Estrogens and Antiestrogens: Basic and Clinical Aspects - Hardcover

Menopause is often of the utmost importance in a woman's life. Years before the last menstrual period, the transition from fertility to sterility can leave its mark. For many women this time of life is one of blood (disorders of the menstrual cycle), sweat (hot flashes and night sweats), and tears (mood swings). During the climacteric, urogenital symptoms such as vaginal dryness start, and bone loss suddenly accelerates to rates unknown in males, protected as they are for much longer by their testosterone levels. Estrogens, or rather decreased estrogen levels, are to blame for all this, and for all that is yet to come: an increased risk of osteoporotic fractures and myocardial infarction, and possibly the early onset of Alzheimer's disease. For those who define the postmenopausal state as a state of estrogen deficiency, estrogen would be a true panacea.

Supplementation with estrogen after menopause is becoming increasingly popular. Progestins are added to estrogens sequentially or continuously to prevent endometrial neoplasia. The routes of administration are multifold; pills, patches, gels, implants, vaginal rings, and nasal sprays are among the options. During the past decade, estrogens (with or without the addition of a progestin) have been convincingly shown to be highly effective in reversing, treating, and preventing menopause-related conditions. Estrogens substantially reduce hot flashes, urogenital symptoms, hip fractures, myocardial infarction, and possibly colon cancer, with important consequences for health and the quality of life. Estrogen replacement may postpone the onset of Alzheimer's disease and extend life. Estrogens would be a panacea if it were not for the risk of breast cancer.

Although estrogens are not mutagens, they may act as tumor promoters. One of the most important prospective studies, the Nurses' Health Study, found that both morbidity and mortality from breast cancer were increased in women who used hormone-replacement therapy for five years or more. Although uncertainty surrounds the use of hormone-replacement therapy in healthy women, many consider estrogen-containing hormone-replacement therapy to be contraindicated after breast cancer. We therefore need estrogen-like drugs that lack a stimulating action on the breast and endometrium while retaining the beneficial effects of estrogen on bone, heart, liver, and brain. The search for such an ideal drug, a tissue-specific partial estrogen agonist-antagonist, has led to the development of a class of compounds now conveniently referred to as selective estrogen-receptor modulators. Raloxifene, a nonsteroidal estrogen-receptor ligand, is the most prominent of this new generation of so-called antiestrogens, whose well-known forerunners are the ovulation-inducer clomiphene and the anti-breast-cancer drug tamoxifen.

These important issues are comprehensively discussed in Estrogens and Antiestrogens, which in 17 chapters covers both the basic and the clinical aspects. All the clinical chapters have been written by acknowledged experts, and the basic aspects are well covered. Intriguing developments in the concept of the estrogen receptor are discussed by its discoverer (Jensen) and the "antiestrogen" concept by a pioneer of tamoxifen studies (Jordan). Both concepts originated independently in 1958. Antiestrogens exert antiestrogenic effects by competitive binding to the estrogen receptor. The site-specific partial agonist effect of antiestrogens is less well understood. Possible explanations that are discussed in some detail include a different conformational state of the receptor after binding and the subsequent interaction of the receptor-ligand complex with a DNA domain that differs from the estrogen-response element.

Some doubt arises about how up to date this book is, since the identification of a raloxifene-response element (reported in 1996) is discussed only in the final chapter, as is the description (in 1996) of the novel estrogen receptor ER beta. These topics would normally have been discussed in other chapters. Allowing for the rapid rate of change in this field, my main criticism is that some of the chapters are not as up to date as one might reasonably expect. The most important and final chapter, apparently written last, discusses the possibility of a universal postmenopausal prevention maintenance therapy that also prevents breast cancer. However, of 92 references, only 13 date from 1996 (and none from 1997). Most chapters have few references, if any, dated later than 1995.

In spite of these criticisms, the editors should be complimented on their efforts in producing this book, which provides a noteworthy overview of a fast-moving field. The book should be considered required reading for researchers and clinicians interested in menopause.

Reviewed by Peter Kenemans, M.D., Ph.D.
Copyright © 1998 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.