Objectives: Myeloid cell-derived factors contribute to the immunopathology of endometriosis. Soluble CD14 (sCD14), CD163 (sCD163), and MIF serve as in vivo markers of myeloid function. However, these soluble molecules are largely unexplored in women with endometriosis-related infertility cases. We investigated three soluble markers, namely sCD14, sCD163, and MIF, in cases of infertility associated with endometriosis and correlated its level to the stage of endometriosis. Design: Eighty-seven women newly diagnosed with endometriosis or other benign gynecologic control cases linked to infertility were prospectively recruited and underwent diagnostic laparoscopy. Participants: Forty-four patients with endometriosis were included in this study, comprising 19 patients with early-endometriosis (stages I and II) and 25 late-endometriosis (stages III and IV) based on the revised American Society for Reproductive Medicine (rASRM) classification. The remaining 43 patients constituted a control group with infertility due to other causes. Methods: The levels of sCD14, sCD163, and MIF in serum and peritoneal fluid were assessed using ELISA. Results: Endometriosis women exhibited significantly higher serum levels of sCD163 and MIF levels compared to the control group. Both sCD163 and MIF levels displayed a positive correlation with the rASRM adhesion score. Moreover, the MIF level in serum had a positive correlation with the rASRM endometriosis score. In receiver operating characteristic analysis, serum sCD163 and MIF could significantly discriminate endometriosis and non-endometriosis in infertility cases. Limitations: Some limitations of the current study deserve to be underlined. First, the sensitive ELISA method was the sole-validated tool for detecting the markers in patient samples. Second, healthy or fertile women were not involved as the control group. Conclusions: The elevated systemic levels of sCD163 and MIF correlated with the severity of endometriosis. These soluble molecules have a potential diagnostic capacity as a non-invasive biomarker. Furthermore, our data warrants future studies on the underlying mechanism of sCD163 and MIF in endometriosis-related infertility.

1.
Wei
Y
,
Liang
Y
,
Lin
H
,
Dai
Y
,
Yao
S
.
Autonomic nervous system and inflammation interaction in endometriosis-associated pain
.
J Neuroinflammation
.
2020
;
17
(
1
):
80
. .
2.
Zondervan
KT
,
Becker
CM
,
Koga
K
,
Missmer
SA
,
Taylor
RN
,
Vigano
P
.
Endometriosis
.
Nat Rev Dis Primers
.
2018
;
4
(
1
):
9
. .
3.
Haas
D
,
Shebl
O
,
Shamiyeh
A
,
Oppelt
P
.
The rASRM score and the Enzian classification for endometriosis: their strengths and weaknesses
.
Acta Obstet Gynecol Scand
.
2013
;
92
(
1
):
3
7
. .
4.
Ferrier
C
,
Boujenah
J
,
Poncelet
C
,
Chabbert-Buffet
N
,
Mathieu D'Argent
E
,
Carbillon
L
, et al
.
Use of the EFI score in endometriosis-associated infertility: a cost-effectiveness study
.
Eur J Obstet Gynecol Reprod Biol
.
2020
;
253
:
296
303
. .
5.
Wei
C
,
Mei
J
,
Tang
L
,
Liu
Y
,
Li
D
,
Li
M
, et al
.
1-Methyl-tryptophan attenuates regulatory T cells differentiation due to the inhibition of estrogen-IDO1-MRC2 axis in endometriosis
.
Cell Death Dis
.
2016
;
7
(
12
):
e2489
. .
6.
Yang
HL
,
Zhou
WJ
,
Chang
KK
,
Mei
J
,
Huang
LQ
,
Wang
MY
, et al
.
The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β
.
Reproduction
.
2017
;
154
(
6
):
815
25
. .
7.
Symons
LK
,
Miller
JE
,
Kay
VR
,
Marks
RM
,
Liblik
K
,
Koti
M
, et al
.
The immunopathophysiology of endometriosis
.
Trends Mol Med
.
2018
;
24
(
9
):
748
62
. .
8.
Yang
Y
,
Degranpre
P
,
Kharfi
A
,
Akoum
A
.
Identification of macrophage migration inhibitory factor as a potent endothelial cell growth promoting agent released by ectopic human endometrial cells
.
J Clin Endocrinol Metab
.
2000
;
85
(
12
):
4721
7
. .
9.
Hogg
C
,
Horne
AW
,
Greaves
E
.
Endometriosis-associated macrophages: origin, phenotype, and function
.
Front Endocrinol
.
2020
;
11
:
7
. .
10.
Hudson
QJ
,
Ashjaei
K
,
Perricos
A
,
Kuessel
L
,
Husslein
H
,
Wenzl
R
, et al
.
Endometriosis patients show an increased M2 response in the peritoneal CD14+low/CD68+low macrophage subpopulation coupled with an increase in the T-helper 2 and T-regulatory cells
.
Reprod Sci
.
2020
;
27
(
10
):
1920
31
. .
11.
Gómez-Rial
J
,
Currás-Tuala
MJ
,
Rivero-Calle
I
,
Gómez-Carballa
A
,
Cebey-López
M
,
Rodríguez-Tenreiro
C
, et al
.
Increased serum levels of sCD14 and sCD163 indicate a preponderant role for monocytes in COVID-19 immunopathology
.
Front Immunol
.
2020
;
11
:
560381
. .
12.
Takebayashi
A
,
Kimura
F
,
Kishi
Y
,
Ishida
M
,
Takahashi
A
,
Yamanaka
A
, et al
.
Subpopulations of macrophages within eutopic endometrium of endometriosis patients
.
Am J Reprod Immunol
.
2015
;
73
(
3
):
221
31
. .
13.
Kim-Chang
JJ
,
Donovan
K
,
Loop
MS
,
Hong
S
,
Fischer
B
,
Venturi
G
, et al
.
Higher soluble CD14 levels are associated with lower visuospatial memory performance in youth with HIV
.
AIDS
.
2019
;
33
(
15
):
2363
74
. .
14.
Lidofsky
A
,
Holmes
JA
,
Feeney
ER
,
Kruger
AJ
,
Salloum
S
,
Zheng
H
, et al
.
Macrophage activation marker soluble CD163 is a dynamic marker of liver fibrogenesis in human immunodeficiency virus/hepatitis C virus coinfection
.
J Infect Dis
.
2018
;
218
(
9
):
1394
403
. .
15.
Novakovic
P
,
Harding
JC
,
Ladinig
A
,
Al-Dissi
AN
,
MacPhee
DJ
,
Detmer
SE
.
Relationships of CD163 and CD169 positive cell numbers in the endometrium and fetal placenta with type 2 PRRSV RNA concentration in fetal thymus
.
Vet Res
.
2016
;
47
(
1
):
76
. .
16.
Shive
CL
,
Jiang
W
,
Anthony
DD
,
Lederman
MM
.
Soluble CD14 is a nonspecific marker of monocyte activation
.
AIDS
.
2015
;
29
(
10
):
1263
5
. .
17.
Tippett
E
,
Cheng
WJ
,
Westhorpe
C
,
Cameron
PU
,
Brew
BJ
,
Lewin
SR
, et al
.
Differential expression of CD163 on monocyte subsets in healthy and HIV-1 infected individuals
.
PLoS One
.
2011
;
6
(
5
):
e19968
. .
18.
Sandler
NG
,
Wand
H
,
Roque
A
,
Law
M
,
Nason
MC
,
Nixon
DE
, et al
.
Plasma levels of soluble CD14 independently predict mortality in HIV infection
.
J Infect Dis
.
2011
;
203
(
6
):
780
90
. .
19.
Mascia
C
,
Pozzetto
I
,
Kertusha
B
,
Marocco
R
,
Del Borgo
C
,
Tieghi
T
, et al
.
Persistent high plasma levels of sCD163 and sCD14 in adult patients with measles virus infection
.
PLoS One
.
2018
;
13
(
5
):
e0198174
. .
20.
Parisi
SG
,
Andreis
S
,
Mengoli
C
,
Menegotto
N
,
Cavinato
S
,
Scaggiante
R
, et al
.
Soluble CD163 and soluble CD14 plasma levels but not cellular HIV-DNA decrease during successful interferon-free anti-HCV therapy in HIV-1-HCV co-infected patients on effective combined anti-HIV treatment
.
Med Microbiol Immunol
.
2018
;
207
(
3–4
):
183
94
. .
21.
Sun
H
,
Jiang
R
,
Han
B
,
Du
X
,
Ma
C
,
Xu
Y
, et al
.
Serum levels of soluble CD163 and soluble CD14 following antibiotic therapy of patients with acute brucellosis
.
J Infect Dev Ctries
.
2019
;
13
(
8
):
714
9
. .
22.
Gómez-Rial
J
,
Currás-Tuala
MJ
,
Rivero-Calle
I
,
Gómez-Carballa
A
,
Cebey-López
M
,
Rodríguez-Tenreiro
C
, et al
.
Increased serum levels of sCD14 and sCD163 indicate a preponderant role for monocytes in COVID-19 immunopathology
.
Front Immunol
.
2020
;
11
:
560381
. .
23.
Elbaradie
SMY
,
Bakry
MS
,
Bosilah
AH
.
Serum macrophage migration inhibition factor for diagnosing endometriosis and its severity: case-control study
.
BMC Womens Health
.
2020
;
20
(
1
):
189
. .
24.
Chekini
Z
,
Poursadoughian Yaran
A
,
Ansari-Pour
N
,
Shahhoseini
M
,
Ramazanali
F
,
Aflatoonian
R
, et al
.
A novel gene-wide haplotype at the macrophage migration inhibitory factor (MIF) locus is associated with endometrioma
.
Eur J Obstet Gynecol Reprod Biol
.
2020
;
247
:
6
9
. .
25.
Cao
WG
,
Morin
M
,
Metz
C
,
Maheux
R
,
Akoum
A
.
Stimulation of macrophage migration inhibitory factor expression in endometrial stromal cells by interleukin 1, beta involving the nuclear transcription factor NFkappaB
.
Biol Reprod
.
2005
;
73
(
3
):
565
70
. .
26.
Akoum
A
,
Metz
CN
,
Al-Akoum
M
,
Kats
R
.
Macrophage migration inhibitory factor expression in the intrauterine endometrium of women with endometriosis varies with disease stage, infertility status, and pelvic pain
.
Fertil Steril
.
2006
;
85
(
5
):
1379
85
. .
27.
Lin
W
,
Chen
S
,
Li
M
,
Wang
B
,
Qu
X
,
Zhang
Y
.
Expression of macrophage migration inhibitory factor in human endometriosis: relation to disease stage, menstrual cycle and infertility
.
J Obstet Gynaecol Res
.
2010
;
36
(
2
):
344
51
. .
28.
Zhang
X
,
Mu
L
.
Association between macrophage migration inhibitory factor in the endometrium and estrogen in endometriosis
.
Exp Ther Med
.
2015
;
10
(
2
):
787
91
. .
29.
Nahm
FS
.
Receiver operating characteristic curve: overview and practical use for clinicians
.
Korean J Anesthesiol
.
2022
;
75
(
1
):
25
36
. .
30.
Bersinger
NA
,
von Roten
S
,
Wunder
DM
,
Raio
L
,
Dreher
E
,
Mueller
MD
.
PAPP-A and osteoprotegerin, together with interleukin-8 and RANTES, are elevated in the peritoneal fluid of women with endometriosis
.
Am J Obstet Gynecol
.
2006
;
195
(
1
):
103
8
. .
31.
Jee
BC
,
Suh
CS
,
Kim
SH
,
Moon
SY
.
Serum soluble CD163 and interleukin-6 levels in women with ovarian endometriomas
.
Gynecol Obstet Invest
.
2008
;
66
(
1
):
47
52
. .
32.
Nielsen
MC
,
Hvidbjerg Gantzel
R
,
Claria
J
,
Trebicka
J
,
Møller
HJ
,
Grønbæk
H
.
Macrophage activation markers, CD163 and CD206, in acute-on-chronic liver failure
.
Cells
.
2020
;
9
(
5
):
1175
. .
33.
Møller
HJ
,
Nielsen
MJ
,
Maniecki
MB
,
Madsen
M
,
Moestrup
SK
.
Soluble macrophage-derived CD163: a homogenous ectodomain protein with a dissociable haptoglobin-hemoglobin binding
.
Immunobiology
.
2010
;
215
(
5
):
406
12
. .
34.
Mascia
C
,
Lichtner
M
,
Zuccala
P
,
Vita
S
,
Tieghi
T
,
Marocco
R
, et al
.
Active HCV infection is associated with increased circulating levels of interferon-gamma (IFN-γ)-inducible protein-10 (IP-10), soluble CD163 and inflammatory monocytes regardless of liver fibrosis and HIV coinfection
.
Clin Res Hepatol Gastroenterol
.
2017
;
41
(
6
):
644
55
. .
35.
Zhang
X
,
Mu
L
.
Association between macrophage migration inhibitory factor in the endometrium and estrogen in endometriosis
.
Exp Ther Med
.
2015
;
10
(
2
):
787
91
. .
36.
Czyzyk
A
,
Podfigurna
A
,
Szeliga
A
,
Meczekalski
B
.
Update on endometriosis pathogenesis
.
Minerva Ginecol
.
2017
;
69
(
5
):
447
61
. .
37.
Ulukus
M
,
Cakmak
H
,
Arici
A
.
The role of endometrium in endometriosis
.
J Soc Gynecol Investig
.
2006
;
13
(
7
):
467
76
. .
38.
Nothnick
WB
,
Falcone
T
,
Olson
MR
,
Fazleabas
AT
,
Tawfik
OW
,
Graham
A
.
Macrophage migration inhibitory factor receptor, CD74, is overexpressed in human and baboon (Papio anubis) endometriotic lesions and modulates endometriotic epithelial cell survival and interleukin 8 expression
.
Reprod Sci
.
2018
;
25
(
11
):
1557
66
. .
39.
Forster
R
,
Sarginson
A
,
Velichkova
A
,
Hogg
C
,
Dorning
A
,
Horne
AW
, et al
.
Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis
.
FASEB J
.
2019
;
33
(
10
):
11210
22
. .
40.
Oertelt-Prigione
S
.
Immunology and the menstrual cycle
.
Autoimmun Rev
.
2012
;
11
(
6–7
):
A486
92
. .
41.
Notbohm
HL
,
Moser
F
,
Goh
J
,
Feuerbacher
JF
,
Bloch
W
,
Schumann
M
.
The effects of menstrual cycle phases on immune function and inflammation at rest and after acute exercise: a systematic review and meta-analysis
.
Acta Physiol
.
2023
;
238
(
4
):
e14013
. .
42.
Haddad
LB
,
Swaims-Kohlmeier
A
,
Mehta
CC
,
Haaland
RE
,
Brown
NL
,
Sheth
AN
, et al
.
Impact of etonogestrel implant use on T-cell and cytokine profiles in the female genital tract and blood
.
PLoS One
.
2020
;
15
(
3
):
e0230473
. .
43.
Sikora
J
,
Mielczarek-Palacz
A
,
Kondera-Anasz
Z
,
Strzelczyk
J
.
Peripheral blood proinflammatory response in women during menstrual cycle and endometriosis
.
Cytokine
.
2015
;
76
(
2
):
117
22
. .
44.
Calan
M
,
Kume
T
,
Yilmaz
O
,
Arkan
T
,
Kocabas
GU
,
Dokuzlar
O
, et al
.
A possible link between luteinizing hormone and macrophage migration inhibitory factor levels in polycystic ovary syndrome
.
Endocr Res
.
2016
;
41
(
3
):
261
9
. .
45.
Greaves
E
,
Temp
J
,
Esnal-Zufiurre
A
,
Mechsner
S
,
Horne
AW
,
Saunders
PT
.
Estradiol is a critical mediator of macrophage-nerve cross talk in peritoneal endometriosis
.
Am J Pathol
.
2015
;
185
(
8
):
2286
97
. .
46.
Adamson
GD
,
Pasta
DJ
.
Endometriosis fertility index: the new, validated endometriosis staging system
.
Fertil Steril
.
2010
;
94
(
5
):
1609
15
. .
47.
Maheux-Lacroix
S
,
Nesbitt-Hawes
E
,
Deans
R
,
Won
H
,
Budden
A
,
Adamson
D
, et al
.
Endometriosis fertility index predicts live births following surgical resection of moderate and severe endometriosis
.
Hum Reprod
.
2017
;
32
(
11
):
2243
9
. .
48.
Vesali
S
,
Razavi
M
,
Rezaeinejad
M
,
Maleki-Hajiagha
A
,
Maroufizadeh
S
,
Sepidarkish
M
.
Endometriosis fertility index for predicting non-assisted reproductive technology pregnancy after endometriosis surgery: a systematic review and meta-analysis
.
BJOG
.
2020
;
127
(
7
):
800
9
. .
49.
Ahn
SH
,
Singh
V
,
Tayade
C
.
Biomarkers in endometriosis: challenges and opportunities
.
Fertil Steril
.
2017
;
107
(
3
):
523
32
. .
50.
Anastasiu
CV
,
Moga
MA
,
Elena Neculau
A
,
Bălan
A
,
Scârneciu
I
,
Dragomir
RM
, et al
.
Biomarkers for the noninvasive diagnosis of endometriosis: state of the art and future perspectives
.
Int J Mol Sci
.
2020
;
21
(
5
):
1750
. .
51.
Irungu
S
,
Mavrelos
D
,
Worthington
J
,
Blyuss
O
,
Saridogan
E
,
Timms
JF
.
Discovery of non-invasive biomarkers for the diagnosis of endometriosis
.
Clin Proteomics
.
2019
;
16
:
14
. .
52.
Tian
Z
,
Chang
XH
,
Zhao
Y
,
Zhu
HL
.
Current biomarkers for the detection of endometriosis
.
Chin Med J
.
2020
;
133
(
19
):
2346
52
. .
53.
May
KE
,
Conduit-Hulbert
SA
,
Villar
J
,
Kirtley
S
,
Kennedy
SH
,
Becker
CM
.
Peripheral biomarkers of endometriosis: a systematic review
.
Hum Reprod Update
.
2010
;
16
(
6
):
651
74
. .
54.
Fassbender
A
,
Burney
RO
,
Dorien
FO
,
D’Hooghe
T
,
D’Hooghe
T
,
Giudice
L
.
Update on biomarkers for the detection of endometriosis
.
BioMed Res Int
.
2015
;
2015
:
130854
. .
55.
Vodolazkaia
A
,
El-Aalamat
Y
,
Popovic
D
,
Mihalyi
A
,
Bossuyt
X
,
Kyama
CM
, et al
.
Evaluation of a panel of 28 biomarkers for the non-invasive diagnosis of endometriosis
.
Hum Reprod
.
2012
;
27
(
9
):
2698
711
. .
56.
Mabrouk
M
,
Elmakky
A
,
Caramelli
E
,
Farina
A
,
Mignemi
G
,
Venturoli
S
, et al
.
Performance of peripheral (serum and molecular) blood markers for diagnosis of endometriosis
.
Arch Gynecol Obstet
.
2012
;
285
(
5
):
1307
12
. .
57.
He
RH
,
Yao
WM
,
Wu
LY
,
Mao
YY
.
Highly elevated serum CA-125 levels in patients with non-malignant gynecological diseases
.
Arch Gynecol Obstet
.
2011
;
283
(
Suppl 1
):
107
10
. .
58.
Mol
BW
,
Bayram
N
,
Lijmer
JG
,
Wiegerinck
MA
,
Bongers
MY
,
van der Veen
F
, et al
.
The performance of CA-125 measurement in the detection of endometriosis: a meta-analysis
.
Fertil Steril
.
1998
;
70
(
6
):
1101
8
. .
59.
Lete
I
,
Mendoza
N
,
de la Viuda
E
,
Carmona
F
.
Effectiveness of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain in the treatment of endometriosis-associated pelvic pain: LEAP study
.
Eur J Obstet Gynecol Reprod Biol
.
2018
;
228
:
221
4
. .
60.
Porpora
MG
,
Brunelli
R
,
Costa
G
,
Imperiale
L
,
Krasnowska
EK
,
Lundeberg
T
, et al
.
A promise in the treatment of endometriosis: an observational cohort study on ovarian endometrioma reduction by N-acetylcysteine
.
Evid Based Complement Alternat Med
.
2013
;
2013
:
240702
. .
You do not currently have access to this content.