W120 - Immune Modulation by Synthetic Progestins: Exploring Inflammatory Responses and Hormonal Interactions

Abstract Text: Synthetic progestogens (progestins) used in hormonal contraceptives can have unintended side effects, including a heightened risk of autoimmune diseases. Research has shown that second-generation synthetic progestin levonorgestrel is linked with increased susceptibility to multiple sclerosis (MS), a CNS inflammatory disease. This study hypothesized that progestins, commonly used in contraceptives, may predispose individuals to inflammatory diseases, potentially exacerbating conditions such as MS. PBMCs from 24 healthy female and 6 healthy male participants were exposed to natural progesterone (P4) and various synthetic progestins at physiological doses: first-generation (norethindrone), second-generation (norgestrel, levonorgestrel), third-generation (norgestimate), and fourth-generation (drospirenone). Inflammatory cytokines were assessed using ELISA and quantitative PCR. Norgestrel, levonorgestrel, and drospirenone significantly increased IL-6 production in PBMCs from female subjects compared to P4, but this effect was not observed in males. The modulation of IL-6 by progestins, specifically levonorgestrel and drospirenone, was also validated at the mRNA level in a subset of samples. While P4 suppressed IL-6 production in PMA/ionomycin-stimulated PBMCs, confirming its anti-inflammatory ability, synthetic progestins failed to replicate this effect, underscoring their pro-inflammatory potential. Further investigation revealed differential effects on the expression of progesterone, androgen, and mineralocorticoid receptors in response to progestins and P4 in female PBMCs. In conclusion, our findings suggest that progestins have inflammatory potential with significant implications for conditions like MS as well as other autoimmune/inflammatory diseases. Further research with a larger cohort is currently underway to validate these findings and elucidate the mechanisms underlying these responses.