4.3 Testosterone plus cyproterone acetate......Page 717
23.4.5 Testosterone plus desogestrel or etonogestrel......Page 718
23.5.1 Testosterone plus GnRH agonists......Page 720
23.5.2 Testosterone plus GnRH antagonists......Page 721
23.6 Side effects and acceptability......Page 722
23.7 Outlook......Page 723
23.9 REFERENCES......Page 724
24.1 Introduction......Page 731
24.2.2 Androgen misuse in non-controlled sports......Page 733
24.3 Prohormones of androgens......Page 735
24.4 Contamination of nutritional supplements with prohormones......Page 737
24.5.1 Organization of doping tests......Page 738
24.5.2 Detection and identification of misused anabolic androgenic steroids......Page 739
24.5.2.1 Metabolism......Page 740
24.5.2.2 Pharmacokinetics......Page 741
24.5.2.4 Derivatization......Page 742
24.5.3 Detection of synthetic anabolic androgenic steroids......Page 743
24.5.4.1 Indirect detection methods......Page 745
24.5.4.2 Direct detection method: gas chromatography – combustion – isotope ratio mass spectrometry (GC-C-IRMS)......Page 746
24.6 Key messages......Page 748
24.7 REFERENCES......Page 749
Subject index......Page 753