Mechanism of Estrogen Action: Lessons from the Estrogen Receptor-α Knockout Mouse1

Abstract

INTRODUCTIONEstradiol-17␤ (E 2 ) stimulates uterine and vaginal epithelial proliferation in vivo [1]. E 2 also plays a critical role in other aspects of uterine and vaginal growth and adult function, and it is obligatory for normal epithelial morphogenesis, cytodifferentiation, and secretory activity in these organs. E 2 elicits its effects via the estrogen receptor (ER), which functions as a ligand-activated transcription factor to turn on target genes in E 2 -responsive tissues.For many years it was believed that E 2 acted through a single type of ER. However, the recent discovery [2, 3] of a second receptor, named ER␤ to distinguish it from the original receptor now termed ER␣, has indicated that mediation of E 2 action is more complicated than originally thought. ER␤, like ER␣, is a member of the steroid receptor superfamily, and low but detectable levels of ER␤ mRNA and protein have been detected in the rodent uterus and vagina [3][4][5]. However, E 2 treatment of ER␣ knockout (ERKO) mice does not produce characteristic estrogenic responses such as vaginal epithelial stratification and cornification, uterine epithelial DNA synthesis, or increases in uterine wet weight and mRNA levels for uterine progesterone receptor, glucose 6-phosphate dehydrogenase, or lactoferrin [6], despite the expression of ER␤ mRNA in the uterus and vagina of these animals [4]. Therefore, although the role of ER␤ in the female reproductive tract has not been established, ER␣ seems to be the critical receptor for mediating vaginal and uterine responses commonly associated with E 2 treatment. This review will therefore address only the role of ER␣ in various E 2 -induced processes such as epithelial proliferation and differentiation and will not deal with ER␤ further.ER is expressed in both epithelial and stromal cells of adult uterus and vagina [7,8], and it was initially assumed that E 2 effects on epithelium and stroma were mediated directly through ER in these tissue compartments. Several findings not consistent with this seemingly obvious mechanism of E 2 action have appeared in recent years and sug-

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