Is it necessary to control the level of estrogen receptor α and β activation in postmenopausal hormone replacement therapy in order to achieve the optimal outcome? (Review)

Abstract

Abstract. Endogenous estrogens exert an array of biological actions on women, many of which are mediated by the estrogen receptors (ERs) α and ß. Results from our recent studies suggest that the human ERα and ERß systems are differentially activated under different physiological conditions. In non-pregnant young women, the ERα system is preferentially activated over the ERß system, mainly by estrone (E1) and its major oxidative metabolite, 2-hydroxy-E1. These two estrogens are among the quantitatively major estrogens present in young women, and have approximately 4-fold preferential activity for ERα over ERß. During pregnancy, however, there is a preponderance of activation of ERß over ERα conferred by various pregnancy estrogens such as estriol and other D-ring derivatives of 17ß-estradiol (E2). These estrogens have an up to 18-fold preference for binding to ERß than for ERα, and some of them are produced in unusually large quantities. Given this new information, it is hypothesized that the estrogens ideal for female hormone replacement therapy (HRT) would be those which produce a hormonal condition mirroring that found in non-pregnant young women rather than in pregnant women. Endogenous estrogen derivatives, such as the sulfated conjugates of E1, may be among the ideal candidates for achieving this clinical purpose. In comparison, Premarin, the most commonly-used HRT containing 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 overstimulation of the human ERß signaling system. Contents 1. Introduction 2. Differences in the composition and quantity of endogenous estrogens produced in pregnant and non-pregnant women 3. Differences in the biological activity of pregnancy and non-pregnancy estrogens 4. Biological activity of estrogens contained in Premarin 5. Which estrogens are ideal for postmenopausal hormone replacement therapy? 6. Concluding remarks IntroductionFemale hormone replacement therapy (HRT), also commonly called menopausal hormone therapy, is a hormonal treatment for peri-or post-menopausal women undertaken to reduce the discomfort and health problems associated with diminished circulating ovarian hormones (namely, estrogens and progesterone). HRT usually provides a low dose of an estrogen (or a mixture of estrogens), often in combination with a progestin. In the past few decades, the most commonly-used estrogen treatment for HRT has been Premarin, which consists of a mixture of mostly sulfated estrogens isolated from pregnant mare's urine. The hormonal activity of these conjugated estrogens in vivo results from their enzymatic hydrolysis and releases biologically active estrogens.Until a few years ago, the generally-held scientific belief was that 'an estrogen is an estrogen', i.e., that all estrogens exert similar pharmacological actions on the body. However, this dogmatic view has gradually changed over the past decade due, in large part, to the emergence of the following body of ...

Estriol has different effects from 17β-estradiol in modulating mouse splenocyte function under inflammatory conditions

“…In recent years, there is growing support for the concept that certain biologically-active estrogen metabolites formed in the body under certain physiological or pathophysiological conditions may serve as new hormones or as local chemical mediators which exert a distinct profile of biological functions (discussed in Zhu and Conney, 1998). E 3 has been suggested to be one of such bioactive estrogen metabolites in light of the fact that this endogenous estrogen derivative has unique biological functions during human pregnancy that are very different from E 2 (Zhu and Conney, 1998;Zhu, 2008;Funeshima-Fuji et al, 2009).…”

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“…These hormones are a major factor formed in sex-related organs such as the breast, ovary, and prostate . Estrogen, a primary sex hormone, exerts its effects through two nuclear receptors: the estrogen receptor alpha (ERα) and beta (ERβ). , After ligand binding, these receptors act as transcription factors and move toward specific estrogen response elements (EREs) on the DNA strand, thereby regulating the expression of target genes …”

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