The effect of progesterone and synthetic progestins on serum- and estradiol-stimulated proliferation of human breast cancer cells.

The results from the Women's Health Initiative study on enhanced breast cancer risk in postmenopausal women using an estrogen/progestin combination clearly indicate the need for a comparison of different progestins with regard to cancer risk. To shed some light on this issue, we have investigated the influence of progesterone and various synthetic C19- and C21-progestins on cell proliferation of a human breast cancer cell line in vitro. Of special interested was the comparison of two different regimens commonly used in HRT, sequential and continuous combination with estradiol. We used the human breast cancer cell line MCF-7 as a model. Progesterone (P), chlormadinone acetate (CMA), dienogest (DNG), gestodene (GSD), 3-ketodesogestrel (KDG), levonorgestrel (LNG), medroxyprogesterone acetate (MPA), and norethisterone (NET) were investigated in the range of 0.01nm to 10 micro M alone and in combination with 10 nM estradiol. Cell proliferation was measured after 7 days using the ATP chemosensitivity test. Tested alone, CMA, DNG, GSD, KDG, MPA and NET significantly stimulated cell proliferation, but only at high dosages. Sequentially combined with estradiol, only CMA inhibited cell proliferation over the whole concentration range. Slight effects were found for DNG, GSD and KDG, whereas P and MPA only showed an effect at the highest concentration. NET had no significant effect on cell proliferation. Continuously combined, all progestins exhibited an inhibitory effect over the whole concentration range. The most prominent effects were found for P, CMA, GSD, and KDG. Only slight effects were found for DNG, MPA and NET. Our in vitro results indicate that the influence on breast cancer risk using HRT in postmenopausal women might depend on the type of progestin used as well as on the regimen applied. However, the net inhibitory in vitro effect of the progestins at clinically relevant dosages is rather minimal, and whether progestins in general can reduce breast cancer risk in long-term treatment remains uncertain. Further clinical trials are urgently needed to clarify this issue.