Perioperative Intervention by β-Blockade and NF-κB Suppression Reduces the Recurrence Risk of Endometriosis in Mice Due to Incomplete Excision

Despite the demonstrated efficacy of surgical treatment of endometriosis, recurrence after surgery still remains a formidable challenge. Surgery, especially when performed repeatedly, decreases ovarian reserve. Clearly, control of recurrence is an unmet medical need. So far nearly all efforts to control recurrence have been devoted to the identification of risk factors, biomarkers, and postoperative medication. One area that has been completely overlooked is the possibility of perioperative intervention. In this study, we tested the hypothesis that perioperative use of a nonspecific β-blocker and/or a nuclear factor-κB (NF-κB) inhibitor can retard the growth of residual endometriotic lesions that are left intact in the primary surgery. We established a mouse model of recurrence due to incomplete lesion removal by deliberately leaving residual lesions intact in the primary excision surgery. One hour before and 24 hours after the surgery, mice were either untreated or treated with andrographolide, propranolol, or both. Two weeks after the primary surgery, all mice were sacrificed and all lesions were excised and evaluated for immunohistochemistry analysis. We found that perioperative use of andrographolide and/or propranolol significantly decelerated the growth of residual lesions that were intentionally left out during the primary surgery. The perioperative intervention also significantly attenuated the generalized hyperalgesia resulting from the presence of residual lesions. It also inhibited the activation of the adrenergic receptor β2 signaling, resulting in reduced angiogenesis, epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation as well as NF-κB suppression and progesterone receptor isoform B induction. These data strongly suggest that perioperative use of β-blockers and/or NF-κB inhibitors may reduce the risk of recurrence in endometriosis.