Nerve fibre infiltration and expression in peritoneal lesions of endometriosis in a nonhuman primate model of endometriosis

Abstract

Baboon (Papio anubis) models of endometriosis are thought to mimic the early stages of spontaneous human peritoneal endometriotic disease. The objective of this study was to investigate the presence and course of nerve fibre ingrowth during peritoneal lesion formation in specimens collected at 3 months (early stage of lesion development) and 15 months (late stage of lesion development) after disease initiation compared to pelvic peritoneum (control). Five-micron sections of paraffin-embedded peritoneal lesions were obtained from normally cycling baboons with 3-month (n = 12), 15-month (n = 12) induced endometriosis and pelvic peritoneum (n = 10) from baboons with no endometriosis. Immunohistochemical staining was performed with specific antibodies: protein gene product 9.5 – broad marker of nerve fibres and neurones, neuropeptide Y – sympathetic neurones, substance P – sensory neurones, vasoactive intestinal peptide – parasympathetic neurones, nerve growth factor – development of new neurones and high-affinity receptor for nerve growth factor (tropomyosin receptor kinase A) – neuronal differential. Significantly, more nerve fibres were identified in peritoneal endometriotic lesions collected 15 months after the initiation of experimental protocols compared with 3-month and control samples (p < 0.001). Nerve fibres were immunoreactive for all the tested markers – protein gene product 9.5, neuropeptide Y, substance P, vasoactive intestinal peptide, nerve growth factor and tropomyosin receptor kinase A – indicating the presence of different types of nerve fibres. In conclusion, peritoneal lesions of endometriosis in a nonhuman primate model of endometriosis were found to be progressively and spontaneously innervated by both myelinated and unmyelinated sensory nerve fibres, parasympathetic and sympathetic neurones. These nerve fibres may play an important role in the mechanisms of pain generation in this condition.

Keywords

Endometriosis nerve fibre peritoneal lesion nonhuman primate

Get full access to this article

View all access options for this article.

References

Fourquet

Gao

Zavala

et al . Patients’ report on how endometriosis affects health, work, and daily life. Fertil Steril 2010; 93(7): 2424–2428.

Lessey

BA.

Medical management of endometriosis and infertility. Fertil Steril 2000; 73(6): 1089–1096.

McLeod

Retzloff

MG.

Epidemiology of endometriosis: an assessment of risk factors. Clin Obstet Gynecol 2010; 53(2): 389–396.

Anaf

Simon

Fayt

et al . Smooth muscles are frequent components of endometriotic lesions. Hum Reprod 2000; 15(4): 767–771.

Berbic

Fraser

IS.

Regulatory T cells and other leukocytes in the pathogenesis of endometriosis. J Reprod Immunol 2011; 88(2): 149–155.

Fassbender

Vodolazkaia

Saunders

et al . Biomarkers of endometriosis. Fertil Steril 2013; 99(4): 1135–1145.

Giudice

Kao

LC.

Endometriosis. Lancet 2004; 364(9447): 1789–1799.

Heinig

von Otte

Greb

et al . Molecular mechanisms contributing to the pathogenesis of endometriosis. Gynecol Endocrinol 2002; 16(6): 493–504.

Nasu

Yuge

Tsuno

et al . Involvement of resistance to apoptosis in the pathogenesis of endometriosis. Histol Histopathol 2009; 24(9): 1181–1192.

10.

Meuleman

Vandenabeele

Fieuws

et al . High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril 2009; 92(1): 68–74.

11.

Rogers

PAW

D’Hooghe

Fazleabas

et al . Priorities for endometriosis research: recommendations from an international consensus workshop. Reprod Sci 2009; 16(4): 335–346.

12.

Barcena

Arellano

M-L

Mechsner

The peritoneum – an important factor for pathogenesis and pain generation in endometriosis. J Mol Med 2014; 92(6): 595–602.

13.

Donnez

Van Langendonckt

Defrere

et al . Induction of endometriotic nodules in an experimental baboon model mimicking human deep nodular lesions. Fertil Steril 2013; 99(3): 783–789.e3.

14.

Ferrero

Haas

Remorgida

et al . Loss of sympathetic nerve fibers in intestinal endometriosis. Fertil Steril 2010; 94(7): 2817–2819.

15.

Medina

Lebovic

DI.

Endometriosis-associated nerve fibers and pain. Acta Obstet Gynecol Scand 2009; 88(9): 968–975.

16.

Miller

Fraser

IS.

The importance of pelvic nerve fibers in endometriosis. Womens Health 2015; 11(5): 611–618.

17.

Tokushige

Markham

Russell

et al . Nerve fibres in peritoneal endometriosis. Hum Reprod 2006; 21(11): 3001–3007.

18.

Tran

LVP

Tokushige

Berbic

et al . Macrophages and nerve fibres in peritoneal endometriosis. Hum Reprod 2009; 24(4): 835–841.

19.

Yan

Liu

Guo

S-W.

Nerve fibers and endometriotic lesions: partners in crime in inflicting pains in women with endometriosis. Eur J Obstet Gynecol Reprod Biol 2017; 209: 14–24.

20.

Zhang

Yao

Huang

et al . Nerve fibres in ovarian endometriotic lesions in women with ovarian endometriosis. Hum Reprod 2010; 25(2): 392–397.

21.

Novella-Maestre

Herraiz

Vila-Vives

et al . Effect of antiangeogenic treatment on peritoneal endometriosis-associated nerve fibers. Obstet Gynecol Surv 2013; 68(3): 203–205.

22.

Tulandi

Felemban

Chen

MF.

Nerve fibers and histopathology of endometriosis-harboring peritoneum. J Am Assoc Gynecol Laparosc 2001; 8(1): 95–98.

23.

Tamburro

Canis

Albuisson

et al . Expression of transforming growth factor beta1 in nerve fibers is related to dysmenorrhea and laparoscopic appearance of endometriotic implants. Fertil Steril 2003; 80(5): 1131–1136.

24.

McKinnon

Bertschi

Bersinger

et al . Inflammation and nerve fiber interaction in endometriotic pain. Trends Endocrinol Metab 2015; 26(1): 1–10.

25.

Barcena

Arellano

Arnold

Lang

et al . Evidence of neurotrophic events due to peritoneal endometriotic lesions. Cytokine 2013; 62(2): 253–261.

26.

Mechsner

Schwarz

Thode

et al . Growth-associated protein 43-positive sensory nerve fibers accompanied by immature vessels are located in or near peritoneal endometriotic lesions. Fertil Steril 2007; 88(3): 581–587.

27.

Tokushige

Markham

Russell

et al . High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Hum Reprod 2006; 21(3): 782–787.

28.

Tokushige

Markham

Russell

et al . Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis. Fertil Steril 2007; 88(4): 795–803.

29.

Bokor

Kyama

Vercruysse

et al . Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic test for minimal to mild endometriosis. Hum Reprod 2009; 24(12): 3025–3032.

30.

Ballard

Lowton

Wright

What’s the delay? A qualitative study of women’s experiences of reaching a diagnosis of endometriosis. Fertil Steril 2006; 86(5): 1296–1301.

31.

Eskenazi

Warner

ML.

Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997; 24(2): 235–258.

32.

Hadfield

Mardon

Barlow

et al . Delay in the diagnosis of endometriosis: a survey of women from the USA and the UK. Hum Reprod 1996; 11(4): 878–880.

33.

Jansen

Russell

Nonpigmented endometriosis: clinical, laparoscopic, and pathologic definition. Am J Obstet Gynecol 1986; 155(6): 1154–1159.

34.

Redwine

DB.

Age-related evolution in color appearance of endometriosis. Fertil Steril 1987; 48(6): 1062–1063.

35.

Hey-Cunningham

Fazleabas

Braundmeier

et al . Endometrial stromal cells and immune cell populations within lymph nodes in a nonhuman primate model of endometriosis. Reprod Sci 2011; 18(8): 747–754.

36.

D’Hooghe

TM.

Clinical relevance of the baboon as a model for the study of endometriosis. Fertil Steril 1997; 68(4): 613–625.

37.

D’Hooghe

Bambra

De Jonge

et al . The prevalence of spontaneous endometriosis in the baboon (Papio anubis, Papio cynocephalus) increases with the duration of captivity. Acta Obstet Gynecol Scand 1996; 75(2): 98–101.

38.

D’Hooghe

Kyama

Chai

et al . Nonhuman primate models for translational research in endometriosis. Reprod Sci 2009; 16(2): 152–161.

39.

Dehoux

J-P

Defrere

Squifflet

et al . Is the baboon model appropriate for endometriosis studies? Fertil Steril 2011; 96(3): 728–733.e3.

40.

Donnez

Orellana

Van Kerk

et al . Invasion process of induced deep nodular endometriosis in an experimental baboon model: similarities with collective cell migration? Fertil Steril 2015; 104(2): 491–497.e2.

41.

Fazleabas

AT.

A baboon model for inducing endometriosis. Methods Mol Med 2006; 121: 95–99.

42.

Fazleabas

Brudney

Gurates

et al . A modified baboon model for endometriosis. Ann N Y Acad Sci 2002; 955: 308–317, discussion 340–342, 396–406.

43.

Hastings

Fazleabas

AT.

A baboon model for endometriosis: implications for fertility. Reprod Biol Endocrinol 2006; 4(Suppl. 1): S7.

44.

Nair

Baker

Owston

et al . An efficient model of human endometriosis by induced unopposed estrogenicity in baboons. Oncotarget 2016; 7(10): 10857–10869.

45.

Braundmeier

Fazleabas

AT.

The non-human primate model of endometriosis: research and implications for fecundity. Mol Hum Reprod 2009; 15(10): 577–586.

46.

D’Hooghe

Bambra

Cornillie

et al . Prevalence and laparoscopic appearance of spontaneous endometriosis in the baboon (Papio anubis, Papio cynocephalus). Biol Reprod 1991; 45(3): 411–416.

47.

Fanton

Hubbard

GB.

Spontaneous endometriosis in a cynomolgus monkey (Macaca fascicularis). Lab Anim Sci 1983; 33(6): 597–599.

48.

McClure

Ridley

Graham

CE.

Disseminated endometriosis in a Rhesus monkey (Macaca mulatta). Histogenesis and possible relationship to irradiation exposure 1, 2. J Med Assoc Ga 1971; 60(1): 11–13.

49.

Merrill

JA.

Spontaneous endometriosis in the Kenya baboon (Papio doguera). Am J Obstet Gynecol 1968; 101(4): 569–570.

50.

Sampson

JA.

Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927; 14: 422–469.

51.

D’Hooghe

Bambra

Suleman

et al . Development of a model of retrograde menstruation in baboons (Papio anubis). Fertil Steril 1994; 62(3): 635–638.

52.

D’Hooghe

Bambra

Raeymaekers

et al . Intrapelvic injection of menstrual endometrium causes endometriosis in baboons (Papio cynocephalus and Papio anubis). Am J Obstet Gynecol 1995; 173(1): 125–134.

53.

Gashaw

Hastings

Jackson

et al . Induced endometriosis in the baboon (Papio anubis) increases the expression of the proangiogenic factor CYR61 (CCN1) in eutopic and ectopic endometria. Biol Reprod 2006; 74(6): 1060–1066.

54.

Harirchian

Gashaw

Lipskind

et al . Lesion kinetics in a non-human primate model of endometriosis. Hum Reprod 2012; 27(8): 2341–2351.

55.

Hastings

Jackson

Mavrogianis

et al . The estrogen early response gene FOS is altered in a baboon model of endometriosis. Biol Reprod 2006; 75(2): 176–182.

56.

Lundberg

Alm

Wharton

et al . Protein gene product 9.5 (PGP 9.5). A new neuronal marker visualizing the whole uterine innervation and pregnancy-induced and developmental changes in the guinea pig. Histochemistry 1988; 90(1): 9–17.

57.

Quinn

Uterine innervation in adenomyosis. J Obstet Gynaecol 2007; 27(3): 287–291.

58.

Le Greves

Nyberg

Terenius

et al . Calcitonin gene-related peptide is a potent inhibitor of substance P degradation. Eur J Pharmacol 1985; 115(2–3): 309–311.

59.

Heinrich

Reinecke

Forssmann

WG.

Peptidergic innervation of the human and guinea pig uterus. Arch Gynecol 1986; 237(4): 213–219.

60.

Lynch

Wharton

Bryant

et al . The differential distribution of vasoactive intestinal polypeptide in the normal human female genital tract. Histochemistry 1980; 67(2): 169–177.

61.

Schlaepfer

WW.

Neurofilaments: structure, metabolism and implications in disease. J Neuropathol Exp Neurol 1987; 46(2): 117–129.

62.

Al-Jefout

Andreadis

Tokushige

et al . A pilot study to evaluate the relative efficacy of endometrial biopsy and full curettage in making a diagnosis of endometriosis by the detection of endometrial nerve fibers. Am J Obstet Gynecol 2007; 197(6): 578.e1–e4.

63.

Tariverdian

Theoharides

Siedentopf

et al . Neuroendocrine-immune disequilibrium and endometriosis: an interdisciplinary approach. Semin Immunopathol 2007; 29(2): 193–210.

64.

Manconi

Fazleabas

Markham

et al . Nerve fibre density in peritoneal lesions of endometriosis in a nonhuman primate model of endometriosis. In: 57th annual scientific meeting of the Society for Gynecologic Investigation (SGI), Orlando, FL, 24–27 March 2010.

65.

Manconi

Fazleabas

Markham

et al . Nerve Fiber populations with peritoneal lesions in a nonhuman primate model of endometriosis. In: 11th world congress on endometriosis, Montpellier, France, 4–7 September 2011, p. 66.

66.

Manconi

Fazleabas

Markham

et al . Nerve fibre density in peritoneal lesions of endometriosis in a baboon (Papio anubis) model of endometriosis. In: The Australian health & medical research congress, Adelaide, SA, Australia, 25–28 November 2012, p. 273. Adelaide, SA, Australia: Adelaide Convention Centre.

67.

Al-Jefout

Tokushige

Hey-Cunningham

et al . Microanatomy and function of the eutopic endometrium in women with endometriosis. Expet Rev Obstet Gynecol 2009; 4: 61–79.

68.

Anaf

Simon

El Nakadi

et al . Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis. Hum Reprod 2002; 17(7): 1895–1900.