Effects of tibolone metabolites on human endometrial cell lines in co-culture.

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 Delta(4)-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 3beta-OH-tibolone was abrogated by low doses of the progesterone receptor antagonist mifepristone. This suggests that 3beta-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 3beta-OH-tibolone back to tibolone. Thus, the unexpected progestagenic effect of 3beta-OH-tibolone in these co-cultures may be due to metabolic activity present in the stromal cells of the co-cultures.