MEDICAL HYPOTHESES AND RESEARCH
VOL. 4, No. 1, January 2008
B. T. Zhu  Med. Hypotheses Res. 1: 53–61.
Controlling the Levels of Estrogen Receptor α and β
Activation in Postmenopausal Women During Hormone
Replacement Therapy: A Novel Strategy for Achieving
Optimal Health Outcomes
Bao Ting Zhu*
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University
of Kansas Medical Center, Kansas City, KS 66160 (USA)
Abstract. Recent studies from our laboratory have lead to the suggestion that the
human ERα and ERβ signaling systems are differentially activated under different
physiological conditions. In a non-pregnant young woman, the ERα system is preferentially
activated over the ERβ system, mainly by estrone and its major oxidative metabolite, 2-
hydroxyestrone. These two estrogens are among the quantitatively major estrogens present in
a young woman, and they have approximately 4-fold preferential activity for ERα over ERβ.
During pregnancy, however, ERβ is preferentially activated over ERα, which is caused by
various pregnancy estrogens, mainly estriol and other D-ring derivatives of 17β-estradiol.
These estrogens have preference for binding to ERβ over ERα, and some of them are
produced in unusually large quantities. In light of this new finding, it is hypothesized that
estrogens ideal for female hormone replacement therapy should be those that will produce a
hormonal condition mirroring what is found in a non-pregnant young woman rather than in
a pregnant woman. The endogenous estrogen derivatives, such as the sulfated conjugates of
estrone, are among the ideal candidates for achieving this clinical purpose. In comparison,
Premarin, the most commonly used hormone replacement therapy that contains a mixture of
conjugated estrogens isolated from pregnant mare's urine, is less suitable because several of
its estrogenic components can produce a strong, preferential over-stimulation of the human
ERβ signaling system.
Correspondence: Dr. Bao Ting Zhu, Department of Pharmacology, Toxicology and
Therapeutics, University of Kansas Medical Center, MS-1018, room KLSIC-4061, 2146 W.
39th Ave, Kansas City, KS 66160, USA. Tel: 913-588-9842. Fax: 913-588-7501. E-MAIL:
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