Modulation of Cytokine Production by the Dydrogesterone Metabolite Dihydrodydrogesterone

Problem Previous studies have shown that dydrogesterone, the orally administered progestogen, upregulates the production of Th2 cytokines and downregulates Th1 cytokine production. This study was designed to ascertain whether dihydrodydrogesterone (DHD), the major metabolite of dydrogesterone, is similarly capable of modulating cytokine production by peripheral blood mononuclear cells (PBMC) from women with a history of unexplained recurrent miscarriage. Method of Study Mitogen-stimulated PBMC from women with unexplained recurrent miscarriage were exposed to progesterone or dydrogesterone or DHD, and the levels of pro-inflammatory (IFN-gamma, TNF-alpha) and anti-inflammatory (IL-4, IL-10, IL-13) cytokines were estimated by ELISA. To ascertain whether DHD mediates its effects via the progesterone receptor, RU486, a progesterone agonist, was added to cultures along with mitogen and DHD. Results The metabolite DHD, like its parent molecule dydrogesterone, suppresses the production of the pro-inflammatory cytokines IFN- gamma and TNF-alpha and upregulates the production of the anti-inflammatory cytokine IL-4. The progesterone antagonist RU486 reverses the effect of DHD, suggesting that this molecule mediates its cytokine-modulating effect via the progesterone receptor. Conclusion Dihydrodydrogesterone retains the immunomodulatory effects of the progestogen dydrogesterone by bringing about a shift in cytokine production profiles that might be conducive to the success of pregnancy.