Endometriosis‐associated nerve fibers and pain

Medina MG, Melissa G Medina, Melissa Medina, Dan I. Lebovic
Acta obstetricia et gynecologica Scandinavica · 2009 · vol. 88(9) , pp. 968–975 · doi:10.1080/00016340903176826 · PMID:19657753 · PMC4554536 · W2108644400
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-09 ⓘ

This review compiles literature on nerve fiber detection in endometriosis, finding similar fibers across tissues with density correlating to pain and hormonal therapy reducing density.

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This paper reviews evidence that endometriosis is associated with differences in nerve fiber types and densities across eutopic endometrium, myometrium, and peritoneal endometriotic lesions, using literature searches (Medline/PubMed) and immunohistological staining with markers such as PGP9.5, NF, substance P, CGRP, VIP, and NPY, among others. Across included studies, functional eutopic endometrial layers in women with endometriosis show positively stained unmyelinated sensory fibers (PGP9.5, with greater densities of PGP9.5/NPY/VIP) and secretory-stage cyclic increases, while myelinated Aδ fibers (NF+) are reported in the basal layer of affected women but not controls; in lesions, nerve fiber density and NGF/NGFRp75 immunoreactivity are reported to be higher than in normal peritoneum. A stated caveat is that definitive diagnosis often depends on laparoscopic visual assessment with variability and that no consistent noninvasive diagnostic technique exists, limiting direct translation of marker-based findings. This paper is centrally about endometriosis — it focuses on nerve fiber composition and density as a mechanism and potential diagnostic signal for endometriosis-associated pain.

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Abstract

Abstract The assessment and diagnosis of endometriosis remain elusive targets. Patient and medical‐related factors add to delays in the detection and treatment. Recently, investigators have revealed specific nerve fibers present in endometriotic tissue, with existing parallels between density and pain severity. The aim of this review is to compile a comprehensive review of existing literature on endometriosis‐related nerve fiber detection, and the effects of medical therapy on these neural fibers. We performed a systematic literature‐based review using Medline and PubMed of nerve fibers detected in eutopic endometrium, endometriotic lesions, and the peritoneum. Various arrangements of significant medical terms and phrases consisting of endometriosis, pelvic pain, nerve fiber detection/density in endometriosis, and diagnoses methodology, including treatment and detection were applied in the search. Subsequent references used were cross‐matched with existing sources to compile all additional similar reports. Similar nerve fibers were detected within lesions, endometrium, and myometrium, though at varying degrees of density. Hormonal therapy is widely used to treat endometriosis and was shown to be related to a reduction in fiber density. A direct result of specific nerve fiber detection within eutopic endometrial layers points to the use of a minimally invasive endometrial biopsy technique in reducing delay in diagnosis and subsequent possible preservation of fertility.
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Intro

Endometriosis is a chronic, complex gynecological disease affecting reproductive age women, characterized by endometrial-like tissue found outside of the uterine cavity. Clinical symptoms are manifested as dysmenorrhea, dysuria, dyspareunia ( 1 ), and/or subfertility. Up to 10–15% of women are approximated to be affected ( 2 ), yet the disease may remain asymptomatic making it a difficult disorder to detect and diagnose. A number of studies have posited biochemical factors involved in immune responses linked to endometriosis such as cytokine production, gene product expression, and various other immunological components ( 2 – 5 ). More recently, there is accumulating literature describing nerve fiber density differences between women with diagnosed endometriosis and women without endometriosis. A significant interval of time exists between the onset of symptoms and a definite diagnosis for endometriosis ( 6 ). Multiple factors, both on individual patient and medical levels, contribute to the delay; the perceived inability to recognize problematic menstrual episodes, mistaking them for ‘normal’ experiences may add to individual reporting variability as well as misdiagnoses. Ballard et al. described possible medical delays, discussing possible instrumental errors in diagnosis or physician ‘dismissal’ of symptoms ( 7 ). A widely used existing method of detection is based on laparoscopic visual assessment followed by histological confirmation; however, this surgical approach poses potential complications and side effects, in addition to physician variability in detecting lesions or ectopic endometrial tissue ( 7 , 8 ). Endometrial biopsies accompanied by immunohistological staining of detected nerve fibers are also being evaluated as a minimally invasive, efficient, and more reliable diagnostic technique ( 9 ), aiming to reduce the time delay from symptom onset to definite endometriosis disease diagnosis.

Nerve

In a recent pilot study investigating the clinical relevance of nerve fibers in peritoneal lesions, the pain symptoms of endometriosis have been correlated with the density of peritoneal nerve fibers. In women with peritoneal endometriosis, those who reported moderate or severe pelvic pain and/or dysmenorrhea were detected to have more nerve fibers in association with endometriosis (82.6% of patients who reported a≥3 on a 10-point scale). Conversely, in the group of patients categorized as having peritoneal endometriosis but who recorded significantly reduced pain symptoms (≤2), only two women (33%) showed the presence of detectable endometriosis-associated fibers, which were considerably less in density ( 25 ). Yet, in continuation of these findings, questions concerning the difference between types of endometriosis manifested in each patient are still in need of further investigation. Although nerve fiber densities have been correlated with the degree of severity of pain in women with endometriosis, it would be valuable to study women confirmed with endometriosis and differentiate those with infertility/subfertility versus normal fecundity, or even women with proven normal fertility but who have endometriosis; or those experiencing endometriosis-related pain and those who do not report such pain. Women inclined to have endometriosis may biologically induce neurotrophic factors to be released, which would subsequently lead to the generation of fibers innervating endometriotic implants. It is therefore important to further study the mechanisms of nerve fiber growth and recruitment in women experiencing endometriosis-associated pain. Future research will attempt to explain the factors driving this phenomenon, whether nerve fiber presence is an underlying cause inducing symptoms or if it is the appearance and recurrence of the disease itself that stimulates neurogenesis mechanisms of these detected fibers in diagnosed women with endometriosis.

Future

The results of staining for nerve fibers within endometrial biopsies point to benefits of employing this minimally invasive procedure as a diagnostic technique, leading to benefits such as eliminating anesthetic use and reducing physician variability in detection; paving the way for earlier detection and diagnosis, and resulting in earlier treatment strategies for affected women ( 9 , 15 ). The reliability of using the ‘Endosampler’ as opposed to current methods of laparoscopy can result in advantages on patient lifestyle changes, including preservation of fertility of women with strong familial predispositions to endometriosis or chronic pelvic pain. In addition to efficiency and its possible use in an outpatient environment, this novel technique offers a more affordable method of diagnosis as well ( 9 ). Future large studies will no doubt address correlations between total peritoneal nerve fiber type and density scores between women with and without diagnosed endometriosis or within patients presenting with other gynecological symptoms. NGF and NGFRp75 expression levels were shown to be reduced using progestogen and estrogen–progestogen compared to those without endometriosis ( 23 ). Continuing research could consider the effect of hormonal therapies on nerve fibers within endometriotic plaques in various locations such as the ovaries, peritoneum, or Fallopian tubes of women with endometriosis-induced pain. A comparison of the effectiveness between current drugs, hormones and other treatment methods might then be used as a surrogate marker for treatment efficacy. In addition to detecting the type of nerve fibers present in eutopic endometrium, future studies may be directed toward certain molecular products that interact with and/or influence these nerve fibers within eutopic endometrium or endometriotic plaques. Although data are accumulating on NGF recruitment and molecular interactions playing a role in disease recurrence, the exact pathogenesis of the disease and its specific mechanism of recurrence still remain poorly understood. To further investigate a definite mechanism of endometriosis-associated pain, further research is needed to reveal the detailed interplay between functional molecules and identified nerve fibers, and their tandem interactions aiding in the progression of symptoms.

Hormone

A significant amount of research has demonstrated the capability of current hormonal treatments to diminish the reported pain associated with endometriosis symptoms ( 21 , 22 ). Current hormonal therapies utilized presently include aromatase inhibitors, oral contraceptives, progestins, gonadotropin releasing hormone agonists, androgenic mediators, as well as various immuno-regulatory elements having a role in disease development ( 19 ). In addition, there are preliminary indications that women undergoing hormonal therapy may have a reduced number of detectable nerve fibers ( 15 ) in peritoneal endometriotic lesions and eutopic endometrium compared to endometriotic women who were not receiving any hormone treatment. Tokushige et al. have previously shown the presence of a greater density of nerve fibers present in women with endometriosis in the endometrium and myometrium ( 16 ); in an effort to reveal what effects hormonal treatment has on nerve fiber density, endometrial and myometrial tissues from women with untreated endometriosis and from those undergoing hormonal therapy (oral progestogens or combined oral contraceptives) were obtained; the tissues were subsequently stained with various biochemical markers for nerve fiber identification and localization. PGP9.5-positive staining was not detected within the functional layer of eight women undergoing hormonal therapy. Moreover, total nerve fiber density in hormonally treated women in the functional and basal layers of endometrium as well as the myometrium (functional: 0.4±0.9/mm 2 ; basal: 0.9±1.3/mm 2 ; myometrium: 1.5±0.8/mm 2 ) was significantly decreased compared to the endometrial functional and basal layers, and myometrium of those without hormone treatment (11±5/mm 2 , 18±8/mm 2 , 3±1/mm 2 , respectively; Table III ) ( 23 ). More specifically, in the immunohistological staining of the functional layer of eutopic endometrium from untreated women, the nerve fibers were detected to be VIP, NPY, SP, and CGRP; whereas in hormonally treated women, the presence of SP and CGRP was not seen. Also, in the basal layer, all four markers were present in both treated and untreated women who exhibited a small amount of nerve fiber presence in the functional layer; however, the presence of TH was not detected in women undergoing therapy. Similarly, in myometrium, positive detection for SP, CGRP, VIP, NPY, vesicular acetylcholine transporter (VAChT), TH nerve fibers were found in both women; NGF and NGFRp75 immunoreactivity densities were significantly reduced with hormone therapy administration as well ( 6 , 23 ). Hence, since hormonal treatment tends to reduce the amount of reported pain in patients diagnosed with endometriosis, this may be partly explained by decreased nerve fiber density in women undergoing hormonal treatment. Regarding peritoneal endometriosis, a number of markers persisted within hormonally treated individuals: NF, TH, VAChT, VIP, NPY, and CGRP. There were more PGP9.5-stained nerve fibers in hormonally treated peritoneum, in comparison to women without peritoneal endometriosis. Nevertheless, more NF immunoreactivity was observed in untreated women and SP was not seen in treated women. With respect to the type of hormone treatment each woman was undergoing (either combined oral contraceptives or progestogens), nerve fiber types and densities stained with NF and PGP9.5 showed no significant association with the treatment mode. The finding of decreased nerve fiber densities in treated women versus untreated individuals was consistent; however this effect was more significantly seen in eutopic endometrium, compared to peritoneal lesions ( 24 ).

Methods

With the goal of providing a current, expansive review of nerve fibers associated with the detection, mechanism and progression of endometriosis, an electronic database search (Medline, PubMed) was implemented. Various arrangements of significant medical terms and phrases consisting of endometriosis, pelvic pain, nerve fiber detection/density in endometriosis, and diagnoses methodology, including treatment and detection were applied in the search. Subsequent references used were cross-matched with existing sources to compile all additional similar reports. A majority of acquired data in relation to nerve fiber density reports were published primarily by Tokushige, Markham, Russell and Fraser, specifically regarding nerve fiber densities within endometrial layers (see Reference list). Studies and reports were selected according to specific topic relevance, subject pool and number, efficacy and specificity. Due to the wide range of published articles, we specifically included a comprehensive number of studies on endometriosis-associated pain as well as observational and pilot studies in relation to current diagnosis techniques and effective treatment regimens.

Endometrial

Currently there is no justifiably consistent or noninvasive technique in diagnosing endometriosis ( 9 ). The standard relies on laparoscopy, occasionally followed by histological confirmation. As a result, diagnosis relies on observer vision of perceived endometrial tissue outside the uterine cavity. This invasive surgical procedure may expose patients to risks associated with surgery ( 15 ), in addition to the possibility of ‘missed’ plaques due to plaques being less evident and observer variability; these seemingly undetectable plaques may perhaps continue to develop into larger lesions without being promptly removed. Although findings of nerve fibers detected as A delta, sensory C, cholinergic, and adrenergic, are present in all women with or without endometriosis, there is substantial evidence indicating the clear presence and greater abundance of these nerve fibers within the endometrial functional and basal layers, as well as within the peritoneum of patients diagnosed with endometriosis ( 14 , 17 ). These findings lead to the potential use of endometrial biopsies as a diagnostic technique to detect endometriosis, in contrast to the variable inconsistency of present methods of diagnosis. The use of endometrial biopsies utilizing the findings regarding increased detectable nerve fiber density has been investigated. Al-Jefout et al. demonstrated nerve fiber detection within the functional layer of eutopic endometrium of all women with laparoscopically confirmed diagnosis, and no detectable fibers in women without endometriosis, which was consistent throughout their studies. Their findings were then used as the basis to conduct a pilot study assessing the efficiency of using endometrial curettage or endometrial biopsies as a detection method for endometriosis. Using a ‘suction-enhanced Endosampler,’ samples of endometrium were obtained from 37 women, with and without endometriosis, and subsequently stained with pan-neuronal marker 9.5 (PGP9.5). Detected nerve fiber densities of 26.7±55.9 per mm 2 were returned by the Endosampler biopsies ( n =20). Results yielded 100% specificity and sensitivity in the detection of present nerve fibers in women with endometriosis and none in those without compared to laparoscopic detection and peritoneal biopsy ( 9 ). Nerve fiber density stained with PGP9.5 in the functional (11±5/mm 2 ) and basal (18±8/mm 2 ) layers of endometrium, and myometrium (3±1/ mm 2 ) of women currently not taking hormonal therapy was notably greater than the functional (0.2±0.7/mm 2 ), basal (0.9±1.3/mm 2 ), and myometrial (1.5±0.8/mm 2 ) nerve fiber densities of those under hormone treatment. Given these findings along with the acquisition of a greater patient subject pool to ascertain greater accountability and completeness, this promising technique seems to be both valuable and efficient for the possibility of earlier diagnosis of endometriosis. Another advantage that earlier detection poses can be the future opportunity to preserve the fertility of reproductive-aged women ( 9 ), due to the potential of measuring the likelihood of future disease development.

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Condition tags

endometriosischronic_pelvic_pain

MeSH descriptors

Endometriosis Endometrium Myometrium Nerve Fibers Pelvic Pain Endometriosis Endometrium Endometrium Female Humans Myometrium Myometrium Nerve Fibers Pelvic Pain Pelvic Pain

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