Steroid Hormone Resistance

This volume represents the first attempt to present in one place the clinical syndromes and the pathophysiologic basis for the "resistance states" to each of the classes of steroid hormones. Glucocorticoids, mineralocorticoids, androgens, estrogens, progesterone and vitamin D have widely diverse roles ranging from the control of homeostasis to reproduction and bone formation. They are similar in that they share a chemical structure and that their action is in the cell nucleus where they induce transcription of specific genes leading to synthesis of function-specific proteins. Clinical syndromes of steroid hormone resistance to androgens (complete and partial testicular feminization), aldosterone (pseudo hypoaldosteronism) and vitamin D (vitamin D-dependent rickets type II) have been known for many years. Progesterone and glucocorticoid resistance syndromes have been described only recently. Resistance to estrogens has not been reported in man or in animals. It is hoped that a detailed reexamination of what is known about each of these conditions at the clinical and molecular levels will enhance our understanding of the function of these hormones and their mechanisms of action. New insight and research initiatives should result. G.P. Chrousos D.L. Loriaus M.B. Lipsett vii ACKNOWLEDGMENTS The contents of this volume are based in part on the proceedings of an International Conference held in Bethesda in the summer of 1984. This conference was sponsored by the National Institute of Child Health and Human Development, Bethesda, Maryland.

Steroid Hormone Action is a comprehensive overview of the molecular mechanisms by which these hormones regulate the expression of specific target genes. The book covers the structure of steroid receptors, transcriptional activation and repression, and also contains chapters on steroid bindingproteins and steroidogenesis. Steroid receptors represent one of the best characterized transcription factors so that the book will be of general interest to Molecular Biologists studying eucaryotic gene regulation. Chapters on the mechanisms of action of steoid antagonists and defective receptorsin target cells will be of particular interest to Endocrinologists and Clinicians. In such a rapidly progressing field it is difficult to keep up with all the literature but this book, written by international experts, focuses on the most important advances that have been made recently.

The past few years have witnessed the emergence of steroid hormones as the wonder molecules which generate as much discussion in the scientific literature as they do in a typical living room. This transition has been a result of the tremendous public and scientific interest in the normal functioning of the hor mones as well their suggested involvement in several clinical conditions. In the recent past, notable scientific and technological advances have been made in the areas of contraception and regulation of fertility. Steroid receptors are the indis pensable mediators of hormonal responses and are complex protein molecules which appear to exist in association with other, yet undefined, proteins and/or factors. Receptors for vitamin D, retinoic acid and the thyroid hormones share structural similarities with steroid receptors, and the roster of this superfamily is still expanding. While our knowledge of the diversity and magnitude of steroid effects has advanced, the precise mode of steroid hormone action has alluded investigators. This volume brings together an international team of prominent investigators who discuss their most recent work on the basic and clinical aspects of steroid/nuclear receptors. The contributions represent updated versions of the invited presentations made at The Second Meadow Brook Conference on Steroid Receptors in Health and Disease. I am grateful to my colleagues on the Scientific Committee: Etienne Baulieu, Jack Gorski, Benita Katzenellenbogen, David Toft and James WittJiff, who provided the vision and guidance in formulating an out standing program.

The Second International CBT (Center for Biotechnology) Synposium was held in Stockholm November 4-5 1988 and had the title "The steroid/thyroid hoITIDne receptor family and gene regulation". This meeting contained contributions from most leading laboratories within the field of steroid/thyroid hOITIDne receptors and gave a very exciting perspective on the dynamic development of this i:ntx>rt. ant research field. Today all known steroid hoITIDne receptors have been cloned and sequenced and novel members of this supergene family are constantly being discovered. Sane of these new receptors remain to be characterized regarding the nature of their ligand. Access to probes for steroid receptors has enabled studies on mechanisms of regulation of receptor gene expression. Deletion and II'Altational analysis of steroid receptor cDNAs followed by expression in cells together with suitable reporter genes has yielded a detailed knowledge about the functional significance of the various domains the receptors are composed of. In certain cases, steroid resistance in patients have been shown to be due to point mutations in the corresponding steroid receptor genes resulting in non-functional receptors. The availability of receptor cDNAs also makes it possible to express receptors at high levels in procaryotic and eucaryotic cells. It is e. g. possible to express the DNA-binding domain of the glucocorticoid receptor in E. coli as a fusion protein with protein A which interacts specifically with DNA. Such studies are necessary for production of sufficient quantities of receptors to allow crystallization and X-ray crystallography for detailed structural information.

During the last two decades, progress in steroid hormone research has resulted in the development of new approaches to contraception as well as diagnosis and treatment of endocrine disorders and cancers. Although significant advances have been made in the purification, characterization, immunochemistry and molecular biology of steroid receptors, the precise molecular mechanism of steroid hormone action has remained obscure. This book captures the detailed presentations made at the first conference on Steroid Receptors in Health and Disease held at Meadow Brook Hall, Oakland University in the fall of 1987. The purpose of this international con ference was to facilitate scientific exchange toward a better understand ing of the mode of action of steroid hormones. The scientific sessions consisted of poster presentations and state-of-the-art lectures, the latter of which make up this volume. The first chapter is meant to provide the reader with a more general background of the topics covered in the book, as well as to discuss certain theme-related issues that are either not yet well-established or accepted or are in the stage of infancy. It is hoped that this volume will serve as a useful treatise for students and investigators interested in basic and clinical aspects of biological regulation by steroid hormones. A task of this magnitude could not have been undertaken without the encouragement, advice and continued generous assistance of the members of the scientific committee. I am gratefully indebted to Drs.

Breast and prostate cancers are both hormone-dependent, at least in some stages of their progression. Hormonal manipulation represents an important therapeutic approach. Although most of breast and prostate cancers initially respond to hormone therapy, most tumors reinitiate to growth. Finally, hormone-resistant and metastatic breast and prostate cancers may develop. Thus, the challenge is the dissection of mechanisms by which steroid receptor signaling pathways continue to influence cell growth and invasiveness. Compelling evidence indicates that steroid hormones elicit non-genomic responses in extra-nuclear compartment of target cells. In this cellular location, steroid-coupled receptors rapidly recruit signaling effectors or scaffold proteins and activate multiple pathways leading to proliferation, survival, migration and invasiveness. The immediate challenge is the dissection of key events regulating the steroid response of target tissues to prevent progression and improve treatment of breast and prostate cancers.

The first Meadowbrook Symposium was held in 1978 and during the intervening ten years our knowledge concerning how steroid hormones function at the level of gene expression has advanced by leaps and bounds. In this volume, which sum marizes our fourth meeting, these advances are very evident. What seemed like science fiction ten years ago has become commonplace science. Who would have imagined that we could synthesize a nucleotide sequence that binds a specific steroid receptor and acts as a controlling element for gene expression? No one; but as is evident from the results reported in several chapters, this technique is yielding a wealth of information. Using these and other techniques it has become apparent that gene transcription is controlled by interactions between transacting factors and DNA recognition sequences (response elements). These transacting factors appear to be members of a large gene family that includes steroid hormone receptors, transcription factors, protooncogenes and homeobox proteins. Thus a great deal has been learned, but as usual, questions remain. Many of these questions are posed by the findings and observations found in several chapters in this volume. Non hormone binding forms of steroid receptors and their relevance to receptor down regulation, recycling and biological response remain a mystery. The quantitative relationship between receptor binding and biological response still presents agonizing problems. These and many other intriguing questions are discussed in this volume and set the stage for what should be a most rewarding time in endocrinology. Winter 1989 ARUN K.

Endocrinology and Metabolism: Progress in Research and Clinical Prac tice is a new series that has been designed to present timely, critical reviews of constantly evolving fields; to provide practical and up-to-date guidance in the solution of pertinent clinical problems; to offer an alterna tive to the laborious search of the literature (and the often frustrating reading of highly technical articles); and to translate the language of the laboratory into that of the practice of medicine. We think that this volume and those to come will prove useful to physi cians (and to physicians in training), as well as to investigators in a wide variety of specialties; in short, to anyone who seeks answers to questions in endocrinology and metabolism. The first chapter of this volume could well serve as a general introduc tion to the entire series. It points out how our growing understanding of the molecular basis of biologic communication has led to the discovery of a growing number of clinical syndromes, as well as to the realization that phenotypically similar diseases may have radically different pathogenetic mechanisms and thus may require radically different therapeutic strata gems.