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Background and purpose:Studies with oestrogen receptorα (ERα)- and ERβ-selective compounds have already shown that the effects of 17β-estradiol (E2) on body weight, movement drive and bone-protection are mediated via ERα. This study was based on the hypothesis that activation of ERβ may antagonize ERα-mediated effects and designed to investigate potential effects of ERα/ERβ heterodimers.Experimental approach:Ovariectomized (OVX) female Wistar rats were treated with combinations of the ERα-specific agonist 16α-LE2 (ALPHA; 1 and 10 μg kg−1 d−1), the ERβ-specific agonist 8β-VE2 (BETA; 100 μg 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 ERβ may modulate ERα-mediated physiological effects in vivo. The observation that substances with selective affinity for ERβ are able to antagonize distinct physiological functions, like RWA, may be of great relevance to the pharmaceutical use of such drugs.British Journal of Pharmacology (2008) 153, 1432–1437; doi:10.1038/sj.bjp.0707664; published online 4 February 2008 [ABSTRACT FROM AUTHOR]