Open Journal of Obstetrics and Gynecology, 2013, 3, 528-535 OJOG
http://dx.doi.org/10.4236/ojog.2013.37095 Published Online September 2013 (http://www.scirp.org/journal/ojog/)
Non-invasive prediction of endometriosis revisited;
3 biomarkers as Angiopoietin-2, Interleukin-1β and
Vascular Endothelial Growth Factor
Hoda Abdel Moety1*, Gihan I. Khalil1, Rania M. El Sharkawy1, Marwa K. El Ghandour1,
Fady S. Moiety2, Hesham A. F. Salem2
1Department of Chemical Pathology, Medical Research Institute, Alexandria University, Alexandria, Egypt
2Department of Obstetrics and Gynecology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
Received 2 July 2013; revised 1 August 2013; accepted 9 August 2013
Copyright © 2013 Hoda Abdel Moety et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Introduction: Endometriosis affects up to 1 every 5
women at their reproductive age, with variable and
complex symptomatology. Patients may be asympto-
matic but may have pain episodes or subfertility. Its
negative impact is on patients’ health and quality of
life. Objective: it was to investigate the serum and
peritoneal fluid (PF) concentrations of Angiopoietin-
2, Interleukin-1β, and Vascular Endothelial Growth
Factor, aiming to evaluate their diagnostic perform-
ance in endometriosis. Methods: Serum and perito-
neal fluid samples were taken from 112 women un-
dergoing laparoscopy for infertility, pelvic pain or
adnexal masses. 61 diagnosed with endometriosis and
51 controlled. Primary outcome was to estimate se-
rum and PF concentrations of Angio-2, IL-1β and
VEGF and secondarily correlate these concentrations
to disease stages thus assuming their diagnostic po-
tential. Results: Significant differences were found
between patients and control as regards serum and
PF concentration of all studied markers except serum
IL-1β. Serum Angio-2 and PF VEGF showed a sig-
nificantly higher level in more advanced stages of en-
dometriosis. PF VEGF showed a positively significant
correlation with the stage of the disease, spearman
coefficient t = 0.442 p = 0.014. PF concentrations of
Angio-2 and Serum VEGF did not show significant
pattern changes with stage-related levels. Diagnostic
potential of serum and PF concentrations of the 3
markers were assessed by the ROC curve. Angio-2
proved an excellent diagnostic ability for endometrio-
sis. PF and serum VEGF proved an equal diagnostic
performance, whereas, PF IL-1β was the least effi-
cient. Based on the results, we suggested preliminary
serum threshold values for these markers to be used
as diagnostic or follow-up landmarks with relatively
acceptable sensitivity, specificity, positive and nega-
tive predictive values. Conclusion: Non-invasive pre-
dictive biomarkers for endometriosis were Serum
Angio-2, IL-1β, and VEGF independently or in com-
bination with the estimated threshold values. Serum
Angio-2 merit is considered as a novel marker for en-
dometriosis due to its diagnostic power.
Keywords: Endometriosis; Angiopoietin-2; VEGF;
IL-1β
1. INTRODUCTION
Endometriosis affects up to 1 every 5 women at their
reproductive age group, with variable and often complex
symptomatology. Patients may be asymptomatic but may
have pain episodes, and/or subfertility [1]. Unlike its ae-
tiopathogenesis, its negative impact is on patients’ health
and quality of life is clear [2,3]. The stage of endome-
triosis can be morphologically classified by using the
revised American Fertility Society (rAFS) staging system
according to the localization and the size of nodes in the
peritoneum and ovaries, and the presence of adhesions in
the ovary and the fallopian tube [3]. This rAFS classifi-
cation includes the following stages: I = Minimal (1 - 5
points); II = Mild (6 - 15 points); III = Moderate (16 - 40
points); IV = Severe (<40 points) [4].
Effective treatment could be achieved; however, di-
agnosis of the disease remains a problem, simply, be-
cause accurate diagnosis can only be attained via laparo-
scopic inspection, preferably with histopathologic con-
firmation of suspected lesions. This remains an invasive
technique, with possible complications and health care
*Corresponding author.

H. A. Moety et al. / Open Journal of Obstetrics and Gynecology 3 (2013) 528-535 529
costs [5]. However, ovarian endometriomas, and deep
infiltrating endometriotic nodules can be detected ade-
quately by vaginal ultrasound, but it does not rule out
peritoneal endometriosis or endometriosis-associated ad-
hesions [1]. This situation has led the researchers re-
cently to refocus on the possible mechanism by which
endometriosis occurs. The fact is that an altered immune
mechanism might be involved in the development of the
condition is now widely accepted, which explains why
some women are more prone than others to develop the
disease. The concentration of some immunological mar-
kers in the peritoneal fluid largely correlates with the
disease occurrence, progression, and symptoms [6].
There is substantial evidence that immunologic factors
play a role in the pathogenesis of endometriosis and en-
dometriosis-associated infertility. Decreased natural kil-
ler cell cytotoxicity leads to an increased likelihood of
implantation of endometriotic tissue and modulation of
growth and inflammatory behavior of ectopic endo-
metrial implants.
The alteration in cytokines level and other angiogenic
factors as Vascular Endothelial Growth Factor (VEGF)
may explain the adhesion, implantation and the progres-
sion of the transported fragment of endometrium in the
different site of endometriosis. Many cytokines have
been studied to prove the immunological theory of en-
dometriosis as Interleukin-1β (IL-1β). It has been gener-
ally accepted that the establishment of new biomarker as
angiopoietin-2 (Angio-2) played a key part in the pro-
gression of endometriosis, however this role still needs
further confirmation to suggest a relation to endometrio-
sis already proven for many pivotal angiogenesis stimu-
lators such as VEGF [7,8].
Setting a non-invasive biochemical diagnostic and
prognostic test for endometriosis with an acceptable level
of accuracy and sensitivity, would fundamentally change
those patients’ quality of life, save their costs and risks of
the more invasive tools, and eventually make it smoother
for health care providers to manage the condition with
ease.
The current study was designed to evaluate the serum
and peritoneal fluid concentrations of Angiopoietin-2,
Interleukin-1β, and Vascular Endothelial Growth Factor
in patients with endometriosis as well as controls, thus
adding some insight to the formulation of a non-invasive
test to screen, detect, or follow up patients with endome-
triosis.
The ultimate objective was to prove any of these mar-
kers independently or in combination as non-invasive
diagnostic biomarker in patients with endometriosis.
2. PATIENTS AND METHODS
Blood and (PF) samples were taken from 112 women
undergoing laparoscopy for infertility, pelvic pain, and/or
adnexal masses in their first half of the menstrual cycle.
Procedures were done at a specialized unit of Gyneco-
logic endoscopy at a University hospital.
Sixty one were histologically confirmed to have en-
dometriosis and 51 were controls. No cases were ex-
cluded. A full informed consent was taken from each
subject. Enrolment took place after formal approval of
the Ethical committee of the Faculty of Medicine, Alex-
andria University was obtained.
PF samples were collected by aspiration from the per-
itoneal cavity during laparoscopy.
Serum samples: Five ml of venous blood were asepti-
cally collected and the clear serum was stored at –70˚C
until analysis.
Measurement of IL-1β, VEGF, and Angio-2 in serum
and PF were done using a commercially available, en-
zyme-linked immunosorbent assays (ELISA) using the
reagents and protocol supplied with the ELISA kit (R&D
Systems, Minneapolis, Minnesota, United States) Frozen
serum and PF samples were thawed and then analyzed.
3. STATISTICAL ANALYSIS
Data distribution was analyzed by using the Statistical
Packages for the Social Sciences (SPSS version 10.0,
Chicago, IL) and the Sigma-Stat software package (ver-
sion 3.5; SPSS, Chicago, IL). Normally distributed data
were presented as mean, standard deviation, whereas
skewed data were expressed as median and range. Pear-
son’s correlation was also used for evaluation of the lin-
ear relationship between different clinical variables. Pair-
wise comparisons between groups were performed using
the Wilcoxon-Mann-Whitney test. In order to determine
which serum marker could best represent patients with
endometriosis, sensitivity and specificity were assessed
with receiver operating characteristic ROC curves. The
area under the curve was approximately the percentage
correctly classified if the test was used as a diagnostic
tool. The same analyses were performed with the PF
measures and statistical significance was assessed using
two-tailed tests and an alpha level of p < 0.05.
4. RESULTS
A total of 112 women underwent laparoscopy for infer-
tility (n = 49), pelvic pain (n = 22), and/or adnexal
masses (n = 41). Sixty one were diagnosed with endome-
triosis and 51 were controls. No cases were excluded.
Out of the 61 patients with endometriosis, 25 (40.98%)
had early disease (stages I and II) and 36 (59.02%) had
late disease (stages III and IV).
The median age of the study group was 33.3 years,
median body mass index (BMI) was 27.0, and median
parity was 1.
No significant differences were found as regards age,
parity and BMI among the studied groups.

H. A. Moety et al. / Open Journal of Obstetrics and Gynecology 3 (2013) 528-535 530
5. CLINICAL DATA
Patients were presented with pain, discharge, and/or in-
fertility, those who presented with the latter were at ad-
vanced stages only (Table 1).
A significant difference was found between patients
and controls’ serum and PF concentration of all studied
markers except serum IL-1β (Table 2).
Meanwhile, significant difference was elicited between
early and late stages in terms of serum Angio-2 and PF
VEGF concentrations with significant increase in more
advanced stages (Z, p = 3.311 (0.042*), 2.188* 0.034
respectively), but the other studied markers with no spe-
cific pattern of stage-related level changes (Table 3).
Table 1. The relation between the serum and peritoneal fluid concentration of the 3 biomarkers and the stage of endometriosis among
women.
Pain Discharge Infertility
(pg/ml) Early Late Early Late Early Late
Serum Angio-2
Min - Max 3400 - 5320 3800 - 6240 3735 - 4300 3900 - 6240 - 3635 - 6530
Mean ± SD 4278.5 ± 618.6 4341.3 ± 692.1 5401.5 ± 399.5 4653.8 ± 1090.5 - 4302.5 ± 550.5
Median 4115.00 4230.00 4017.50 4237.50 - 4280.00
Z (p) 0.272 (0.786) 0.355 (0.533) -
PF Angio-2
Min - Max 2980 - 3990 3120 - 9000 2980 - 3990 3280 - 4840 - 3120 - 9500
Mean ± SD 3524.2 ± 372.4 4653.9 ± 2128.3 3575.0 ± 435.5 4060.0 ± 1103.1 - 4524.6 ± 1969.2
Median 3605.00 3805.00 3665.00 3842.50 - 4060.00
Z (p) 1.414 (0.157) 0.643 (0.800) -
Serum VEGF
Min - Max 600 - 3600 800 - 3750 650 - 1950 1210 - 3540 - 600 - 4020
Mean ± SD 1975.5 ± 971.2 2229.2 ± 961.3 1300.0 ± 919.2 2512.5 ± 1005.8 - 2060.1 ± 1128.8
Median 2008.00 2150.00 1300.00 2650.00 - 2054.00
Z (p) 0.571 (0.568) 0.165 (0.267) -
PF VEGF
Min - Max 650 - 3600 1100 - 14000 850 - 3600 2400 - 3900 - 1100 - 14000
Mean ± SD 2047.5 ± 1059.6 4233.1 ± 3967.8 2187.5 ± 1141.9 3150.0 ± 1060.7 - 4596.7 ± 4029.3
Median 2375.00 3000.00 2150.00 3150.00 - 3085.00
Z (p) 1.687 (0.092) 0.240 (0.267) -
Serum IL-1β
Min - Max 33 - 254 56 - 260 65 - 201 198 - 215 - 33 - 254
Mean ± SD 138.9 ± 74.5 147.8 ± 65.6 143.5 ± 62.2 206.5 ± 12.0 - 142.2 ± 71.0
Median 122.00 142.00 154.00 206.50 - 132.50
Z (p) 0.381 (0.703) 0.165 (0.267) -
PF IL-1β
Min - Max 39 - 456 46 - 490 101 - 355 278 - 378 - 39 - 480
Mean ± SD 238.9 ± 126.2 289.3 ± 131.9 257.5 ± 114.2 328.0 ± 70.7 - 293.9 ± 147.4
Median 245.00 316.50 287.00 328.00 - 331.50
Z (p) 1.142 (0.253) 0.355 (0.533) -
Z: Z for Mann Whitney test. *Significant at p < 0.05.

H. A. Moety et al. / Open Journal of Obstetrics and Gynecology 3 (2013) 528-535 531
Table 2. The relation between endometriosis and serum and PF levels of the studied biomarkers.
Endometriosis
Cases n = 61 Control n = 51 Z (p)
Serum Angio II (pg/ml)
Min - Max 3400.00 - 6240.00 2566.00 - 5211.00
Mean ± SD 4307.83 ± 775.30 3765.30 ± 604.94
Median 4232.50 3642.50
2.794* (0.005)
PF Angio II (pg/ml)
Min - Max 2985.00 - 9500.00 2980.00 - 6169.00
Mean ± SD 4843.00 ± 1682.46 4211.83 ± 873.00
Median 4803.50 3700.00
3.622* (<0.001)
Serum VEGF (pg/ml)
Min - Max 600.00 - 4020.00 160.00 - 402.00
Mean ± SD 2158.37 ± 1026.87 286.83 ± 77.07
Median 2024.00 291.50
6.653* (<0.001)
PF VEGF (pg/ml)
Min - Max 650.00 - 14000.00 96.00 - 322.00
Mean ± SD 3174.67 ± 2857.60 214.30 ± 68.74
Median 2700.00 207.00
6.654* (<0.001)
Serum IL-1β (pg/ml)
Min - Max 33.00 - 260.00 25.00 - 240.00
Mean ± SD 142.73 ± 67.29 129.73 ± 66.24
Median 135.50 108.00
0.673 (0.501)
PF IL-1β (pg/ml)
Min - Max 39.00 - 490.00 35.00 - 302.00
Mean ± SD 277.63 ± 134.27 174.43 ± 84.04
Median 282.50 191.00
3.149* (0.002)
Z: Z for Mann Whitney test. *Statistically significant at p < 0.05.
In addition, a positive correlation of PF VEGF with
the stages of the disease was found, (spearman coeffi-
cient = 0.442*) (Table 4).
Non-invasive prediction of endometriosis and the di-
agnostic potential of the serum and PF concentrations of
the 3 markers were assessed by the Receiver-operating
characteristic (ROC) curves. Serum Angio-2 proved best
diagnostic performance of 100% with an outstanding
area under the curve AUC 1.000 followed by serum
VEGF AUC 0.920 and the PF AUC 0.810, then serum
IL-1β AUC 0.737 and PF IL-1β AUC 0.515 was the least
efficient.
Preliminary threshold values for the 3 studied markers
in serum were assumed to serve as diagnostic or fol-
low-up landmarks with relatively acceptable sensitivity,
specificity, positive and negative predictive values (Ta-
ble 5).
6. DISCUSSION
Our results confirmed that serum VEGF, Angio-2, and
IL-1β respectively have an excellent diagnostic ability to
screen cases with endometriosis with a good level of
sensitivity and specificity. This was not related to the
stage of the disease which makes these markers, prefera-
bly in combination, more suitable to construct a non-
surgical, screening system prototype rather than a staging
module. All samples were taken during the first half of

H. A. Moety et al. / Open Journal of Obstetrics and Gynecology 3 (2013) 528-535 532
Table 3. Comparison between the two stages of endometriosis according to serum and PF of the 3 biomarkers.
Stages of e n dometriosis
Early Late Z (p)
Serum Angio-2 (pg/ml)
Min - Max 3400 - 5320 3800 - 6240
Mean ± SD 4285.6 ± 559.5 4341.3 ± 692.1
Median 4115.00 4550.00
3.311 (0.042*)
PF Angio-2 (pg/ml)
Min-max 2980 - 3990 3120 - 9500
Mean ± SD 3524.2 ± 372.4 4670.3 ± 2045.2
Median 3605.00 3842.50
1.566 (0.117)
Serum VEGF (pg/ml)
Min - Max 600 - 3750 800 - 4020
Mean ± SD 2111.2 ± 109.31 2229.2 ± 961.3
Median 2024 2150
0.233 (0.816)
PF VEGF (pg/ml)
Min - Max 650 - 1400 1100 - 3600
Mean ± SD 2047.5 ± 1059.6 3926.1 ± 3421.8
Median 2375.00 3005.0
2.188 (0.034*)
Serum IL-1β (pg/ml)
Min - Max 33 - 254 56 - 260
Mean ± SD 139.4 ± 65.3 147.8 ± 68.6
Median 132.50 142.00
0.381 (0.703)
PF IL-1β (pg/ml)
Min - Max 39 - 480 46 - 490
Mean ± SD 269.8 ± 131.1 289.3 ± 139.9
Median 273.00 316.50
0.381 (0.703)
*Statistically significant at p < 0.05.
Table 4. Correlation between serum and PF levels of Ang-2, VEGF and IL-1β with the stages of the disease.
Serum PF
Angio-2 VEGF IL-1B Angio-2 VEGF IL-1B
r 0.152 0.112 0.011 0.062
Angio-2
p 0.422 0.557 0.954 0.744
r 0.241 0.032
VEGF
p 0.199 0.865
r
IL-1β
p
rho 0.102 0.034 0.036 0.296 0.442* 0.034
Stages
Early & Late p 0.592 0.858 0.850 0.112 0.014 0.859
r: Pearson coefficient. rho: Spearman coefficient. *Statistically significant at p ≤ 0.05.

H. A. Moety et al. / Open Journal of Obstetrics and Gynecology 3 (2013) 528-535 533
Table 5. Diagonstic performance of the studied biomarkers with suggested threshold values.
Serum Ang-2 (pg/ml) Seru m VEGF (pg/ml) Serum IL-1β (pg/ml)
Threshold (cut of values) 3700 500 120
Sensitivity 100.00 90.00 60.00
Specificity 100.00 60.00 53.33
Positive predictive value (PPV) 100.00 69.23 56.25
Negative predictive value (NPV) 100.00 85.71 57.14
Accuracy 100.00 75.00 56.67
the menstrual cycle to neglect any effect of the sampling
time on the results. Bedaiwy et al. [5] made the sampling
time all through the menstrual cycle and found differ-
ences related to sampling time that they claimed not sig-
nificant, so we preferred to avoid those differences.
PF laparoscopic sampling; especially for VEGF, and
IL-1β can be more supportive in establishing diagnostic
tests in subtle or atypically-presenting cases, where evi-
dent endometriosis lesions would be hardly present to
assess histologically. We did not, however find any sig-
nificant correlation between symptoms such as pain with
the levels of PF studied markers including the cytokine;
IL-1β. This contradicts what Scholl et al. [9] stated about
an increased level of PF cytokine with the severe pain and
dysmenorrhea in endometriosis.
We were also able to estimate a preliminary cut-off
values, based on the number of patients studied, for the
serum markers in this cohort of patients, where Angio-2
showed the best sensitivity, and specificity followed by
VEGF and IL-1β respectively. There were relatively ac-
ceptable positive and negative predictive values, as well,
at the estimated cut-off levels. We assumed a promising
role for these makers that could be extended to similar
substances as diagnostic or follow-up landmarks in cases
destinated to develop endometriosis. Similarly, Mihalyi et
al. [10] concluded a diagnostic role of a panel of six
selected plasma biomarkers in the diagnosis of different
stages of endometriosis with good sensitivity and spe-
cificity. They studied, however, different biomarkers than
those in the present study, including some cytokines, and
obtained serum samples during the secretory phase or
during menstruation. Bedaiwy et al. [5] also assumed a
non- surgical diagnosis of endometriosis be possible by
measuring serum IL-6 and PF TNF-α.
VEGF is a heparin-binding glycoprotein with potent
angiogenic, endothelial cell-specific mitogenic and vas-
cular permeability activities.
Studies have demonstrated that VEGF is involved in
both the etiology and maintenance of peritoneal endome-
triosis [11]. Moreover, in normal endometrium the ex-
pression of VEGF is potentiated by a variety of cytokines,
especially Interleukin-1β (IL-1β) [12].
In this study we confirmed a good diagnostic per-
formance of VEGF both in serum and PF.
We found significant differences of PF VEGF and se-
rum Angio-2 levels related to the stage of endometriosis,
this was in accordance with Meresman et al. [13] who
reported same results stating that VEGF-A levels in the
serum and PF of patients with severe endometriosis
(stages III-IV) were significantly higher than in those
with minimal endometriosis owing to the modulation of
this marker by the disease itself.
Angio-2 is a cytokine that can amplify the effects of
other angiogenic factors, mainly VEGF but it can not
independently activate angiogenesis. Angio-2 is the en-
dogenous antagonist of Angiopoietin-1, binding the same
receptor. Angio-1 has been demonstrated in endometrial
and periendothelial cells and in glandular and stromal
cells of endometriotic lesions.
Zhang et al. [14] suggested overexpression of Angio-2
gene responsible for development and/or progression of
endometriosis.
Data on Angio-1 and Angio-2 remain too scarce to
clarify any role or mechanism in the aetiopathogenesis of
endometriosis. We assumed a role for serum Angio-2 in
non-invasive prediction of endometriosis based on our
results which demonstrated an out-standing diagnostic
ability for serum Angio-2 of 100% with (AUC 1.000),
however It was much less efficient for PF Angio-2 (AUC
= 0.937), this results were in accordance with Di Carlo et
al. [15] who stated that patients with endometriosis had
higher levels of angiogenic factors including Angio-2
compared with normal controls. Meanwhile, those an-
giogenic factors’ concentrations in serum and PF, as re-
ported by Bourlev et al. [16] normalize within a week
after surgical removal of endometriotic lesions in women
with advanced endometriosis.
IL-1β, a proinflammaory cytokine, was produced main-
ly by monocytes macrophages, and dendritic cells. In
health, circulating human blood monocytes or bone mar-
row aspirate do not constitutively express IL-1  , Stimu-
lants such as the complement component C5a, hypoxia,
and adherence to surfaces or clotting of blood induce the
synthesis of large amounts of IL-1 mRNA in monocytic

H. A. Moety et al. / Open Journal of Obstetrics and Gynecology 3 (2013) 528-535 534
cells [17-19].
A predictive performance of IL-1  was also suggested
in the light of this work. Based on our analysis, the PF
IL-1  was significantly higher in patients than controls
wit—h better diagnostic potential compared to serum IL-
1
 . This could be assumed to the fact that, being a proin-
flammatory cytokine, locally released in the vicinity of
active endometriotic lesions. Menstrual pain scores with
endometriosis were assessed in relation to PF cytokine
concentration in a study by Scholl et al. [9] where a sig-
nificant difference was found according to the pain score.
Cytokine profiles were also tackled in a study by Kalu et
al. [20] where an elevated level of PF interleukins but
not serum confirmed a role in the pathogenesis of endo-
metriosis.
Hou et al. [21] suggested a possible clinical strategy
for the treatment of endometriosis by neutralization of
IL-1
 , thus counteracting its effect on endometrial stro-
mal cells.
Serum Angio-2 and VEGF markers with the estimated
peritoneal fluid levels would be an addition to the diag-
nostic potential in endometriosis.
7. CONCLUSION
Non-invasive predictive biomarkers for endometriosis as
Serum Angio-2, VEGF and IL-1β independently or in
combination were estimated with threshold values. Se-
rum angio-2 merit is considered as a novel marker for
endometriosis due to its diagnostic power.
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