Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2021

Open Access 01-12-2021 | Endometriosis | Research

Possible involvement of neuropeptide and neurotransmitter receptors in Adenomyosis

Authors: Xiaofang Xu, Xianjun Cai, Xishi Liu, Sun-Wei Guo

Published in: Reproductive Biology and Endocrinology | Issue 1/2021

Login to get access

Abstract

Background

Accumulating data indicate that sensory nerve derived neuropeptides such as substance P and calcitonin gene related-protein (CGRP) can accelerate the progression of endometriosis via their respective receptors, so can agonists to their respective receptors receptor 1 (NK1R), receptor activity modifying protein 1 (RAMP-1) and calcitonin receptor-like receptor (CRLR). Adrenergic β2 receptor (ADRB2) agonists also can facilitate lesional progression. In contrast, women with endometriosis appear to have depressed vagal activity, concordant with reduced expression of α7 nicotinic acetylcholine receptor (α7nAChR). The roles of these receptors in adenomyosis are completely unknown.

Methods

Adenomyotic tissue samples from 30 women with adenomyosis and control endometrial tissue samples from 24 women without adenomyosis were collected and subjected to immunohistochemistry analysis of RAMP1, CRLR, NK1R, ADRB2 and α7nAChR, along with their demographic and clinical information. The extent of tissue fibrosis was evaluated by Masson trichrome staining.

Results

We found that the staining levels of NK1R, CRLR, RAMP1 and ADRB2 were all significantly elevated in adenomyotic lesions as compared with control endometrium. In contrast, α7nAChR staining levels were significantly reduced. The severity of dysmenorrhea correlated positively with lesional ADRB2 staining levels.

Conclusions

Our results suggest that SP, CGRP and noradrenaline may promote, while acetylcholine may stall, the progression of adenomyosis through their respective receptors on adenomyotic lesions. Additionally, through the activation of the hypothalamic-pituitary-adrenal (HPA)-sympatho-adrenal-medullary (SAM) axes and the lesional overexpression of ADRB2, adenomyosis-associated dysmenorrhea and adenomyotic lesions may be mutually promotional, forming a viscous feed-forward cycle.
Appendix
Available only for authorised users
Literature
1.
Vercellini P, Vigano P, Somigliana E, Daguati R, Abbiati A, Fedele L. Adenomyosis: epidemiological factors. Best Pract Res Clin Obstet Gynaecol. 2006;20:465–77.PubMedCrossRef
2.
Farquhar C, Brosens I. Medical and surgical management of adenomyosis. Best Pract Res Clin Obstet Gynaecol 2006.
3.
Harada T, Khine YM, Kaponis A, Nikellis T, Decavalas G, Taniguchi F. The impact of Adenomyosis on Women's fertility. Obstet Gynecol Surv. 2016;71:557–68.PubMedPubMedCentralCrossRef
4.
Vercellini P, Consonni D, Dridi D, Bracco B, Frattaruolo MP, Somigliana E. Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis. Hum Reprod. 2014;29:964–77.PubMedCrossRef
5.
Gordts S, Grimbizis G, Campo R. Symptoms and classification of uterine adenomyosis, including the place of hysteroscopy in diagnosis. Fertil Steril 2018;109:380–388 e1.
6.
Bergeron C, Amant F, Ferenczy A. Pathology and physiopathology of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006;20:511–21.PubMedCrossRef
7.
Vannuccini S, Tosti C, Carmona F, Huang SJ, Chapron C, Guo SW, et al. Pathogenesis of adenomyosis: an update on molecular mechanisms. Reprod BioMed Online. 2017;35:592–601.PubMedCrossRef
8.
Garcia-Solares J, Donnez J, Donnez O, Dolmans MM. Pathogenesis of uterine adenomyosis: invagination or metaplasia? Fertil Steril. 2018;109:371–9.PubMedCrossRef
9.
Benson RC, Sneeden VD. Adenomyosis: a reappraisal of symptomatology. Am J Obstet Gynecol 1958;76:1044–1057; discussion 57-61.
10.
Li X, Liu X, Guo SW. Clinical profiles of 710 premenopausal women with adenomyosis who underwent hysterectomy. J Obstet Gynaecol Res. 2014;40:485–94.PubMedCrossRef
11.
Zhang Q, Duan J, Liu X, Guo SW. Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation. Mol Cell Endocrinol. 2016;428:1–16.PubMedCrossRef
12.
Guo SW. Fibrogenesis resulting from cyclic bleeding: the holy grail of the natural history of ectopic endometrium. Hum Reprod. 2018.
13.
Guo SW, Ding D, Shen M, Liu X. Dating Endometriotic ovarian cysts based on the content of cyst fluid and its potential clinical implications. Reprod Sci. 2015;22:873–83.PubMedPubMedCentralCrossRef
14.
Liu X, Shen M, Qi Q, Zhang H, Guo SW. Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis. Hum Reprod. 2016;31:734–49.PubMedCrossRef
15.
Shen M, Liu X, Zhang H, Guo SW. Transforming growth factor beta1 signaling coincides with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice. Hum Reprod. 2016;31:355–69.PubMed
16.
Laverdet B, Danigo A, Girard D, Magy L, Demiot C, Desmouliere A. Skin innervation: important roles during normal and pathological cutaneous repair. Histol Histopathol. 2015;30:875–92.PubMed
17.
Micera A, Lambiase A, Stampachiacchiere B, Bonini S, Bonini S, Levi-Schaffer F. Nerve growth factor and tissue repair remodeling: trkA (NGFR) and p75(NTR), two receptors one fate. Cytokine Growth Factor Rev. 2007;18:245–56.PubMedCrossRef
18.
Hughes SR, Williams TJ, Brain SD. Evidence that endogenous nitric oxide modulates oedema formation induced by substance P. Eur J Pharmacol. 1990;191:481–4.PubMedCrossRef
19.
20.
Ansel JC, Brown JR, Payan DG, Brown MA. Substance P selectively activates TNF-alpha gene expression in murine mast cells. J Immunol. 1993;150:4478–85.PubMedCrossRef
21.
Columbo M, Horowitz EM, Kagey-Sobotka A, Lichtenstein LM. Substance P activates the release of histamine from human skin mast cells through a pertussis toxin-sensitive and protein kinase C-dependent mechanism. Clin Immunol Immunopathol. 1996;81:68–73.PubMedCrossRef
22.
Brain SD. Sensory neuropeptides: their role in inflammation and wound healing. Immunopharmacology. 1997;37:133–52.PubMedCrossRef
23.
Cheret J, Lebonvallet N, Buhe V, Carre JL, Misery L, Le Gall-Ianotto C. Influence of sensory neuropeptides on human cutaneous wound healing process. J Dermatol Sci. 2014;74:193–203.PubMedCrossRef
24.
Kant V, Kumar D, Kumar D, Prasad R, Gopal A, Pathak NN, et al. Topical application of substance P promotes wound healing in streptozotocin-induced diabetic rats. Cytokine. 2015;73:144–55.PubMedCrossRef
25.
Leal EC, Carvalho E, Tellechea A, Kafanas A, Tecilazich F, Kearney C, et al. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am J Pathol. 2015;185:1638–48.PubMedPubMedCentralCrossRef
26.
Yang L, Di G, Qi X, Qu M, Wang Y, Duan H, et al. Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor. Diabetes. 2014;63:4262–74.PubMedCrossRef
27.
Smith PG, Liu M. Impaired cutaneous wound healing after sensory denervation in developing rats: effects on cell proliferation and apoptosis. Cell Tissue Res. 2002;307:281–91.PubMedCrossRef
28.
Engin C, Demirkan F, Ayhan S, Atabay K, Baran NK. Delayed effect of denervation on wound contraction in rat skin. Plast Reconstr Surg. 1996;98:1063–7.PubMedCrossRef
29.
Buckley G, Wong J, Metcalfe AD, Ferguson MW. Denervation affects regenerative responses in MRL/MpJ and repair in C57BL/6 ear wounds. J Anat. 2012;220:3–12.PubMedCrossRef
30.
Kim LR, Whelpdale K, Zurowski M, Pomeranz B. Sympathetic denervation impairs epidermal healing in cutaneous wounds. Wound Repair Regen. 1998;6:194–201.PubMedCrossRef
31.
Souza BR, Cardoso JF, Amadeu TP, Desmouliere A, Costa AM. Sympathetic denervation accelerates wound contraction but delays reepithelialization in rats. Wound Repair Regen. 2005;13:498–505.PubMedCrossRef
32.
Nisolle M, Casanas-Roux F, Anaf V, Mine JM, Donnez J. Morphometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril. 1993;59:681–4.PubMedCrossRef
33.
Berkley KJ, Dmitrieva N, Curtis KS, Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci U S A. 2004;101:11094–8.PubMedPubMedCentralCrossRef
34.
Tokushige N, Markham R, Russell P, Fraser IS. Nerve fibres in peritoneal endometriosis. Hum Reprod. 2006;21:3001–7.PubMedCrossRef
35.
Wang G, Tokushige N, Markham R, Fraser IS. Rich innervation of deep infiltrating endometriosis. Hum Reprod. 2009;24:827–34.PubMedCrossRef
36.
Wang G, Tokushige N, Russell P, Dubinovsky S, Markham R, Fraser IS. Hyperinnervation in intestinal deep infiltrating endometriosis. J Minim Invasive Gynecol. 2009;16:713–9.PubMedCrossRef
37.
Anaf V, El Nakadi I, De Moor V, Chapron C, Pistofidis G, Noel JC. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol Obstet Investig. 2011;71:112–7.CrossRef
38.
Anaf V, Simon P, El Nakadi I, Fayt I, Simonart T, Buxant F, et al. Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis. Hum Reprod. 2002;17:1895–900.PubMedCrossRef
39.
Nie J, Liu X, Zheng Y, Geng JG, Guo SW. Increased immunoreactivity to SLIT/ROBO1 and its correlation with severity of dysmenorrhea in adenomyosis. Fertil Steril. 2011;95:1164–7.PubMedCrossRef
40.
Harmsen MJ, Wong CFC, Mijatovic V, Griffioen AW, Groenman F, Hehenkamp WJK, et al. Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review. Hum Reprod Update. 2019;25:647–71.PubMedPubMedCentralCrossRef
41.
Zhang X, Lu B, Huang X, Xu H, Zhou C, Lin J. Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids. Fertil Steril. 2010;94:730–7.PubMedCrossRef
42.
Barcena de Arellano ML, Oldeweme J, Arnold J, Schneider A, Mechsner S. Remodeling of estrogen-dependent sympathetic nerve fibers seems to be disturbed in adenomyosis. Fertil Steril. 2013;100:801–9.PubMedCrossRef
43.
44.
Liu X, Yan D, Guo SW. Sensory nerve-derived neuropeptides accelerate the development and fibrogenesis of endometriosis. Hum Reprod. 2019;34:452–68.PubMedCrossRef
45.
Yan D, Liu X, Guo SW. Neuropeptides substance P and calcitonin gene related peptide accelerate the development and Fibrogenesis of endometriosis. Sci Rep. 2019;9:2698.PubMedPubMedCentralCrossRef
46.
Long Q, Liu X, Qi Q, Guo SW. Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor beta2. Hum Reprod. 2016;31:2506–19.PubMedCrossRef
47.
Ding D, Wang X, Chen Y, Benagiano G, Liu X, Guo S-W. Evidence in support for the progressive nature of ovarian endometriomas. J Clin Endocrinol Metab 2020;In press.
48.
Hao M, Liu X, Rong P, Li S, Guo S-W. Reduced Vagal Tone in Women with Endometriosis and Auricular Vagus Nerve Stimulation as a Potential Therapeutic Approach. Sci Rep 2020;In press. .
49.
Steinman L. Elaborate interactions between the immune and nervous systems. Nat Immunol. 2004;5:575–81.PubMedCrossRef
50.
51.
52.
He X, Zhao M, Bi X, Sun L, Yu X, Zhao M, et al. Novel strategies and underlying protective mechanisms of modulation of vagal activity in cardiovascular diseases. Br J Pharmacol. 2015;172:5489–500.PubMedPubMedCentralCrossRef
53.
54.
Yamada-Nomoto K, Yoshino O, Akiyama I, Ushijima A, Ono Y, Shima T, et al. Alpha-7 nicotinic acetylcholine receptor (nAChR) agonist inhibits the development of endometriosis by regulating inflammation. Am J Reprod Immunol. 2016;76:491–8.PubMedCrossRef
55.
Liu X, Ding D, Ren Y, Guo SW. Transvaginal Elastosonography as an imaging technique for diagnosing Adenomyosis. Reprod Sci. 2018;25:498–514.PubMedCrossRef
56.
Ding D, Liu X, Duan J, Guo SW. Platelets are an unindicted culprit in the development of endometriosis: clinical and experimental evidence. Hum Reprod. 2015;30:812–32.PubMedCrossRef
57.
Team RDC. R: a language and environment for statistical computing. In. Vienna: R Foundation for Statistical Computing; 2016.
58.
59.
60.
Guo SW, Zhang Q, Liu X. Social psychogenic stress promotes the development of endometriosis in mouse. Reprod BioMed Online. 2017;34:225–39.PubMedCrossRef
61.
McKinnon BD, Evers J, Bersinger NA, Mueller MD. Induction of the neurokinin 1 receptor by TNFalpha in endometriotic tissue provides the potential for neurogenic control over endometriotic lesion growth. J Clin Endocrinol Metab. 2013;98:2469–77.PubMedCrossRef
62.
Chen Y, Zhu B, Zhang H, Ding D, Liu X, Guo SW. Possible loss of GABAergic inhibition in mice with induced Adenomyosis and treatment with Epigallocatechin-3-Gallate attenuates the loss with improved Hyperalgesia. Reprod Sci. 2014;21:869–82.PubMedPubMedCentralCrossRef
63.
Singtripop T, Mori T, Park MK, Sakamoto S, Kawashima S. Development of uterine adenomyosis after treatment with dopamine antagonists in mice. Life Sci. 1991;49:201–6.PubMedCrossRef
64.
Kelly MA, Rubinstein M, Asa SL, Zhang G, Saez C, Bunzow JR, et al. Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron. 1997;19:103–13.PubMedCrossRef
65.
Novella-Maestre E, Carda C, Ruiz-Sauri A, Garcia-Velasco JA, Simon C, Pellicer A. Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium: a novel molecular target for endometriosis therapy. Biol Reprod. 2010;83:866–73.PubMedCrossRef
66.
Richards EG, Zheng Y, Shenoy CC, Ainsworth AJ, Delaney AA, Jones TL, et al. KLF11 is an epigenetic mediator of DRD2/dopaminergic signaling in endometriosis. Reprod Sci. 2017;24:1129–38.PubMedCrossRef
67.
Yin B, Jiang H, Liu X, Guo SW. Enriched environment decelerates the development of endometriosis in mouse. Reprod Sci. 2020;27:1423–35.PubMedCrossRef
68.
Siedentopf F, Tariverdian N, Rucke M, Kentenich H, Arck PC. Immune status, psychosocial distress and reduced quality of life in infertile patients with endometriosis. Am J Reprod Immunol. 2008;60:449–61.PubMedCrossRef
69.
Tariverdian N, Rucke M, Szekeres-Bartho J, Blois SM, Karpf EF, Sedlmayr P, et al. Neuroendocrine circuitry and endometriosis: progesterone derivative dampens corticotropin-releasing hormone-induced inflammation by peritoneal cells in vitro. J Mol Med (Berl). 2010;88:267–78.CrossRef
70.
Karlsson TS, Marions LB, Edlund MG. Heavy menstrual bleeding significantly affects quality of life. Acta Obstet Gynecol Scand. 2014;93:52–7.PubMedCrossRef
71.
Shapley M, Jordan K, Croft PR. Increased vaginal bleeding and psychological distress: a longitudinal study of their relationship in the community. BJOG. 2003;110:548–54.PubMedCrossRef
72.
Strine TW, Chapman DP, Ahluwalia IB. Menstrual-related problems and psychological distress among women in the United States. J Women's Health (Larchmt). 2005;14:316–23.CrossRef
73.
Karatsoreos IN, McEwen BS. Annual research review: the neurobiology and physiology of resilience and adaptation across the life course. J Child Psychol Psychiatry. 2013;54:337–47.PubMedCrossRef
Metadata
Title
Possible involvement of neuropeptide and neurotransmitter receptors in Adenomyosis
Authors
Xiaofang Xu
Xianjun Cai
Xishi Liu
Sun-Wei Guo
Publication date
01-12-2021
Publisher
BioMed Central
Keyword
Endometriosis
Published in
Reproductive Biology and Endocrinology / Issue 1/2021
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-021-00711-6

Other articles of this Issue 1/2021

Reproductive Biology and Endocrinology 1/2021 Go to the issue

Review

Dose adjustment of follicle-stimulating hormone (FSH) during ovarian stimulation as part of medically-assisted reproduction in clinical studies: a systematic review covering 10 years (2007–2017)

Research

Tumor susceptibility gene 101 is required for the maintenance of uterine epithelial cells during embryo implantation

Research

Involvement of impaired CD8+ mucosal-associated invariant T cells and myeloid-derived suppressor cells in polycystic ovary syndrome

Research

Label-free proteomics uncovers SMC1A expression is Down-regulated in AUB-E

Research

Maternal and infant outcomes during the COVID-19 pandemic: a retrospective study in Guangzhou, China

Research

Irisin deletion induces a decrease in growth and fertility in mice