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\begin{document}

\title{Preoperative pain measurements in correlation to deep endometriosis
classification with Enzian.}



\author[1]{Jeroen Metzemaekers}%
\author[2]{Mathijs Blikkendaal}%
\author[1]{Kim Nieuwenhuizen}%
\author[1]{Kim  Bronsgeest}%
\author[2]{Johann Rhemrev}%
\author[2]{Mathilde  Smeets}%
\author[2]{James English}%
\author[1]{Frank Willem Jansen}%
\author[1]{Andries Twijnstra }%
\affil[1]{LUMC}%
\affil[2]{Medical Centre Haaglanden}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective To study pain symptoms and their correlation with the
anatomical location (and extent) of deep endometriosis lesion(s)
classified by the Enzian score. Design Prospective multi-centre study
Setting Web-based application called EQUSUM (www.equsum.org) to classify
and report surgical procedures Population or Sample A total of 419
surgical DE (deep endometriosis) cases Methods Collection of surgical
data in DE cases and their endometriosis classification and pain scores.
Main Outcome Measures Preoperative reported pain scores in each domain
(dysmenorrhea, dyschezia, dysuria, dyspareunia, chronic pelvic pain)
were collected along with the Enzian classification. Baseline
characteristics, pain scores, surgical procedure and extent of the
disease were also collected. Results In general, more extensive
involvement of DE does not lead to an increase in numerical rating scale
for pain measures. However, dysuria and bladder involvement do show a
clear correlation AUC 0.62 (SE 0.04, CI 0.54-0.71, p\textless{} 0.01).
Regarding the predictive value of dyschezia, we found a weak, but
significant correlation with ureteric involvement; AUC 0.60 (SE 0.04, CI
0.53-0.67, p\textless{} 0.01). Conclusions Pain symptoms poorly
correlate with anatomical locations of deep endometriosis in almost all
pain scores, with the exception of bladder involvement and dysuria which
did show a correlation. Also dyschezia seems to have predictive value
for DE ureteric involvement and therefore MRI or ultrasound imaging
(ureter and kidney) is recommended in the preoperative workup in these
patients.%
\end{abstract}%



\sloppy


Preoperative pain measurements in correlation to deep endometriosis
classification with Enzian.

\textbf{Running title:} Correlation of pain and deep endometriosis

J. Metzemaekers\textsuperscript{a}, M.D. Blikkendaal\textsuperscript{b},
K.E. v. Nieuwenhuizen\textsuperscript{a}, K.
Bronsgeest\textsuperscript{a}, J.P.T. Rhemrev\textsuperscript{b},
M.J.G.H. Smeets\textsuperscript{b}, J. English\textsuperscript{b}, F.W.
Jansen\textsuperscript{a,c}, A.R.H.Twijnstra\textsuperscript{a}*

\textsuperscript{a} Department of Gynaecology, Leiden University Medical
Center, Leiden, the Netherlands.

\textsuperscript{b} Department of Gynaecology, Haaglanden Medisch
Centrum-Bronovo, Den Haag, the Netherlands.

\textsuperscript{c} Department of Biomechanical Engineering, Delft
University of Technology, Delft, the Netherlands.

* \textbf{Corresponding author contact information:}

dr. A.R.H. Twijnstra, MD, PhD Department of Gynaecology Leiden
University Medical Center

PO Box 9600, 2300 RC Leiden, the Netherlands E-mail:
a.r.h.twijnstra@lumc.nl

\textbf{Abstract}

\textbf{Objective}

To study pain symptoms and their correlation with the anatomical
location (and extent) of deep endometriosis lesion(s) classified by the
Enzian score.

\textbf{Design}

Prospective multi-centre study

\textbf{Setting}

Web-based application called EQUSUM (www.equsum.org) to classify and
report surgical procedures

\textbf{Population or Sample}

A total of 419 surgical DE (deep endometriosis) cases

\textbf{Methods}

Collection of surgical data in DE cases and their endometriosis
classification and pain scores.

\textbf{Main Outcome Measures}

Preoperative reported pain scores in each domain (dysmenorrhea,
dyschezia, dysuria, dyspareunia, chronic pelvic pain) were collected
along with the Enzian classification. Baseline characteristics, pain
scores, surgical procedure and extent of the disease were also
collected.

\textbf{Results}

In general, more extensive involvement of DE does not lead to an
increase in numerical rating scale for pain measures. However, dysuria
and bladder involvement do show a clear correlation AUC 0.62 (SE 0.04,
CI 0.54-0.71, p\textless{} 0.01). Regarding the predictive value of
dyschezia, we found a weak, but significant correlation with ureteric
involvement; AUC 0.60 (SE 0.04, CI 0.53-0.67, p\textless{} 0.01).

\textbf{Conclusions}

Pain symptoms poorly correlate with anatomical locations of deep
endometriosis in almost all pain scores, with the exception of bladder
involvement and dysuria which did show a correlation. Also dyschezia
seems to have predictive value for DE ureteric involvement and therefore
MRI or ultrasound imaging (ureter and kidney) is recommended in the
preoperative workup in these patients.

\textbf{Funding:}

The author(s) received no financial support for the research,
authorship, and/or publication of this article.

\textbf{Key words:}

Endometriosis, surgery, rASRM, Enzian, classification

\textbf{Tweetable abstract:}

Poor correlation of pain intensity and anatomical locations of deep
endometriosis nodules in patients with deep endometriosis.

\textbf{Introduction}

An ideal classification system should meet three core principles: it
should be simple, allow description of the disease and correlate with
clinical findings (1). Currently, the two most used classifications
systems for endometriosis are the rASRM (2) and Enzian (3), of which
neither shows strong clinical correlation with pain symptoms (4, 5).
This could be explained by the fact that the rASRM is not directly
suitable to describe deep endometriosis (6). On the other hand, the
Enzian classification is not able to describe the tubes, ovaries and
peritoneum which is covered by the rASRM classification. An attempt to
overcome these difficulties has recently been made by
the\emph{Stiftung~Endometriose Forschung} (SEF) at their annual
Weisensee endometriosis meeting, during which an update of the Enzian
classification was created: the \#Enzian (7).

\textbf{Clinical correlations with the Enzian}

Previous studies (4) (8) reported the correlations between the Enzian
and pain symptoms in deep endometriosis. Haas et al reported no
combinations of compartments, but choose to report the compartment with
the highest severity: for example, A1B0C3 would become a solitary C in
the analysis. In real life, endometriosis does not respect the
compartment boundaries of the Enzian classification and therefore it is
difficult to translate these findings directly to the clinical symptoms.
Montanari et al performed a similar analysis with a more robust cohort.
Nevertheless, both studies failed to study the solitary compartments and
combinations of compartments in correlation to pain symptoms.

Therefore, our research questions that we addressed are: 1) Which
compartment is responsible for the severity of the different types of
pain? 2) Does pain increase with an increase in compartment involvement.
3) Do specific clinical symptoms correlate with the scoring in the
Enzian.

The primary aim of our study was to find a correlation of the Enzian
score with pain symptoms in DE. Secondly, we wished to determine whether
a correlation exists between the extent of the disease and the reported
intensity of pain (regarding solitary compartments and combinations of
compartments).

\textbf{Methods}

\textbf{Study design}

We performed a multi-centre study (university hospitals, non-university
hospitals and specialised clinics for endometriosis) with prospectively
collected surgical data in DE cases and their endometriosis
classification from 6 European countries.

\textbf{Data collection}

Data was collected from February 2019 through June 2020 with the EQUSUM
application (9). Registered data included: general data on patients'
characteristics, previous abdominal surgery, pain scores for
dysmenorrhoea, dyschezia, dysuria, chronic pelvic pain, dyspareunia,
accurate localisation of endometriosis lesions, and in case of fertility
wish, the EFI scores (9). The EQUSUM application automatically generates
the following classifications: rASRM, Enzian and EFI scores. For this
research question only the Enzian classification is studied.

The inclusion criterion was the presence of deep endometriosis in one or
more of the main Enzian compartments A, B, C or F. Deep endometriosis
was staged on the clinical intra-operative view combined with
preoperative imaging.

Exclusion criteria were diagnostic laparoscopy procedures or procedures
without disease involvement in one of the main compartments (A,B,C or
F). Pain scores were preoperatively documented with a numeric rating
scale (NRS) ranging from 0-10. The Enzian scores were assigned according
to the original manuscript (3).

\textbf{DE and not DIE}

For this study we did not use the definition of Koninckx et al., in 1990
for deep infiltrating endometriosis (DIE) (10), which can only be
confirmed by the pathologist (endometrial implants penetrate more than 5
mm into the peritoneum). We used the definition described by Donnez
(11), which is a nodular form of deep endometriosis (DE) which we
classified with the Enzian based on clinical expertise combined with
radiological and intra-operative findings.

\textbf{Compartment involvement}

Main pain scores were calculated for all main compartments solitary.
This implies that for example only options of A1/2/3,B0,C0,Fx would be
assigned to compartment A. Combinations were also possible, for example
A1B2C0, would result in the group AB and so on. The assignment to the
main compartments was irrespective of the involvement of F. Solitary
mean pain calculations for the compartments F (FB, FA, FU and FI). This
was performed to present the pain scores with the least bias of other
compartments. To present the overlay of certain compartments we used
euler diagrams (12).

\textbf{Predictive value of pain symptoms in correlation to
endometriosis involvement with the Receiver Operating Characteristic
curve}

To test if endometriosis pain symptoms could predict deep endometriosis
involvement, we calculated receiver operating characteristic (ROC)
curves. The test in this case is the presence of endometriosis
classified with the Enzian (involvement yes or no), and the continuous
variable is the severity of symptoms measured with the NRS scale (0-10).

\textbf{Data analysis}

IBM SPSS version 25.0 for Windows was used for our analysis and we used
the Shapiro--Wilk test to evaluate the distribution of the data. Data
are presented as mean \selectlanguage{ngerman}± standard deviation (SD) or median (with
interquartile range) for normally distributed or skewed data,
respectively. Euler eclips diagrams were created with online software
based on an R package called eulerr (12). To test the accuracy of
symptoms in correlation to the anatomical location, ROC curves and the
areas under the curves were obtained for each anatomical location. We
considered a 2-tailed p-value of \textless{} 0.05 as statistically
significant. And for the ROC curve we considered an area under the curve
of \selectlanguage{english}[?]0.6 as a discriminating test (13).

\textbf{Results}

\textbf{Study population}

In total 475 procedures were registered. Nine cases were removed because
of diagnostic procedures and 47 cases were removed because no deep
endometriosis was present in compartment A, B, C or F. This resulted in
a total of 419 DE cases. Baseline characteristics are presented in Table
1. The mean age of women who underwent surgery was 35.3+-6.5 years, with
a median BMI of 24 (IQR 21-28) kg/m\textsuperscript{2}. The majority of
women had one or more previous abdominal surgeries; 13\% reported more
than 2 procedures. The primary indication for surgery were pain symptoms
(82\%).

Table 2 shows all classification types. Regarding the Enzian
classification, compartment A was involved in 110 cases (26.3\%), with a
majority being A3 (55.5\%). Compartment B was reported in 244 cases
(58.2\%) on the left side and 229 cases (52.3\%) on the right side. The
majority had a B2 severity (50.4\% left and 53.7\% right). Sacro-uterine
involvement was reported the most, and cardinal ligaments the least.
Compartment C was reported in 189 cases (45.1\%), with the majority
having a C3 severity (55.6\%). Adenomyosis (FA) was reported in 58\% of
all cases, with a majority of the diffuse type (62.6\%). Bladder (FB)
involvement was reported in 71 cases (16.9\%). Intestinal involvement
(FI) was reported in 94 cases (22.4\%), with 49.6\% rectum involvement
cranial to the recto-sigmoid junction, appendix involvement in 33.6\%,
ileocecal in 7.6\%, coecum in 6.7\% and ileum in 2.5\% of the FI cases.
Ureteric involvement (FU left) was reported in 60 cases (14.3\%), with
hydronephrosis in 6 cases (10\%). FU on the right side was reported in
44 cases (10.5\%), with 6 cases hydronephrosis (13.6\%). Other Enzian
involvement (FO) was reported in 23 cases (5.5\%), with 95.6\% umbilical
and 4.3\% diaphragmatic lesions.

\textbf{Preoperative numeric pain scale}

Table 3 shows the median pain scores, ranging from most painful
(dysmenorrhea) to least painful (dysuria). For dysmenorrhea (NRS 0-10) a
median of 8 (IQR 7-9) was reported. A mean dyschezia of 4.9+-3.7,
dyspareunia 4.5+-3.5, chronic pelvic pain (CPP) 4.5+-3.5 and dysuria
symptoms with a mean pain score of 2.1+-3.0.

\textbf{Solitary and grouped pain scores (0-10) for the different Enzian
compartments are presented in Figure 1.}

Dysmenorrhoea figure 1.1 (red)

A mean pain for compartment A was found of 5.5, SE 2.10 (n=6), B 7.4, SE
0.27 (n=125), C 7.3, SE 0.54 (n=34), A\&B 7.5 SE 0.62 (n=24), A\&C 6.5
SE 0.68 (n=19), B\&C 7.6 SE 0.33(n=75) and A\&B\&C 7.3 SE 0.39 (n=61).
For the F compartments: FB 5.6 SE 1.42 (n=10), FA 6.8 SE 0.47 (n=63), FI
5.1 SE 1.15 (n=15), FU 5.4 SE 2.27 (n=6). No dysmenorrhoea but with
Enzian involvement is present in Supplementary table S1 n=1 (16.7\%) in
compartment A, n=10 (8\%) in compartment B, n=3 (8.8\%) in compartment
C, n=3 (30\%) in compartment FB, n=11(17.5\%) in compartment FA, n=4
(26.7\%) in compartment FI and n=2 (33.3\%) in FU.

Dyschezia figure 1.2 (purple)

A mean pain for compartment A was found of 5.0, SE 2.05 (n=6), B 4.5, SE
0.36 (n=125), C 5.4, SE 0.63 (n=34), A\&B 6.2 SE 0.73 (n=24), A\&C 6.1
SE 0.76 (n=19), B\&C 5.6 SE 0.41 (n=75) and A\&B\&C 5.8 SE 0.43 (n=61).
For the F compartments: FB 2.4 SE 1.25 (n=10), FA 3.0 SE 0.46 (n=63), FI
4.7 SE 1.12 (n=15), FU 4.2 SE 1.90 (n=6). No dyschezia but with Enzian
involvement is present in Supplementary table S1 n=2 (33.3\%) in
compartment A, n=40 (32.0\%) in compartment B, n=8 (23.5\%) in
compartment C, n=7 (70.0\%) in compartment FB, n=31 (49.2\%) in
compartment FA, n=5 (33.3\%) in compartment FI and n=3 (50.0\%) in FU.

Chronic pelvic pain figure 1.3 (grey)

A mean pain for compartment A was found of 5.0, SE 1.10 (n=6), B 4.6, SE
0.33 (n=125), C 4.5, SE 0.59 (n=34), A\&B 4.4 SE 0.79 (n=24), A\&C 3.5
SE 0.81 (n=19), B\&C 4.8 SE 0.39(n=75) and A\&B\&C 4.1 SE 0.45 (n=61).
For the F compartments: FB 1.7 SE 1.14 (n=10), FA 5.0 SE 0.47 (n=63), FI
4.5 SE 1.18 (n=15), FU 7.33 SE 1.54 (n=6). No chronic pelvic pain but
with Enzian involvement is present in Supplementary table S1 n=0 (0.0\%)
in compartment A, n=38 (30.4\%) in compartment B, n=10 (29.4\%) in
compartment C, n=8 (80.0\%) in compartment FB, n=18 (28.6\%) in
compartment FA, n=6 (40.0\%) in compartment FI and n=1 (16.7\%) in FU.

Dyspareunia figure 1.4 (blue)

A mean pain for compartment A was found of 3.8, SE 1.59 (n=6), B 4.5, SE
0.35 (n=125), C 3.9, SE 0.58 (n=34), A\&B 3.8 SE 0.70 (n=24), A\&C 3.7
SE 0.82 (n=19), B\&C 4.4 SE 0.43 (n=75) and A\&B\&C 4.6 SE 0.44 (n=61).
For the F compartments: FB 4.6 SE 1.09 (n=10), FA 5.7 SE 0.41 (n=63), FI
4.1 SE 1.02 (n=15), FU 6.0 SE 1.29 (n=6). No dyspareunia but with Enzian
involvement is present in Supplementary table S1 n=2 (33.3\%) in
compartment A, n=41 (32.8\%) in compartment B, n=12 (35.3\%) in
compartment C, n=3 (30.0\%) in compartment FB, n=11 (17.5\%) in
compartment FA, n=6 (40.0\%) in compartment FI and n=1 (16.7\%) in FU.

Dysuria figure 1.5 (yellow)

A mean pain for compartment A was found of 1.4, SE 1.4 (n=6), B 1.7, SE
0.25 (n=125), C 1.9, SE 0.51 (n=34), A\&B 2.6 SE 0.68 (n=24), A\&C 1.5
SE 0.55 (n=19), B\&C 1.7 SE 0.34(n=75) and A\&B\&C 2.3 SE 0.40 (n=61).
For the F compartments: FB 7.1 SE 0.89 (n=10), FA 2.3 SE 0.42 (n=63), FI
2.43 SE 1.00 (n=15), FU 4.2 SE 1.60 (n=6). No dysuria but with Enzian
involvement is present in Supplementary table S1 n=4 (66.7\%) in
compartment A, n=73 (58.4\%) in compartment B, n=22 (64.7\%) in
compartment C, n=1 (10.0\%) in compartment FB, n=35 (55.6\%) in
compartment FA, n=9 (60.0\%) in compartment FI and n=2 (33.3\%) in FU.

\par\null

\textbf{ROC curve for ureter and bladder}

ROC curves in correlation to the median pain scores were calculated for
the Enzian locations A, B, C, FB, FU, FA and FI. We only present the ROC
curves with an area under the curve \selectlanguage{english}[?]0.6, since in that case this test
can provide a discrimination. This was only the case for the ureter and
bladder involvement (table 4).

Figure 2.1 shows the ROC curve for the ureter, with an area under the
curve for dysmenorrhea of 0.52 (SE 0.04, CI 0.45-0.60, p=0.04), dysuria
0.51 (SE 0.04, CI 0.44-0.59, p=0.68), CPP 0.52 (SE 0.04, CI 0.44-0.60,
p=0.67), dyspareunia 0.49 (SE 0.04, CI 0.41-0.56, p=0.70) and dyschezia
0.6 (SE 0.04, CI 0.53-0.67, p\textless{} 0.01) (table 4). We chose the
cut-off point for dyschezia of NRS 6.50, while a high sensitivity is
important regarding ureter involvement (cave silent hydronephrosis).
Using this as a cutoff point, our sensitivity (true positive rate) would
be 63\% and our 1 -- specificity would be 45\% (false positive rate).

For the bladder (figure 2.2), with an area under the curve for
dysmenorrhea of 0.49 (SE 0.04, CI 0.41-0.56, p=0.73), dysuria 0.62 (SE
0.04, CI 0.54-0.71, p\textless{}0.01), CPP 0.39 (SE 0.04, CI 0.31-0.47,
p\textless{}0.01), dyspareunia 0.44 (SE 0.04, CI 0.36-0.52, p=0.13) and
dyschezia 0.57 (SE 0.04, CI 0.49-0.66, p\textless{} 0.07) (table 4). We
chose the cut-off point for dysuria of NRS 0.5. Using this as a cutoff
point, our sensitivity would be 54\% and our 1 -- specificity would be
36\%.

\textbf{Discussion}

\textbf{Main findings}

Preoperative reported endometriosis related pain scores correlate poorly
with intra-operative of the locations of DE lesions. This underlines and
explains the difficulty doctors and patients face, before the diagnosis
endometriosis is set (an average of 9 years) (14). The correlation of
endometriosis involvement to pain symptoms is not a 1-on-1 relationship,
this partly explains why undiagnosed patients often see numerous doctors
and try several treatment options before the diagnosis endometriosis is
made. This delay makes women lose faith in the healthcare system or they
start doubting themselves (Are my symptoms real? Nobody is able to find
anything) (15). When the diagnosis is finally made, surgery for removing
the endometriosis is not the only solution. These women often developed
chronic pain symptoms which need a broader treatment process than solely
removing the physical stimuli (endometriosis nodules). A more holistic
approach, which also includes psychological support and pain
management/insight is mandatory to help these women regain their normal
life (16).

\textbf{Interpretation}

\textbf{Pain is more than a physical stimulus from an anatomical
location}

The theory that endometriosis has a multifactorial pathogenesis could
explain why endometriosis remains difficult to classify regarding
prognosis and clinical correlation. This multifactorial pathogenesis
includes endometriosis severity (stage, location, depth of invasion),
co-morbidity conditions, myofascial factors (muscle and fascial
involvement), and central sensitisation (17). According to the
International Association for the Study of Pain, the definition of pain
is ``an unpleasant sensory and emotional experience associated with
actual or potential tissue damage''. Besides, it has become more clear
that pain experience is also influenced by psychological factors (e.g.
catastrophising, anxiety, coping) (18, 19) and central sensitisation
(persistent state of high reactivity) (20). This supports the theory
that not only the severity of the endometriosis is responsible for pain
symptoms. Endometriosis lesions on anatomical structures are not solely
responsible for the pain sensation: it seems far more complex than that.

\textbf{No pain symptoms, but DE is present}

It is interesting to find that one third of the patients do not report
dyschezia, but do have intestinal DE involvement. This phenomenon is
present in more compartments like adenomyosis whereby 17\% do not report
dysmenorrhea and 24\% of the cases do not report dyschezia, but there is
rectal involvement. However, in the bladder it is shown that only in 1
out of 10 cases is no dysuria reported while there is DE involvement of
the bladder. This translates to a stronger correlation of bladder
involvement and dysuria symptoms.

\textbf{The predictive value of symptoms and endometriosis involvement}

\textbf{Dyschezia and the ureters}

Unfortunately, endometriosis invasion of the ureters is often
asymptomatic or presents with nonspecific symptoms (21), which can lead
to silent, obstructive uropathy and renal failure, with a high rate of
kidney loss (23--47\%) (22).

To detect ureteric involvement, an MRI is the first choice diagnostic
tool (21), while it allows proper evaluation of the whole pelvis and
helps to decide the surgical approach. In our study we found that
dyschezia has a predictive value in detecting ureteric involvement. From
an anatomical point of view this can easily be explained, an
endometriosis nodule in, or close to the rectum (which causes dyschezia)
can also involve or press against the ureter. Translating our research
evidence to clinical practice: if endometriosis patients report
dyschezia (NRS\textgreater{}6.5), the clinician should be aware of
possible ureteric involvement and extend the transvaginal ultrasound
with a mandatory MRI (pelvis with kidneys) or at least an ultrasound of
the kidneys/ureters.

\textbf{Dysuria and the bladder}

The majority of patients with bladder endometriosis are symptomatic
(dysuria, voiding problems, etc.) (23) (24) (25). This supports our
finding of the symptom of dysuria having a predictive value for the
presence of bladder endometriosis and is seen clearly in the euler
diagram (Figure 1.5). However the finding in the ROC curve was not
strong, but we can carefully conclude that even low NRS for dysuria
(\textgreater{}0.5), could indicate bladder endometriosis. Translated to
clinical practice, patients presenting with very little dysuria symptoms
can still have bladder endometriosis.

\textbf{Importance of classification despite poor clinical correlation}

Despite the limited correlations, anatomical based endometriosis
classification remains important. Classification provides a uniform
language to communicate, monitor and report the disease (26). This
enables standardisation of outcome measures and provides a universal way
to communicate about endometriosis in clinical and research settings.

Our study differs from other clinical correlation studies on DE, because
we analysed solitary anatomical structures classified with Enzian
(compartment A, B and C) related to preoperative pain symptoms as well
combinations of compartments (AB, AC, BC, ABC). The results of our study
shows that an increase in pain does not correlate with the extent of
anatomical involvement. This means that an increase in endometriosis
involvement, does not automatically lead to an increase in pain
symptoms. This knowledge is new and provides insight in the pain
behaviour/symptoms of DE patients. Therefore, clinicians cannot rely on
the clinical presentation of DE patients in relation to the disease
extent and equally, doctors cannot give information pre-operatively on
the severity of the disease.

\textbf{Strengths and limitations}

An important strength of our study is the fact that this is, to our
knowledge, the first study which compared solitary and combinations of
anatomical locations in correlation to pain reporting and created ROC
curves to determine if certain symptoms could predict the presence of
endometriosis in specific compartments. Because of the use of the
EQUSUM, data was collected in a uniform way, making it easy to analyse
the data without inconsistencies in the datafile.

A limitation of this study is the fact that no medication usage was
registered and the NRS pain reporting is pre-operative in patients with
and without medication. However, a subgroup analysis within the study
from Montanari et al. (5) showed that preoperative use of hormonal
therapy did not influence the associations and correlations for reported
pain symptoms described by the Enzian. Only a weak correlation was found
with the rASRM and dysmenorrhoea when patients used hormonal therapy.
So, medication use is obviously of influence, but it seems to have
little effect on the results.

A different limitation of this study is that no pathology results are
recorded. The endometriosis is staged on the clinical subjective measure
of the surgeon and not confirmed by the pathologist. However, there is
no debate of a C1 nodule, whether this is DE of not.

\textbf{Conclusion}

Our study showed that an increase in pain symptoms does not necessarily
lead to an increase in DE involvement. The symptom dyschezia has some
predictive value for ureteric involvement, and therefore patients with
dyschezia should preferably get an MRI of the pelvis or an ultrasound
scan of the kidneys/ureters for an optimal surgical workup. Already
minor dysuria symptoms can indicate the presence of endometriosis in the
bladder. More and more evidence is showing that pain symptoms in deep
endometriosis have a multifactorial cause, which partly explains the
poor correlations in studies focussing solely on anatomical locations
and pain symptoms.

\textbf{Disclosure of interest}

None declared.

\textbf{Contribution to authorship}

J.M. performed the analyses together with K.N. and K.B.. J.M, M.B, F.J,
A.T, took the lead in writing the manuscript. All authors were
responsible for interpreting the data and final review of the
manuscript. All authors approved the final manuscript.

\textbf{Details of ethics approval}

Ethical approval was given by the Medical Ethics Committee of the Leiden
University Medical Centre (LUMC) (G20.019).

\textbf{Funding:} The author(s) received no financial support for the
research, authorship, and/or publication of this article.

\textbf{Acknowledgements}

N/A

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