Pain in Endometriosis

Abstract

Endometriosis is a chronic and debilitating condition affecting ∼10% of women. Endometriosis is characterized by infertility and chronic pelvic pain, yet treatment options remain limited. In many respects this is related to an underlying lack of knowledge of the etiology and mechanisms contributing to endometriosis-induced pain. Whilst many studies focus on retrograde menstruation, and the formation and development of lesions in the pathogenesis of endometriosis, the mechanisms underlying the associated pain remain poorly described. Here we review the recent clinical and experimental evidence of the mechanisms contributing to chronic pain in endometriosis. This includes the roles of inflammation, neurogenic inflammation, neuroangiogenesis, peripheral sensitization and central sensitization. As endometriosis patients are also known to have co-morbidities such as irritable bowel syndrome and overactive bladder syndrome, we highlight how common nerve pathways innervating the colon, bladder and female reproductive tract can contribute to co-morbidity via cross-organ sensitization.

Keywords: chronic pelvic pain; hyperalgesia; inflammation; neuroangiogenesis; peripheral sensitization; sensory afferents; uterus; vagina.

FIGURE 1

Schematic overview of an enhanced immune response leading to chronic pelvic pain in endometriosis. Endometrial fragments in the peritoneum, originating from the uterus during retrograde menstruation, lead to the production and build-up of iron, reactive oxygen species (ROS), prostaglandins (PGE₂) and acidosis in the peritoneal fluid (peritoneal inflammation). This immune response is also seen at lesions sites throughout the peritoneal cavity, where the increased production of cytokines, chemokines, growth factors and neutrophils also contribute to an enhanced inflammatory environment present in the peritoneal cavity of women with endometriosis (lesion inflammation). Of these inflammatory mediators, PGE₂, tumor necrosis factor α (TNFα), nerve growth factor (NGF), RANTES and interleukins (IL) IL-8 and IL-1β are able to directly activate sensory nerve endings and activate a positive feedback loop, further increasing proinflammatory modulator production (neurogenic inflammation). The enhanced stimulation and activation of peripheral nerve endings in the peritoneal cavity (peripheral sensitization) increases the painful stimuli transmitted to the spinal cord, initiating and maintaining chronic pelvic pain (central sensitization).

FIGURE 2

Schematic overview of the sensory innervation of the colon, bladder and uterus/vagina allowing for cross organ sensitization. The colon is innervated by spinal afferents within the splanchnic and pelvic pathways. These spinal afferents can travel via the splanchnic or pelvic nerves (with some afferents traversing the hypogastric nerve) and have cell bodies located within the thoracolumbar and lumbosacral dorsal root ganglia (DRG). The bladder is also innervated by both splanchnic and pelvic pathways (de Groat et al., 2015). The central terminals of colon and bladder afferents terminate within the dorsal horn of the thoracolumbar and lumbosacral dorsal horn (Harrington et al., 2012, 2019; Grundy et al., 2018). Afferents innervating the uterus and vagina also share the splanchnic and pelvic pathways, whilst the vagina is also innervated by the pudendal nerves, with cell bodies within the lumbosacral DRG and central terminals within the lumbosacral dorsal horn (Berkley, 2005). The central terminals of colon, bladder, uterus and vaginal afferents synapse onto second order dorsal horn neurons in the spinal cord, which ultimately transmit signals to the brain. Accordingly, these different visceral organs share common nerve pathways to the DRG and spinal cord, allowing the potential for cross-organ sensitization. TL, Thoracolumbar; LS, Lumbosacral; IMG, Inferior Mesenteric Ganglion; MPG, Major Pelvic Ganglion.