Inhibition of the Uterotropic Activity of Estrogens and Antiestrogens by the Short Acting Antiestrogen LY117018*

Abstract

The aim of the study was to determine whether the dihydroxylated antiestrogen LY117018, with a high affinity for the estrogen receptor and low intrinsic estrogenic activity, could inhibit the uterotropic actions of steroidal [estradiol-17 beta (E2)] and nonsteroidal [ICI 3188 and trianisylchloroethylene (TACE)] estrogens in immature rats and also the uterotropic actions of tamoxifen and monohydroxytamoxifen in the ovariectomized mouse and immature rat. In the first series of experiments, LY117018 was compared with monohydroxytamoxifen. Both antiestrogens inhibited the uterotropic actions of E2 (0.32 micrograms daily), ICI 3188 (5 micrograms daily), and TACE (40 and 160 micrograms daily) in a dose-related manner (0.32-82 micrograms daily). The potency of the antiestrogens against E2 and ICI 3188 was similar, however, at higher doses (20.48 and 82 micrograms daily) LY117018 reduced uterine weights to below the lowest level achieved by monohydroxytamoxifen. In contrast, LY117018 was less effective against the long acting estrogen TACE. The competitive interaction of LY117018 with tamoxifen and monohydroxytamoxifen was compared in 3-day ovariectomized mouse and immature rat uterine weight tests. Tamoxifen and monohydroxytamoxifen were fully estrogenic in the mouse (5 micrograms daily) and partially estrogenic in the rat (1.5-20 micrograms daily). LY117018 was a partial estrogen in the mouse and a weekly active partial estrogen in the rat (2.5-120 micrograms daily). LY117018 produced dose-related decreases in the uterine weight increases induced by tamoxifen and monohydroxytamoxifen in both species. However, in the rat, LY117018 was more effective against the less potent compound tamoxifen, at a 6:1 dosage ratio compared with a 24:1 dosage ratio required for the potent compound monohydroxytamoxifen. LY117018 had a short duration of action as an antiestrogen when compared with monohydroxytamoxifen. LY117018 (120 micrograms) was only completely effective as an antiestrogen if administered repeatedly with E2 whereas a single injection of monohydroxytamoxifen (120 micrograms) was sufficient to inhibit fully E2 action in the uterus for up to 4 days. Because LY117018 has a shorter duration of action than monohydroxytamoxifen, a high dosage ratio of LY117018 over monohydroxytamoxifen is required to maintain effective competitive antagonism in the uterus. Overall, these findings suggest that monohydroxytamoxifen and LY117018 probably act through the same mechanism of action via the estrogen receptor.

Effects of tamoxifen and ethynylestradiol cotreatment on uterine gene expression in immature, ovariectomized mice

“…We have used it to examine differential uterine gene expression elicited by EE (Fertuck et al 2003, Moggs, et al 2004, Kwekel et al 2005, Naciff et al 2007) and, more recently, the partial agonist effects of TAM (Fong et al 2007). Although TAM inhibits ER-mediated estrogen-induced increases in UWW (Jordan et al 1978a, Jordan & Gosden 1983, the effects of cotreatment on gene expression have not been comprehensively examined. In this study, the same model, study design, and analysis methods reported earlier for EE and TAM differential gene expression investigations (Fertuck et al 2003, Kwekel et al 2005, Fong et al 2007) were used to examine the inhibition of EE-induced uterotrophy by TAM cotreatment in order to re-examine several hypotheses regarding the mechanisms involved in the anti-estrogenicity of TAM.…”

Effect of raloxifene on salivary sex steroid concentrations in premenopausal women

“…Potentially, the elevation in oestradiol could compete with raloxifene for the ER. Unfortunately, benzothiophene types of SERMs are extremely short-acting (Jordan & Gosden 1983) and therefore do not have the ability to block completely oestrogen target tissues such as the breast . This may be the reason for the poor effectiveness of raloxifene as a breast cancer treatment in ER-positive breast cancers (Gradishar et al 2000) as there is only 2% bioavailability after oral doses of raloxifene (Snyder et al 2000).…”

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

“…The compounds were known to be less uterotrophic than tamoxifen in rodents [127] but they were short acting [128] which could explain their poor antitumor properties when compared with tamoxifen. Interestingly enough, keoxifene was already known to partially inhibit the growth of tamoxifen-stimulated human endometrial tumors under laboratory conditions [129].…”