Blok L J, De Ruiter P E, Kühne E C M, Hanekamp E E, Grootegoed J A, Smid-Koopman E, Gielen S C J P, De Gooyer M E, Kloosterboer H J, Burger C W
Department of Reproduction and Development, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
J Clin Endocrinol Metab. 2003 May;88(5):2327-34. doi: 10.1210/jc.2002-021737.
Tibolone, a synthetic steroid acting in a tissue-specific manner and used in hormone replacement therapy, is converted into three active metabolites: a Delta(4) isomer (exerting progestogenic and androgenic effects) and two hydroxy metabolites, 3 alpha-hydroxytibolone (3 alpha-OH-tibolone) and 3beta-OH-tibolone (exerting estrogenic effects). In the present study an endometrial carcinoma cell line (Ishikawa PRAB-36) was used to investigate the progestogenic properties of tibolone and its metabolites. This cell line contains progesterone receptors A and B, but lacks estrogen and androgen receptors. When tibolone was added to the cells, complete conversion into the progestogenic/androgenic Delta(4) isomer was observed within 6 d. Furthermore, when cells were cultured with tibolone or when the Delta(4) isomer or the established progestagen medroxyprogesterone acetate was added to the medium, marked inhibition of growth was observed. Interestingly, 3 beta-OH-tibolone also induces some inhibition of growth. These growth inhibitions were not observed in progesterone receptor-negative parental Ishikawa cells, and progestagen-induced growth inhibition of PRAB-36 cells could readily be reversed using the antiprogestagen Org-31489. Upon measuring the expression of two progesterone-regulated genes (fibronectin and IGF-binding protein-3), tibolone, the Delta(4) isomer and medroxyprogesterone acetate showed similar gene expression regulation. These results indicate that tibolone, the Delta(4) metabolite, and to some extent 3 beta-OH-tibolone exert progestogenic effects. Tibolone and most likely 3 beta-OH-tibolone are converted into the Delta(4) metabolite.
替勃龙是一种以组织特异性方式发挥作用并用于激素替代疗法的合成类固醇，它可转化为三种活性代谢物：一种Δ⁴异构体（具有孕激素和雄激素作用）以及两种羟基代谢物，即3α-羟基替勃龙（3α-OH-替勃龙）和3β-OH-替勃龙（具有雌激素作用）。在本研究中，使用子宫内膜癌细胞系（Ishikawa PRAB-36）来研究替勃龙及其代谢物的孕激素特性。该细胞系含有孕激素受体A和B，但缺乏雌激素和雄激素受体。当将替勃龙添加到细胞中时，在6天内观察到其完全转化为具有孕激素/雄激素作用的Δ⁴异构体。此外，当用替勃龙培养细胞或向培养基中添加Δ⁴异构体或已确定的孕激素醋酸甲羟孕酮时，观察到明显的生长抑制。有趣的是，3β-OH-替勃龙也会诱导一定程度的生长抑制。在孕激素受体阴性的亲本Ishikawa细胞中未观察到这些生长抑制，并且使用抗孕激素Org-31489可以轻易逆转孕激素诱导的PRAB-36细胞的生长抑制。在测量两种孕激素调节基因（纤连蛋白和IGF结合蛋白-3）的表达时，替勃龙、Δ⁴异构体和醋酸甲羟孕酮显示出相似的基因表达调节。这些结果表明，替勃龙、Δ⁴代谢物以及在一定程度上3β-OH-替勃龙发挥孕激素作用。替勃龙以及很可能3β-OH-替勃龙会转化为Δ⁴代谢物。
