Abstract
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 3α-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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Article info
Publication history
Accepted:
June 10,
2004
Received in revised form:
May 5,
2004
Received:
January 12,
2004
Identification
Copyright
© 2004 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
