Preface

In "Sex Steroids", we have compiled a collection of insightful and timely chapters meant to provide the reader with expert analyses on our current state of knowledge in select areas of sex steroid research. Sex steroids are central players in many fundamental biologic processes. In addition to their roles in reproduction, development, growth, differentiation, homeostasis, behavior, memory, etc., sex steroids are fundamentally involved in many diseases and disorders. Throughout the years, great progress have been made in our understanding of sex steroid actions at the molecular level. The classical model of sex steroid signaling involves diffusion of an androgen, estrogen, or progesterone across the cell membrane, where it binds to its cognate steroid receptor. This receptor then translocates to the cell nucleus, where it modulates the expression of steroid responsive genes. While many of the pleiotropic effects attributed to sex steroids are explained by this classical model, we know that their mechanisms of action are far more complex and intricate.

Aberrant sex steroid signaling programs are responsible for many aspects of altered sexual characteristics and development. Furthermore, the pioneering work of visionaries, such as George Beatson and Charles Huggins on hormone ablation as treatment for breast and prostate cancer, respectively, highlights the importance of sex steroids in the development and progression of these diseases. Sex steroids are implicated in cardiovascular disease, CNS diseases, memory loss, and a host of other afflictions. In this age of advancements in "–omics", platforms, computational and systems biology, and many other rapidly emerging areas, we should continue to anticipate tremendous advances in our understanding of sex steroid actions, their biologic properties, and their influence on disease prevention and progression.

The initial section of "Sex Steroids" entitled, "The Biology of Sex Steroids", features chapters on the evolutionary and functional overview of sex steroids, sex hormonebinding globulin and its effects on androgen responsiveness, estrogens and growth hormone action in the liver, hormonal feedback, and reproductive aging. Additional chapters include sex steroid receptors in teleocytes, and the influence of sex steroids on stress responsiveness. This is then followed by "Sex Steroids, Memory, and the Brain", which offers chapters on estrogen and brain protection, and estrogen influences on cognition and memory. The third section, "Sex Steroids and the Immune Response", includes chapters describing the fish immune response, the reciprocal

#### XII Preface

nature of the reproductive and immune systems during ontogeny, modulation of the immune response by menopause and hormone therapy, and the role of sex steroids in the host-parasite interaction. The final section, entitled, "Therapy", presents chapters on the effect of postmenopausal therapy on adipose tissue, gonadotropin-suppressive therapy, and hormonal therapy for the treatment of malignant salivary gland tumors.

It is my hope, as editor of "Sex Steroids", that this book provides insights into the fascinating complexity of sex steroid biology that are of interest to seasoned researchers in this field. In addition, I hope it will stimulate newer investigators who are intrigued by the many exciting areas of sex steroid research that remains to be explored. I offer my sincerest appreciation to the many authors and scientists who devoted themselves to the work presented in this book.

I would like to close on a personal note. Earlier this year, the field of sex steroid research lost one of its most devoted and highly respected colleagues. Dr. Jonathan J. Li was a beloved mentor, and also a generous and dear friend who dedicated his professional life to understanding the role that estrogens play in breast cancer. For those of us who were fortunate to spend long hours with Dr. Li on the history of sex steroid research, discussing his views on the interplay between steroids and cancer, he will be greatly missed. Dr. Li, together with his wonderfully bright and talented wife, Sara, have impacted many areas of hormonal research, most recently on estrogen as an initiator of breast cancer. As one who greatly valued discourse in science and the field of sex hormones and cancer, Jonathan co-founded the International Symposium on Hormonal Oncogenesis (ISHO). As one of the more successful and highly acclaimed academic research symposia, the ISHO series has brought together renowned leaders from all over the world, as well as junior researchers in a warm and collegial manner. It is with this spirit of Jonathan's that I hope this book serves the complex and captivating field of sex steroids.

#### **Scott M. Kahn**

Director of Basic Urologic Research St. Luke's-Roosevelt Health Science Center Adjunct Associate Research Scientist Department of Urology Member, Herbert Irving Comprehensive Cancer Center Columbia University Chairman, Biomarkers Council, International Cancer Advocacy Network (ICAN), New York, USA

**Part 1** 

**Biology of Sex Steroids** 

**1** 

*USA* 

Nigel C. Noriega

*University of California at Davis, Department of Neurobiology, Physiology and Behavior* 

**Evolutionary Perspectives on** 

**Sex Steroids in the Vertebrates** 

The term "sex-steroids" refers to estrogen, androgen and progestin products of vertebrate gonads. Sex steroids were so named for their influence on the sexually dimorphic development of the reproductive tract, secondary sex characters and central nervous system, which cause subsequent sexually dimorphic behavior and physiology (Phoenix et al. 1959b; Breedlove & Arnold 1983b). Receptors for sex-steroids are present in almost all tissues, and sex-steroids may be synthesized from cholesterol in the gonads, adrenals and brain. Although commonly described as endocrine components released into the bloodstream, sexsteroids may be generated through conversion from other (particularly adrenal) circulating steroids (Hinson et al. 2010) or generated de novo from cholesterol via intracrine pathways,

In this chapter we examine how sex-steroids fit into the larger themes of metazoan physiology and reproduction, and examine why these compounds may function the way they do in vertebrates. I aim to present broad concepts in a manner that is easily accessible to the nonspecialized reader. It will be useful for the reader to be able to navigate modern versions of metazoan systematics. Therefore I aim to utilize the open-source nature of this publication by providing links that encourage the reader to use the Tree of Life web project (http://tolweb.org/tree/) for up-to-date "locations" of animals within the organization of living things. Navigation instructions for the Tree of Life web project are located at: (http://tolweb.org/tree/home.pages/navigating.html). In summary, clicking the leftwardpointing arrow on a given tree will navigate to the next broader category. Clicking text on the right side of the tree will navigate inside the highlighted group (the next narrower category).

**2. Hormonal axes, gonadotropins and gonadotropin releasing hormones** 

In vertebrates, gonadal activity and steroid release are stimulated by members of a family of glycoprotein hormones known as gonadotropins. Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) typify the gonadotropins, which may be derived from multiple sources, but have highly conserved functionality across species. For example, chorionic gonadotropins (CG) are produced by primate fetus, placenta and pituitary gland (Cole 2009). The human chorionic gonadotropin (hCG) is an effective gonadotropin in amphibians

as in the case of the brain neurosteroids (Baulieu 1997).

**1. Introduction** 
