title: Peripheral changes in endometriosis-associated pain.
abstract: BACKGROUND
  Pain remains the cardinal symptom of endometriosis. However, to date, the underlying mechanisms are still only poorly understood. Increasing evidence points towards a close interaction between peripheral nerves, the peritoneal environment and the central nervous system in pain generation and processing. Recently, studies demonstrating nerve fibres and neurotrophic and angiogenic factors in endometriotic lesions and their vicinity have led to increased interest in peripheral changes in endometriosis-associated pain. This review focuses on the origin and function of these nerves and factors as well as possible peripheral mechanisms that may contribute to the generation and modulation of pain in women with endometriosis.
  
  
  METHODS
  We conducted a systematic search using several databases (PubMed, MEDLINE, EMBASE and CINAHL) of publications from January 1977 to October 2013 to evaluate the possible roles of the peripheral nervous system in endometriosis pathophysiology and how it can contribute to endometriosis-associated pain.
  
  
  RESULTS
  Endometriotic lesions and peritoneal fluid from women with endometriosis had pronounced neuroangiogenic properties with increased expression of new nerve fibres, a shift in the distribution of sensory and autonomic fibres in some locations, and up-regulation of several neurotrophins. In women suffering from deep infiltrating endometriosis and bowel endometriosis, in which the anatomical distribution of lesions is generally more closely related to pelvic pain symptoms, endometriotic lesions and surrounding tissues present higher nerve fibre densities compared with peritoneal lesions and endometriomas. More data are needed to fully confirm a direct correlation between fibre density in these locations and the amount of perceived pain. A better correlation between the presence of nerve fibres and pain symptoms seems to exist for eutopic endometrium. However, this appears not to be exclusive to endometriosis. No correlation between elevated neurotrophin levels and pain severity appears to exist, suggesting the involvement of other mediators in the modulation of pain.
  
  
  CONCLUSIONS
  The increased expression of neurotrophic factors and nerve fibres in endometriotic lesions, eutopic endometrium and the peritoneum imply a role of such peripheral changes in the pathogenesis of endometriosis-associated pain. However, a clear link between these findings and pain in patients with endometriosis has so far not been demonstrated.
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK Department of Obstetrics and Gynaecology, University of Genoa, Genoa 16100, Italy matteo.morotti@obs-gyn.ox.ac.uk.
authors.forename: Matteo
authors.initials: M
authors.lastname: Morotti
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Katy
authors.initials: K
authors.lastname: Vincent
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brawn
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Becker
mesh_terms: D001202:Ascitic Fluid / Q000502:physiology; D004715:Endometriosis / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D004717:Endometrium / Q000098:blood supply / Q000294:innervation; D005260:Female; D006801:Humans; D009389:Neovascularization, Pathologic / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D009412:Nerve Fibers / Q000473:pathology; D055495:Neurogenesis / Q000502:physiology; D010146:Pain / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology
keywords: Endometriosis; nerve fibres; neuroangiogenesis; neurotrophins; peripheral changes