In human endometrium, cell proliferation is regulated by ovarian steroids through heterotypic interactions between stromal and epithelial cells populating this tissue. The authors test the proliferative effects of tibolone and its metabolites using endometrial co-cultures that mimic the normal proliferative response to hormones. They found that both the Δ4-tibolone metabolite and the pure progestin ORG2058 counteract estradiol-driven epithelial cell proliferation. Surprisingly, the estrogen receptor binding 3-hydroxyl-metabolites of tibolone also counteracted estradiol-driven proliferation. Inhibition of proliferation by 3β-OH-tibolone was abrogated by low doses of the progesterone receptor antagonist mifepristone. This suggests that 3β-OH-tibolone is converted to a progestagenic metabolite. The authors found that the stromal cells used in the co-cultures express high levels of the ketosteroid dehydrogenase AKR1C2, which is able to oxidize 3β-OH-tibolone back to tibolone. Thus, the unexpected progestagenic effect of 3β-OH-tibolone in these co-cultures may be due to metabolic activity present in the stromal cells of the co-cultures.
Arnold JT, Kaufman DG, Seppala M., Lessey BAEndometrial stromal cells regulate epithelial cell growth in vitro: a new co-culture model. Hum Reprod. 2001;16(5):836-845.
2.
Barbier CS, Becker KA, Troester MA, Kaufman DGExpression of exogenous human telomerase in cultures of endometrial stromal cells does not alter their hormone responsiveness. Biol Reprod . 2005;73(1):106-114.
3.
Modelska K., Cummings S.Tibolone for postmenopausal women: systematic review of randomized trials . J Clin Endocrinol Metab.2002;87(1):16-23.
4.
Bruce D., Robinson J., Rymer J.Long-term effects of tibolone on the endometrium as assessed by bleeding episodes, trans-vaginal scan and endometrial biopsy. Climacteric. 2004;7(3): 261-266.
5.
Timmer CJ, Houwing NSDose proportionality of three different doses of tibolone. Pharmacotherapy. 2002;22(1):6-13.
6.
de Gooyer ME , Deckers GH, Schoonen WG, Verheul HA, Kloosterboer HJReceptor profiling and endocrine interactions of tibolone. Steroids . 2003;68(1):21-30.
Steckelbroeck S., JinY, Oyesanmi B, Kloosterboer HJ, Penning TM. Tibolone is metabolized by the 3α/3β-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a δ5(10)-3-ketosteroid. Mol Pharmacol.2004; 66(6):1702-1711.
9.
Nishida M., Kasahara K., Kaneko M., Iwasaki H., Hayashi K.Establishment of a new human endometrial adenocarcinoma cell line, Ishikawa cells, containing estrogen and progesterone receptors [in Japanese] . Nippon Sanka Fujinka Gakkai Zasshi. 1985 ;37(7):1103-1111.
10.
Arnold JT, Lessey BA, Seppala M., Kaufman DGEffect of normal endometrial stroma on growth and differentiation in Ishikawa endometrial adenocarcinoma cells. Cancer Res.2002;62(1):79-88.
11.
Groothuis PG , De Gooyer ME, ten Kate J., et al. Tibolone and metabolites induce prolactin production in human endometrial stromal cells in vitro: evidence for cell-specific metabolism. J Steroid Biochem Mol Biol.2006 ;100(4-5):152-160.
12.
Penning TM, Burczynski ME, Jez JM, et al. Human 3αhydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones . Biochem J.2000; 351(pt 1):67-77.
13.
Pierro E., Minici F., Alesiani O., et al. Stromal-epithelial interactions modulate estrogen responsiveness in normal human endometrium. Biol Reprod. 2001;64(3):831-838.
14.
Genazzani AR , Benedek-Jaszmann LJ, Hart DM, Andolsek L., Kicovic PM, Tax L.Org OD 14 and the endometrium . Maturitas.1991;13(3):243-251.
15.
Volker W., Coelingh Bennink HJ, Helmond FAEffects of tibolone on the endometrium. Climacteric.2001;4(3):203-208.
16.
Markiewicz L. , Gurpide E.In vitro evaluation of estrogenic, estrogen antagonistic and progestagenic effects of a steroidal drug (Org OD-14) and its metabolites on human endometrium. J Steroid Biochem.1990;35(5):535-541.
17.
Schatz F., Kuczynski E., Kloosterboer HJ, et al.Tibolone and its metabolites enhance tissue factor and PAI-1 expression in human endometrial stromal cells: evidence of progestogenic effects . Steroids. 2005;70(12):840-845.
18.
Schatz F., Kuczynski E., Kloosterbooer L., et al.Tibolone exerts progestational inhibition of matrix metalloproteinase expression in human endometrial stromal cells. Steroids. 2006;71(9): 768-775.
19.
Zhang W., Mazella J., Kloosterboer HJ, Tseng L.Progestagenic effects of tibolone are target gene-specific in human endometrial cells. J Soc Gynecol Investig. 2006;13(6):459-465.
20.
Hanifi-Moghaddam P., Gielen SC, Kloosterboer HJ, et al. Molecular portrait of the progestagenic and estrogenic actions of tibolone: behavior of cellular networks in response to tibolone. J Clin Endocrinol Metab.2005 ;90(2):973-983.
21.
Edwards DP, Altmann M., DeMarzo A., Zhang Y., Weigel NL, Beck CAProgesterone receptor and the mechanism of action of progesterone antagonists . J Steroid Biochem Mol Biol. 1995;53(1-6):449-458.
22.
Ouellet M., Percival MDEffect of inhibitor time-dependency on selectivity towards cyclooxygenase isoforms. Biochem J.1995;306(pt 1):247-251.
23.
Steckelbroeck S., Oyesanmi B., Jin Y., Lee SH, Kloosterboer HJ, Penning TMTibolone metabolism in human liver is catalyzed by 3α/3β-hydroxysteroid dehydrogenase activities of the four isoforms of the aldo-keto reductase (AKR)1C subfamily . J Pharmacol Exp Ther.2006;316(3): 1300-1309.
