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Cited by 259Endometriosis Research and TreatmentMast cells and histaminePlant and fungal interactions

Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis

Open access
Anaf, Vincent, Chapron, Charles, El Nakadi, Issam, De Moor, Veronique, Simonart, Thierry, Noël, Jean-Christophe·2006·Fertility and Sterility
DOI 10.1016/j.fertnstert.2006.03.057
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Abstract

Objective To detect and quantify mast cells in peritoneal, ovarian, and deep infiltrating endometriosis and to study the relationship between mast cells and nerves in endometriosis. Design Prospective histological and immunohistochemical study. Setting University of Brussels, Belgium. Patient(s) Sixty-nine women undergoing laparoscopic excision of endometriosis for pain. Thirty-seven biopsies of normal tissue were obtained from women without endometriosis. Intervention(s) Excision of endometriosis from different anatomical locations. Main outcome measure(s) Immunohistochemistry with chymase and tryptase to confirm the presence of mast cells and activated mast cells, respectively, in endometriotic lesions. Quantification of mast cells, activated mast cells, and degranulating mast cells in the different locations of endometriosis. Study of the relationship between mast cells and nerves by quantifying mast cells located less than 25 mum from nerves immunohistochemically stained with S-100 protein. Preoperative pain score evaluation by visual analogue scales. Result(s) Patients with deeply infiltrating lesions had significantly higher preoperative pain scores than patients with peritoneal or ovarian endometriosis. Mast cells and degranulating mast cells are significantly more abundant in endometriotic lesions than in nonaffected tissues. Deep infiltrating lesions show a significantly higher number of mast cells, activated mast cells, and mast cells located Conclusion(s) The prese…

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Written from the paper’s full text.

TL;DR

This prospective immunohistochemical study compared mast cell populations and their proximity to nerves across peritoneal, ovarian, and deep infiltrating endometriosis, alongside preoperative pain scores. Deep infiltrating lesions had more mast cells, activated and degranulating mast cells, and mast cells near nerves, and patients with these lesions reported higher pain, suggesting mast cells may contribute to endometriosis-related pain and hyperalgesia.

Key findings

  • Patients with deep infiltrating endometriosis had higher preoperative pain scores than those with peritoneal or ovarian endometriosis: dysmenorrhea 9 ± 1 vs 5 ± 3, deep dyspareunia 9 ± 1 vs 4 ± 1.5, and rectalgia 8 ± 1 vs 3 ± 1 (P<.001).
  • Endometriotic lesions contained significantly more chymase-positive mast cells than unaffected tissues across all studied locations, and deep infiltrating lesions had significantly more than peritoneal or ovarian lesions (P<.001).
  • Tryptase-positive (activated) mast cells were significantly more numerous in endometriotic lesions than controls in all locations (P<.001) except peritoneal and uterosacral lesions, where the difference was not significant; deep infiltrating lesions generally had more than peritoneal or ovarian lesions, except uterosacral vs ovarian.
  • Mast cells located <25 µm from nerves were significantly more abundant in endometriotic lesions than controls, and deep infiltrating lesions had significantly more than peritoneal or ovarian lesions (P<.001). Degranulating mast cells were also significantly increased in endometriotic lesions, with deep infiltrating lesions showing more than peritoneal lesions (P<.001) but not more than ovarian lesions.

Methods

  • Prospective histological and immunohistochemical study at the University of Brussels. Sixty-nine women with pain underwent laparoscopic or laparotomy excision of endometriosis from peritoneum (n=15), ovary (n=11), uterosacral ligaments (n=15), vaginal Douglas pouch (n=12), and rectosigmoid (n=16). Thirty-seven control biopsies came from women without endometriosis: peritoneum (n=7), ovary (n=8), vaginal (n=6), uterosacral ligament (n=8), and large bowel (n=8).
  • Tissues were fixed, paraffin-embedded, stained with hematoxylin and eosin and toluidine blue, and processed with immunohistochemistry for chymase, tryptase, and S-100 protein. Mast cells were counted by two blinded investigators in at least 20 randomly selected high-power fields; proximity to nerves was defined as <25 µm. Preoperative pain was assessed by mailed visual analogue scales for dysmenorrhea, deep dyspareunia, and rectalgia.
  • Comparisons of mast cell counts used Student’s t-test with Bonferroni correction; pain scores between deep infiltrating and non-deep infiltrating groups were compared with the nonparametric Wilcoxon signed rank test.

Limitations

  • The paper does not include a dedicated limitations section.
  • Evident from the text: the observational design cannot establish that mast cells cause pain or hyperalgesia; the findings are associations.
  • Evident from the text: control biopsies came from women undergoing different procedures (tubal ligation, hysterectomy for leiomyomas, or colectomy for rectosigmoid adenocarcinoma), which may limit comparability, and subgroup sample sizes were modest (ranging from 6 to 16 per location).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.fertnstert.2006.03.057

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 37 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Deep infiltrating lesions contain significantly more degranulating mast cells than peritoneal endometriosis.

    “Deep infiltrating lesions contain significantly more degranulating mast cells than peritoneal endometriosis (PϽ.001) but not more than ovarian endometriotic lesions (Table 4).”
    Quote in the paperSubstantial claim
  • Findingown data

    Patients with deep infiltrating endometriosis had significantly higher preoperative pain scores than patients with peritoneal or ovarian endometriosis.

    “Patients with deeply infiltrating lesions had significantly higher preoperative pain scores than patients with peritoneal or ovarian endometriosis.”
    • Also stated in: § Pain Evaluation · plain
      “Patients with deep infiltrating endometriosis had significantly higher pain scores than patients without deep infiltrating endometriosis (PϽ.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    Deep infiltrating lesions contain significantly more mast cells located <25 μm from nerves than peritoneal and ovarian endometriosis.

    “Deep infiltrating lesions contain significantly more mast cells in close relationship with nerves than peritoneal and ovarian endometriosis (PϽ.001) (Table 4).”
    Quote in the paperSubstantial claim
  • Findingown data

    Endometriotic lesions contain significantly more tryptase-positive mast cells located <25 μm from nerve structures than unaffected tissues.

    “Endometriotic lesions contain significantly more tryptasepositive mast cells (activated) located Ͻ25 m from nerve structures than the unaffected tissues (Table 2; Fig. 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Endometriotic lesions contain significantly more mast cells than nonaffected tissues.

    “Mast cells and degranulating mast cells are significantly more abundant in endometriotic lesions than in nonaffected tissues.”
    • Also stated in: § DISCUSSION · plain
      “In this study, we found a significantly greater number of mast cells in endometriotic lesions (Fig. 3) than in controls, which is consistent with previous findings in peritoneal and ovarian endometriosis (18,23,24).”
    Quote in the paperSubstantial claim
  • May combine two claims. 10
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    Deep infiltrating lesions contain significantly more tryptase-positive mast cells than peritoneal and ovarian endometriosis, except between uterosacral lesions and ovarian lesions.

    “Deep infiltrating lesions contain significantly more tryptase-positive mast cells than peritoneal and ovarian endometriosis except between uterosacral lesions and ovarian lesions (Table 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The mean preoperative pain scores for patients with peritoneal and ovarian endometriosis were 5 ± 3 for dysmenorrhea, 4 ± 1.5 for deep dyspareunia, and 3 ± 1 for rectalgia.

    “The mean preoperative pain scores for patients with peritoneal and ovarian endometriosis were 5 Ϯ 3, 4 Ϯ 1.5, and 3 Ϯ 1, respectively, for dysmenorrhea, deep dyspareunia, and rectalgia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The mean preoperative pain scores for patients with deep infiltrating endometriosis were 9 ± 1 for dysmenorrhea, 9 ± 1 for deep dyspareunia, and 8 ± 1 for rectalgia.

    “The mean preoperative pain scores for patients with deep infiltrating endometriosis were 9 Ϯ 1, 9 Ϯ 1, and 8 Ϯ 1, respectively, for dysmenorrhea, deep dyspareunia, and rectalgia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Endometriotic lesions contain significantly more tryptase-positive (activated) mast cells than unaffected tissues in all studied locations, except peritoneal and uterosacral lesions where the difference was not significant.

    “Endometriotic lesions contain significantly more tryptase-positive mast cells (activated) than the unaffected tissues in all the different studied locations (PϽ.001), except for peritoneal and uterosacral lesions, where it was not significant (Table 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Neurotransmitters such as substance P or NGF can trigger mast cell degranulation.

    “Mast cells can not only release mediators that increase excitability of neurons, but in turn, neurotransmitters such as substance P or NGF can trigger mast cell degranulation (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Kessler, 1980, Nerve growth factor stimulates the development of substance P in sensory ganglia, Proc Nat Acad Sci USA source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Neuronal histamine receptors are upregulated or modulated by nerve injury.

    “Histamine is a key mediator released by activated mast cells.It can sensitize nociceptors (14, 15), and neuronal histamine receptors are upregulated or modulated by nerve injury (33,34).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Kashiba, 1999, Gene expression of histamine H1 receptor in guinea pig sensory neurons: a relationship between H1 receptor mRNE-expressing neurons and peptidergic neurons, Mol Brain Res source

      Not checked in the free run.

    • cites [34] Baron, 2001, Histamine-induced itch converts into pain in neuropathic hyperalgesia, NeuroReport source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    There is cumulative evidence that mast cells play an important role in the pathogenesis of chronic pain and neuropathic pain in many pathological conditions.

    “There is cumulative evidence that mast cells play an important role in the pathogenesis of chronic pain and neuropathic pain in many pathological conditions (10 -15).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [10] Dines, 1997, Mast cell interactions with the nervous system: relationship to mechanisms of disease, J Neuropathol Exp Neurol source

      Not checked in the free run.

    • cites [11] Theodosiou, 1999, Hyperalgesia due to nerve damage: role of nerve growth factor, Pain source

      Not checked in the free run.

    • cites [12] Liu, 2000, Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury, Pain source

      Not checked in the free run.

    • cites [13] Perkins, 2000, Hyperalgesia due to nerve injury: role of neutrophils, Neuroscience source

      Not checked in the free run.

    • cites [14] Mizumura, 2000, Possible contribution of proteine kinase C in the effects of histamine on the visceral nociceptor activities in vitro, Neurosci Res source

      Not checked in the free run.

    • cites [15] Herbert, 2001, Histamine excites group III and IV afferents from the cat knee joint depending on their resting activity, Neurosci Lett source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The content of mast cells in the eutopic endometrium of patients with endometriosis is very low and is not significantly different from that of the endometrium of unaffected patients.

    “The capacity of NGF to attract mast cells could explain the higher number of mast cells in endometriotic lesions since it has been shown that the content of mast cells in the eutopic endometrium of patients with endometriosis is very low and is not significantly different from that of the endometrium of unaffected patients (18).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Sugamata, 2005, Increase of activated mast cells in human endometriosis, Am J Reprod Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NGF is released and functions as a chemoattractant for mast cells.

    “NGF is released and functions as a chemoattractant for mast cells, but it can also trigger mast cell degranulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (11,(27)(28)(29)(30)(31)

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The technique of random field selection is considered simple and acceptable.

    “This technique is considered to be a simple and acceptable method to randomly select fields or tissue elements for microscopic study (22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Hansen, 1998, Angiogenesis in breast cancer, Lab Investig

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    When the difference in mean mast cell count per case between the two observers exceeded 10%, cases were reevaluated using a multiheaded microscope and final agreement was reached in all cases.

    “When the difference in mean mast cell count per case between the two observers exceeded 10% (which occurred in 7.2% of cases), the cases were reevaluated using a multiheaded microscope and a final agreement was reached in all cases.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The microscopic fields examined were randomly selected using a Chalkley grid.

    “The fields that were examined were randomly selected using a Chalkley grid (0.196 mm 2 ) (21) containing 25 points that was overlaid on the digitized fields.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Chalkley, 1943, Method for the quantitative morphologic analysis of tissues, J Nat Cancer Instit

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with histamine receptor antagonists suppressed the development of hyperalgesia after nerve injury and alleviated hyperalgesia once it was established.

    “Treatment with histamine receptor antagonists also suppressed the development of hyperalgesia after nerve injury and alleviated hyperalgesia once it was established (45).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Zuo, 2003, Inflammation and hyperalgesia induced by nerve injury in the rat: a key role of mast cells, Pain source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Mast cells were counted by two different investigators who were blinded to the site.

    “Mast cells were counted by two different investigators (JCN and VA) who were blinded to the site in Ն20 nonoverlapping randomly selected high power fields (ϫ400).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    All 69 patients (100%) answered mailed questionnaires in the preoperative phase.

    “All 69 patients (100%) answered mailed questionnaires in the preoperative phase.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The corresponding author of the questionnaires was unknown to the patients and had not participated in the preoperative consultations or in the operations.

    “The corresponding author of the questionnaires was unknown to the patients and had not participated in the preoperative consultations or in the operations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Immunohistochemistry included negative and positive controls to control for nonspecific binding.

    “To control for nonspecific binding of the primary antibodies, nonimmune mouse sera at the same concentration as the primary antibodies preparations were substituted as the first layers of the serial sections for mast cell chymase, mast cell tryptase, and S-100 protein immunohistochemistry. Positive controls consisted of schwannomas for S-100 protein and tonsils for mast cell chymase and tryptase.”
    Quote in the paperNot a substantial claim
17 of 17

  • The paper relies on this without support.

    The mechanisms by which deep infiltrating lesions cause pain and hyperalgesia are poorly understood.

    “The mechanisms by which deep infiltrating lesions cause pain and very often hyperalgesia are poorly understood.”

  • The paper relies on this without support.

    This is the first study on mast cells and nerves in endometriosis and deep infiltrating endometriosis.

    “To our knowledge this is the first study on mast cells and nerves in endometriosis and deep infiltrating endometriosis.”

  • The paper relies on this without support.

    Histamine is a key mediator released by activated mast cells.

    “Histamine is a key mediator released by activated mast cells.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • One chymase comparison does not meet the stated P threshold

    Minor

    The results give P<.001 for comparisons of deep infiltrating lesions with peritoneal and ovarian lesions, but Table 4 reports .01 for the ovarian-uterosacral chymase comparison.

  • An additional tryptase comparison is nonsignificant

    Minor

    The results name the ovarian-uterosacral comparison as the only exception, but Table 4 also marks the peritoneal-uterosacral comparison as nonsignificant for tryptase-positive mast cells.

2 of 2

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Authors
Anaf, V., Chapron, C., El Nakadi, I., De Moor, V., Simonart, T., & Noël, J.-C.
Affiliations
  • Université Libre de Bruxelles (BE)
  • Délégation Paris 5 (FR)
Corresponding author
Anaf, Vincent
ORCID
Venue
Fertility and Sterility
Publisher
Elsevier BV
Published
2006-11
Volume
86
Issue
5
Pages
1336-1343
ISSN
0015-0282 (ISSN-L)
DOI
10.1016/j.fertnstert.2006.03.057
OpenAlex
W2033247060
Cited by
258
References
48
Citations by year
2026: 16 · 2025: 14 · 2024: 14 · 2023: 15 · 2022: 13 · 2021: 16 · 2020: 15 · 2019: 8 · 2018: 8 · 2017: 17 · 2016: 10 · 2015: 20 · 2014: 12 · 2013: 12 · 2012: 14
FWCI
11.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Fertility and Sterility (publishedVersion)
  • PubMed (publishedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Plant and fungal interactions
Keywords
endometriosis, deep infiltrating endometriosis, peritoneal endometriosis, endometrioma, mast cells, mast cell degranulation, mast cell activation, chymase, tryptase, S-100 protein, nerves, endometriosis-associated pain, hyperalgesia, preoperative pain
MeSH terms
Adult, Endometriosis, Female, Humans, Hyperalgesia, Mast Cells, Ovarian Diseases, Ovary, Peritoneal Diseases, Peritoneum

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