EFFECTS OF ESTRADIOL AND TAMOXIFEN ON OXYTOCIN-INDUCED PHOSPHOLIPASE-C ACTIVATION IN HUMAN MYOMETRIAL CELLS

The role of oestradiol in the control of uterine responsiveness to oxy tocin was investigated by measuring oxytocin-induced phospholipase C a ctivation in [H-3]inositol-labelled cultured human myometrial cells. A ddition of oestradiol to steroid-free culture medium (10% (v/v) fetal calf serum treated with dextran-coated charcoal in phenol red-free med ium) enhanced formation of inositol phosphates and this effect was com pletely abolished by the anti-oestrogen tamoxifen. The inhibitory effe ct of tamoxifen on oxytocin-induced phospholipase C activation occurre d in both steroid-free and complete culture medium; it was time- and c oncentration-dependent and was only partly reversed by oestradiol. Whe n phospholipase C was activated with PGF(2 alpha) or fluoroaluminate i nstead of oxytocin, oestradiol and tamoxifen had the same stimulatory and inhibitory effects, respectively. The inhibitory effect of tamoxif en could not be prevented by treating the cells with pertussis toxin. Moreover, the effect of tamoxifen was not mediated by inhibition of pr otein kinase C, since the use of staurosporine (a protein kinase inhib itor) resulted in potentiation of phospholipase C activation by oxytoc in. Both oestradiol and tamoxifen increased [H-3]inositol incorporatio n into cellular lipids and cell proliferation. These results suggest t hat oestradiol enhances myometrial responsiveness to oxytocin and othe r agonists by facilitating phospholipase C activation at a post-recept or level. This effect is antagonized by tamoxifen; however, tamoxifen also has oestrogen-independent inhibitory effects.