Research Article| Volume 49, ISSUE 1, PS5-S15, September 24, 2004

Tissue-selective effects of tibolone on the breast


      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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        • Lindsay R.
        • MacKay Hart D.
        • Kraszewski A.
        • Coope J.
        Prospective double-blind trial of synthetic steroid (Org OD 14) for preventing postmenopausal osteoporosis.
        Br. Med. J. 1980; 280: 1207-1209
        • Modelska K.
        • Cummings S.
        Tibolone for postmenopausal women: systematic review of randomized trials.
        J. Clin. Endocrinol. Metab. 2002; 87: 16-23
        • Albertazzi P.
        • Di Micco R.
        • Zanardi E.
        Tibolone: a review.
        Maturitas. 1998; 30: 295-305
        • Moore R.A.
        Livial: a review of clinical studies.
        Br. J. Obstet. Gynaecol. 1999; : 1-21
        • Kloosterboer H.J.
        Tibolone: a steroid with a tissue-specific mode of action.
        J. Steroid Biochem. Mol. Biol. 2001; 76: 231-238
        • Timmer C.J.
        • Houwing N.S.
        Dose proportionality of three different doses of tibolone.
        Pharmacotherapy. 2002; 22: 6-13
        • de Gooyer M.
        • Deckers G.H.
        • Schoonen WGEJ
        • Verheul HAM
        • Kloosterboer H.J.
        Receptor profiling and endocrine interactions of tibolone.
        Steroids. 2003; 68: 21-30
        • Kloosterboer H.J.
        • Ederveen A.G.
        Tibolone- its tissue specificity and bone-preserving effects.
        J. Menopause. 2002; 1: 16-19
      1. De Gooyer M. Tibolone: possible mechanism for its tissue-selectivity. University of Utrecht. Thesis. Chapter 6, 2003.

      2. Blom MJ. Steroids and steroid analogues for hormone replacement therapy: metabolism in target tissues. University of Utrecht. Thesis Chapter 5. 2001.

        • Mueck A.O.
        • Lippert C.
        • Seeger H.
        • Wallwiener D.
        Effects of tibolone on human breast cancer cells and human vascular coronary cells.
        Arch. Gynecol. Obstet. 2003; 267: 139-144
        • Kloosterboer H.J.
        • Schoonen W.G.
        • Deckers G.
        • Klijn J.G.
        Effects of progestogens and Org OD14 in in vitro and in vivo tumour models.
        J. Steroid Biochem. Mol. Biol. 1994; 49: 311-318
        • Dobson R.
        • Chan K.
        • Knox W.F.
        • Potten C.
        • Kloosterboer H.L.
        • Bundred N.J.
        Tibolone does not stimulate epithelial proliferation in the breast.
        Breast Cancer Res. Treat. 2001; 69: 292
        • Desreux J.
        • Kloosterboer H.J.
        • Noël A.
        • Frankenne F.
        • Lemaire M.
        Foidart JM. Effects of tibolone (Org OD14) on steroid sulfatase activity and growth of MCF-7 human breast tumors implanted in ovariectomized nude mice.
        Int. J. Gynecologic. Cancer. 2003; 13: 31
        • Deckers G.
        • Verheul H.A.
        • Aalst G.
        • van Cremers E.
        • de Gooijer M.E.
        • Kloosterboer H.J.
        Tibolone and 5-alpha-dihydrotestosterone alone or in combination with an anti-androgen in a rat breast tumour model.
        Eur. J. Cancer. 2002; 38: 443-448
        • Suzuki T.
        • Nakata T.
        • Miki Y.
        • Kaneko C.
        • Moriya T.
        • Ishida T.
        • et al.
        Estrogen sulfotransferase and steroid sulfatase in human breast carcinoma.
        Cancer Res. 2003; 63: 2762-2770
        • de Gooyer M.E.
        • Oppers-Tiemissen H.M.
        • Leysen D.
        • Verheul HAM
        • Kloosterboer H.J.
        Tibolone is not converted by human aromatase to 7α-methyl-17α-ethynylestradiol (7α-MEE); analyses with sensitive bioassays for estrogens and androgens and LC-MSMS.
        Steroids. 2003; 68: 235-243
        • Pasqualini J.R.
        • Chetrite G.
        • Blacker C.
        • et al.
        Concentration of estrone, estradiol, estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and post-menopausal breast cancer patients.
        J. Clin. Endocrinol. Metab. 1996; 81: 1460-1464
        • Chetrite G.
        • Kloosterboer H.J.
        • Pasqualini J.R.
        Effect of tibolone (Org OD14) and its metabolites on estrone sulphatase activity in MCF-7 and T-47D mammary cancer cells.
        Anticancer Res. 1997; 17: 135-140
        • de Gooyer M.E.
        • Kleyn G.T.
        • Smits K.C.
        • Ederveen A.G.
        • Verheul H.A.
        • Kloosterboer H.J.
        Tibolone: a compound with tissue specific inhibitory effects on sulfatase.
        Mol. Cell Endocrinol. 2001; 183: 55-62
        • Purohit A.
        • Malini B.
        • Hooymans C.
        • Newman S.P.
        Inhibition of oestrone sulphatase activity by tibolone and its metabolites.
        Horm. Metab. Res. 2002; 34: 1-6
        • Chetrite G.S.
        • Kloosterboer H.J.
        • Philippe J.C.
        • Pasqualini J.R.
        Effects of Org OD14 (Livial) and its metabolites on 17 beta- hydroxysteroid dehydrogenase activity in hormone-dependent MCF-7 and T- 47D breast cancer cells.
        Anticancer Res. 1999; 19: 261-267
        • Chetrite G.S.
        • Kloosterboer H.J.
        • Philippe J.C.
        • Pasqualini J.R.
        Effect of Org OD14 (Livial) and its metabolites on human estrogen sulphotransferase activity in the hormone-dependent MCF-7 and T-47D, and the hormone-independent MDA-MB-231, breast cancer cell lines.
        Anticancer Res. 1999; 19: 269-275
        • Gompel A.
        • Chaouat M.
        • Jacob D.
        • Perrot J-Y.
        • Kloosterboer H.J.
        • Rostene W.
        In vitro studies of tibolone in breast cells.
        Fertil. Steril. 2002; 78: 351-359
        • Doeren M.
        • Ruebig A.
        • Coelingh Bennink HJT
        • Holzgreve W.
        Differential effects on the androgen status of postmenopausal women treated with ’tibolone’ and continuous combined estradiol and norethindrone acetate replacement therapy.
        Fertil. Steril. 2001; 75: 554-559
        • Desreux J.
        • Van den Brulle F.
        • Noel A.
        • Delansone R.
        • Foidart J.-M.
        The effects of progesterone on breast tissue.
        J. Fuer Menopause. 2001; 8: 14-18
        • Cline J.M.
        • Register T.C.
        • Clarkson T.B.
        Effects of tibolone and hormone replacement therapy on the breast of cynomolgus monkeys.
        Menopause. 2002; 9: 422-429
        • Valdivia I.
        • Campodónico I.
        • Tapia A.
        • Olivares M.
        • Espinoza A.
        Effect of two different continuous combined HRT regimes, tibolone 2.5 mg or CEE 0.625 mg + MPA 5 mg, on mammographic density and histological breast markers in postmenopausal women.
        Climacteric. 2002; 5: 50
        • Boyd N.F.
        • Lockwood G.A.
        • Byng J.W.
        • Tritchler D.L.
        • Yaffe M.J.
        Mammographic densities and breast cancer risk.
        Cancer Epidemiol. Biomarkers Prev. 1998; 7: 1133-1144
        • Palomba S.
        • Di Carlo C.
        • Morelli M.
        • Russo T.
        • Noia R.
        • Nappi C.
        • et al.
        Effect of tibolone on breast symptoms resulting from postmenopausal hormone replacement therapy.
        Maturitas. 2003; 45: 267-273
        • Valdivia I.
        • Ortega D.
        Mammographic density in postmenopausal women treated with tibolone, estriol or conventional hormone replacement therapy.
        Clin. Drug Invest. 2000; 20: 101-107
        • Egarter C.
        • Eppel W.
        • Vogel S.
        • Wolf G.
        A pilot study of hormone replacement therapy with tibolone in women with mastopathic breasts.
        Maturitas. 2001; 40: 165-171
        • Collaborative Group on Hormonal Factors in Breast Cancer
        Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52705 women with breast cancer and 108411 women without breast cancer.
        Lancet. 1997; 350: 1047-1059
        • Million Women Study Collaborators
        Breast cancer and hormone replacement therapy in the million women study.
        Lancet. 2003; 362: 419-427
        • Speroff L.
        The Million Women Study and breast cancer (editorial).
        Maturitas. 2003; 46: 1-6
        • Writing Group for the Women’s Health Initiative Investigators
        Risks and benefits of Estrogen plus Progestin in healthy postmenopausal women. principle results from WHI RCT.
        JAMA. 2002; 288: 321-333
        • The Women’s Health Initiative Steering Committee
        Effects of conjugated equine estrogen in postmenopausal women with hysterectomy.
        JAMA. 2004; 291: 1701-1712
        • Landgren M.B.
        • Coelingh Bennink HJT
        • Helmond F.A.
        • Engelen S.
        Dose-response analysis of effects of tibolone on climacteric symptoms. BJOG. 2002; 109: 1109-1114
        • Cosman F.
        • Lindsay R.
        Selective estrogen receptor modulators: clinical spectrum.
        Endo. Rev. 1999; 20: 418-434
      3. Jones MEE, Reutens AT, Boon WC, Erderveen AG, Kloosterboer HJ, Simpson ER. The aromatase knockout (Arko) mouse as a model to study the oestrogenic action of tibolone. Abstract 157. Proceedings of the 46th Annual Scientific Meeting of the Endocrine Society of Australia, Melbourne, 2003 p. 112.

        • Voelker W.
        • Coelingh Bennink HJT
        • Helmond F.
        Effects of tibolone on the endometrium.
        Climacteric. 2001; 4: 203-208
        • Simoncini T.
        • Genazzani A.R.
        Tibolone inhibits leukocyte adhesion molecule expression in human endothelial cells.
        Mol. Cell Endocrinol. 2000; 162: 87-94
        • Dubey R.K.
        • Gillespie D.G.
        • Groegli M.
        • Kloosterboer H.J.
        • Imthurm B.
        Tibolone and its metabolites induce antimitogenesis in human coronary artery smooth muscle cells: role of estrogen, progesterone and androgen receptors.
        J. Clin. Endocrinol. Metab. 2004; 89: 852-859