Selective Estrogen Receptor Modulators

by Sanchez, Antonio Cano; Calaf I Alsina, Joacquim; Duenas-diez, Jose Luis

• ISBN13: 9783540242277
• ISBN10: 3540242279
• Edition: 1st
• Format: Hardcover
• Copyright: 2006-08-15
• Publisher: Springer Verlag

Summary

The experience gained with tamoxifen has been the basis for the new concept of selective estrogen receptor modulators (SERMs). The action of these substances has been investigated in both basic and clinical studies, but there is not an integrated view of all the facets of this recent area in modern medicine. This book offers an up-to-date compilation of the most relevant information on the topic carried out by experienced basic and clinical investigators. The first section revises the basic determinants required to understand the functional versatility of SERMs. This part includes chapters that review the main SERM families and their principal components, the mechanisms of action of steroid hormones, SERMs and pure antiestrogens, or and the action of SERMs on the hypothalamic-pituitary unit. The second part focuses on the clinical areas where SERMs have demonstrated efficacy, such as osteoporosis, breast cancer, cardiovascular disease, and benign gynecological pathology, including actions on the endometrium, etc. There is a final chapter offering a thoughtful reflection on the role that SERMs may have in clinical practice.

Table of Contents

Part I Basic Area
1 Molecular Mechanisms of Estrogen Action in Target Tissues
B. Nicolás Diaz Chico, Domingo Navarro Bosch, Juan C. Diaz Chico, Eduardo Escrich Escriche	3	(46)
1.1 Introduction	3	(1)
1.2 General Aspects	4	(3)
1.2.1 The Discovery of Hormone Receptors for Steroid Hormones	4	(1)
1.2.2 Nuclear Hormone Receptors?	5	(2)
1.3 Structure of Estrogen Receptors	7	(5)
1.3.1 Primary Structure of Estrogen Receptors	7	(1)
1.3.2 Activity Domains in the Molecules of Estrogen Receptors	8	(1)
1.3.3 Genetic Encoding of Estrogen Receptors	8	(2)
1.3.4 Native Receptor	10	(1)
1.3.5 Estrogen Transforms the Native Receptor	11	(1)
1.3.6 Domain of Nuclear Location	11	(1)
1.4 Hormone-Receptor Interaction	12	(6)
1.4.1 Ligand Binding Domain	12	(2)
1.4.2 Structure of Receptor and Hormonal Antagonism	14	(2)
1.4.3 Receptor Folding in Separate Domains	16	(1)
1.4.4 Dimerization Domains	17	(1)
1.5 Receptor-Genome Interaction	18	(5)
1.5.1 Specific DNA Sequences for the Hormone Response	18	(1)
1.5.2 DNA-Binding Domain	19	(2)
1.5.3 Recognition of Hormone Response Element	21	(1)
1.5.4 Role of Receptor-Hormone Response Element Complex	22	(1)
1.6 Hormonal Regulation of Gene Transcription	23	(10)
1.6.1 Domains of Transcription Activation (Transactivators)	24	(1)
1.6.2 Intermediary Transcription Cofactors	25	(2)
1.6.3 Interaction of Receptor with Transcription Cofactors	27	(1)
1.6.4 Coactivators in Cellular and Gene Promoter Context	27	(2)
1.6.5 Concept of SERM from Point of View of Coactivator	29	(1)
1.6.6 Structure of Chromatin and Hormone Response	29	(2)
1.6.7 Specificity of Gene Transcription Induced by Hormones	31	(1)
1.6.8 Multiple Regulation of Gene Expression	31	(1)
1.6.9 Nuclear Hormone Receptors and Endocrine Disruptors	32	(1)
1.7 Regulation of Intensity of Hormone Response	33	(2)
1.7.1 Membrane Receptors for Steroid Hormones	33	(1)
1.7.2 Regulation of Concentration of Receptors per Cell	34	(1)
1.7.3 Receptor Destiny After Activation	35	(1)
1.8 Cross-Talk Signaling	35	(2)
1.9 Silencing of Genes for Nuclear Hormone Receptors	37	(2)
1.10 Summary	39	(2)
References	41	(8)
2 Clinical Pharmacology of Selective Estrogen Receptor Modulators (SERMs)
Fernando Marin, Ma Carmen Barbancho	49	(22)
2.1 Introduction	49	(1)
2.2 Classification	50	(2)
2.3 Pharmacological Characteristics of SERMs	52	(10)
2.3.1 Triphenylethylenes	52	(3)
2.3.2 Benzothiophenes	55	(2)
2.3.3 Naphthalenes	57	(1)
2.3.4 Indoles	58	(2)
2.3.5 Benzopyrans	60	(2)
2.4 Conclusions	62	(3)
References	65	(6)
3 Action of Selective Estrogen Receptor Modulators (SERMs) Through the Classical Mechanism of Estrogen Action
Fernando Marin, Ma Carmen Barbancho	71	(8)
3.1 Introduction	71	(1)
3.2 Estrogen Receptor Subtypes	72	(1)
3.3 Conformation of Ligand-ER Complex	73	(1)
3.4 Coregulator Protein Cell Content and Coactivators/Corepressors Ratio	73	(2)
3.5 Transrepression: Regulation of Gene Expression by an ERE-Independent Mechanism	75	(1)
References	76	(3)
4 Cellular and Molecular Basis for Acute Nongenomically Mediated Actions of SERMs
Mario Diaz, Jorge Marrero-Alonso, Benito Garcia Marrero, Raquel Marin, Tomás Gomez, Rafael Alonso	79	(24)
4.1 Introduction	79	(1)
4.2 Cellular and Molecular Targets for Rapid Actions	79	(16)
4.2.1 Interaction with Ion Channels	79	(7)
4.2.2 Multidrug Resistance and P-glycoprotein	86	(1)
4.2.3 Signalling Transducers	87	(5)
4.2.4 Lipids, Membrane Lipids, and Fluidity	92	(2)
4.2.5 Specific Antiestrogen-Binding Sites (AEBS)	94	(1)
4.3 Final Considerations	95	(1)
References	96	(7)
5 The Hypothalamus-Pituitary-Ovarian Axis as a Model System for the Study of...SERM Effects: An Overview of Experimental and Clinical Studies
R. Alonso, F. Marin, M. González, P. Guelmes, C. Bellido, G. Hernández, R. Marin, M. Diaz, J.E. Sánchez-Criado	103	(38)
5.1 Introduction	103	(1)
5.2 Hypothalamus-Pituitary-Ovarian Axis of Mammals	104	(10)
5.2.1 General Aspects	104	(1)
5.2.2 Functional Organization	105	(1)
5.2.3 Estrogen Feedback Regulation of Hypothalamus-Pituitary Axis	106	(6)
5.2.4 Overview of Hypothalamic-Pituitary Function at Time of Gonadotropin Surge	112	(2)
5.3 Effects of SERMs on Hypothalamus-Pituitary-Ovarian Axis	114	(12)
5.3.1 Experimental Studies in the Rat	115	(4)
5.3.2 Lessons in SERM Behavior from Effects of Tamoxifen on Rat Pituitary Function	119	(3)
5.3.3 Clinical Studies	122	(4)
5.4 Summary and Conclusions	126	(1)
References	127	(14)
6 Pure Antiestrogens
Carlos Hermenegildo	141	(20)
6.1 Introduction	141	(1)
6.1.1 Type I	141	(1)
6.1.2 Type II	141	(1)
6.2 Chemical Structure and Classification	142	(1)
6.3 Mechanism of Action	143	(3)
6.4 Effects of Pure Antiestrogens	146	(6)
6.4.1 In Vitro Studies	146	(1)
6.4.2 Experiments in Animals	147	(3)
6.4.3 Clinical Studies	150	(2)
6.5 Clinical Utility	152	(1)
References	153	(8)
Part II Clinical Area
7 Physiological Regulation of Bone Metabolism and Estrogen Agonism
Miguel Angel Garcia-Pérez	161	(26)
7.1 Normal Bone Remodeling	162	(1)
7.2 Executive Cells: Osteoblasts and Osteoclasts	163	(3)
7.3 Role of Proinflammatory Cytokines in Bone Resorption	166	(1)
7.4 The RANKL/RANK/OPG System	167	(4)
7.5 Bone Remodeling After Estrogen Deficiency	171	(3)
7.6 Effects of Estrogen and Agonist of Estrogen Receptor on Bone Cells	174	(3)
7.7 Conclusions	177	(1)
References	177	(10)
8 The Role of SERMs in the Treatment of Osteoporosis
Adolfo Diez-Pérez, José Luis Dueñas-Diez	187	(20)
8.1 Introduction	187	(1)
8.2 Experimental Results	188	(1)
8.2.1 Tamoxifen	188	(1)
8.2.2 Raloxifene	188	(1)
8.3 Other SERMs	189	(1)
8.4 Clinical Effects of SERMs	190	(5)
8.4.1 Tamoxifen	190	(2)
8.4.2 Raloxifene	192	(3)
8.5 Bone Quality and Its Relevance	195	(4)
8.6 Future SERMs	199	(1)
References	199	(8)
9 Cardiovascular Disease and SERMs
Antonio Cano	207	(32)
9.1 The Focal Phenotype of CVD	208	(4)
9.1.1 The Crucial Role of the Endothelium	210	(2)
9.2 Estrogen Agonism and CVD	212	(2)
9.2.1 Lipids	212	(1)
9.2.2 Vascular Wall	213	(1)
9.3 SERMs as an Alternative to Estrogens in CVD	214	(2)
9.4 Actions of SERMs	216	(11)
9.4.1 Arterial Disease	216	(10)
9.4.2 VTED	226	(1)
9.5 Conclusion and Outlook for the Future	227	(1)
References	228	(11)
10 SERMs and the Breast
Joaquim Calaf i Alsina, Antonio Cano Sanchez	239	(32)
10.1 Introduction	239	(1)
10.2 Biology of Breast Development and its Endocrine Regulation	240	(1)
10.3 Framework of Breast Cancer Research	241	(2)
10.4 Relationship Between Estrogens and Breast Cancer	243	(4)
10.4.1 Endogenous Estrogens	243	(1)
10.4.2 Exogenous Estrogens	244	(3)
10.5 Pharmacological Blockade of Estrogen Receptors: The Concept of Chemoprophylaxis	247	(8)
10.5.1 Tamoxifen as Adjuvant Therapy in Early ER(+) Breast Cancer	248	(2)
10.5.2 Tamoxifen in Primary Prevention of ER(+) Breast Cancer	250	(2)
10.5.3 Drawbacks of Tamoxifen as a Preventive Agent	252	(3)
10.6 Raloxifene and Breast Cancer	255	(10)
10.6.1 Clinical Studies	255	(3)
10.6.2 Estrogen Receptor Status	258	(1)
10.6.3 Estrogen Circulating Levels and Raloxifene Protection	258	(2)
10.6.4 Bone Density and Effect of Raloxifene on the Breast	260	(2)
10.6.5 Other Conditions Related to Raloxifene Protection	262	(2)
10.6.6 Raloxifen as a Breast Cancer Preventive Agent	264	(1)
10.7 New Perspectives	265	(1)
References	266	(5)
11 Endometrial Effects of SERMs
Santiago Palacios	271	(20)
11.1 Introduction	271	(1)
11.2 Mechanism of Action in the Endometrium	271	(4)
11.2.1 Tamoxifen	272	(2)
11.2.2 Raloxifene	274	(1)
11.3 Tamoxifen and Endometrium: Clinical Consideration	275	(4)
11.3.1 Ultrasonographic Findings	275	(1)
11.3.2 Hystological Findings	275	(2)
11.3.3 Tamoxifen and Risk of Endometrial Cancer	277	(2)
11.4 Raloxifene	279	(4)
11.4.1 Data Obtained from Biopsy	279	(1)
11.4.2 Ultrasonographic Data and Symptomatology	280	(3)
11.5 Others SERMs	283	(2)
11.5.1 Arzoxifene	283	(1)
11.5.2 Bazedoxifene Acetate	283	(1)
11.5.3 Lasofoxifene	284	(1)
11.5.4 Ospemifene	284	(1)
11.6 Conclusions	285	(1)
References	285	(6)
12 Benign Gynecological Diseases and SERMs
Stefano Palomba, Fulvio Zullo	291	(22)
12.1 Introduction	291	(1)
12.2 Uterine Leiomyomas	291	(11)
12.2.1 Treatments of Uterine Leiomyomas	292	(2)
12.2.2 SERMs and Uterine Leiomyomas	294	(8)
12.3 Endometriosis	302	(3)
12.3.1 Treatments of Endometriosis	303	(1)
12.3.2 SERMs and Endometriosis	304	(1)
12.4 Conclusions	305	(1)
References	306	(7)
13 Other Clinical Effects of SERMs
P. Acién, F. Quereda, M.I. Acién	313	(20)
13.1 Urogenital Tract	314	(4)
13.1.1 Vaginal Trophism and Dyspareunia	314	(1)
13.1.2 Pelvic Floor Function and Urinary Disorders	315	(3)
13.2 Central nervous system	318	(6)
13.2.1 Hot Flashes and Beta Endorphins	320	(1)
13.2.2 Mood, Sleep, Waking Episodes	321	(1)
13.2.3 Cognitive Function, Alzheimer's Disease (AD)	321	(2)
13.2.4 Libido, Sexual Function	323	(1)
13.3 Gallbladder and Hepatobiliar System	324	(1)
13.4 Desmoids and Mesenteric Fibromatosis	325	(1)
13.5 Endocrine Functions	325	(1)
13.5.1 Insulin Sensitivity and Diabetes	325	(1)
13.5.2 Thyroid Function	325	(1)
13.6 Eye, Cataracts	326	(2)
13.7 Other Effects	328	(1)
13.7.1 Arthritis	328	(1)
13.7.2 Hemorheological Effects	328	(1)
13.7.3 Quality of Life (QoL)	328	(1)
References	329	(4)
14 The Role of SERMs in the Management of Postmenopausal Women
Joaquim Calaf i Alsina	333	(18)
14.1 Introduction	333	(1)
14.2 Identifying Troubles and Threats	334	(4)
14.2.1 Cardiovascular Risk	334	(1)
14.2.2 Menopausal Syndrome	335	(1)
14.2.3 Osteoporosis	336	(1)
14.2.4 Breast Cancer	337	(1)
14.3 Intervention Tools	338	(2)
14.3.1 Lifestyle Optimization	338	(1)
14.3.2 Hormone Therapy	338	(1)
14.3.3 Cardioprotective Treatments	339	(1)
14.3.4 Bone Resorption Inhibitors	339	(1)
14.3.5 Breast Cancer Risk	340	(1)
14.4 Adressing Health Expectancy Improvement	340	(4)
14.4.1 Poly Approach and Multitasking	340	(1)
14.4.2 Pharmacological Poly Approach	341	(1)
14.4.3 Multitasking Drugs	342	(2)
14.5 Dynamic Decision-Making Diagram	344	(2)
References	346	(5)
Subject Index	351