Endometriosis-Related Chronic Pelvic Pain

Abstract

Endometriosis, which is the presence of endometrial stroma and glands outside the uterus, is one of the most frequently diagnosed gynecologic diseases in reproductive women. Patients with endometriosis suffer from various pain symptoms such as dysmenorrhea, dyspareunia, and chronic pelvic pain. The pathophysiology for chronic pain in patients with endometriosis has not been fully understood. Altered inflammatory responses have been shown to contribute to pain symptoms. Increased secretion of cytokines, angiogenic factors, and nerve growth factors has been suggested to increase pain. Also, altered distribution of nerve fibers may also contribute to chronic pain. Aside from local contributing factors, sensitization of the nervous system is also important in understanding persistent pain in endometriosis. Peripheral sensitization as well as central sensitization have been identified in patients with endometriosis. These sensitizations of the nervous system can also explain increased incidence of comorbidities related to pain such as irritable bowel disease, bladder pain syndrome, and vulvodynia in patients with endometriosis. In conclusion, there are various possible mechanisms behind pain in patients with endometriosis, and understanding these mechanisms can help clinicians understand the nature of the pain symptoms and decide on treatments for endometriosis-related pain symptoms.

Keywords: central sensitization; chronic pelvic pain; cross sensitization; endometriosis; inflammation; peripheral sensitization.

Figure 1

Involvement of macrophages and mast cells in the generation of pain associated with endometriosis. Macrophages can release inflammatory mediators including TNF-α, IL-6, IL-1β, and TGF–β, and nerve growth factors. Mast cells can release inflammatory cytokines including IL-2, IL-3, IL-6, IL-7, IL-9, IL-10, IFN-γ, TNF-α, and chemokines (CXCL8, CCL2, and CCL5) and nerve growth factor. These inflammatory mediators recruit neutrophils that induce angiogenesis, vasodilation, and vascular hyperpermeability. Mast cells can sensitize nociceptive neurons via releasing mediators such as leukotriene, histamine, tryptase, TNF-α, prostaglandins, and serotonin. Mediators released from macrophages, mast cells, and other inflammatory cells can activate their receptors ILR, TNFR, TrkA, CXC chemokine receptor, and C-C motif chemokine receptors expressed on the nociceptive neurons. NGF from mast cells and macrophages can increase the number of sensory neurons and expression of pain-related mediators such as substance P and calcitonin gene-related peptide. IL, interleukin; TNF, tumor necrosis factor; NGF, nerve growth factor; IFN, interferon; CXCL, C-C motif chemokine ligand; CCL, C-C motif chemokine ligand; IL1R, interleukin 1 receptor; TNFR, tumor necrosis factor receptor; TrkA, tropomyosin receptor kinase A; CXCR, CXC chemokine receptor; CCR, C-C motif chemokine receptor; TRPV, transient receptor potential vanilloid 1 cation channel subfamily V member; 5-HT3, 5-hydroxytryptamine receptor; H1R, istamine-1 receptor; NaV1.8, voltage-gated sodium ion channel subtype.

Figure 2

Peripheral, central, and cross-organ sensitization of the nervous system in patients with endometriosis. H-P-A, hypothalamus–pituitary–adrenal.