Endometrial cell proliferation and cell death are regulated by ovarian hormones. The fall of ovarian progesterone in late secretory phase, or the artificial withdrawal of ovarian hormones during early pregnancy, are followed by programmed cell death of uterine epithelial cells. Aspects of this cell-specific response have been reproduced in a newly established rat endometrial cell line which expresses functional progesterone receptor. At low concentrations of serum and in the absence of glucocorticoids, these cells were dependent on progestins for survival. Removal of progesterone or addition of the antiprogestins RU38486 or ZK98299 led to a substantial increase of apoptotic cells indicated by the accumulation of internucleosomally degraded DNA. The hormonal control of cell proliferation and cell death correlated with the overall quantity and distribution of the different bcl-X transcripts. Progesterone administration not only increased total bcl-X mRNA level but also shifted the quantitative ratio between the different mRNA isoforms in favor for the apoptosis inhibiting form, bcl-XL, compared with the apoptosis promoting form, bcl-XS. These effects were rapid and could not be prevented by inhibitors of protein synthesis. As the low level of bcl-2 and bax mRNA was not influenced by progesterone treatment, the observed changes in total amount of bcl-X transcripts and spliced isoforms could represent the mechanism by which progesterone controls cell death in epithelial cells of the endometrium.