Original Report| Volume 17, ISSUE 1, P1-13, January 2016

Functional Connectivity Is Associated With Altered Brain Chemistry in Women With Endometriosis-Associated Chronic Pelvic Pain

  • Sawsan As-Sanie
    Address reprint requests to Sawsan As-Sanie, MD, MPH, Department of Obstetrics and Gynecology, University of Michigan Health System, L4100 Women's Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109.
    Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan
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  • Author Footnotes
    1 Permanent address: Korea Institute of Oriental Medicine, Daejeon, Korea.
    Jieun Kim
    1 Permanent address: Korea Institute of Oriental Medicine, Daejeon, Korea.
    Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts
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  • Author Footnotes
    2 Permanent address: Department of Neurology, BG Universitätsklinikum Bergmannsheil, Ruhr Universität Bochum, Bochum, Germany.
    Tobias Schmidt-Wilcke
    2 Permanent address: Department of Neurology, BG Universitätsklinikum Bergmannsheil, Ruhr Universität Bochum, Bochum, Germany.
    Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan Health Center, Ann Arbor, Michigan
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  • Pia C. Sundgren
    Department of Radiology, University of Michigan, Ann Arbor, Michigan
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  • Daniel J. Clauw
    Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan Health Center, Ann Arbor, Michigan
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  • Vitaly Napadow
    Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts
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  • Richard E. Harris
    Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan Health Center, Ann Arbor, Michigan
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  • Author Footnotes
    1 Permanent address: Korea Institute of Oriental Medicine, Daejeon, Korea.
    2 Permanent address: Department of Neurology, BG Universitätsklinikum Bergmannsheil, Ruhr Universität Bochum, Bochum, Germany.
Published:October 05, 2015DOI:


      • Chronic pelvic pain is a symptom in some, but not all, women with endometriosis.
      • The mechanism by which only some women with endometriosis experience pain is not understood.
      • Endometriosis-associated pelvic pain was associated with altered brain chemistry and function.
      • These differences were not identified in a pain-free endometriosis subgroup.
      • Central nervous system changes likely contribute to the mechanism of endometriosis pain.


      In contrast to women with relatively asymptomatic endometriosis, women with endometriosis-associated chronic pelvic pain (CPP) exhibit nonpelvic hyperalgesia and decreased gray matter volume in key neural pain processing regions. Although these findings suggest central pain amplification in endometriosis-associated CPP, the underlying changes in brain chemistry and function associated with central pain amplification remain unknown. We performed proton spectroscopy and seed-based resting functional connectivity magnetic resonance imaging to determine whether women with endometriosis display differences in insula excitatory neurotransmitter concentrations or intrinsic brain connectivity to other pain-related brain regions. Relative to age-matched pain-free controls, women with endometriosis-associated CPP displayed increased levels of combined glutamine-glutamate (Glx) within the anterior insula and greater anterior insula connectivity to the medial prefrontal cortex (mPFC). Increased connectivity between these regions was positively correlated with anterior insula Glx concentrations (r = .87), as well as clinical anxiety (r = .61, P = .02), depression (r = .60, P = .03), and pain intensity (r = .55, P = .05). There were no significant differences in insula metabolite levels or resting-state connectivity in endometriosis patients without CPP versus controls. We conclude that enhanced anterior insula glutamatergic neurotransmission and connectivity with the mPFC, key regions of the salience and default mode networks, may play a role in the pathophysiology of CPP independent of the presence of endometriosis.


      Similar to other chronic pain conditions, endometriosis-associated pelvic pain is associated with altered brain chemistry and function in pain processing regions. These findings support central pain amplification as a mechanism of chronic pelvic pain, and clinicians should consider the use of adjunctive therapies that target central pain dysfunction in these women.

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