Besides the estrogen concentration, the response level of a tissue to estrogen is also dependent on both the state of the ERs (active vs. inactive) and ER concentration. After dissociation of estrogen the ER can either be recycled directly to its active form, reside in a refractory state and become activated later, or degrade to an inactive form . It is known that estrogen pretreatment increases the concentration of ERs in several target tissues and that it is associated with an increased sensitivity to subsequent estrogen treatments . Our understanding of the complexity of estrogen and estrogen receptor interaction increased considerably after Simerly and Young  and Shupnik et al.  pointed out that ER expression, induced by estrogen, is down-regulated instead of up-regulated in tissues like the hypothalamus and uterus, creating a paradox. However, the recent discovery of a second ER isoform, called ER-6  (the tra ditional ER is currently called ER-a), might explain this difference. Because ERs work as dimers, the complexity is increased since a-a homodimers, ft-ft ho-modimers, and a-fi heterodimers can form . Barkhem et al.  showed that the two ER isoforms respond similar to some ligands but that there are also receptor specific responses. This latter action was confirmed by Paech et al. . Different levels of expression of these ER isoforms in different tissues could be an explanation for the differences in response between target tissues.
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