1．Introduction to Endocrinology John D.Baxter, MD, Ralff C.J.Ribeiro, MD,PhD 1
The Endocrine System 1
Paracrine Autocrine Actions 3
Chemical Composition of Hormones 3
Vitamins Hormones 4
Hormones Oncogenes 4
Hormones the Immune System 5
Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, Related Compounds 5
Mechanisms of Hormone Action 6
Hormone Receptors 6
Regulation of Responsiveness to Hormones 7
Interactions Between Hormone Response Systems 8
Classes of Hormone Action 8
Use of Receptors for Classifying Types of Hormone Action 9
Classification of Hormones by the Types of Ligands: Agonists, Antagonists, Partial Agonists-Partial Antagonists, Inactive Compounds 10
Hypothalamic-Pituitary Relationships 11
Neurotransmitters Hormones 11
Endocrine Nervous System Relationships: Neuroendocrinology 11
Gene Expression in Endocrinology Metabolism: Molecular Basis for Function of the System Genetic Endocrine Disease 13
Evolution of the Endocrine System 14
Cellular Control Networks the Origins of Regulatory Chemicals 15
The Origins of Regulatory Proteins 15
The Origins of Hormones 15
Intracellular Communication 16
Evolution of Genes Involved in the Endocrine System 16
Integrative Networks 16
Evolution of the Endocrine Glands 16
Hormone Synthesis Release 17
Hormone Transport 17
Steroid Thyroid Hormones Vitamin D 18
Polypeptide Hormones 18
Catecholamine Eicosanoid Metabolism 19
Steroid Thyroid Hormones Vitamin D 19
Peptide Hormones 19
Metabolism Elimination of Hormones 19
Regulation of the Endocrine System 20
Actions of Hormones 20
Developmental Effects 20
Cell Growth Cancer 20
Central Nervous System Effects 21
Effects on Metabolism 21
Effects on Cardiovascular Renal Function 21
Effects on Mineral Water Metabolism 22
Effects on Skeletal Functions 22
Effects on Reproductive Function 22
Release of Other Hormones 22
Effects on Immunologic Functions 23
Disorders of the Endocrine System 23
Endocrine Hypofunction 23
Endocrine Hyperfunction 24
Defects in Sensitivity to Hormones 25
Syndromes of Hormone Excess Due to Administration of Exogenous Hormone or Medication 26
Disorders of the Endocrine Glands not Associated With Endocrine Disease 27
Approach to the Patient With Endocrine Disease 27
History Physical Examination 27
Laboratory Studies 28
Screening for Endocrine Diseases 32
Treatment of Endocrine Diseases 33
Uses of Hormones in Therapy of Nonendocrine Disease 34
2．Hormone Synthesls Release Vishwanath R.Lingappa, MD, PhD, Synthia H.Mellon, PhD 38
Overview of Hormone Biosynthesis 38
Membrane Vesicle-Mediated Hormone Export 39
Hormone Export not Mediated by Membrane VesicIes 49
Metabolism. Transport. Elimination. Regulation of Hormones 55
3．Mechanisms of Hormone Action David G.Gardner, MD 59
Receptors 59
Neurotransmitter Peptide Hormone Receptors 61
Seven-Transmembrane Receptors 62
G Protein Transducers 62
Effectors 63
G Protein-Linked Receptors Human Disease 66
Growth Factor Receptors 67
Cytokine Receptors 69
Guanylyl Cyclase-Linked Receptors 70
Nuclear Action of Peptide Hormones 71
Nuclear Receptors 72
Steroid Receptor Family 72
Thyroid Receptor Family 74
Nongenomic Effects of the Steroid Hormones 77
Steroid Thyroid Hormone Receptor Resistance Syndromes 77
4．Endocrine Autoimmunity Juan Carlos Jaume, MD 80
Immune Recognition Response 81
Basic Immune Components Mechanisms 81
Tolerance 85
Autoimmunity Is Multifactorial 90
Genetic Factors in Autoimmunity 90
Environmental Factors in Autoimmunity 90
Single Gland Autoimmune Syndromes 91
Autoimmune Aspects of Thyroid Disease 91
Autoimmune Aspects of Type I Diabetes 93
Autoimmune Aspects of Other Endocrinopathies 95
Autoimmune Polyglandular Syndromes 97
Autoimmune Polyglandular SyndromeⅠ(APS-Ⅰ) 97
Autoimmune Polyglandular SyndromeⅡ(APS-Ⅱ) 98
Management of Autoimmune Polyglandular Syndromes 98
5．Hypothalamus Pituitary David C.Aron, MS, MD, James W.Findling, MD, J.Blake Tyrrell, MD 100
Hypothalamic Hormones 105
Anterior Pituitary Hormones 110
ACTH Related Peptides 110
Growth Hormone 112
Prolactin 114
Thyrotropin 116
Gonadotropins:Luteinizing Hormone Follicle-Stimulating Hormone 117
Endocrinologic Evaluation of the Hypothalamic-Pituitary Axis 119
Evaluation of ACTH 120
Evaluation of Growth Hormone 121
Evaluation of Prolactin 122
Evaluation of TSH 122
Evaluation of LH FSH 122
Problems in Evaluation of the Hypothalamic-Pituitary Axis 122
Effects of Pharmacologic Agents on Hypothalamic-Pituitary Function 123
Endocrine Tests of Hypothalamic-Pituitary Function 123
Neuroradiologic Evaluation 123
Pituitary Hypothalamic Disorders 126
Empty Sella Syndrome 128
Hypothalamic Dysfunction 129
Hypopituitarism 130
Pituitary Adenomas 136
Posterior Pituitary 151
Antidiuretic Hormone(ADH:Vasopressin) 151
Oxytocin 152
Control of Water Balance 152
Diabetes Insipidus 154
Syndrome of Inappropriate Secretion of Antidiuretic Hormone(SIADH) 158
6．Growth Dennis Styne, MD 163
Normal Growth 163
Intrauterine Growth 163
The Placenta 164
Classic Hormones of Growth Fetal Growth 164
Growth Factors Oncogenes in Fetal Growth 164
Insulin-like Growth Factors, Receptors, Binding Proteins 164
Insulin 165
Epidermal Growth Factor 165
Postnatal Growth 166
Fetal Origins of Adult Disease 166
Measurement of Growth 176
Skeletal (Bone)Age 178
Disorders of Growth 178
Short Stature Due to Nonendocrine Causes 178
Short Stature Due to Endocrine Disorders 184
The Diagnosis of Short Stature 195
Tall Stature Due to Nonendocrine Causes 196
Tall Stature Due to Endocrine Disorders 197
7．The Thyroid Gland Francis S.Greenspan, MD, FACP 201
Anatomy Histology 202
Physiology 204
Structure of Thyroid Hormones 204
Iodine Metabolism 204
Thyroid Hormone Synthesis Secretion 206
Thyroid Hormone Transport 210
Abnormalities in Thyroid Hormone Synthesis Release 210
Metabolism of Thyroid Hormones 213
Control of Thyroid Function 217
The Action of Thyroid Hormones 222
Physiologic Changes in Thyroid Function 225
Thyroid Autoimmunity 226
Tests of Thyroid Function 227
Tests of Thyroid Hormones in Blood 227
Evaluation of the Hypothalamic-Pituitary-Thyroid Axis 228
Iodine Metabolism Biosynthetic Activity 229
Thyroid Imaging 231
Thyroid Ultrasonography or Magnetic Resonance Imaging 231
Thyroid Biopsy 232
Effects of Thyroid Hormones on Peripheral Tissues 232
Measurement of Thyroid Autoantibodies 232
Summary: Clinical Use of Thyroid Function Tests 233
Disorders of the Thyroid 233
Hypothyroidism 235
Hyperthyroidism Thyrotoxicosis 242
Thyroid Hormone Resistance Syndromes 253
Nontoxic Goiter 254
Thyroiditis 256
Effects of Ionizing Radiation on the Thyroid Gland 258
Thyroid Nodules Thyroid Cancer 260
8．Mineral Metabolism Metabolic Bone Disease Dolores Shoback, MD, Robert Marcus, MD, Daniel Bikle, MD, PhD, Gordon Strewler, MD 273
Cellular Extracellular Calcium Metabolism 273
Parathyroid Hormone 274
Calcitonin 279
Vitamin D 281
Integrated Control of Mineral Homeostasis 288
Medullary Thyroid Carcinoma 288
Hypercalcemia 288
Hypocalcemia 300
Bone Anatomy Remodeling 306
Osteoporosis 310
Osteomalacia Rickets 320
Paget s Disease of Bone (Osteitis Deformans) 326
Renal Osteodystrophy 329
9．Glucoctorioids Adrenal Androgens David C.Aron, MD, MS, James W.Findling, MD, J.Blake Tyrrell, MD 334
Embryology Anatomy 334
Biosynthesis of Cortisol Adrenal Androgens 337
Circulation of Cortisol Adrenal Androgens 342
Metabolism of Cortisol Adrenal Androgens 342
Biologic Effects 343
Glucocorticoids 343
Adrenal Androgens 347
Laboratory Evaluation 347
Disorders of Adrenocortical Insufficiency 351
Primary Adrenocortical Insufficiency (Addison s Disease) 351
Secondary Adrenocortical Insufficiency 355
Diagnosis of Adrenocortical Insufficiency 355
Treatment of Adrenocortical Insufficiency 358
Prognosis of Adrenocortical Insufficiency 360
Cushing s Syndrome 360
Hirsutism Virilism 371
Incidental Adrenal Mass 371
Glucocorticoid Therapy for Nonendocrine Disorders 373
10．Endocrine Hypertension Burl R.Don, MD, Morris Schambelan, MD 377
Hypertension of Adrenal Origin 377
Hypertension of Renal Origin 389
Other Hormone Systems Hypertension 395
11．Adrenal Medulla Alan Goldfien, MD 399
Anatomy 399
Hormones of the Adrenal Medulla 400
Catecholamines 400
Other Hormones 409
Adrenal Medullary Hyperfunction 410
Adrenal Medullary Hypofunction 410
Disorders of Adrenal Medullary Function 410
Pheochromocytoma 411
12．Testes Glenn D.Braunstein, MD 422
Anatomy Structure-Function Relationships 422
Testes 422
Accessory Structures 424
Physiology of the Male Reproductive System 424
Gonadal Steroids 424
Control of Testicular Function 426
Evaluation of Male Gonadal Function 428
Clinical Evaluation 428
Laboratory Tests of Testicular Function 428
Pharmacology of Drugs Used to Treat Male Gonadal Disorders 431
Androgens 431
Gonadotropins 433
Clinical Male Gonadal Disorders 434
Klinefelter s Syndrome 434
Gonadotropin-Releasing Hormone 434
Bilateral Anorchia 436
Leydig Cell Aplasia 437
Cryptorchidism 437
Noonan s Syndrome (Male Turner s Syndrome) 439
Myotonic Dystrophy 440
Adult Seminiferous Tubule Failure 440
Adult Leydig Cell Failure (Andropause) 441
Erectile Dysfunction (Impotence) 442
Male Infertility 444
Gynecomastia 446
Testicular Tumors 448
13．Ovaries Alan Goldfien, MD 453
Anatomy of the Ovaries 453
Hormones of the Ovary 454
Steroid Hormones 454
Other Ovarian Hormones Regulatory Substances 460
Relaxin 460
The Menstrual Cycle 461
Hormonal Profiles During the Menstrual Cycle 461
The Ovarian Cycle 463
Hormone Interaction Regulation During the Menstrual Cycle 466
Cyclic Changes in the Female Reproductive Tract 467
Histology of the Endometrium Throughout the Menstrual Cycle 467
Cervical Mucus 469
Vaginal Epithelium 470
Extragenital Symptoms Associated With Normal Menstrual Function 471
Premenstrual Dysmorphic Disorder (Premenstrual Syndrome) 471
Dysmenorrhea 472
Disorders of Ovarian Menstrual Function 473
Amenorrhea in the Absence of Sexual Maturation 474
Amenorrhea in Patients With Normal Secondary Sex Characteristics 474
Disorders of Androgen Metabolism 480
Hirsutism 483
Clomiphene Citrate 488
Ovulation Induction 488
Anovulatory Bleeding 488
Human Menopausal Gonadotropins (Menotropins) 489
Gonadotropin-Releasing Hormone 490
Bromocriptine 490
Therapeutic Use of Ovarian Hormones Their Synthetic Analogs 490
Treatment of Primary Hypogonadism 490
Ovarian Suppression 490
Threatened Abortion 490
Inadequate Luteal Phase 491
Diagnostic Uses 491
Inhibitors of Ovarian Function 491
Gonadotropin-Releasing Hormone Analogs Antagonists 491
Sclective Estrogen Receptor Modulators Antiestrogens 491
Antiprogestins 492
Antiandrogens 492
Danazol 492
Menopause 493
Hormonal Changes 493
Clinical Manifestations of Menopause 494
Management of Menopause 495
Hormonal Contraception (Oral Contraceptives) 498
Pharmacologic Effects of Estrogens Synthetic Progestins 498
Clinical Uses of Oral Contraceptives 499
Adverse Effects of Oral Contraceptives 500
Noncontraceptive Advantages of Hormonal Contraception 502
Contraindications Cautions 502
Drug Interactions With Oral Contraceptives 502
Contraception With Progestins 503
Postcoital Contraceptives Emergency Contraception 503
Infertility 503
Semen Abnormalities 503
Infertility in the Presence of Ovulation 504
Ovulatory Disorders 504
In Vitro Fertilization 505
Gamete Intrafollicular Transfer(GIFT) 505
14．Abnormalities of Sexual Determination Differentiation Felix A.Conte, MD, Melvin M.Grumbach, MD 509
Normal Sex Differentiation 509
Testicular Ovarian Differentiation 515
Psychosexual Differentiation 517
Abnormal Sex Differentiation 519
Seminiferous Tubule Dysgenesis: Chromatin-Positive Klinefelter s Syndrome Its Variants 520
Syndrome of Gonadal Dysgenesis: Turner s Syndrome Its Variants 522
46.XX 46.XY Gonadal Dysgenesis 524
True Hermaphroditism 526
Female Pseudohermaphroditism 527
P450 Aromatase Deficiency 531
Maternal Androgens Progestogens 531
Male Pseudohermaphroditism 531
Unclassified Forms of Abnormal Sexual Development in Males 540
Unclassified Forms of Abnormal Sexual Development in Females 542
Management of Patients With Intersex Problems 542
15．Puberty Dennis Styne, MD 547
Physiology of Puberty 547
Delayed Puberty or Absent Puberty (Sexual Infantilism) 556
Precocious Puberty (Sexual Precocity) 566
16．The Endocrinology of Pregnancy Robert N.Taylor, MD, PhD, Dan I.Lebovic, MD, Mary C.Martin-Cadieux, MD 575
Conception Implantation 575
Fetal-Placental-Decidual Unit 576
Polypeptide Hormones 577
Steroid Hormones 580
Maternal Adaptation to Pregnancy 581
Fetal Endocrinology 584
Endocrine Control of Parturition 586
Endocrinology of the Puerperium 587
Endocrine Disorders Pregnancy 589
Pregnancy Pituitary Pathology 589
Pregnancy Breast Cancer 590
Hypertensive Disorders of Pregnancy 591
Hyperthyroidism in Pregnancy 592
Hypothyroidism in Pregnancy 593
Diabetes Mellitus Pregnancy (by John L.Kitzmiller, MD) 593
17．Regulatory Peptides of the Gut Sean J.Mulvihill, MD, Haile T.Debas, MD 603
Gastrin 607
Cholecystokinin 608
Somatostatin 609
Secretin 609
Bombesin Gastrin-Releasing Peptide 610
Calcitonin Gene-Related Peptidc 611
Gastric Inhibitory Peptide 611
Vasoactive Intestinal Peptide 611
Galanin 612
Substance P 612
Enkephalins 612
Motilin 613
Neurotensin 613
Pancreatic Polypeptide Family 614
Enteroglucagon 614
Abnormalities of Regulatory Peptides in Diseases of the Gastrointestinal Tract 614
Duodenal Ulcer 614
Motility Disorders of the Gastrointestinal Tract 615
Intlammatory Bowel Disease 615
Neuroendocrine Tumors of the Gut 616
Multiple Endocrine Neoplasia Syndromes 616
Zollinger-Ellison Syndrome 616
VIPoma 617
Glucagonoma 617
Carcinoid Tumors Carcinoid Syndrome 617
Miscellaneous Tumors 618
Minimally Invasive Approaches to Gut Endocrine Tumors 619
Clinical Uses of Gut Peptides 619
Anatomy Histology 623
18．Pancreatic Hormones Diabetes Mellitus Umesh Masharani, MRCP(UK), John H.Karam, MD 623
The Endocrine Pancreas 623
Hormones of the Endocrine Pancreas 624
Diabetes Mellitus 633
Classification 633
Type 1 Diabetes Mellitus 633
Type 2 Diabetes 636
Other Specific Types of Diabetes 638
Clinical Features of Diabetes Mellitus 641
Type 1 Diabetes 641
Type 2 Diabetes 642
Laboratory Findings in Diabetes Mellitus 643
Urialysis 643
Blood Glucose Testing 644
Serum Ketone Determinations 645
Glycosylated Hemoglobin Assays 645
Lipoproteins in Diabetes 646
Capillary Morphometry 646
Diagnosis of Diabetes Mellitus 647
Oral Glucose Tolerance Test 647
Insulin Levels 648
Intravenous Glucose Tolerance Test 648
Treatment of Diabetes Mellitus 648
Diet 651
Oral Agents for the Treatment of Hyperglycemia 653
Insulin 661
Steps in the Management of the Diabetic Patient 666
Acute Complications of Diabetes Mellitus 675
Hypoglycemia 675
Coma 678
Chronic Complications of Diabctes Mellitus 686
Specific Chronic Conplications of Diabetes Mellitus 688
Diabetics Taking Insulin 694
Diabetics Taking Oral Hypoglycemic Agents 694
Surgery in the Diabetic Patient 694
Diabetics Regulated by Diet Alone 694
Prognosis for Patients With Diabetes Mellitus 695
19．Hypoglycemic Disorders John H.Karam, MD 699
Pathophysiology of the Counterregulatory Response to Neuroglycopenia 699
Classification of Hypoglycemic Disorders 703
Clinical Presentation of Hypoglycemia 704
Specific Hypoglycemic Disorders 706
Symptomatic Fasting Hypoglycemia With Hyperinsulinism 706
Symptomatic Fasting Hypoglycemia Without Hyperinsulinism 712
Nonfasting Hypoglycemia (Reactive Hypoglycemia) 713
20．Disorders of Lipoprotein Metabolism Mary J.Malloy, MD, John P.Kane, MD,PhD 716
Atherosclerosis 716
Overview of Lipid Transport 717
Differentiation of Disorders of Lipoprotein Metabolism 722
The Hypertriglyceridemias 724
Clinical Descriptions of Primary Secondary Disorders of Lipoprotein Metabolism 724
Primary Hypertriglyceridemia 725
Secondary Hypertriglyceridemia 727
The Primary Hypercholesterolemias 731
Familial Hypercholesterolemia 731
Familial Combined Hyperlipidemia 732
LP(a) Hyperlipoproteinemia 732
Familial Ligand-Defective Apo B 732
Secondary Hypercholesterolemia 732
Hypothyroidism 732
Nephrosis 733
Immunoglobulin Disorders 733
Anorexia Nervosa 733
Cholestasis 733
The Primary Hypolipidemias 733
Primary Hypolipidemia Due to Deficiency of High-Density Lipoproteins 734
Primary Hypolipidemia Due to Deficiency of Apo B-Containing Lipoproteins 735
Other Disorders of Lipoprotein Metabolism 736
The Lipodystrophies 736
Secondary Hypolipidemia 736
Rare Disorders 737
Treatment of Hyperlipidemia 737
Dietary Factors in the Management of Lipoprotein Disorders 738
Drugs Used in Treatment of Hyperlipoproteinemia 739
Bile Acid Sequestrants 739
Niacin (Nicotinic Acid) 740
Fibric Acid Derivatives 741
HMGA-CoA Reductase Inhibitors 741
Combined Drug Therapy 742
Possible Untoward Consequences of Lipid-Lowering Therapy 743
21．Obesity Overweight Marc K.Hellerstein, MD, PhD, Elizabeth J.Parks, PhD 745
Controversies Uncertainties Regarding the Pathogenesis of Obesity 754
Dietary Therapies 755
Survey of Treatment Approaches Their Efficacy 755
Surgical Treatment of Obesity 756
Pharmacologic Therapies 756
Other Conditions Affected by Treatment of Obesity or Overweight 759
Type 2 Diabetes Mellitus 759
Hyperlipidemia 759
Polycystic Ovarian Syndrome 759
Hypertension 759
Gallstones 759
Osteoarthritis Other Weight-Sensitive States 759
A Systematic Approach to the Treatment of Obesity 759
22．Hormones Cancer Debasish Tripathy, MD, Christopher C.Benz, MD 762
Hormonal Effects on Tumors 762
Growth Promotion Malignant Transformation 762
Tumor Growth Mediated by Autocrine Paracrine Factors 764
Nonsecretory Tumors 765
Secretory Tumors 765
Tumors Affecting Endocrine Status 765
Steroid-Dependent Tumors 765
Treatment-Induced Endocrinopathy 766
Endocrine Therapy for Cancer 767
Steroid Receptors Treatment 767
Primary Modalities of Endocrine Intervention 768
Combination Endocrine Therapy 769
Breast Cancer in Women 770
Clinical Problems 770
Chemo-Endocrine Therapy 770
Breast Cancer in Men 774
Endometrial Cancer 774
Prostatic Cancer 775
Miscellaneous Tumors 776
23．Humoral Manifestatlons of Mallgnancy Dolores Shoback, MD, Janet Funk, MD 778
Ectopic Hormone Receptor Syndromes 778
Hypercalcemia of Malignancy 779
Ectopic Cushing s Syndrome 783
Syndrome of Inappropriate ADH(SIADH) Secretion 785
Non-Islet Cell Tumors Hypoglycemia 786
Other Hormones Secreted by Tumors 787
Oncogenic Osteomalacia 788
Gut Hormones 789
Erythropoietin 789
Renin 789
Multiple Endocrine Neoplasia Type 1 (MEN 1) 792
24．Multiple Endocrine Neoplasia David G.Gardner, MD 792
Multiple Endocrine Neoplasia Type 2 (MEN 2) 797
25．Geriatric Endocrinology Susan L.Greenspan, MD, Neil M.Resnick, MD 802
Thyroid Function Disease 802
Disorders of the Thyroid Gland 803
Carbohydrate Intolerance Diabetes Mellitus 805
Aging the Physiology of Carbohydrate Intolerance 805
Diabetes Mellitus 806
Osteoporosis 808
Nonketotic Hyperosmolar Coma 808
Osteoporosis Calcium Homeostasis 808
Hyperparathyroidism 815
Changes in Water Balance 816
Hypernatremia 816
Hyponatremia 816
Hyporeninemic Hypoaldosteronism 816
Glucocorticoids Stress 817
Disorders of the Hypothalamid-Pituitary-Adrenal Axis 817
Changes in Reproductive Function in Men 818
Benign Prostatic Hyperplasia 819
26．Endocrine Emergencies David G.Gardner, MD, Francis S.Greenspan, MD 823
Myxedema Coma 823
Thyroid Storm 824
Thyrotoxic Periodic Paralysis 825
Amiodarone Induced Thyrotoxicosis 826
Acute Adrenal Insufficiency 827
Pituitary Apoplexy 828
Diabetic Ketoacidosis 829
Nonketotic Hyperosmolar Coma 832
Hypercalcemic Crisis 835
Acute Hypocalcemia 837
Hyponatremia 839
Diabetes Insipidus 841
27．AIDS Endocrinopathies Deborah E.Sellmeyer, MD, Carl Grunfeld, MD, PhD 846
Thyroid Disorders 846
Adrenal Disorders 847
Bone Mineral Disorders 849
Gonadal Disorders 849
Pituitary Disorders 850
Pancreatic Disorders 850
Lipid Disorders 851
Conclusion 851
Appendix: Table of Normal Hormone Reference Ranges 853
Index 867