ICI-182,780 - A PURE ANTIESTROGEN THAT AFFECTS BEHAVIORS AND ENERGY-BALANCE IN RATS WITHOUT ACTING IN THE BRAIN

ICI 182,780 is one of a new class of steroidal antiestrogens that diff ers from nonsteroidal antiestrogens, such as tamoxifen, in a number of respects. 1) It is bound by estrogen receptors with a high affinity, similar to that for estradiol. 2) It is a ''pure'' antiestrogen in tha t it does not mimic any of the effects of estradiol. 3) This class of anti-estrogens does not seem to be bound by antiestrogen binding sites . 4) ICI 182,780 may not be active in the brain after peripheral admin istration. Indeed, ICI 182,780 blocked in vivo cell nuclear binding of [H-3]estradiol in uterus, pituitary, and adipose tissue but not in hy pothalamus-preoptic area. In vitro, ICI 182,780 competed for binding b y neural estrogen receptors with an affinity comparable with that for estradiol. When given to ovariectomized rats, ICI 182,780 did not mimi c any of the actions of estradiol. Instead, ICI 182,780 treatment comp letely blocked the uterotrophic effects of estradiol and attenuated th e actions of estradiol on linear growth, carcass fat content, fat pad weight, and sexual receptivity. Treatment with ICI 182,780 also attenu ated the estrogenic effects of tamoxifen on food intake, body weight a nd composition, linear growth, and uterine weight. These findings supp ort the concept that, in addition to its actions in the brain, estradi ol can act peripherally to modulate regulatory behaviors, energy balan ce, and estrous behavior. They are also consistent with the hypothesis that nonsteroidal antiestrogens, such as tamoxifen, affect energy bal ance via estrogen receptors, rather than antiestrogen binding sites.