Suffering in Silence

 

Endometriosis-associated pain is a complex condition that is traditionally difficult to treat, as the mechanisms of initiation and persistence seem to be, well in all fairness, all over the place. Dysmenorrhea, cyclical pain related to organ function, and persistent pelvic pain are all common symptoms of the condition. In words you may be more familiar with - severe cramps, painful bladder, painful urination or bowel movements and painful sex.

This pain often does not correlate with the extent of disease, some women can have little pain in severe cases, others agonizing pain and have the initial stages of endometriosis.

The various components of endometriosis-associated pain, such as peripheral sensitization, central sensitization, and cross sensitization, all of which are triggered by different factors. Peripheral sensitization is caused by inflammation or tissue damage, while central sensitization is caused by changes in the central nervous system. Cross sensitization occurs when pain is transferred from one area of the body to another.

All of these systems are activated by endometriosis via various pathways. These factors make the sensation of Endometriosis-associated Pain multi-faceted and further complicated by the complexity of endometriotic lesion development and the diversity of lesion placements.

However, factors that should always be highlighted include the alteration of pelvic nerve fibers, inflammation, secreted factors, and anything that drives neuronal growth. Additionally, how these painful stimuli are relayed.

If one highlights these important factors you naturally flow into the next concepts.

endometriosis-peritoneal-cavity

The peritoneal and visceral tissues are highly innervated with sensory, sympathetic, myelinated, and unmyelinated nerve fibers, presynaptic vesicles, and neuropeptides that can all sense pain, pressure, touch, friction, cutting, and temperature. In addition, here, there is a high presence of cytokines, angiogenic factors, and nerve growth factors that, when in presence of endometriotic lesions, can and does trigger inflammation and pain.

While it has been previously thought that the shedding of endometriotic lesions is cyclical and related to changes in the eutopic endometrium, recent research suggests that this may not always be the case. It is essential to recognize the heterogeneity of endometriotic lesions to better comprehend the complexity of Endometriosis-associated pain and its treatment. (This is why a multi-faceted approach to combating the condition is a must.)

 

Sensory Receptors, Neuronal Circuits for Processing Information - The  Nervous System: A. General Principles and Sensory Physiology - Guyton and  Hall Textbook of Medical Physiology, 12th Ed

The nerve endings in the peritoneal fluid can detect painful stimuli. Endometriosis lesions are a source of inflammation, cytokines, angiogenic factors, and nerve growth factors. The inflammatory components found in the peritoneal fluid and the lesions have been studied to assess if they can spark nociceptive pathways.

These components include interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), regulated upon activation, normal T cell expressed and secreted chemokine ligand 5 (CCL5) and tumor necrosis factor alpha (TNF-α), and chemokines including monocyte chemotactic protein 1 [chemokine ligand 2 (CCL2)]. These components have been found to be increased in the peritoneal fluid of endometriosis patients.

In the traditionally sense, it is also known that, like the endometrial tissue, most endometriosis lesions have cyclic bleeding in response to the shifts in estrogen and progesterone during the menstrual cycle. This generally does cause inflammation and pain, however, in cases of endometriosis the overall peripheral pain sensitization is augmented.

The result is generally associated with changes in the peripheral nervous system, including altered nerve density at lesion sites, changes in the peritoneal fluid, perineural invasion, and alterations in the sympathetic nervous system.

Significant nerve fiber density increases in endometriotic lesions compared to normal tissue have been demonstrated, and increased density of calcitonin gene-related peptide positive nerve fibers in lesions is associated with pain severity. Neurotrophins and other growth factors are increased in the peritoneal fluid of women with endometriosis. This increases perineural invasion which is associated with higher pain scores, dysmenorrhea, dyspareunia, persistent pelvic pain, sciatica and unilateral leg pain.

Central sensitization is also an issue when addressing endometriosis referred pain. Central sensitization refers to increased excitability of nociceptive neurons in the dorsal horn of the spinal cord in response to noxious stimuli, tissue injury or nerve damage, leading to decreased pain threshold, increased pain response and central facilitation.

Women with endometriosis demonstrate hyperalgesia, that is an increased sensitivity to feeling pain and an extreme response to pain, when compared to healthy pain-free controls.

Functional MRI has demonstrated increased resting-state connectivity between pain processing regions in women with Endometriosis-associated pain compared to those who have to healthy controls. Women with dysmenorrhea also have increased activation of pain processing regions and reduced levels of cortisol.

The hypothalamic-pituitary-adrenal (HPA) axis may be affected due to the presence of central sensitization. Those with ongoing pain show changes in the HPA axis, which has an effect on their reaction to pain. Research has shown that women with endometriosis have lower levels of cortisol than those without pain. The HPA axis is typically activated by stress in the short-term, but chronic exposure can lead to a decrease in its response.

This has been hypothesized to cause maladaptation of converging pain pathways, contributing to increased pain severity. In addition to its own mechanisms, endometriosis-associated pain can be complicated by a number of comorbid pain conditions, such as bladder pain syndrome, irritable bowel syndrome, abdomino-pelvic myalgia, and vulvodynia. These conditions can further contribute to the already complex pain mechanisms of endometriosis-associated pain.

The complexities of endometriosis-associated pain and the mechanisms responsible for its onset and maintenance make it a difficult condition to treat. This article explains the basic methodology and mechanisms of Endometriosis-associated pain and points out key concepts that need to be targeted. It is evident that peripheral sensitization, central sensitization, and cross-sensitization are therapeutic objectives to consider. It is important for clinicians to consider the biological, psychological, and social aspects of Endometriosis-associated pain in individual cases, and to detect the presence of other comorbid pelvic pain syndromes.

 

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