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Pathophysiology of endometriosis-associated pain: A review of pelvic and central nervous system mechanisms

https://doi.org/10.1016/j.bpobgyn.2018.01.014Get rights and content

Highlights

  • There are changes in the periphery, which are associated with endometriosis-associated pain.

  • Central changes also occur in endometriosis-associated pain.

  • The use of the characteristics of the pain experienced has led to useful discoveries.

Abstract

Although pain is one of the main symptoms women with endometriosis present with, there is poor correlation between symptom severity and disease burden and the underlying biological mechanisms by which pain arises are still only poorly understood. We briefly review the neurobiology of pain before considering mechanisms that may be specifically relevant in the context of endometriosis. The role of pelvic factors such as new nerve fibre growth, peritoneal fluid and inflammation is explored with a particular focus on studies where these factors have been associated with pain symptoms rather than just being compared between women with endometriosis and disease-free controls. We then consider the role of the central nervous system and associated systems, including the stress axis and psychological factors, in the modulation of pain. The potential for changes in these systems to be a cause and/or a consequence of the pain and how they might explain some of the known associations between endometriosis and other somatic symptoms is discussed. The chapter concludes by considering the implications of these mechanisms on treatment strategies for these women.

Introduction

Pelvic pain is the commonest presenting symptom of endometriosis. Chronic pelvic pain (i.e. pain perceived to originate in the pelvis lasting for longer than 6 months [1]) and endometriosis are often comorbid but each can exist without the other. For example, it is described that up to 82% of women with chronic pelvic pain have endometriosis [2], but it is also well known that some women with endometriosis experience no pain at all [3]. Furthermore, the relationship between pain and the extent/location/type of endometriosis found at laparoscopy (as measured using rAFS [4]) is much more complex than might be expected [5], [6].

In this review, we will consider mechanisms in the pelvis (periphery) and the central nervous system (central), which may contribute to the generation and/or maintenance of pain in women with endometriosis. Whilst we focus on evidence from the literature on endometriosis, we also focussed parallel on studies with other conditions associated with chronic pain. Finally, we discuss what this means looking forward to the future, both in terms of treatment regimens and research in endometriosis-associated pain.

Section snippets

What is pain?

Before we specifically consider endometriosis-associated pain, it is important to understand pain more generally. Pain is defined as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’ [7]. Pain is a very complex, subjective experience and is thus difficult to pin down; however, it can be described both in terms of the mechanism(s) by which it arises and by the location/triggers of the pain. For definitions of

Nerve fibres & the autonomic nervous system

As described above, nerves are responsible for conveying nociceptive signals from the periphery to the brain. Therefore, it is logical to try to determine whether, in patients with pain, there is a change to these nerves, which could lead to alterations in the signals the brain is receiving about nociception. Alterations in the structure or function of peripheral nerves have been demonstrated in a variety of conditions associated with chronic pain (e.g. osteoarthritis [24], painful

Brain function

There is a very large body of work that shows that there are changes in brain function associated with chronic pain. The most commonly used techniques to investigate brain function in pain are functional MRI (fMRI) and PET imaging. These both give an indirect measurement of activity, as they measure metabolic activity (which increases in active areas), as opposed to electrical activity. One problem with neuroimaging studies that investigate the response to a noxious stimulus is the

Summary

In this chapter, we have reviewed evidence for mechanisms by which endometriosis-associated pain may arise. The key mechanisms discussed are summarised in Fig. 2, which pulls together different factors that influence the perception of endometriosis-associated pain.

We have presented evidence showing changes in the periphery during endometriosis, which includes changes in the nerve growth in the pelvis such as increased sensory nerve fibre growth and decreased sympathetic nerve fibre growth.

Conflicts of interest

Lydia Coxon has no conflicts of interest. Andrew Horne receives grant funding from Ferring and research support from Roche. Katy Vincent receives grant funding from Bayer Healthcare and has received fees for consultancy and honoraria for conference presentations from Bayer HealthcareBayer HealthCare, Grunenthal GmBH and AbbeVie.

References (97)

  • B. McKinnon et al.

    Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations

    Fertil Steril

    (2012)
  • S. Capellino et al.

    Chapter 1 neuroendocrine immune control mechanisms and their influence on autoimmune disease

  • T. Tulandi et al.

    Nerve fibers and histopathology of endometriosis-harboring peritoneum

    J Am Assoc Gynecol Laparoscopists

    (2001)
  • S. Mechsner et al.

    A pilot study to evaluate the clinical relevance of endometriosis-associated nerve fibers in peritoneal endometriotic lesions

    Fertil Steril

    (2009)
  • R.Y. Walder et al.

    TRPV1 is important for mechanical and heat sensitivity in uninjured animals and development of heat hypersensitivity after muscle inflammation

    Pain

    (2012)
  • N.A. Bersinger et al.

    PAPP-A and osteoprotegerin, together with interleukin-8 and RANTES, are elevated in the peritoneal fluid of women with endometriosis

    Am J Obstet Gynecol

    (2006)
  • S. Tamburro et al.

    Expression of transforming growth factor β1 in nerve fibers is related to dysmenorrhea and laparoscopic appearance of endometriotic implants

    Fertil Steril

    (2003)
  • K. Vincent et al.

    Dysmenorrhoea is associated with central changes in otherwise healthy women

    Pain

    (2011)
  • C.H. Tu et al.

    Abnormal cerebral metabolism during menstrual pain in primary dysmenorrhea

    Neuroimage

    (2009)
  • S. As-Sanie et al.

    Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study

    Pain

    (2012)
  • T. Frodl et al.

    How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans

    Neurobiol Dis

    (2013)
  • E. Fries et al.

    A new view on hypocortisolism

    Psychoneuroendocrinology

    (2005)
  • K. Wiech et al.

    The influence of negative emotions on pain: behavioral effects and neural mechanisms

    Neuroimage

    (2009)
  • C. Berna et al.

    Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness

    Biol Psychiatr

    (2010)
  • M. Fairhurst et al.

    Anticipatory brainstem activity predicts neural processing of pain in humans

    Pain

    (2007)
  • P. Schweinhardt et al.

    Investigation into the neural correlates of emotional augmentation of clinical pain

    Neuroimage

    (2008)
  • J.A. Turner et al.

    Catastrophizing is associated with pain intensity, psychological distress, and pain-related disability among individuals with chronic pain after spinal cord injury

    Pain

    (2002)
  • R.J. Smeets et al.

    Reduction of pain catastrophizing mediates the outcome of both physical and cognitive-behavioral treatment in chronic low back pain

    J Pain

    (2006)
  • M.A.W. van Aken et al.

    Pain cognition versus pain intensity in patients with endometriosis: toward personalized treatment

    Fertil Steril

    (2017)
  • Q. Aziz

    Complementary alternative medicine and autonomic nervous system and functional bowel disorders

    Auton Neurosci

    (2013)
  • J.J. Thompson et al.

    Autonomic functioning during REM sleep differentiates IBS symptom subgroups

    Am J Gastroenterol

    (2002)
  • A.D. Farmer et al.

    Psychophysiological responses to pain identify reproducible human clusters

    Pain

    (2013)
  • I. Chen et al.

    An evaluation model for a multidisciplinary chronic pelvic pain clinic: application of the RE-AIM framework

    J Obstet Gynaecol Can

    (2015)
  • A.P. Baranowski et al.

    Taxonomy of pelvic pain

    (2012)
  • A.J. Mao et al.

    Diagnosis and management of endometriosis: the role of the advanced practice nurse in primary care

    J Am Acad Nurse Pract

    (2010)
  • A. Fauconnier et al.

    Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications

    Hum Reprod Update

    (2005)
  • Revised american society for reproductive medicine classification of endometriosis: 1996

    Fertil Steril

    (1997)
  • P. Vercellini et al.

    Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients

    Hum Reprod

    (2007)
  • I. Tracey

    Finding the hurt in pain

    Cerebrum

    (2016)
  • R. Melzack

    From the gate to the neuromatrix

    Pain

    (1999)
  • F. Denk et al.

    Neurobiological basis for pain vulnerability: why me?

    Pain

    (2017)
  • A. May

    Structural brain imaging: a window into chronic pain

    Neuroscientist

    (2011)
  • C.J. Woolf

    Central sensitization: implications for the diagnosis and treatment of pain

    Pain

    (2011)
  • G. Pongratz et al.

    The sympathetic nervous response in inflammation

    Arthritis Res Ther

    (2014)
  • L.H. Whitaker et al.

    An exploratory study into objective and reported characteristics of neuropathic pain in women with chronic pelvic pain

    PLoS One

    (2016)
  • D.J. Clauw

    Fibromyalgia: a clinical review

    J Am Med Assoc

    (2014)
  • P. Stratton et al.

    Association of chronic pelvic pain and endometriosis with signs of sensitization and myofascial pain

    Obstet Gynecol

    (2015)
  • P.I. Mapp et al.

    Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis

    Nat Rev Rheumatol

    (2012)
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