PubMed · 14192032
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V K GANDHI. 1964. CONGENTIAL HEMI-HYPERTROPHY.. https://pubmed.ncbi.nlm.nih.gov/14192032/
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Hormone treatment with an estrogen plus a progestagen (EPT) increases the risk of breast cancer. Both hormone activities are also induced by tibolone. In order to assess the breast safety of tibolone, it was evaluated in several pre-clinical models. The effects were inconclusive in breast cancer cell lines but, in various in vivo models, it did not stimulate the breast. In the 17,12-dimethylbenz(a)anthracene (DMBA) model, tibolone clearly inhibited the growth of breast tumors and, when given prophylactally, far less tumors developed. Ovariectomized monkeys showed no increase in the expression of the proliferation marker Ki67. The effects of tibolone and its metabolites on the steroid metabolizing enzymes in breast tissues were investigated in order to unravel its mode of action in the breast. Tibolone and its metabolites did not inhibit aromatase, but sulfatase was profoundly inhibited. The sulfated 3alpha-OH tibolone metabolite even showed irreversible inhibition of sulfatase. In addition, 17ss-hydroxysteroid dehydrogenase activities were slightly inhibited and sulfotransferase activity was stimulated at low concentrations. The consequence of these effects is that, for both endogenous estrogens and estrogenic-metabolites of tibolone, the equilibrium is preferential for the sulfated forms. The intracellular hormonal milieu tibolone and its metabolites also influence cellular homeostasis. It inhibits cell proliferation of normal breast epithelial cells and stimulates apoptosis. In this respect, tibolone behaves differently from estrogens. Clinical studies have shown that tibolone users experience less breast tenderness and do not show an increase in mammographic density as found with continuous combined EPT. The data concerning tibolone and breast cancer risk are inconclusive and require further investigation.
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Enzymes, such as steroid sulphatase, sulphotransferases and 17 beta-hydroxydehydrogenases, are important in regulating the tissue-specific actions of steroids. These enzymes can exist in different isoforms in different tissues and can be regulated by tissue-specific promoters and factors such as cytokines, prostaglandins and growth factors. The activity of these enzymes and the mechanisms by which they are regulated may help to account for some of the tissue-specific effects of the hormone replacement therapy drug tibolone, which has oestrogenic effects on the bone but not on the breast or endometrium.