Abstract
Endometriosis is a chronic inflammatory disease. Pain is the most common symptom in endometriosis. Endometriosis-associated pain is caused by inflammation, and is related to aberrant innervation. Although the specific mechanism between endometriosis-associated pain and the interaction of aberrant innervation and inflammation remains unclear, many studies have confirmed certain correlations between them. In addition, we found that some chronic inflammatory autoimmune diseases (AIDs) such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) share similar characteristics: the changes in dysregulation of inflammatory factors as well as the function and innervation of the autonomic nervous system (ANS). The mechanisms underlying the interaction between the ANS and inflammation have provided new advances among these disorders. Therefore, the purpose of this review is to compare the changes in inflammation and ANS in endometriosis, IBD, and RA; and to explore the role and possible mechanism of sympathetic and parasympathetic nerves in endometriosis-associated inflammation by referring to IBD and RA studies to provide some reference for further endometriosis research and treatment.
Keywords: Endometriosis, Autonomic nervous system, Inflammation, Pain
Background
Endometriosis is an estrogen-dependent benign gynecological disease. Approximately 10% of reproductive-age women are affected by endometriosis worldwide. This disease is characterized by the presence of ectopic endometrial tissue outside of the uterine cavity [1, 2]. Ectopic endometrial tissues consist of glandular and stromal cells, macrophages, nerves, and blood vessels [3]. Even if the pathogenesis is unclear, endometriosis is certainly a chronic inflammation disorder [4]. The levels and concentrations of active macrophages; interleukin (IL)-1β, IL-6, IL-8; nerve growth factor (NGF); other immune cells; and inflammatory factors are increased in peritoneal fluid (PF) and endometriotic lesions [4–6]. These changes are believed to contribute to serious symptoms of pain such as chronic pelvic pain, dysmenorrhea, and dyspareunia [7]. Notably in deep infiltrating endometriosis (DIE) and intestinal endometriosis, the anatomical distribution of lesions is normally more closely related to pelvic pain symptoms [2]. Abnormal innervations are observed in most endometriotic lesions: an increased number of total intact nerve fibers, increased sensory and decreased sympathetic nerve fiber density (NFD) [6], the occurrence of cholinergic and unmyelinated nerve fibers, etc. [8] In various studies, these abnormal phenomena have been correlated with endometriosis associated pain [6, 8–10]. More importantly, sympathetic and parasympathetic systems have different inflammation-related effects in different stages of inflammation [10]. Many researchers have found that the function and innervation of the autonomic nervous system (ANS) are altered in chronic inflammatory AIDs [6], such as Crohn’s disease (CD) [11]. However, whether the inflammation induced by abnormal sympathetic and parasympathetic innervation has any effect on endometriotic lesions is unclear. The purpose of this review is to elaborate on the effects of sympathetic and parasympathetic nerve fibers on endometriosis-associated inflammation and to explain the underlying mechanism of action.
