Exercise modulates estrogen receptors in a rat animal model of endometriosis

Abstract

Endometriosis, an estrogen dependent disease, is a gynecological disorder characterized by the growth of endometrial tissue outside the uterine cavity resulting in pain and discomfort. Estrogen plays an important role in the growth and persistence of endometriotic tissue along with inflammation. Estrogen receptor alpha (ERα) expression is significantly higher than estrogen receptor beta (ERβ) in normal endometrium. Endometriosis patients have increased abdominal fat which might contribute to a local endometriotic inflammatory environment characterized by infiltration of macrophages and secretion of proinflammatory cytokines. Furthermore, there is a dysregulation in this ratio, where lesions show increased expression of the ERβ and reduced expression of ERα. These receptors are also present in visceral fat and dysregulation of their function is known to correlate with increased adipose tissue. Preliminary data in our lab found increased mesenteric fat and serum leptin levels in endometriosis animals, which are decreased by exercise. However, it is still unclear how exercise modulates ER expression and whether it can improve endometriosis in an animal model.HypothesisVoluntary exercise can decrease endometriosis lesions through modulation of ERs, downregulating estrogen receptor beta, as well as macrophage infiltration in vesicles and mesenteric fat.MethodsEndometriosis (ENDO) was induced in female Sprague Dawley rats by the implantation of four pieces of uterine tissue next to the intestinal mesentery. The exercised endometriosis group (ENDO‐Ex) had access to a running wheel before and after surgery. After sixty days, rats were sacrificed; the developed vesicles were measured and collected with mesenteric fat for immunological staining of ERα, ERβ and macrophages. Hematoxylin and eosin staining was used for assessment of adipocyte morphology.ResultsA significantly reduced percentage of developed vesicles per rat (p<0.01), total vesicle area (p<0.01), and percentage of fat/body weight (p<0.001) was observed in ENDO‐Ex group when compared to ENDO group (n=10/group). A positive correlation between percentage of fat and vesicle size was found (p<0.01). Adipocyte size was also significantly reduced in the ENDO‐Ex group (p<0.05). Exercise produced an increase in ERα expression (p<0.01), while decreasing ERβ immune‐positive cells (p<0.01) and macrophage infiltration (p<0.05) in vesicles. A positive correlation between ERβ and number of macrophages was found in vesicles (p<0.01), with a similar pattern observed in the mesenteric fat. Furthermore, ERβ mRNA levels were significantly decreased in the exercise group (p<0.05), while no difference was shown in ERα.ConclusionsOur results suggest that voluntary exercise might protect against endometriosis and alleviate the associated symptomatology via impact on macrophage infiltration and modulation of ERs in vesicles and the adipose tissue. This offers the potential for further exploration of this complementary therapy in the patient population.