Progestogenic effects of tibolone on human endometrial cancer cells.
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.
Blok
L J
LJ
Department of Reproduction and Development, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands. Blok@endov.fgg.eur.nl
De Ruiter
P E
PE
Kühne
E C M
EC
Hanekamp
E E
EE
Grootegoed
J A
JA
Smid-Koopman
E
E
Gielen
S C J P
SC
De Gooyer
M E
ME
Kloosterboer
H J
HJ
Burger
C W
CW
D002455:Cell Division / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005353:Fibronectins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D009652:Norpregnenes / Q000378:metabolism / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000032:analysis; D014407:Tumor Cells, Cultured
D005353:Fibronectins; D018972:Insulin-Like Growth Factor Binding Protein 3; D009652:Norpregnenes; D011372:Progestins; D011980:Receptors, Progesterone; D011374:Progesterone; D017258:Medroxyprogesterone Acetate; C027385:tibolone