Analysis of the effects of oestrogen receptor α (ERα)- and ERβ-selective ligands given in combination to ovariectomized rats

Background and purpose: Studies with oestrogen receptora ( ER alpha)- and ER beta-selective compounds have already shown that the effects of 17-beta estradiol (E-2) on body weight, movement drive and bone-protection are mediated via ER alpha. This study was based on the hypothesis that activation of ER beta may antagonize ER alpha-mediated effects and designed to investigate potential effects of ER alpha/ER beta heterodimers. Experimental approach: Ovariectomized (OVX) female Wistar rats were treated with combinations of the ER alpha-specific agonist 16 alpha-LE2 (ALPHA; 1 and 10 mu g kg(-1)d(-1)), the ER beta-specific agonist 8 beta-VE2 (BETA; 100 mu g kg(-1) d(-1)), the phytoestrogen, genistein 10 mg kg(-1) d(-1)) and with the anti-oestrogen compound, ICI 182,780 (3 mg kg(-1) d(-1)) for three weeks. The combined effects of the substances on body weight increase, tibial bone mineral density (BMD) and the influence on running wheel activity (RWA) were investigated. Key results: OVX-induced body weight increase was reduced by co-administration of genistein and BETA. Co-application of BETA or genistein with ALPHA had no effect on ALPHA-mediated bone-protection. The RWA of OVX animals was significantly reduced by treatment with genistein but stimulated by application of ALPHA. The stimulatory effect of ALPHA on RWA could be antagonized by co-treatment with the pure antioestrogen ICI 182,780 but also by co-administration of genistein or BETA. Conclusions and implications: Our results indicate that activation of ERb may modulate ERa-mediated physiological effects in vivo. The observation that substances with selective affinity for ER beta are able to antagonize distinct physiological functions, like RWA, may be of great relevance to the pharmaceutical use of such drugs.