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This Is Your Brain On Steroids
rings, and progestins for emergency contraception are examined sequentially. The mode of action, the specific progestins used and the risks and benefits of each of these methods is detailed. Chapter 16 reviews the various progestins utilized in HRT. Evidence to support reduced cardiovascular mortality with postmenopausal estrogen replacement therapy is reviewed in detail. The significance of ongoing trials, such as the Women’s Health Initiative (WHI) study and Medical Research Council (MRC)-HRT study, are discussed. The importance of finding a progestin that will inhibit endometrial proliferation while minimizing adverse effects is emphasized as a research area of great importance in women’s health care, particularly as the ‘baby boomers’ enter menopause. The effect of progestins on stroke, venous thromboembolism, lipid metabolism, carbohydrate metabolism, blood pressure and atherosclerosis is examined in detail. Sitruk-Ware encapsulates the current opinion on HRT as well as any text or review that I have read. Chapters 17 and 18 address the role of progestins in the pathogenesis and treatment of benign and malignant breast disease. Particularly effective, I found, was the discussion of the sulfatase and aromatase enzymatic mechanisms involved in the production of estrogens in breast cancer. Once again, charts and diagrams are effectively used. A discussion of the effect of progestogenic compounds on enzymes involved in estrogen production concludes Chapter 17
with a look at potential new hormonal treatments for breast cancer. Chapter 19 is titled ‘Therapeutic use of progestins: practical recommendations’. This chapter is, in essence, a quick recap of material presented in other chapters. Nevertheless, the chapter is brief and to the point. It is a well-constructed overview that I will recommend to medical students and house staff alike at my institution. As an excellent summary of the properties of synthetic progestins and their desired effects on target tissue, it will be of particular interest to the clinician. For instance, when an antiestrogenic effect is required, the author suggests use of a progestin with high antigonadotropic properties. On the other hand, women with hirsutism should use progestin compounds with anti-androgenic properties. The treatment of luteal phase defects, premenstrual mood disorders, endometriosis, and breast cancer, as well as the role of progestins in male contraception and pregnancy maintenance are detailed. The chapter concludes with a discussion of the androgenic, glucocorticoid, CNS and metabolic side effects of synthetic progestins. Again, some of the material is redundant, but perhaps by its repetition salient points in patient management are re-emphasized. Chapters 20 and 21 examine the effects of progestins on lipids and glucose metabolism. These chapters are excellent reviews, but once again, there is some redundancy of previous material. Antiprogestins, particularly mefipristone (RU-486) are covered in a mere 11 pages. Nevertheless, multiple clinical ap-
This Is Your Brain On Steroids Neurosteroids. A New Regulatory Function in the Nervous System Edited by Etienne-Emile Baulieu, Paul Robel, and Michael Schumacher. Totowa, Humana, 1999, $135.00 (xvi 1 378 pages), ISBN 0-896-0345-X. Early in the introductory chapter, the editors of this volume of the ContemTEM Vol. 11, No. 8, 2000
porary EndocrinologyTM series provide a definition of a ‘neurosteroid,’ i.e. a steroid which is accumulated in the central and peripheral nervous systems independently, at least in part, of the steroidogenic endocrine glands and which can be synthesized de novo in the nervous system from sterol precursors. The major steroids which meet this definition, and for which there is an extensive and credible literature, are the sulfated derivatives of pregnenolone (PREG-S) and
plications are reviewed, including the role of mefipristone in pregnancy termination, cervical ripening for labor and contraceptive use. Postcoital contraception is also presented as a possible indication. Ongoing trials involving antiprogestins in the treatment of breast and other cancers increase my enthusiasm for future studies. Indeed, upon completing the chapter, one realizes the harmful effect when politics enters drug research. The final chapter examines pharmacokinetics of exogenously administered progestins. Various routes of administration (oral, vaginal, sublingual, intramuscular, and transcutaneous) are reviewed, and the need for future research to establish the optimal route of administration is emphasized. A book on progestins and their clinical use is long overdue. Most of the topics covered in this book typically receive little more than a passing glance in reproductive endocrinology textbooks. As noted in the introduction to the book, obstetricians and gynecologists, endocrinologists, psychiatrists and oncologists will find this book useful in day-to-day practice and medical students and residents may find it useful in their training. As new progestins (and antiprogestins) become available in the future, this book (and future editions) will remain an invaluable resource to the clinician. Robert P. Kauffman Department of Obstetrics and Gynecology Texas Tech University Health Sciences Center, School of Medicine Amarillo, Texas 79106, USA
dehydroepiandrosterone (DHEA-S) and the 5a-reduced metabolites of progesterone and deoxycorticosterone (3a,5aTH PROG or allopregnanolone and 3a,5a-TH DOC, respectively). Much of this book focuses on the biochemistry and actions of neurosteroids and when it does, it is of interest to the general reader, with the caveat that such a reader is best served if he or she has a working knowledge of the basics of steroid biochemistry. Moreover, all readers should be aware that a number of the chapters, particularly those that emphasize structure or activity relationships,
1043-2760/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S1043-2760(00)00289-7
343
will require a very detailed familiarity with steroid structure to make them readable. The editors have attempted to make the steroid nomenclature more manageable by providing a table listing steroids at the beginning of the book, giving their chemical and current names, both approved and incorrect abbreviations and main steroid-metabolizing enzymes. Still, this aspect of the book remains daunting for anyone who wishes to use it to gain familiarity with this field or to obtain a concise update on recent developments. Following the initial chapter, all the other chapters are grouped by related themes. Chapters 2–6 discuss the enzymes or associated proteins (e.g. steroidogenic factor-1, the peripheral-type benzodiazepine receptor) which are responsible for and which regulate the synthesis of neurosteroids. Apparent contradictions to the definition provided above exist within this area of investigation as some necessary enzymes in the pathway of neurosteroid synthesis (most notably, P450c17, which is needed for the synthesis of DHEA) cannot be demonstrated in the adult brain, even with very sensitive reverse transcriptase-PCR methodology. In contrast, expression of other enzymes, such as 5a-reductase that produces active PROG and DOC derivatives, is readily detected in the brain at both the mRNA and protein levels. Although a peripheral source of DHEA would eliminate the P450c17 discrepancy, the continued presence of DHEA in the brains of adrenalectomized and gonadectomized animals (removing the most obvious possible sources), leaves the mystery of the missing P450c17 unresolved. These chapters also reflect the complexity of steroidogenic enzyme expression in that patterns can differ in relation to species, developmental age, or brain region and with regard to the synthesis and site of action of this class of steroids in glial cells and in neurons, respectively. In direct proportion to its significance, a major section of the book (Chapters 7–13) is devoted to interactions of neurosteroids with ligand-gated neurotransmitter receptors. As is true for much of the steroid field, this mechanism was initially implied by Selye almost 60 years
344
ago, when, without knowing about GABA receptors, he noted the anesthetic properties of progesterone and deoxycorticosterone. Following the initial proposal, in 1981, of the existence of a distinct class of steroids with the brain as a target, the interaction of these compounds with neurotransmitter receptors was soon identified as the principal criterion by which their actions could be distinguished from the receptor-mediated, genome-based effects of classic steroids. Allosteric modulation of ligand-gated neurotransmitter receptors, principally the GABAA and N-methyl-D-aspartate (NMDA) receptors, constitutes the most significant and relevant mechanism by which the former steroids affect neuronal function to produce their mixed anxiolytic/anxiogenic and memory-enhancing effects. The pharmacological characteristics of the abilities of 3a,5a-TH PROG and 3a,5a-TH DOC to enhance GABAA receptor function and of PREG-S and DHEA-S to act as GABAA receptor antagonists are consistent with their opposing behavioral effects. Moreover, the simultaneous inhibition of the GABAA receptor and positive modulation of the NMDA glutamatergic receptor by PREGS, which would be expected to synergistically increase neuronal activity, are indicative of an integrative influence of these steroids on the brain. The generality of steroid-mediated receptor modulation is supported by the inclusion of additional chapters on the effects of neurosteroids on other subtypes of glutamate receptors, the sigma receptor, the nicotinic acetylcholine receptor and voltagegated calcium channels. The book takes a four-chapter detour at this point, turning to more classic aspects of steroid action in Chapters 14–17. These chapters emphasize receptorbased mechanisms by which steroids, principally estrogen, promote synaptic plasticity in the brain either alone or in combination with growth factors. The content of the chapters includes not only a discussion of the standard cytosolic or nuclear steroid receptors, but also evidence for a membrane-bound estrogen receptor in the brain that might directly interact with components of intracellular signaling pathways that are initiated at the cell membrane. The inclusion of this
section initially seems to disrupt the main flow of the book as there is essentially no mention of the neurosteroids defined above. But, in combination with the discussion in the last chapter of the ability of 5a-reduced compounds to activate the progesterone receptor in a speciesspecific manner, they serve to increase awareness of the possibility of significant overlap between classic receptor-mediated and neurosteroid-specific mechanisms in the brain. An intracellular receptor-mediated action of reduced progesterone metabolites may also be pertinent to their clinically relevant ability to promote myelination. The final three chapters discuss behavioral analysis, concerning the effects of neurosteroids in relation to anxiety and memory. The subject is an important area of investigation because of its potential to establish a causal relationship between the behavioral effects of neurosteroids and neurotransmitter receptor-based mechanisms that underlie them. Although the paradigm-by-paradigm organization that characterizes much of this section is not the most lively format to read, it serves to summarize logically a complex set of observations so that the generalities become apparent: compounds which positively modulate GABAA receptor function are anxiolytic, while compounds with GABAA receptor antagonist properties are memory enhancers. In conclusion, the research described in this volume demonstrates that the original literature from the mid-1980s on the subject of neurosteroids has remained solid in its general outline, while the detail that is now apparent in this volume testifies to the amount of growth in the field. Novel and intriguing aspects of steroid ‘neurochemistry’ are likely to be revealed while the many questions still remaining (e.g. What are the cellular sources of neurosteroids and/or their precursors? Which extracellular signals regulate neurosteroid synthesis? Is there overlapping regulation by neurosteroids of neurotransmitter and steroid receptors?) are being answered. Linda Dokas Department of Neurology, Medical College of Ohio, Toledo, OH 43614, USA TEM Vol. 11, No. 8, 2000
with a look at potential new hormonal treatments for breast cancer. Chapter 19 is titled ‘Therapeutic use of progestins: practical recommendations’. This chapter is, in essence, a quick recap of material presented in other chapters. Nevertheless, the chapter is brief and to the point. It is a well-constructed overview that I will recommend to medical students and house staff alike at my institution. As an excellent summary of the properties of synthetic progestins and their desired effects on target tissue, it will be of particular interest to the clinician. For instance, when an antiestrogenic effect is required, the author suggests use of a progestin with high antigonadotropic properties. On the other hand, women with hirsutism should use progestin compounds with anti-androgenic properties. The treatment of luteal phase defects, premenstrual mood disorders, endometriosis, and breast cancer, as well as the role of progestins in male contraception and pregnancy maintenance are detailed. The chapter concludes with a discussion of the androgenic, glucocorticoid, CNS and metabolic side effects of synthetic progestins. Again, some of the material is redundant, but perhaps by its repetition salient points in patient management are re-emphasized. Chapters 20 and 21 examine the effects of progestins on lipids and glucose metabolism. These chapters are excellent reviews, but once again, there is some redundancy of previous material. Antiprogestins, particularly mefipristone (RU-486) are covered in a mere 11 pages. Nevertheless, multiple clinical ap-
This Is Your Brain On Steroids Neurosteroids. A New Regulatory Function in the Nervous System Edited by Etienne-Emile Baulieu, Paul Robel, and Michael Schumacher. Totowa, Humana, 1999, $135.00 (xvi 1 378 pages), ISBN 0-896-0345-X. Early in the introductory chapter, the editors of this volume of the ContemTEM Vol. 11, No. 8, 2000
porary EndocrinologyTM series provide a definition of a ‘neurosteroid,’ i.e. a steroid which is accumulated in the central and peripheral nervous systems independently, at least in part, of the steroidogenic endocrine glands and which can be synthesized de novo in the nervous system from sterol precursors. The major steroids which meet this definition, and for which there is an extensive and credible literature, are the sulfated derivatives of pregnenolone (PREG-S) and
plications are reviewed, including the role of mefipristone in pregnancy termination, cervical ripening for labor and contraceptive use. Postcoital contraception is also presented as a possible indication. Ongoing trials involving antiprogestins in the treatment of breast and other cancers increase my enthusiasm for future studies. Indeed, upon completing the chapter, one realizes the harmful effect when politics enters drug research. The final chapter examines pharmacokinetics of exogenously administered progestins. Various routes of administration (oral, vaginal, sublingual, intramuscular, and transcutaneous) are reviewed, and the need for future research to establish the optimal route of administration is emphasized. A book on progestins and their clinical use is long overdue. Most of the topics covered in this book typically receive little more than a passing glance in reproductive endocrinology textbooks. As noted in the introduction to the book, obstetricians and gynecologists, endocrinologists, psychiatrists and oncologists will find this book useful in day-to-day practice and medical students and residents may find it useful in their training. As new progestins (and antiprogestins) become available in the future, this book (and future editions) will remain an invaluable resource to the clinician. Robert P. Kauffman Department of Obstetrics and Gynecology Texas Tech University Health Sciences Center, School of Medicine Amarillo, Texas 79106, USA
dehydroepiandrosterone (DHEA-S) and the 5a-reduced metabolites of progesterone and deoxycorticosterone (3a,5aTH PROG or allopregnanolone and 3a,5a-TH DOC, respectively). Much of this book focuses on the biochemistry and actions of neurosteroids and when it does, it is of interest to the general reader, with the caveat that such a reader is best served if he or she has a working knowledge of the basics of steroid biochemistry. Moreover, all readers should be aware that a number of the chapters, particularly those that emphasize structure or activity relationships,
1043-2760/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S1043-2760(00)00289-7
343
will require a very detailed familiarity with steroid structure to make them readable. The editors have attempted to make the steroid nomenclature more manageable by providing a table listing steroids at the beginning of the book, giving their chemical and current names, both approved and incorrect abbreviations and main steroid-metabolizing enzymes. Still, this aspect of the book remains daunting for anyone who wishes to use it to gain familiarity with this field or to obtain a concise update on recent developments. Following the initial chapter, all the other chapters are grouped by related themes. Chapters 2–6 discuss the enzymes or associated proteins (e.g. steroidogenic factor-1, the peripheral-type benzodiazepine receptor) which are responsible for and which regulate the synthesis of neurosteroids. Apparent contradictions to the definition provided above exist within this area of investigation as some necessary enzymes in the pathway of neurosteroid synthesis (most notably, P450c17, which is needed for the synthesis of DHEA) cannot be demonstrated in the adult brain, even with very sensitive reverse transcriptase-PCR methodology. In contrast, expression of other enzymes, such as 5a-reductase that produces active PROG and DOC derivatives, is readily detected in the brain at both the mRNA and protein levels. Although a peripheral source of DHEA would eliminate the P450c17 discrepancy, the continued presence of DHEA in the brains of adrenalectomized and gonadectomized animals (removing the most obvious possible sources), leaves the mystery of the missing P450c17 unresolved. These chapters also reflect the complexity of steroidogenic enzyme expression in that patterns can differ in relation to species, developmental age, or brain region and with regard to the synthesis and site of action of this class of steroids in glial cells and in neurons, respectively. In direct proportion to its significance, a major section of the book (Chapters 7–13) is devoted to interactions of neurosteroids with ligand-gated neurotransmitter receptors. As is true for much of the steroid field, this mechanism was initially implied by Selye almost 60 years
344
ago, when, without knowing about GABA receptors, he noted the anesthetic properties of progesterone and deoxycorticosterone. Following the initial proposal, in 1981, of the existence of a distinct class of steroids with the brain as a target, the interaction of these compounds with neurotransmitter receptors was soon identified as the principal criterion by which their actions could be distinguished from the receptor-mediated, genome-based effects of classic steroids. Allosteric modulation of ligand-gated neurotransmitter receptors, principally the GABAA and N-methyl-D-aspartate (NMDA) receptors, constitutes the most significant and relevant mechanism by which the former steroids affect neuronal function to produce their mixed anxiolytic/anxiogenic and memory-enhancing effects. The pharmacological characteristics of the abilities of 3a,5a-TH PROG and 3a,5a-TH DOC to enhance GABAA receptor function and of PREG-S and DHEA-S to act as GABAA receptor antagonists are consistent with their opposing behavioral effects. Moreover, the simultaneous inhibition of the GABAA receptor and positive modulation of the NMDA glutamatergic receptor by PREGS, which would be expected to synergistically increase neuronal activity, are indicative of an integrative influence of these steroids on the brain. The generality of steroid-mediated receptor modulation is supported by the inclusion of additional chapters on the effects of neurosteroids on other subtypes of glutamate receptors, the sigma receptor, the nicotinic acetylcholine receptor and voltagegated calcium channels. The book takes a four-chapter detour at this point, turning to more classic aspects of steroid action in Chapters 14–17. These chapters emphasize receptorbased mechanisms by which steroids, principally estrogen, promote synaptic plasticity in the brain either alone or in combination with growth factors. The content of the chapters includes not only a discussion of the standard cytosolic or nuclear steroid receptors, but also evidence for a membrane-bound estrogen receptor in the brain that might directly interact with components of intracellular signaling pathways that are initiated at the cell membrane. The inclusion of this
section initially seems to disrupt the main flow of the book as there is essentially no mention of the neurosteroids defined above. But, in combination with the discussion in the last chapter of the ability of 5a-reduced compounds to activate the progesterone receptor in a speciesspecific manner, they serve to increase awareness of the possibility of significant overlap between classic receptor-mediated and neurosteroid-specific mechanisms in the brain. An intracellular receptor-mediated action of reduced progesterone metabolites may also be pertinent to their clinically relevant ability to promote myelination. The final three chapters discuss behavioral analysis, concerning the effects of neurosteroids in relation to anxiety and memory. The subject is an important area of investigation because of its potential to establish a causal relationship between the behavioral effects of neurosteroids and neurotransmitter receptor-based mechanisms that underlie them. Although the paradigm-by-paradigm organization that characterizes much of this section is not the most lively format to read, it serves to summarize logically a complex set of observations so that the generalities become apparent: compounds which positively modulate GABAA receptor function are anxiolytic, while compounds with GABAA receptor antagonist properties are memory enhancers. In conclusion, the research described in this volume demonstrates that the original literature from the mid-1980s on the subject of neurosteroids has remained solid in its general outline, while the detail that is now apparent in this volume testifies to the amount of growth in the field. Novel and intriguing aspects of steroid ‘neurochemistry’ are likely to be revealed while the many questions still remaining (e.g. What are the cellular sources of neurosteroids and/or their precursors? Which extracellular signals regulate neurosteroid synthesis? Is there overlapping regulation by neurosteroids of neurotransmitter and steroid receptors?) are being answered. Linda Dokas Department of Neurology, Medical College of Ohio, Toledo, OH 43614, USA TEM Vol. 11, No. 8, 2000