Meclizine Improves Endometrial Repair and Reduces Simulated Menstrual Bleeding in Mice with Induced Adenomyosis

Background Adenomyosis is one of the structural causes of abnormal uterine bleeding, which often presents as heavy menstrual bleeding (HMB). Mostly due to poor understanding of its pathophysiology, medical management of adenomyosis-induced HMB is still a challenge. We have previously reported that glycolysis is crucial to endometrial repair following menstruation and that suppressed glycolysis can cause HMB. Objective(s) To test the hypothesis that meclizine, a drug with excellent safety profile, alleviates HMB in mice with induced adenomyosis using a simulated menstruation model. Study Design Adenomyosis was induced in 36 female C57BL/6 mice using endometrial-myometrial interface disruption. Three months after induction, the mice were randomly divided into three groups: low- and high-dose meclizine, and controls. Treatment with meclizine or vehicle started shortly before the simulated menstruation procedure and ended before progesterone withdrawal. The amount of blood loss was quantitated and uterine tissue was harvested for histological evaluation of the grade of endometrial repair. We performed immunohistochemistry analysis of 4 proteins critically involved in glycolysis, namely glucose transporter 1 (Glut1), hexokinase 2 (Hk2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3) and pyruvate kinase 2 (Pkm2). The extent of tissue fibrosis in both ectopic and eutopic endometrium was evaluated using Masson trichrome staining. Results In mice with induced adenomyosis, meclizine accelerated endometrial repair in a dose-dependent manner and reduced the amount of menstrual bleeding. Meclizine administration raised endometrial immunoexpression of Hk2 and Pfkfb3 but not of Glut1 or Pkm2.The extent of endometrial fibrosis was reduced following the meclizine administration. Remarkably, these favorable changes were accompanied with suppression of lesional progression, as evidenced by the dose-dependent reduction in the extent of fibrosis (a surrogate for lesional progression). Conclusion(s) These encouraging results, taken together, suggest that glycolysis may be a promising therapeutic target and that meclizine may hold a therapeutic potential as a non-hormonal treatment for adenomyosis-induced HMB without exacerbating the disease.