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Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies

Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, Department of Internal Medicine (J.L.T.), University of California, Davis, Davis, California 95616; Division of Endocrinology, Metabolism, and Molecular Medicine (M.C.C.), Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611; Department of Psychiatry and Psychology (P.M.M.), University of Illinois at Chicago, Chicago, Illinois 60612; Molecular Cardiology Research Institute, Department of Medicine, and Division of Cardiology (M.E.M.), New England Medical Center Hospitals and Tufts University School of Medicine, Boston, Massachusetts 02111; and Departments of Physiology and Biophysics, and Biology (P.M.W.), University of Washington, Seattle, Washington 98195

Correspondence: Address all correspondence and requests for reprints to: Judith Turgeon, Ph.D., Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, University of California Davis, Davis, California 95616. E-mail: jlturgeon{at}ucdavis.edu

Recent publications describing the results of the Women’s Health Initiative (WHI) and other studies reporting the impact of hormone therapy on aging women have spurred reexamination of the broad use of estrogens and progestins during the postmenopausal years. Here, we review the complex pharmacology of these hormones, the diverse and sometimes opposite effects that result from the use of different estrogenic and progestinic compounds, given via different delivery routes in different concentrations and treatment sequence, and to women of different ages and health status. We examine our new and growing appreciation of the role of estrogens in the immune system and the inflammatory response, and we pose the concept that estrogen’s interface with this system may be at the core of some of the effects on multiple physiological systems, such as the adipose/metabolic system, the cardiovascular system, and the central nervous system. We compare and contrast clinical and basic science studies as we focus on the actions of estrogens in these systems because the untoward effects of hormone therapy reported in the WHI were not expected. The broad interpretation and publicity of the results of the WHI have resulted in a general condemnation of all hormone replacement in postmenopausal women. In fact, careful review of the extensive literature suggests that data resulting from the WHI and other recent studies should be interpreted within the narrow context of the study design. We argue that these results should encourage us to perform new studies that take advantage of a dialogue between basic scientists and clinician scientists to ensure appropriate design, incorporation of current knowledge, and proper interpretation of results. Only then will we have a better understanding of what hormonal compounds should be used in which populations of women and at what stages of menopausal/postmenopausal life.

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