Effects of Tibolone on Sulfatase Pathway of Estrogens Metabolism and on Growth of MCF-7 Human Breast Tumors Implanted in Ovariectomized Nude Mice

Abstract

Background: The benefits of estrogen plus progestin in healthy post-menopausal women remain uncertain. Tibolone, with its in vitro documented inhibitory effects on estrogens metabolism and its selective action on breast, may be an alternative that could favorably influence the health benefit of hormone replacement therapy. Methods: We studied the effect of tibolone on the tumor growth of MCF-7 cells implanted in 40 ovariectomized nude mice, receiving subcutaneous pellets of 17β-estradiol, estrone, estrone-sulfate or vehicle, and daily gavages of tibolone or placebo. Results: Tibolone, although used at high dose, did not stimulate nor inhibit the estrogen-induced tumors, nor the tumors in estrogen-deprived mice. Measurements of plasma levels of estrogens indicated that tibolone potently stimulated sulfotransferase activity, but intra-tumor levels of estrogens were not significantly modified by tibolone. Conclusions: This in vivo study performed with high dose of orally administered tibolone that allowed its hepatic conversion into active metabolites has shown no significant effect on breast tumors growth. Tibolone increased the circulating sulfated estrogens by its activity on the hepatic sulfation but not the intra-tumor levels of estrogens (free or sulfated). However, further studies of dose-response curve and molecular markers are needed to exclude definitely a stimulatory effect of tibolone on tumor growth.

The impact of testosterone, tibolone and black cohosh on purified mammary and placental 17β-hydroxysteroid dehydrogenase type 1

“…Thus, independently from serum hormone levels, locally produced E2 may have an impact on mammary carcinogenesis 16 . For tibolone [17][18][19][20][21][22] , testosterone 23 , and an isopropanolic extract of black cohosh (iCR) 24 an inhibitory effect on STS activity was found in vitro and ex vivo, respectively.…”

Tibolone and Breast Tissue: a Review

“…Moreover, in nude mice, tibolone did not stimulate normal breast cells, as demonstrated by the evaluation of estrogenic activity markers [3], and it did not stimulate MCF-7 cells transplanted in the same experimental model [13].…”

Anti-Tumor-Promoting Activity of Tibolone and its Metabolites

“…In this paper, the inhibitory effect of tibolone (1), ∆ 4 -ene isomer 2 and 3α-and 3β-hydroxy metabolites 3 and 4, was assayed using a short term in vitro assay for EBV-EA activation in Raji cells induced by the tumor promoter TPA, as described in [12] and [13] (see experimental parts therein). Although the test substances are known to interact with and influence the female reproductive endocrine system [1,[16][17][18], are under study for breast cancer prevention [19][20][21][22][23][24][25], and are known to increase human breast cancer cells proliferation in vitro, alone and in combination with estradiol [26,27], we did not use a post menopausal model for their in vivo study, but focused our attention on mouse skin tumor promotion inhibition activity of compounds 1 and 3 trough an in vivo two-stage mouse skin carcinogenesis test (see experimental) previously used also for other steroids [6,14]. In fact many compounds inhibiting the in vitro EBV-EA activation by TPA are also inhibitors of tumor promotion in vivo, and the mouse skin model of multistage carcinogenesis is widely used for studying carcinogenesis mechanisms and the means for inhibiting specific stages of carcinogenesis [3,4,28].…”