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Mechanisms and Treatment of Endometriosis Associated Pain
INTRODUCTION
Endometriosis is a common, benign gynecologic disease which is characterized by the presence of uterine endometrial tissue outside of the uterus [63]. The prevalence of pelvic endometriosis is 6–10% in the general female population, up to 70% in women with pelvic pain and more than 80% if they have both pelvic pain and subfertility [45,71,81,130].
The pain symptoms most commonly attributed to endometriosis are dysmenorrhoea, dyspareunia, dysuria, dyschesia, painful gastrointestinal symptoms (such as colicky pains and irritable bowel-type symptoms), and chronic pelvic pain [56,104]. Nerve entrapment pain is a relatively rare type of endometriosis associated pain. It occurs as a result of anatomical nerve distortion by active, fibrotic lesions, especially around the sciatic and obturator nerves [93,117]. It is also postulated that nerve entrapment occurs in the complex fibrous and hypertrophic deep invasive endometriotic lesions in the recto-vaginal septum, where distortion of nerve trunks appears to occur [7], moreover adhesions can play a role in painful symptoms [69,82].
BASIC ASPECTS
Endometriosis associated pain is pelvic pain that occurs in the presence of laparoscopically confirmed endometriosis. Although the association of pain and endometriosis is widely accepted by gynecologists, the mechanisms involved in endometriosis associated pain remains unclear. The cause of pain in endometriosis is likely multifactorial, however, critical, common pathways or mechanisms may exist [55].
The most commonly suggested mechanisms for pain production in endometriosis are; production of substances such as growth factors and cytokines, the effects of active bleeding from endometriotic implants, and irritation or direct invasion of pelvic floor nerves by infiltrating endometriotic implants, especially in the cul-de-sac [111,112,119]. There is evidence that more elusive mechanisms such as neuroangiogenesis, nociceptive, or neuropathic mechanisms contribute to endometriosis associated pain [9,69,70].
These mechanisms may explain why pain relief for more than 6 months occures in only 40% to 70% of affected women treated with conventional medical or surgical therapies [9]. They may also explain the poor correlation between the extent or morphological characteristics of endometriosis and the intensity and character of the pain symptoms [15,64,78,82,88,91,100,101,116,138]. This chapter discusses these mechanisms as well as current and future treatment modalities.
DESCRIBING THE SUBJECT
Cyclical Bleeding Within Lesions
Ectopic endometriotic lesions retain their endocrine responsiveness and undergo episodes of intraperitoneal bleeding during menstruation. This is supported by the observation of visible intraperitoneal bleeding when laparoscopy is performed during menses and by the presence of localized hemorrhage and hemosiderin-laden macrophages in lesions examined microscopically [9].
Cyclic recurrent micro-bleeding occurs as a common feature in all macroscopic entities of endometriosis [31]. It may explain the reason for severe dysmenorrhoea related to endometriosis and the fact that women with deeply infiltrating endometriosis (DIE) have the most severe dysmenorrhoea [41].
Cyclical bleeding within the implants is believed to result in a chronic inflammatory nidus that causes pelvic pain, such bleeding may explain why medical therapies such as progestins, danazol, and GnRHa that induce amenorrhea are partially effective in the relief of this symptom [9].
Immune and Inflammatory Factors
Endometriosis is described as a pelvic inflammatory process with altered immune cells function and increased number of activated macrophages in the peritoneal environment that secrete various mediators including, growth factors and cytokines [1,128]. Endometriotic lesions themselves secrete pro-inflammatory cytokines such as interleukin-8 (IL-8), which recruit macrophages and T cells to the peritoneum mediating inflammatory responses. The concentration of some chemokines such as monocyte chemoattractant protein 1(MCP-1) is increased in the peritoneal fluid of patients [63].
The evidence for IL-6 is inconsistent. Increased concentrations of IL-6 have been found in peritoneal fluid of women with endometriosis in some studies but not in others [113,115].
Concentrations of tumor necrosis factor (TNF) in peritoneal fluid are higher in women with endometriosis than those with normal pelvic anatomy [52]. It has been suggested that TNF is one of the essential factors for the pathogenesis and maintenance of endometriosis and its role in chronic pain is well documented [34,134]. The concentrations of cytokines in peritoneal fluid however, do not correlate with pain symptoms or severity of endometriosis [107].
There is little doubt that immune cells play important roles in pain generation in endometriosis. It was shown that macrophage numbers and function are greatly modified in, ectopic lesions, peritoneal fluid and eutopic endometrium of women with endometriosis [20,65]. Macrophages cause symptoms by releasing inflammatory substances such as ILs and transforming growth factors (TGFs) [153]. There is also a direct relationship between the numbers of macrophages and the density of nerve fibers in ectopic lesions [153] and in peritoneal endometriotic lesions is much higher than in normal peritoneum [148]. The nerve endings of these fibres can be stimulated by many inflammatory substances, such as histamine, serotonin, bradykinin, prostaglandins (PGs), leukotrienes, ILs, vascular endothelial growth factor (VEGF), tumor necrosis factor- alpha (TNF-alpha), epidermal growth factors, TGF-beta, platelet-derived growth factor (PDGF) and nerve growth factor (NGF) which are secreted from macrophages and endometriotic lesions [7,22] and are proposed to contribute to the generation of pain in endometriosis [148].
Moreover, there is substantial disturbance in the numbers of immature and mature dendritic cells in eutopic endometrium and in the ectopic lesions in women with endometriosis [120,121]. It was stated that macrophages and their products may play important roles in the growth and repair of nerve fibres rather than only stimulating nerve fibre endings to induce pain. Nerve fibre growth is regulated by many substances, including NGF, brain derived neurotropic factor (BDNF) and VEGF [7]. Their synthesis is also affected by macrophage activities. NGF is released from endometriotic lesions and many other cell types including macrophages. It is important in the development of the peripheral and central nervous systems (CNS). The synthesis of NGF can be up-regulated by IL-1 and basic fibroblast growth factor (FGF), both of which can increase the content of NGF mRNA up to 6-fold in astrocytes [16,87,137,158]. BDNF, another neurotrophin has a crucial role for the growth and differentiation of the peripheral system and is secreted from activated macrophage also the synthesis of BDNF, NGF and NGF receptors were up-regulated by estrogens [29,44,60,83,90,125].
Recent studies have demonstrated that VEGF produced by macrophages can act as a neurotrophic factor stimulating the growth of nerve fibres and the peritoneal fluid from women with endometriosis contains a greater concentration of VEGF than that of controls [61,114]. These studies suggest that VEGF may also play a role in increased nerve fibre density of peritoneal endometriotic lesions.
Other studies show that macrophages are essential during nerve fibre regeneration in the peripheral nervous system. It has been demonstrated that when peripheral nerve fibres are injured, macrophages invade the distal stump of damaged nerve fibres within 1 day, secrete growth factors with neurotropic properties to regenerate nerve fibres and induced Schwann cell proliferation [67]. Sensory nerve fibre regeneration is impaired when macrophage invasion is delayed [32].
Increased numbers of activated and degranulating mast cells have been found near endometriotic lesions, often close to nerve fibres [8]. In endometriosis patients activated mast cells were also shown to be abundant on the myometrial side, but in very low density in the endometrium [3]. Also mast cells produce a variety of degranulation products such as NGF that may activate and/or sensitize primary nociceptive neurons [30,53,127–129,146,163]. NGF functions as a chemoattractant for mast cells, but it can also trigger mast cell degranulation [8,139].
NGF interacts with two specific receptors: TRK-A (a high affinity receptor) and p75 (a low affinity receptor). These receptors are barely detectable in normal endometrium, but are both intensely expressed in nerve fibers and stroma in eutopic endometrium and in the stroma of ectopic lesions. This up-regulation of neurotrophin and its receptors can be a potent stimulus to branching and ingrowth of new nerve fibers [56].
Irritation and Invasion of Pelvic Nerves
Currently the most popular thesis explaining endometriosis associated pain is irritation or direct invasion of pelvic floor nerves by infiltrating implants, particularly in the cul-de-sac via secretion of matrix-degrading enzymes and acquired migratory behaviour of endometriotic cells [7,123]. Patients with the highest preoperative pain scores displayed the highest density of nerve encapsulation within endometriotic lesions and more frequent perineurial and endoneurial invasion by endometriotic cells than patients with lower preoperative pain scores [6].
Visceral Nociceptors
Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage [97]. Pain signals in sensory nerve fibers are generated through receptors called nociceptors [37]. These receptors are responsive to ‘noxious’ stimuli that have the potential to do harm and the potential to trigger a reflex response. They respond to excessive pressure, excessive stretch, inflammatory processes and a range of injurious chemical substances. They send signals which initiate the sensation of pain. These signals are processed in the dorsal root ganglia and the lower spinal cord, before onward transmission of a modified signal to the thalamus, limbic system and higher centres, where pain is perceived and the emotional response developed [56].
Nociceptors are found in most tissues, including the viscera including the uterus and cervix [23,24,36,54,151]. They are present in high densities in both the functional and basal layers of the endometrium of women with endometriosis, virtually none are found in the endometrium of women without endometriosis [25,26,28,147] and are also noted in ectopic endometriotic lesions [27,91,147]. It was shown that ectopic endometriotic implants developed a sensory and sympathetic nerve supply both in rats and in women [26,27]. There is a correlation between nerve fibre density in endometriotic lesions and pain severity [95]. It was demonstrated that nociceptors invaded peritoneal endometriotic lesions in women and also found invading endometriotic cysts in experiments on rats [26,27,148].
Pelvic nociceptors in adjacent organs are strongly stimulated by NGF and prostaglandin E2 [18,110]. Expression of NGF in endometriotic tissue is reported to be higher than in eutopic endometrium [7,148]. NGF plays a key role in the occurrence of pain, hyperalgesia, and neuropathic pain. NGF is strongly expressed in deep infiltrating endometriosis and its specific receptor (Trk-A) is expressed in nerves lying within deep lesions or in the vicinity of deep endometriotic lesions [7]. They are significantly sensitized by estrogen and can be regulated by molecules secreted from immune competent cells, such as mast cells, macrophages, dendritic cells, neutrophils, natural killer cells and plasma cells [56].
Neuropathic Pain
Neuropathic pain is increasingly recognized as a significant component of persistent endometriosis pain [62]. Neuropathic pain arises from damage to peripheral or central nerve fibers, resulting in erratic or persistent axonal discharges. These persistent stimuli can set up abnormal neural circuits at a spinal cord or central level resulting in persistent, prolonged or intermittent signals to the central processing and perception centres. This may lead to persistent perception of pain long after the original stimulus has been removed [56].
Neuropathic pain is usually accompanied by a nerve injury such as invasion of the brachial plexus in Pancoast’s syndrome. This phenomenon occurs in deep infiltrating endometriosis where nerve invasion by endometriotic stromal cells is frequently observed [6]. Repeated surgery may cause damage to nerve fibers and especially repeated damage may trigger persistent, abnormal discharges from these damaged and regenerating pelvic and endometriotic nerve fibers, leading to the development of neuropathic pain [56].
Neuropathic pain symptoms can also be induced by inflammatory stimuli in the absence of nerve injury [38,53]. Macrophages and neutrophils release algesic mediators such as prostaglandin E2, eicosanoids, and reactive oxygen intermediates, which can sensitize nociceptors and induce hyperalgesia [85,89,109,143,152]. Histamine is a key mediator released by activated mast cells which can sensitize nociceptors [66,99]. Neuronal histamine receptors are upregulated or modulated by nerve injury [17,74]. Histamine also plays a critical role in leukocyte recruitment after mast cell activation [162]. Activated mast cells contribute directly to neuropathic hyperalgesia by releasing other mediators such as tryptase, TNF-alpha, PGs, serotonin, and IL-1 [72,127,128,131–133,141,152,154].
There is cumulative evidence that mast cells play an important role in the pathogenesis of chronic pain and neuropathic pain in many pathological conditions [49,66,89,99,109,146]. Mast cells release mediators that increase excitability of neurons, and neurotransmitters such as substance P or NGF can trigger mast cell degranulation [76].
Women with deep infiltrating endometriosis experience exacerbation of pain when pressure is exerted on deep nodular or indurated lesions at physical examination. This phenomenon of exquisite pain from a non-painful stimulus is called hyperalgesia, which is a major characteristic of neuropathic pain. It is a pain sensation that is out of proportion with the intensity of nociceptors stimulation [30]. Sympathetic and classical sensory nerve fibers contribute to hyperalgesia [164]. It was shown that the peritoneum of women with endometriosis are rich in sympathetic nerve fibers. Increased excitability of viscero-visceral convergent neurons to the spinal cord are associated with persistent neuropathic pain and hyperalgesia [14].
Generalized hypersensitivity has been demonstrated earlier in women with fibromyalgia, primary dysmenorrhea and pelvic pain during pregnancy [12,13,84]. Central hyperexcitability of the nociceptive system has been demonstrated in patients with chronic pain [11,14,79,135]. The nociceptive barrage from endometriotic tissue might also cause central hyperexcitability of dorsal horn neurons [25,59]. This central hyperexcitability might cause pelvic pain aggravated during menstruation and persist after medical or surgical ablation of the endometriotic tissue. Bajaj et al demonstrated an increased muscle nociceptor input in the form of increased post-saline pain intensity. They also showed that there are pain areas at the first dorsal interosseous muscle (FDI) of the hand, and hypersensitivity to pressure in women with endometriosis central sensitization was increased [14].
It is not yet clear how the central hyperexcitability is maintained. Evidences suggest that noxious stimuli from peripheral tissue damage sensitize central mechanisms involved in pain perception which causes alterations in central nervous system function and subsequent pain experience [42]. Muscle hyperalgesia and hyperexcitability of dorsal horn neurons might be induced by a decrease in the efficacy of the descending antinociceptive system, central sensitization due to long-lasting activation of receptive fields, or heterotopic facilitation caused by active nociceptive fibers outside the receptive fields [156].
NEUROANGIOGENESIS
The endometrium has intrinsic angiogenic potential, and endometriotic lesions tend to grow in areas with rich vascularization, suggesting that angiogenesis is a prerequisite for endometriosis development [103]. Angiogenesis is important not only for implant establishment but also for supporting ongoing lesion growth and progression [47,72,103]. In several rodent models of endometriosis, it was noted that treatment with antiangiogenic drugs reduced the surface area or volume of the endometriotic lesions. These findings indicate that a continuous angiogenic process is required for survival of the lesion after implantation [4,72,103].
Peripheral nerves track alongside blood vessels in discrete neurovascular bundles. Recent elucidation of developmental mechanisms of embryonic neurovascular patterning provides evidence for a direct link between neurogenesis and angiogenesis [80,160]. It was hypothesized that neuroangiogenesis provided innervation and engraftment of refluxed endometrial fragments [9,145]. The patterning and branching of vessels and nerves are shown to be molecularly linked with signals from each influencing the migration of the other. Ligand-receptor pairs implicated in axonal and vessel guidance include ephrins and their Eph receptors, slit ligands and their roundabout (Robo) receptors, semaphorins and their plexin and neuropilin receptors, and netrins and their DCC/neogenin and Unc5 receptors [9].
Ephrin A1 mRNA transcripts were reduced in endometrium of women with endometriosis compared to women without endometriosis [73]. In a recent study higher expression of Slit and Robo1 proteins and increased microvascular density were observed in cases of endometrioma recurrence [124]. SemaphorinE (also referred as semaphorin 3c) is upregulated in the endometrium of women with endometriosis [73]. Class 3 semaphorins bind to neuropilinplexin receptor complexes on the axonal surface membranes of neurons and endothelial cells and stimulate cell migration [98]. The neuropilins, also described as semaphorin receptors have nanomolar affinities for vascular endothelial growth factor (VEGF) isoforms and can mediate angiogenesis [9].
Other factors may coordinate the close physical association between larger nerves and vessels. Nerve-derived VEGF is essential for the formation of arteries in skin [102]. Secretoneurin, a neuropeptide expressed in nerve fibers that are found in close apposition to blood vessels, stimulates endothelial cell migration and angiogenesis in vitro and in vivo assays [77]. This protein has been identified in capsaicin-sensitive C-afferent nerve fibers in rat endometrium, although loss-of-function studies are not yet available to definitively assign its role [43].
Vessels also provide cues for the growth and alignment of adjacent nerves. The blood vessel–derived artemin protein, a member of the glial cell–derived neurotrophic factor (GDNF) family of ligands, acts as a guidance factor for the growth of sympathetic nerve fibers along blood vessels in a variety of mouse tissues, including the gastrointestinal tract [9,68]. Knockouts of artemin or its preferred receptor GFRα cause severe defects in the migration and axonal projection of sympathetic neurons but not other types of neurons. Artemin expression in endometriosis is unknown; but artemin appears to increase cancer cell migration and invasiveness in the endometrium [108].
NGF, FGF, BDNF and neurotrophin-3 are all expressed by endometrial cells. However, only the latter two proteins appear to be quantitatively upregulated in women with endometriosis [33]. Growth-associated protein 43, a marker of neural outgrowth and regeneration, is expressed in endometriosis-associated nerve fibers but not in existing peritoneal nerves. The fibers appear to sprout from para- and perivascular nerve fibers that accompany the blood vessels [95].
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