Progesterone acts to maintain uterine quiescence during pregnancy. In contrast to many other species, no decrease in maternal serum levels of progesterone can be observed in humans before the onset of labour. Therefore, a `functional' progesterone withdrawal in association with labour has been proposed. In humans the progesterone receptor (PR) exists in two isoforms, PR-A and PR-B. While PR-B generally mediates the effects of progesterone upon gene transcription, the role of PR-A during pregnancy, and in parturition, is unknown. In this study, term myometrium cells cultured before the onset of labour were transiently transfected with expression vectors for either PR-A or PR-B. Only those cells expressing PR-B significantly increased expression of a progesterone-sensitive reporter when stimulated with progesterone. Co-transfection of both isoforms of PR demonstrated that PR-A is a dominant repressor of transactivation in these cells. Western blot analysis showed that PR-A is present in human myometrium samples taken only after, but not before, the onset of labour. These data suggest that increased expression of PR-A in human myometrium may contribute to `functional' progesterone withdrawal and the initiation of human labour.