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Science 28 May 2004:
Vol. 304. no. 5675, pp. 1269 - 1273
DOI: 10.1126/science.1096725
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Review

Hormone Therapy: Physiological Complexity Belies Therapeutic Simplicity

Judith L. Turgeon,1 Donald P. McDonnell,3 Kathryn A. Martin,4 Phyllis M. Wise2

The results of the Women's Health Initiative, a study anticipated to provide definitive answers about health benefits and risks of postmenopausal hormone therapy, have generated debate and confusion among clinicians, researchers, and the lay public. The ovarian hormones estrogen and progesterone, which decline at menopause, normally elicit complex tissue-specific responses throughout the body. Major advances are providing a detailed molecular definition of how that differential action is achieved. Here we review estrogen and progestin actions, discuss how effectively knowledge of steroid hormone endocrinology has been incorporated into clinical studies, and consider the impact on modern hormone therapy protocols and pharmaceutical development.

1 Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, University of California–Davis, Davis, CA 95616, USA.
2 Department of Neurobiology, Physiology and Behavior, Division of Biological Sciences, University of California–Davis, Davis, CA 95616, USA.
3 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
4 Harvard Medical School, Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

* To whom correspondence should be addressed. E-mail: jlturgeon{at}ucdavis.edu

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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P. Y. Liu, K. A. Hoey, K. L. Mielke, J. D. Veldhuis, and S. Khosla (2005)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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U. Ohnemus, M. Uenalan, F. Conrad, B. Handjiski, L. Mecklenburg, M. Nakamura, J. Inzunza, J.-A. Gustafsson, and R. Paus (2005)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S. E. Anderson, D. M. Kirkland, A. Beyschau, and P. M. Cala (2005)
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   Abstract »    Full Text »    PDF »
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M. B. Sporn (2004)
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   Full Text »    PDF »
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N. Madamanchi, X. Liu, and M. S. Runge (2004)
Circ. Res. 95, 228-229
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