Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids
Open accessAbstract
Objective To determine whether nerve fibers can be detected in the endometrium and myometrium in women with painful uterine fibroids and adenomyosis.Design A retrospective immunohistochemical study.Setting An academic training hospital.Patient(s) Thirty-seven women with uterine fibroids and 29 women with adenomyosis.Intervention(s) Histologic sections of contiguous endometrial and myometrial tissues were stained immunohistochemically using the highly specific polyclonal rabbit antiprotein gene product 9.5 (PGP9.5) and monoclonal mouse antineurofilament protein (NF).Main outcome measure(s) Results were determined through immunohistochemical staining using PGP9.5 and NF.Result(s) We detected PGP9.5-immunoactive nerve fibers in the functional layer of the endometrium in women with pain but not in women without pain. PGP9.5-immunoactive nerve fiber density in the basal layer of the endometrium or myometrium significantly increased in women with pain, however, PGP9.5-immunoactive nerve fiber density had no statistical differences between women with adenomyosis and uterine fibroids. We identified NF-immunoactive nerve fibers in the basal layer of the endometrium and myometrium in women with adenomyosis and uterine fibroids, but found no significant differences.Conclusion(s) These results suggest that PGP9.5-immunoactive nerve fibers appearing in the endometrium and myometrium of women with painful adenomyosis and uterine fibroids may play a role in pain generation in these two disorders.
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The specificity of endometrial nerve fiber density was further challenged by the finding of similar endometrial innervation and neuronal growth fibers in women with adenomyosis, with expression reported to be more correlated with pelvic pain than diagnosis.
“The specificity of endometrial nerve fiber density was further challenged by the finding of similar endometrial innervation and neuronal growth fibers in women with adenomyosis, with expression reported to be more correlated with pelvic pain than diagnosis [144].”
From Update on biomarkers for the detection of endometriosis (2015) · cites this paper as [144]
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BackgroundPossible involvement of neuropeptide and neurotransmitter receptors in Adenomyosis
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“5-positive, nerve fibers are found in the basal layer of the endometrium and myometrium in women with adenomyosis [41].”
BackgroundAnatomic and functional mapping of human uterine innervation
Pinsard, M., Mouchet, N., Dion, L., Bessède, T., Bertrand, M. M., Daraï, É., Bellaud, P., Loget, P., Mazaud‐Guittot, S., Morandi, X., et al. (2022) · Fertility and Sterility · doi:10.1016/j.fertnstert.2022.02.013 · Cited by 26 · see citing works
The new application of mifepristone in the relief of adenomyosis-caused dysmenorrhea
Che, X., Wang, J., He, J., Guo, X., Li, T., & Zhang, X. (2020) · International Journal of Medical Sciences · doi:10.7150/ijms.39252 · Cited by 27 · see citing works
“5-immunoactive nerve fibers in the basal layer of the endometrium and myometrium [30].”
BackgroundSelf-citationNeurovascular bundle in fibroid pseudocapsule and its neuroendocrinologic implications
Mettler, L., Tinelli, A., Hurst, B. S., Teigland, C. M., Sammur, W., Dell’Edera, D., Negro, R., Gustapane, S., & Malvası, A. (2011) · Expert Review of Endocrinology & Metabolism · doi:10.1586/eem.11.62 · Cited by 25 · see citing works
Gori, M., Luddi, A., Belmonte, G., Piomboni, P., Tosti, C., Funghi, L., Zupi, E., Lazzeri, L., & Petraglia, F. (2015) · Fertility and Sterility · doi:10.1016/j.fertnstert.2015.10.024 · Cited by 24 · see citing works
Is the Detection of Endometrial Nerve Fibers Useful in the Diagnosis of Endometriosis?
Leslie, C., Ma, T., McElhinney, B., Leake, R., & Stewart, C. J. R. (2013) · International Journal of Gynecological Pathology · doi:10.1097/pgp.0b013e31825b0585 · Cited by 23 · see citing works
Libretti, A., Vitale, S. G., Saponara, S., Corsini, C., Aquino, C. I., Savasta, F., Tizzoni, E., Troìa, L., Surico, D., Angioni, S. L., et al. (2023) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-023-07172-9 · Cited by 23 · see citing works
“This anxiety, occasionally manifesting as increased pain sensitivity, can be triggered by various factors, including cervical dilatation, intrauterine pressure, manipulation, and emotional states [38–40].”
Eutopic endometrium from women with endometriosis does not exhibit neurotrophic properties
Barcena, M. L., Arnold, J., Sacher, F., Bloechle, M., Staube, M., Bartley, J., Vercellino, G. F., Chiàntera, V., Schneider, A., & Mechsner, S. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.04.020 · Cited by 23 · see citing works
“In contrast other studies demonstrate that nerve fibers in the functional layer are endometriosis independent but pain dependent (Zhang et al., 2009, 2010).”
Immunohistochemical localization of nerve fibers in the pseudocapsule of fibroids
Sun, Y., Zhu, L., Huang, X., Zhou, C., & Zhang, X. (2014) · European Journal of Histochemistry · doi:10.4081/ejh.2014.2249 · Cited by 23 · see citing works
Self-citationTinelli, A., Mynbaev, O. A., Mettler, L., Hurst, B. S., Pellegrino, M., Nicolardi, G., Kosmas, I. P., & Malvası, A. (2014) · Reproductive Sciences · doi:10.1177/1933719114537719 · Cited by 23 · see citing works
“They identified NF-immunoactive nerve fibers in the basal layer of the endometrium and myometrium in women with adenomyosis and uterine fibroids but found no significant differences.(47) Probably, the different concentrations of PGP9.”
BackgroundWu, H., Tsai, T.-C., Liu, S.-M., Pai, A. H.-Y., & Chen, L.-H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168937 · Cited by 21 · see citing works
“Distinct bacterial taxa were identified in the endometrial, vaginal, and gut microbiota of patients with adenomyosis compared with the controls, suggesting a potential link between the microbiota profile and adenomyosis [91].”
BackgroundFassbender, A., Dorien, O., Moor, B. D., Waelkens, E., Meuleman, C., Tomassetti, C., Peeraer, K., & D’Hooghe, T. M. (2014) · Springer eBooks · doi:10.1007/978-4-431-54421-0_20 · Cited by 22 · see citing works
The Role of Platelets in the Pathogenesis and Pathophysiology of Adenomyosis
Guo, S. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12030842 · Cited by 17 · see citing works
Neurotrophin Expression Is Not Affected in Uteri of Women with Adenomyosis
Barcena, M. L., Wagner, M. F., Oldeweme, J., Arnold, J., Ebert, A. D., Schneider, A., & Mechsner, S. (2012) · Journal of Molecular Neuroscience · doi:10.1007/s12031-012-9757-x · Cited by 17 · see citing works
“Zhang et al. (2009, 2010) found that nerve fibres were only present in the functional layer of women reporting pain symptoms and that the density of PGP9.”
BackgroundUpdate of recent studies of adenomyosis-associated dysmenorrhea
Jiang, C., & Cheng, Z. (2016) · Gynecology and Minimally Invasive Therapy · doi:10.1016/j.gmit.2016.06.002 · Cited by 14 · see citing works
Innervation in women with uterine myoma and adenomyosis
Choi, Y. J., Chang, J.-A., Kim, Y. A., Chang, S. H., Chun, K., & Koh, J. W. (2015) · Obstetrics & Gynecology Science · doi:10.5468/ogs.2015.58.2.150 · Cited by 14 · see citing works
Whitehill, K., Yong, P. J., & Williams, C. (2012) · Journal of Obstetrics and Gynaecology Canada · doi:10.1016/s1701-2163(16)35271-9 · Cited by 14 · see citing works
Advanced Insights into Human Uterine Innervation: Implications for Endometriosis and Pelvic Pain
Astruc, A., Roux, L., Robin, F., Sall, N. R., Dion, L., Lavoué, V., Legendre, G., Lévêque, J., Bessède, T., Bertrand, M. M., et al. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13051433 · Cited by 11 · see citing works
“Furthermore, no significant differences in PGP 9.5 nerve fiber density were observed between these conditions when pain was a symptom [42,45,46].”
BackgroundInfluentialBariani, M. V., Grimm, S. L., Coarfa, C., Edwards, D. R. V., Yang, Q., Walker, C. L., Ali, M. K., & Al-Hendy, A. A. (2024) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2024.05.048 · Cited by 10 · see citing works
Giray, B., Büyükbayrak, E. E., Keser, S. H., Karşıdağ, A. Y. K., & Türkgeldi, A. (2018) · Geburtshilfe und Frauenheilkunde · doi:10.1055/a-0591-1751 · Cited by 8 · see citing works
“There is only one study on the innervation of endometrial and myometrial tissue in patients with painful uterine leiomyomas [7].”
Influence of endometrial nerve fibers and hormones on pain in women with endometriosis
Sommar, A., Bahat, P. Y., Özaydin, I. Y., Bixo, M., Bäckström, T. C., Oral, E., & Türkmen, Ş. (2025) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2025.113950 · Cited by 7 · see citing works
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Oxytocinergic regulation in pathogenesis of pelvic pain caused by adenomyosis
Orazov, M. R., Radzinsky, V., Viktorovna, S. O., Костин, И. Н., & Сhitanava, Y. S. (2020) · Gynecological Endocrinology · doi:10.1080/09513590.2020.1816723 · Cited by 7 · see citing works
A Review and Reconsideration of Nonneoplastic Myometrial Pathology
Cramer, S. F., & Heller, D. S. (2017) · International Journal of Surgical Pathology · doi:10.1177/1066896917748194 · Cited by 7 · see citing works
“Studies of uterine innervation suggest that these tears may be symptomatic because nerve endings for pain sensation are mainly in the inner third of the wall (61,62).”
BackgroundMacrophage polarization in adenomyosis: A review
Qiu, Y., Cao, J., Li, S., Liu, Y., Wan, G., & Gui, T. (2024) · American Journal of Reproductive Immunology · doi:10.1111/aji.13841 · Cited by 7 · see citing works
“71,72 Stratopoulou et al. revealed that macrophages at the lesionsiteofpatientswithpainfulAMmayexhibitneurogenicandneu-rosensitizing activities, which play a role in neurogenesis or interact with other factors to cause pain.”
BackgroundPostablation neuroma of the myometrium—a report of 5 cases
Cramer, S. F., & Heller, D. S. (2017) · Human Pathology · doi:10.1016/j.humpath.2017.08.013 · Cited by 6 · see citing works
“that an increase in innervation of the inner myometrium and endometrium may play a role in the pathogenesis of chronic pelvic pain [2,3,5].”
BackgroundInfluentialDecreased nerve fibers in the oviduct isthmus of women with endometriosis
Zhu, L., Huang, Q., Huang, X., Zhang, J., Xu, H., & Zhang, X. (2014) · Acta Histochemica · doi:10.1016/j.acthis.2014.02.005 · Cited by 6 · see citing works
Self-citationSensory neuron LKB1 mediates ovarian and reproductive function
Lenert, M. E., Debner, E. K., & Burton, M. D. (2024) · Scientific Reports · doi:10.1038/s41598-024-79947-2 · Cited by 5 · see citing works
Distribution of Nerve Fibers in Abdominal Wall Endometriosis and Their Clinical Significance
Zhang, C., Dai, Y. Q., Zhang, J., Li, X., Jia, S., Shi, J., & Leng, J. (2024) · Journal of Pain Research · doi:10.2147/jpr.s453148 · Cited by 5 · see citing works
Vieira, M. D. C., Andres, M. P., Riccio, L. G. C., Schlindwein, S. S., Arcoverde, F. V. L., Sardo, A. D. S., & Abrão, M. S. (2024) · Reproductive Sciences · doi:10.1007/s43032-024-01587-8 · Cited by 4 · see citing works
“PGP 9.5 is a very specific pan-neuronal marker found in both myelinated and unmyelinated nerve fibers, which is widely distributed in the central and peripheral nervous systems [14] and it was evaluated by immunohistochemistry.”
InfluentialIncreased Nerve Fibers in Placental Bed Myometrium in Women With Preeclampsia
Fan, R., Qiu, L., Huang, X., Chen, Z., Xu, H., Zhou, C., & Zhang, X. (2011) · Reproductive Sciences · doi:10.1177/1933719111411730 · Cited by 4 · see citing works
“Immunohistochemical staining with anti-S100 protein and anti-CD34 was performed to determine the presence of nerves and vessels in the decidua and myometrium, respectively.(26) Briefly, after retrieving the antigen for S100 and CD34, we stained serial, 4m thickness sections, with polyclonal rabbit anti-S100 antibody (…”
MethodSelf-citationYe, Z., Zhao, A., Li, X., Hao, Y., Huang, D., Chen, J., Li, T., Dai, Y., Sun, W., Ma, L., et al. (2025) · Advanced Science · doi:10.1002/advs.202507128 · Cited by 6 · see citing works
Impaired PIEZO1 function drives uterine hypercontractility in adenomyosis-associated dysmenorrhea
Yan, D., Wang, Y., Liu, X., & Guo, S. (2026) · Human Reproduction Open · doi:10.1093/hropen/hoag013 · Cited by 3 · see citing works
“…adenomyosis-associated dysmenorrhea given its role in uterine hypercontractility and in light of the report that PIEZO1 is reported to inhibit axon regeneration via the NOS-protein kinase G pathway (Song et al. , 2019), which may account for hyperinnervation in adenomyosis (Zhang et al. , 2010).”
InfluentialDrug development for adenomyosis based on pathophysiology
Guo, S. (2025) · Journal of obstetrics and gynaecology research · doi:10.1111/jog.16322 · Cited by 4 · see citing works
“Aside from uterine hyperactivity, for which only a handful of culprits are rounded up, hyperin-nervation 134,136 and impaired descending transmission 138 may also play a role.”
Endometriose: Pathogenese, Symptome und Diagnostik
Mechsner, S. (2015) · Springer eBooks · doi:10.1007/978-3-662-43669-1_5 · Cited by 3 · see citing works
Endometrial Determinism of Endometriosis: An Unnecessary Adjunct to Retrograde Menstruation
Habiba, M. A., Guo, S., & Benagiano, G. (2024) · Current Obstetrics and Gynecology Reports · doi:10.1007/s13669-024-00378-x · Cited by 3 · see citing works
“Endo-metriosis has been linked to abnormalities in gene expression [84–86], local estrogen production [87, 88], altered endometrial response to progesterone [89], increased nerve density [90–92], oxidative stress [93, 94], and angiogenesis [95].”
Adamyan, L. V., Sokolov, A. D., Arakelyan, A. S., Станиславовна, Б. А., & Asaturova, A. V. (2025) · Russian Journal of Human Reproduction · doi:10.17116/repro20253101135 · Cited by 2 · see citing works
An integrated approach to the treatment of pelvic pain associated with adenomyosis
Татарчук, Т. Ф., Kaluginа, L. V., Danylova, A. О., & Pavlova, K. S. (2021) · Reproductive Endocrinology · doi:10.18370/2309-4117.2021.59.53-60 · Cited by 2 · see citing works
The Endometrium in Adenomyosis
Habiba, M. A., & Benagiano, G. (2015) · Springer eBooks · doi:10.1007/978-3-319-13012-5_6 · Cited by 2 · see citing works
Surcel, M., Iancu, M., Rotar, I. C., Goidescu, I. G., Staicu, A., Nemeti, G. I., Borza, D. B., Lucaciu, R. L., Hangan, A. C., Mureșan, D., et al. (2026) · Medicina · doi:10.3390/medicina62030571 · Cited by 1 · see citing works
“In contrast, symptom generation appeared more tightly linked to pathways such as angiogenesis [6,43,46], neurogenesis [57,58], inflammatory signaling [6,55–57], vascular permeability [6,44], and discrete components of the fibrogenic program that interface with nociceptive and hemodynamic regulation…”
The Myometrium in Heath and Disease
Taylor, A. H., & Habiba, M. A. (2015) · Springer eBooks · doi:10.1007/978-3-319-13012-5_4 · Cited by 1 · see citing works
Kaur, K. K. (2024) · Open Access Journal of Gynecology · doi:10.23880/oajg-16000278 · Cited by 1 · see citing works
The Role of Biomarkers in the Early Diagnosis of Endometriosis
Worku, D. A. (2017) · Investigations in Gynecology Research & Womens Health (IGRWH) · doi:10.31031/igrwh.2017.01.000512 · Cited by 1 · see citing works
“Indeed antiendometrial antibody essay has shown to have a positive predictive value of 88% when used before laparoscopy in the diagnosis of endometriosis [20].”
Pelvic organ cross-talk: A new paradigm for endometriosis-related pelvic pain?
Monten, L., Forman, A., & Andersson, K. (2018) · Journal of Endometriosis and Pelvic Pain Disorders · doi:10.1177/2284026518810573 · Cited by 1 · see citing works
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Analyse von Nervenfasern und Nervenwachstumsfaktoren in der Adenomyose
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Endometrial nerve fibers in women with endometriosis, adenomyosis, and uterine
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Étude anatomique et immunohistochimique de l’innervation utérine
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Temas selectos de ginecología y obstetricia
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Reduced Numbers of Nerve Fibers in the Oviduct Ampulla of Women with Tubal Ectopic Pregnancy
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“[10] reported that PGP9.”
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“Moreover, in endometriosis and other painful gynaecologic disorders like adenomyosis and uterine fibroids, an increase in the number of nerve fibres can be observed [46,48].”
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Association Between Impaired Dendritic Cell Maturation and Uterine Adenomyosis Pain
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“5 [7, 10, 11], suggesting that neurogenesis may be closely related to the mechanism of AM pain symptoms.”
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- Authors
- Zhang, X., Lu, B., Huang, X., Xu, H., Zhou, C., & Lin, J.
- Affiliations
- Women's Hospital, School of Medicine, Zhejiang University (CN)
- Corresponding author
- Lin, Jun
- Venue
- Fertility and Sterility
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 94
- Issue
- 2
- Pages
- 730-737
- ISSN
- 0015-0282 (ISSN-L)
- OpenAlex
- W1992638684
- Cited by
- 100
- References
- 55
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 10 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 4 · 2015: 10 · 2014: 9 · 2013: 6 · 2012: 5
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Fertility and Sterility (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Uterine Myomas and Treatments
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Health Sciences › Medicine › Obstetrics and Gynecology › Gynecological conditions and treatments
- Keywords
- adenomyosis, uterine fibroids, nerve fibers, PGP 9.5, neurofilaments, pain generation, endometrium
- MeSH terms
- Adult, Antibody Specificity, Endometriosis, Endometrium, Female, Humans, Immunohistochemistry, Leiomyoma, Myometrium, Nerve Fibers, Retrospective Studies, Neurofilament Proteins, Pelvic Pain, Ubiquitin Thiolesterase
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