Estrogen receptor (cid:1) – a new dimension in estrogen mechanism of action

The cloning of estrogen receptor (ER ) has provided the first example of a steroid hormone receptor existing as two isoforms, each of which is encoded by a separate gene (Kuiper et al. 1996). The finding of ER was met with great surprise, as the existence of more than one estrogen receptor had been actively denied for several decades. Attempts to clone a second estrogen receptor on the basis of sequence homology to the classical estrogen receptor (ER ) were not successful, although this approach did lead to the identification of two orphan receptors, namely estrogen receptor-related receptors (ERR) 1 and 2 (Giguere et al. 1988). However, none of these ER-related orphan receptors binds estrogens and it is still unclear whether they require specific ligands in order to be activated. ER seems to be a most important factor in the mechanism of action of estrogen, and it is expressed in many tissues, including the central nervous system, the cardiovascular system, the immune system, the urogenital tract, the gastrointestinal tract, the kidneys and the lungs (Arts et al. 1997, Enmark et al. 1997, Kuiper et al. 1997, 1998a, c, Lindner et al. 1998, O} sterlund et al. 1998). Although ER is also expressed in the mammary gland, it appears that ER is an important estrogen receptor in this particular tissue, and in the uterus also there seems to be much more ER present than ER (Fig. 1). This dominant role of ER in the uterus probably explains why it was the first cloned estrogen receptor, as most purification and cloning attempts were based on uterine tissue. As will be referred to below, it is now obvious that ER plays an important role in the physiology of several tissues, and it cannot be excluded that it is the more generally expressed estrogen receptor, whereas ER dominates in some few specific tissues and is mainly involved in reproductive events. Obviously, these differences in tissue distribution are of extreme importance from the pharmaceutical point of view, as hormone replacement therapy in postmenopausal women is such an increasingly significant health issue. Although the DNA-binding domains of ER and ER show a high degree of homology (only three amino acids differ), the ligand-binding domain shows only 59% homology (Fig. 2). Closer inspection indicates that it should be possible to develop ER and ER -specific ligands. In view of the facts presented above, it is not unreasonable to assume that it might be possible to develop ER -specific estrogen agonists targeting the central nervous system, the urogenital tract, the cardiovascular system and bone, but leaving the mammary gland and uterus relatively unaffected. In this way, much of the current controversy concerning estrogen treatment of postmenopausal women might be resolved (Barkhem et al. 1998, Gustafsson 1998a,b, Kuiper et al. 1998b, Nilsson et al. 1998).