Heme induced progesterone-resistant profiling and promotion of endometriosis in vitro and in vivo

Endometriosis is an estrogen-dependent, progesterone-resistant gynecological disease with an unknown pathogenesis. Compared to women without endometriosis, women with endometriosis have a remarkably high heme level in the peritoneal fluid. To further investigate the pathomechanisms of heme in endometriosis, we aimed to identify the dysregulated expression of heme-trafficking proteins, such as PGRMC1/2 that are also receptors that mediate the non-genomic responses to progesterone, and heme-degrading enzymes between ectopic endometrial stromal cells and their normal counterparts. We found that heme could regulate progesterone receptor-related gene expression. Functional human endometrial stromal cell experiments showed that heme promotes cell proliferation and migration in a heme oxygenase-1-independent manner; moreover, blocking oxidative phosphorylation/ATP generation could abolish these effects of heme in vitro, whereas intraperitoneal hemopexin administration could alleviate heme-triggered ectopic lesions in vivo. Therefore, heme likely mediates the induction of progesterone resistance and simultaneously induces endometriosis via the mitochondrial oxidative phosphorylation pathway.