Long-term progestin treatment inhibits RANTES (regulated on activation, normal T cell expressed and secreted) gene expression in human endometrial stromal cells

RANTES (regulated on activation, normal T cell expressed and secreted) is synthesized by endometrial and endometriotic stromal cells and circulates in peritoneal fluid. Reports indicate that medroxyprogesterone acetate (MPA) is clinically effective in alleviating pelvic pain in the majority of endometriosis patients, which leads us to hypothesize that MPA may be antiinflammatory. Prolonged treatment (8 d) with MPA resulted in 36% and 50% decreases in luciferase activity and RANTES protein production, respectively, whereas shorter treatment (2 or 4 d) with MPA had no significant effect. We also observed that 8 d of MPA increased PR expression. Both effects were blocked by RU486. Cotransfection of endometrial stromal cells with PR enhanced the effects mediated by endogenous PR. In addition, its action via progesterone response element cis-elements, PR appeared to inhibit trans-activation of a nuclear factor-kappaB-responsive element, further suppressing RANTES expression. These studies indicate that prolonged progestin exposure down-regulates endometrial RANTES gene transcription in vitro. The effect is PR dependent and mediated in part through a nuclear factor-kappaB pathway. The clinical effectiveness of chronic progestin treatment in endometriosis-associated pelvic pain may be attributed to its inhibition of RANTES production and its suppression of inflammatory responses in the pelvis.