Skip to main content
Top
Published in: Journal of Assisted Reproduction and Genetics 3/2017

01-03-2017 | Reproductive Physiology and Disease

Intrafollicular inflammatory cytokines but not steroid hormone concentrations are increased in naturally matured follicles of women with proven endometriosis

Authors: Gengxiang Wu, N. A. Bersinger, M. D. Mueller, M. von Wolff

Published in: Journal of Assisted Reproduction and Genetics | Issue 3/2017

Login to get access

Abstract

Purpose

The aim of this study was to assess whether the intrafollicular cytokine profile in naturally developed follicles is different in women with endometriosis, possibly explaining the lower reproductive outcome in endometriosis patients.

Methods

A matched case-control study was conducted at a university-based infertility and endometriosis centre. The study population included 17 patients with laparoscopically and histologically confirmed endometriosis (rAFS stages II–IV), each undergoing one natural cycle IVF (NC-IVF) treatment cycle between 2013 and 2015, and 17 age-matched NC-IVF women without diagnosed endometriosis (control group). Follicular fluid and serum was collected at the time of follicle aspiration. The concentrations of inflammatory cytokines (IL-1β, IL-6, IL-8, IL-15, IL-18, TNF-α) and hormones (testosterone, estradiol, AMH) were determined in follicular fluid and serum by single or multiplexed immunoassay and compared between both groups.

Results

In the follicular fluid, IL-1β and IL-6 showed significantly (P < 0.001 and 0.01, respectively) higher median concentrations in the endometriosis group than in the control group and a tendency towards endometriosis severity (rAFS stage) dependence. The levels of the interleukins detectable in follicular fluid were significantly higher than those in the serum (P < 0.01). Follicular estradiol concentration was lower in severe endometriosis patients than in the control group (P = 0.036). Follicular fluid IL-1β and IL-6 levels were not correlated with estradiol in the same compartment in neither patient group.

Conclusions

In women with moderate and severe endometrioses, some intrafollicular inflammatory cytokines are upregulated and not correlated with intrafollicular hormone concentrations. This might be due to the inflammatory microenvironment in endometriosis women, affecting follicular function and thereby possibly contributing to the reproductive dysfunction in endometriosis.
Literature
1.
go back to reference Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3:93–110.43.PubMedPubMedCentral Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3:93–110.43.PubMedPubMedCentral
2.
go back to reference Wunder DM, Mueller MD, Birkhäuser MH, Bersinger NA. Steroids and protein markers in the follicular fluid as indicators of oocyte quality in patients with and without endometriosis. J Assist Reprod Genet. 2005;22:257–64.CrossRefPubMedPubMedCentral Wunder DM, Mueller MD, Birkhäuser MH, Bersinger NA. Steroids and protein markers in the follicular fluid as indicators of oocyte quality in patients with and without endometriosis. J Assist Reprod Genet. 2005;22:257–64.CrossRefPubMedPubMedCentral
4.
go back to reference Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98:591–8.CrossRef Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012;98:591–8.CrossRef
5.
go back to reference Sikora J, Mielczarek-Palacz A, Kondera-Anasz Z. Association of the precursor of interleukin-1β and peritoneal inflammation-role in pathogenesis of endometriosis. J Clin Lab Anal. 2016. Sikora J, Mielczarek-Palacz A, Kondera-Anasz Z. Association of the precursor of interleukin-1β and peritoneal inflammation-role in pathogenesis of endometriosis. J Clin Lab Anal. 2016.
6.
go back to reference Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohí J, Simón C. The follicular and endocrine environment in women with endometriosis: local and systemic cytokine production. Fertil Steril. 1998;70:425–31.CrossRefPubMed Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohí J, Simón C. The follicular and endocrine environment in women with endometriosis: local and systemic cytokine production. Fertil Steril. 1998;70:425–31.CrossRefPubMed
7.
go back to reference Kashanian M, Sariri E, Vahdat M, Ahmari M, Moradi Y, Sheikhansari N. A comparison between serum levels of interleukin-6 and CA125 in patients with endometriosis and normal women. Med J Islam Repub Iran. 2015;29:280.PubMedPubMedCentral Kashanian M, Sariri E, Vahdat M, Ahmari M, Moradi Y, Sheikhansari N. A comparison between serum levels of interleukin-6 and CA125 in patients with endometriosis and normal women. Med J Islam Repub Iran. 2015;29:280.PubMedPubMedCentral
8.
go back to reference Malhotra N, Karmakar D, Tripathi V, Luthra K, Kumar S. Correlation of angiogenic cytokines-leptin and IL-8 in stage, type and presentation of endometriosis. Gynecol Endocrinol. 2012;28:224–7.CrossRefPubMed Malhotra N, Karmakar D, Tripathi V, Luthra K, Kumar S. Correlation of angiogenic cytokines-leptin and IL-8 in stage, type and presentation of endometriosis. Gynecol Endocrinol. 2012;28:224–7.CrossRefPubMed
9.
go back to reference Arici A, Matalliotakis I, Goumenou A, Koumantakis G, Vassiliadis S, Mahutte NG. Altered expression of interleukin-18 in the peritoneal fluid of women with endometriosis. Fertil Steril. 2003;80:889–94.CrossRefPubMed Arici A, Matalliotakis I, Goumenou A, Koumantakis G, Vassiliadis S, Mahutte NG. Altered expression of interleukin-18 in the peritoneal fluid of women with endometriosis. Fertil Steril. 2003;80:889–94.CrossRefPubMed
10.
go back to reference Hammadeh ME, Ertan AK, Zeppezauer M, Baltes S, Georg T, Rosenbaum P, et al. Immunoglobulins and cytokines level in follicular fluid in relation to etiology of infertility and their relevance to IVF outcome. Am J Reprod Immunol. 2002;47:82–90.CrossRefPubMed Hammadeh ME, Ertan AK, Zeppezauer M, Baltes S, Georg T, Rosenbaum P, et al. Immunoglobulins and cytokines level in follicular fluid in relation to etiology of infertility and their relevance to IVF outcome. Am J Reprod Immunol. 2002;47:82–90.CrossRefPubMed
11.
go back to reference von Wolff M, Kollmann Z, Flück CE, Stute P, Marti U, Weiss B, et al. Gonadotrophin stimulation for in vitro fertilization significantly alters the hormone milieu in follicular fluid: a comparative study between natural cycle IVF and conventional IVF. Hum Reprod. 2014;29:1049–57.CrossRef von Wolff M, Kollmann Z, Flück CE, Stute P, Marti U, Weiss B, et al. Gonadotrophin stimulation for in vitro fertilization significantly alters the hormone milieu in follicular fluid: a comparative study between natural cycle IVF and conventional IVF. Hum Reprod. 2014;29:1049–57.CrossRef
12.
go back to reference Hauzman EE, Garcia-Velasco JA, Pellicer A. Oocyte donation and endometriosis: what are the lessons? Semin Reprod Med. 2013;31:173–7.CrossRefPubMed Hauzman EE, Garcia-Velasco JA, Pellicer A. Oocyte donation and endometriosis: what are the lessons? Semin Reprod Med. 2013;31:173–7.CrossRefPubMed
13.
go back to reference Bersinger NA, Kollmann Z, Von Wolff M. Serum but not follicular fluid cytokine levels are increased in stimulated versus natural cycle IVF: a multiplexed assay study. J Reprod Immunol. 2014;106:27–33.CrossRefPubMed Bersinger NA, Kollmann Z, Von Wolff M. Serum but not follicular fluid cytokine levels are increased in stimulated versus natural cycle IVF: a multiplexed assay study. J Reprod Immunol. 2014;106:27–33.CrossRefPubMed
14.
go back to reference Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817–21. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817–21.
15.
go back to reference von Wolff M, Schneider S, Kollmann Z, Weiss B, Bersinger NA. Exogenous gonadotropins do not increase the blood-follicular transportation capacity of extra-ovarian hormones such as prolactin and cortisol. Reprod Biol Endocrinol. 2013;11:87.CrossRef von Wolff M, Schneider S, Kollmann Z, Weiss B, Bersinger NA. Exogenous gonadotropins do not increase the blood-follicular transportation capacity of extra-ovarian hormones such as prolactin and cortisol. Reprod Biol Endocrinol. 2013;11:87.CrossRef
16.
go back to reference Wunder DM, Mueller MD, Birkhäuser MH, Bersinger NA. Increased ENA-78 in the follicular fluid of patients with endometriosis. Acta Obstet Gynecol Scand. 2006;85:336–42.CrossRefPubMed Wunder DM, Mueller MD, Birkhäuser MH, Bersinger NA. Increased ENA-78 in the follicular fluid of patients with endometriosis. Acta Obstet Gynecol Scand. 2006;85:336–42.CrossRefPubMed
17.
go back to reference Falconer H, Sundqvist J, Gemzell-Danielsson K, von Schoultz B, D’Hooghe TM, Fried G. IVF outcome in women with endometriosis in relation to tumour necrosis factor and anti-Müllerian hormone. Reprod Biomed Online. 2009;18:582–8.CrossRefPubMed Falconer H, Sundqvist J, Gemzell-Danielsson K, von Schoultz B, D’Hooghe TM, Fried G. IVF outcome in women with endometriosis in relation to tumour necrosis factor and anti-Müllerian hormone. Reprod Biomed Online. 2009;18:582–8.CrossRefPubMed
18.
go back to reference Choi YS, Cho S, Seo SK, Park JH, Kim SH, Lee BS. Alteration in the intrafollicular thiol-redox system in infertile women with endometriosis. Reproduction. 2015;149:155–62.CrossRefPubMed Choi YS, Cho S, Seo SK, Park JH, Kim SH, Lee BS. Alteration in the intrafollicular thiol-redox system in infertile women with endometriosis. Reproduction. 2015;149:155–62.CrossRefPubMed
19.
go back to reference Lambert S, Santulli P, Chouzenoux S, Marcellin L, Borghese B, de Ziegler D, et al. Endometriosis: increasing concentrations of serum interleukin-1β and interleukin-1sRII is associated with the deep form of this pathology. J Gynecol Obstet Biol Reprod (Paris). 2014;43:735–43.CrossRef Lambert S, Santulli P, Chouzenoux S, Marcellin L, Borghese B, de Ziegler D, et al. Endometriosis: increasing concentrations of serum interleukin-1β and interleukin-1sRII is associated with the deep form of this pathology. J Gynecol Obstet Biol Reprod (Paris). 2014;43:735–43.CrossRef
20.
go back to reference Liu Z, de Matos DG, Fan HY, Shimada M, Palmer S, Richards JS. Interleukin-6: an autocrine regulator of the mouse cumulus cell-oocyte complex expansion process. Endocrinology. 2009;150:3360–8.CrossRefPubMedPubMedCentral Liu Z, de Matos DG, Fan HY, Shimada M, Palmer S, Richards JS. Interleukin-6: an autocrine regulator of the mouse cumulus cell-oocyte complex expansion process. Endocrinology. 2009;150:3360–8.CrossRefPubMedPubMedCentral
21.
go back to reference Borrelli GM, Abrão MS, Mechsner S. Can chemokines be used as biomarkers for endometriosis? A systematic review. Hum Reprod. 2014;29:253–66.CrossRefPubMed Borrelli GM, Abrão MS, Mechsner S. Can chemokines be used as biomarkers for endometriosis? A systematic review. Hum Reprod. 2014;29:253–66.CrossRefPubMed
22.
23.
go back to reference Schneider S, Kollmann Z, Bersinger NA, Mueller MD, Dahinden C, von Wolff M. Charakterisierung der immunzellpopulation in Follikelflüssigkeitsaspiraten: Ein Vergleich zwischen natural cycle IVF und konventioneller IVF. J Reproduktionsmed Endokrinol. 2013;10:310–1. Schneider S, Kollmann Z, Bersinger NA, Mueller MD, Dahinden C, von Wolff M. Charakterisierung der immunzellpopulation in Follikelflüssigkeitsaspiraten: Ein Vergleich zwischen natural cycle IVF und konventioneller IVF. J Reproduktionsmed Endokrinol. 2013;10:310–1.
24.
go back to reference Altun T, Jindal S, Greenseid K, Shu J, Pal L. Low follicular fluid IL-6 levels in IVF patients are associated with increased likelihood of clinical pregnancy. J Assist Reprod Genet. 2011;28:245–51.CrossRefPubMed Altun T, Jindal S, Greenseid K, Shu J, Pal L. Low follicular fluid IL-6 levels in IVF patients are associated with increased likelihood of clinical pregnancy. J Assist Reprod Genet. 2011;28:245–51.CrossRefPubMed
25.
go back to reference Zollner KP, Hofmann T, Zollner U. Good fertilization results associated with high IL-1beta concentrations in follicular fluid of IVF patients. J Reprod Med. 2013;58:485–90.PubMed Zollner KP, Hofmann T, Zollner U. Good fertilization results associated with high IL-1beta concentrations in follicular fluid of IVF patients. J Reprod Med. 2013;58:485–90.PubMed
26.
go back to reference Asimakopoulos B, Demirel C, Felberbaum R, Waczek S, Nikolettos N, Köster F, et al. Concentrations of inflammatory cytokines and the outcome in ICSI cycles. In Vivo. 2010;24:495–500.PubMed Asimakopoulos B, Demirel C, Felberbaum R, Waczek S, Nikolettos N, Köster F, et al. Concentrations of inflammatory cytokines and the outcome in ICSI cycles. In Vivo. 2010;24:495–500.PubMed
27.
go back to reference Bersinger NA, Dechaud H, McKinnon B, Mueller MD. Analysis of cytokines in the peritoneal fluid of endometriosis patients as a function of the menstrual cycle stage using the Bio-Plex® platform. Arch Physiol Biochem. 2012;118:210–8.CrossRefPubMed Bersinger NA, Dechaud H, McKinnon B, Mueller MD. Analysis of cytokines in the peritoneal fluid of endometriosis patients as a function of the menstrual cycle stage using the Bio-Plex® platform. Arch Physiol Biochem. 2012;118:210–8.CrossRefPubMed
28.
go back to reference Malizia BA, Wook YS, Penzias AS, Usheva A. The human ovarian follicular fluid level of interleukin-8 is associated with follicular size and patient age. Fertil Steril. 2010;93:537–43.CrossRefPubMed Malizia BA, Wook YS, Penzias AS, Usheva A. The human ovarian follicular fluid level of interleukin-8 is associated with follicular size and patient age. Fertil Steril. 2010;93:537–43.CrossRefPubMed
29.
go back to reference Runesson E, Bostrom EK, Janson PO, Brannstrom M. The human preovulatory follicle is a source of the chemotactic cytokine interleukin-8. Mol Hum Reprod. 1996;2:245–50.CrossRefPubMed Runesson E, Bostrom EK, Janson PO, Brannstrom M. The human preovulatory follicle is a source of the chemotactic cytokine interleukin-8. Mol Hum Reprod. 1996;2:245–50.CrossRefPubMed
30.
go back to reference Gutman G, Soussan-Gutman L, Malcov M, Lessing JB, Amit A, Azem F. Interleukin-18 is high in the serum of IVF pregnancies with ovarian hyperstimulation syndrome. Am J Reprod Immunol. 2004;51:381–4.CrossRefPubMed Gutman G, Soussan-Gutman L, Malcov M, Lessing JB, Amit A, Azem F. Interleukin-18 is high in the serum of IVF pregnancies with ovarian hyperstimulation syndrome. Am J Reprod Immunol. 2004;51:381–4.CrossRefPubMed
31.
go back to reference Sarapik A, Velthut A, Haller-Kikkatalo K, Faure GC, Béné MC, de Carvalho Bittencourt M, et al. Follicular proinflammatory cytokines and chemokines as markers of IVF success. Clin Develop Immunol. 2012;2012:606459.CrossRef Sarapik A, Velthut A, Haller-Kikkatalo K, Faure GC, Béné MC, de Carvalho Bittencourt M, et al. Follicular proinflammatory cytokines and chemokines as markers of IVF success. Clin Develop Immunol. 2012;2012:606459.CrossRef
32.
go back to reference Fanchin R, Mendez Lozano DH, Frydman N, Gougeon A, di Clemente N, Frydman R, et al. Anti-Müllerian hormone concentrations in the follicular fluid of the preovulatory follicle are predictive of the implantation potential of the ensuing embryo obtained by in vitro fertilization. J Clin Endocrinol Metab. 2007;92:1796–802.CrossRefPubMed Fanchin R, Mendez Lozano DH, Frydman N, Gougeon A, di Clemente N, Frydman R, et al. Anti-Müllerian hormone concentrations in the follicular fluid of the preovulatory follicle are predictive of the implantation potential of the ensuing embryo obtained by in vitro fertilization. J Clin Endocrinol Metab. 2007;92:1796–802.CrossRefPubMed
33.
go back to reference Takahashi C, Fujito A, Kazuka M, Sugiyama R, Ito H, Isaka K. Anti-Müllerian hormone substance from follicular fluid is positively associated with success in oocyte fertilization during in vitro fertilization. Fertil Steril. 2008;89:586–91.CrossRefPubMed Takahashi C, Fujito A, Kazuka M, Sugiyama R, Ito H, Isaka K. Anti-Müllerian hormone substance from follicular fluid is positively associated with success in oocyte fertilization during in vitro fertilization. Fertil Steril. 2008;89:586–91.CrossRefPubMed
34.
go back to reference Pabuccu R, Kaya C, Cağlar GS, Oztas E, Satiroglu H. Follicular-fluid anti-Mullerian hormone concentrations are predictive of assisted reproduction outcome in PCOS patients. Reprod Biomed Online. 2009;19:631–7.CrossRefPubMed Pabuccu R, Kaya C, Cağlar GS, Oztas E, Satiroglu H. Follicular-fluid anti-Mullerian hormone concentrations are predictive of assisted reproduction outcome in PCOS patients. Reprod Biomed Online. 2009;19:631–7.CrossRefPubMed
35.
go back to reference Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, et al. European society of human reproduction and embryology. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29:400–12.CrossRefPubMed Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, et al. European society of human reproduction and embryology. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29:400–12.CrossRefPubMed
36.
go back to reference Vercellini P, Fedele L, Aimi G, De Giorgi O, Consonni D, Crosignani PG, et al. Reproductive performance, pain recurrence and disease relapse after conservative surgical treatment for endometriosis: the predictive value of the current classification system. Hum Reprod. 2006;21:2679–85.CrossRefPubMed Vercellini P, Fedele L, Aimi G, De Giorgi O, Consonni D, Crosignani PG, et al. Reproductive performance, pain recurrence and disease relapse after conservative surgical treatment for endometriosis: the predictive value of the current classification system. Hum Reprod. 2006;21:2679–85.CrossRefPubMed
37.
go back to reference Pop-Trajkovic S, Popović J, Antić V, Radović D, Stefanović M, Vukomanović P. Stages of endometriosis: does it affect in vitro fertilization outcome. Taiwan J Obstet Gynecol. 2014;53:224–6.CrossRef Pop-Trajkovic S, Popović J, Antić V, Radović D, Stefanović M, Vukomanović P. Stages of endometriosis: does it affect in vitro fertilization outcome. Taiwan J Obstet Gynecol. 2014;53:224–6.CrossRef
Metadata
Title
Intrafollicular inflammatory cytokines but not steroid hormone concentrations are increased in naturally matured follicles of women with proven endometriosis
Authors
Gengxiang Wu
N. A. Bersinger
M. D. Mueller
M. von Wolff
Publication date
01-03-2017
Publisher
Springer US
Published in
Journal of Assisted Reproduction and Genetics / Issue 3/2017
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI
https://doi.org/10.1007/s10815-016-0865-3

Other articles of this Issue 3/2017

Journal of Assisted Reproduction and Genetics 3/2017 Go to the issue