Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications

Abstract

Background: Many clinicians and patients believe that endometriosis-associated pain is due to the lesions. Yet causality remains an enigma, because pain symptoms attributed to endometriosis occur in women without endometriosis and because pain symptoms and severity correlate poorly with lesion characteristics. Most research and reviews focus on the lesions, not the pain. This review starts with the recognition that the experience of pain is determined by the central nervous system (CNS) and focuses on the pain symptoms.

Methods: Comprehensive searches of Pubmed, Medline and Embase were conducted for current basic and clinical research on chronic pelvic pain and endometriosis. The information was mutually interpreted by a basic scientist and a clinical researcher, both in the field of endometriosis. The goal was to develop new ways to conceptualize how endometriosis contributes to pain symptoms in the context of current treatments and the reproductive tract.

Results: Endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the CNS. This engagement provides a mechanism by which the dynamic and hormonally responsive nervous system is brought directly into play to produce a variety of individual differences in pain that can, in some women, become independent of the disease itself.

Conclusions: Major advances in improving understanding and alleviating pain in endometriosis will likely occur if the focus changes from lesions to pain. In turn, how endometriosis affects the CNS would be best examined in the context of mechanisms underlying other chronic pain conditions.

Figure 1

This figure illustrates how endometrial lesions can engage the nervous system to give rise to different types of pain associated with endometriosis and co-morbid conditions. Part 1: This part of the diagram depicts the usual laparoscopic view of pelvic organs (seen by inserting the laparoscope at the umbilicus looking towards the reproductive organs) in which a deeply infiltrating lesion on the left uterosacral ligament is expanded in the inset. Both peptidergic sensory (blue) and sympathetic nerve fibers (green) sprout axon branches (red dashed lines) from nerve fibers that innervate nearby blood vessels to innervate this lesion. Sensory fibers that sprouted new axons become sensitized (red asterisk). The extent of sensitization is dynamically-modulated by estradiol and sympathetic-sensory coupling. Part 2: Two-way connection between innervated lesions and spinal cord is concentrated within sacral segments of the pelvic region. Sensitized peripheral nerve fibers, in turn, sensitize spinal sacral segment neurons. This ‘central sensitization’, shown by the red asterisk in the sacral segment, can become independent of and is modulated differently from peripheral sensitization, described in the text. Part 3: Although input from peripheral afferent fibers to the spinal cord via their dorsal roots is concentrated in the segment associated with the body part the fibers innervate (sacral segments), branches of the fibers extend to other segments (blue dashed lines). Normally, these dorsal root branches have minimal impact on neurons in other segments unless the fibers become sensitized. If, however, the fibers become sensitized, they can in turn sensitize neurons in the other segments. Such remote actions are depicted byred dashed branches into the lumbar, thoracic and cervical spinal cord dorsal horn and the red asterisks at those levels. Part 4: Normally, multiple intersegmental spinal connections exist to coordinate healthy bodily functions via excitatory and inhibitory synaptic connections, shown by double-arrowed black lines. This intersegmental communication can influence how central sensitization modifies how neurons in remote segments process nociceptive and non-nociceptive sensory information (‘remote central sensitization’), shown as red asterisks. Together, actions in Parts 3 and 4 can lead to increased nociception not only at sacral entry segments but also in any other segment. Part 5: Multiple connections exist that ascend from every level of the spinal cord to the brain (shown by blue lines) and descend from the brain to the spinal cord (shown by green lines). Thus, in health, input from the spinal cord engages neurons throughout the brain that themselves are interconnected via complex ascending and descending inhibitory/excitatory synapses. Input from sensitized spinal neurons can affect activity throughout the neuroaxis, altering normal processing of nociceptive and non-nociceptive information. Some regions that can be influenced are depicted by red asterisks. Although asterisks are shown on the medial surface of the cortex, some influenced areas extend to parts of the lateral prefrontal, frontal, parietal lobes and within the temporal lobe (dotted black ellipses). These influences can become independent of peripheral sensitization associated with lesions’ innvervation (Part 1). Such actions provide mechanisms for different types of endometriosis-associated and co-morbid pain, not only in the pelvis, but also elsewhere.