EFFECTS OF A NONSTEROIDAL PURE ANTIESTROGEN, ZM-189,154, ON ESTROGEN TARGET ORGANS OF THE RAT INCLUDING BONES

ZM 189,154 ([1RS,2RS]-2-(4-hydroxyphenyl)-2-methyl (4,4,5,5,5-penta-fl uoropentyl)sulphinylnonyl]-1,2, 3,4-tetrahydronaphth-6-ol) is a non-st eroidal pure antioestrogen. It has a high relative affinity for the oe strogen receptor, completely blocks the trophic action of oestradiol ( OE(2)) on the uterus in immature and ovariectomized (OVX) adult rats a nd, in the latter, also completely blocks the trophic action of OE(2) on vagina, bone and growth rate. ZM 189,154 displays no intrinsic oest rogen-agonist activity on uterus, vagina, bone, LH secretion or growth rate in OVX rats. Differential sensitivity of OE(2)-regulated process es was more apparent in intact rats. Daily doses of 0.6 mg/kg per day of ZM 189,154 blocked ovulation; 2 mg/kg per day achieved maximal uter ine atrophy but did not affect bone density or growth rate; 10 mg/kg p er day produced a broader spectrum of effects (reduced bone density, i ncreased basal LH, slightly increased growth rate), but the magnitude of these was smaller than after ovariectomy; the 10 mg/kg dose also pr oduced multiple ovarian follicular cysts. The failure of ZM 189,153 to achieve complete ovariectomy-like effects in intact rats may be due t o the action of ovarian factors other than OE(2), or to the circulatin g OE(2) levels resulting from the disturbance to ovarian function posi ng too strong a challenge to the antagonist.