In considering the potential of known reproductive hormones to act as immunoregulatory substances during pregnancy, progesterone clearly is an attractive candidate for the following reasons: 1) progesterone is a primitive hormone occurring in virtually all species; 2) it is the only hormone which has been shown to be absolutely essential for maintenance of pregnancy in a variety of mammals, including the human; 3) it has demonstrable in vivo and in vitro immunosuppressive effects when present in concentrations known to be present in the human placenta; 4) it has weak systemic effects compared to cortisol; 5) in many species including primates, it is produced by trophoblastic cells: potential targets of the maternal immune system. Inhibitory effects of progesterone on immune cells have been demonstrated despite the absence of classical steroid receptors for progesterone (Lippman 1979). Specific functions of human T-lymphocytes and macrophages are inhibited by concentrations of progesterone known to occur in the placenta (10 (-6)-10 (-5) M). Although similar effects are produced by cortisol, clear-cut differences exist in the mechanisms by which cortisol and progesterone act on immune cells. The results suggest, but do not prove, that progesterone does not act on immune cells by binding to the glucocorticoid receptor. This can be considered to be advantageous, for otherwise pregnancy could be associated with glucocorticoid toxicity. Remarkable local anti-inflammatory activity of progesterone has been observed in vivo, although the mechanism of this effect is poorly understood. The striking absence of inflammatory cells in the pregnant uterus until a few days before birth is consistent with known effects of progesterone from animal studies. Whether this regulatory effect on cell traffic is exerted directly by progesterone or by secondary mediators produced within the uterus remains to be determined. In either case, appropriate timing of the removal of progesterone's influence may constitute an integral part of the process of parturition. Post-partum resolution of the placental attachment-site has many of the cellular characteristics of transplant rejection. Furthermore, it has recently been proposed that inflammatory cells which invade the cervix may generate prostaglandins which mediate the biochemical changes that are essential for its dilation to allow escape of the fetus (Liggins 1981). If the processes begin prior to delivery as a consequence either of progesterone withdrawal or inhibition of its activity, parturition may in fact be considered as a delayed rejection process.(ABSTRACT TRUNCATED AT 400 WORDS)