Distinct immunomodulatory effects of synthetic progestins compared with natural progesterone in human immune cells

Progesterone exerts important immunomodulatory functions, yet the immune effects of structurally diverse synthetic progestins remain incompletely defined. Given their variable receptor-binding profiles and links to altered inflammatory outcomes, we examined how commonly used progestins regulate immune signaling in primary human cells. Peripheral blood mononuclear cells from healthy female donors were exposed to physiologically relevant concentrations of natural progesterone (P4) and representative synthetic progestins spanning multiple generations. Cytokine responses were quantified at both the protein and transcript levels. Baseline steroid receptor expression and age of donor was correlated with cytokine output. High-dimensional flow cytometry coupled with unsupervised clustering was used to define the cellular sources of inflammatory cytokine production. In parallel, naïve CD4+ T-cell differentiation was performed to determine effects on T helper (Th) cell polarization. Only P4 induced immunoregulatory cytokine IL-10, whereas all progestins, except first-generation norethindrone, induced markedly higher IL-6 production compared with media control. Gene expression analysis confirmed induction of multiple proinflammatory genes at physiologically relevant concentrations. High-dimensional flow cytometry identified CD14+ monocytes as the dominant cellular source of IL-6 following progestin exposure. In contrast, P4 selectively suppressed Th1 differentiation and promoted Th2 lineage commitment, whereas synthetic progestins failed to reproduce these immunoregulatory effects. Together, these findings demonstrate that synthetic progestins differentially regulate innate and adaptive immune responses compared with P4 and promote proinflammatory responses that may influence immune homeostasis.