Pelvic pain in endometriosis: is success of

therapy gone
in cigarette smoke?
Agnes Koppan1*, Judit Hamori2, Ildiko Vranics1, Janos Garai3, Ildiko
Kriszbacher1,
Jozsef Bodis2, Frank Oehmke4, Hans-Rudolph Tinneberg4, Miklos
Koppan2,4
Received 17 January 2011; revised 1 June 2011; accepted 10 August 2011.

ABSTRACT
The objective of the study was to assess potential individual factors
influencing the efficacy of
combined surgical and medical therapy in endometriosis patients with pelvic
pain. For this
purpose we performed a prospective study using a specifically designed
questionnaire among
patients suffering from persistent pelvic pain
and undergoing laparoscopy and further GnRH
analogue therapy in a university-based gynecologic department. Eighty-one
women of reproductive age with histologically confirmed
endometriosis were enrolled. A questionnaire
gathered information from women on the following groups of variables: age,
marital status,
education, reproductive and medical history
including previous pregnancies and parity,
knowledge of accompaniing pelvic disorders,
concurrent cigarette smoking, as well as general quality of life estimates
including self-image. Pelvic pain was scored using a visual analogue scale.
Patients filled out the questionnaires before surgery and upon completing
medical therapy. Data were statistically evaluated. After cessation of therapy,
53% of patients
reported absence of pain. Only 12% of pain-free
patients were smokers. This corresponded to
slightly more than one third (35%) of all smokers in the study. However, 56% of
non-smoker
participants reported a positive outcome that
proved to be significantly larger than the ratio of
pain-free smoker participants (p = 0.02). Improvement in quality of life was
reported by 74%
of all patients, and only 9% of them were smokers. However, 47% were
smokers among patients reporting no change or worsening in
quality of life (p < 0.01). Based on our results,
we can conclude, that regular smoking might
have a disadvantageous impact on the success
rate of combined surgical and medical therapy
for endometriosis related pelvic pain.
Keywords: Pelvic Pain; Endometriosis; Cigarette
Smoke

1. INTRODUCTION
Endometriosis affects millions of women world wide.
It can severely alter quality of life and leads to extensive
problems with fertility and loss of work time [1]. Endometriosis might remain
asymptomatic and discovered
accidentally. However, it may cause symptoms, which
include chronic pelvic pain, bleeding, infertility, and
increases susceptibility to development of adenocarcinoma [2]. Signs and symptoms
arise from cyclic bleeding into the surrounding tissues, resulting in inflammation and
formation of scarring and adhesions. It is peculiar, that symptom severity does not
correlate well with
the extent or progression of the lesions [3]. Minor
laparoscopic findings might come with severe complaints, while extensive lesions might
remain undetected
and revealed only accidentally. The exact roles of different factors contributing to the
establishment and persistence of the endometriotic lesion are still not fully
understood. Despite the high associated morbidity and
health care costs, the incidence, prevalence, and risk
factors of endometriosis remain uncertain.
Symptomatic endometriosis can be managed surgically and/or medically. The aim is pain
relief and/or
amelioration of infertility. Medical treatment is usually
long term, and recurrence is frequent after its cessation.
Classic endometriosis pharmacotherapy is represented
by GnRH agonists, oral contraceptives and Type II progesterone receptor ligands [4]. All
medical treatments
seem to be equally effective in managing endometriosis.
Although about 80% - 85% of patients have improvement in their symptoms [5], many
women experience
unsatisfactory results. However, little is known about
factors on patients side influencing the efficacy of generally accepted therapeutic
approaches used to alleviate
symptoms caused by endometriosis.
In our study, we investigated the effectiveness of
combined surgical and medical therapy of patients with
histologically confirmed endometriosis with regard to
pain relief and overall quality of life issues. To determine these parameters we used a
questionnaire before
laparoscopic surgery and upon cessation of post-surgery
medical therapy. With that, we determined efficacy of
therapy from the patients point of view, with relation to
several non-medical variables such as marital status,
level of education and smoking.

2. MATERIALS AND METHODS

2.1. Study Population and Sample
The prospective cohort study population consisted of
patients of reproductive age complaining about persistent pelvic pain and undergoing
laparoscopy in our departments (Department of Obstetrics and Gynecology,
Faculty of Medicine, University of Pcs, Hungary and
Department of Obstetrics and Gynecology, Faculty of
Medicine, University of Giessen, Germany). Following

laparoscopy and histological examination, a random

sample of 150 patients with histologically proven endometriosis were then recruited. This
initial number of
recruited patients was arbitrarily set and reached in a 6
month period between June and December, 2008. Randomization was based on the
unpaired character of patients social security number. The refusal rate upon
reaching the desired number of 150 was less than 5%,
however, the drop-out rate during the entire study period
was 46%. Those who were lost for follow-up did not
differ in any characteristics based on the collected data
comparing to those who completed both questionnaires.
Final statistics were carried out using data from those 81
patients completing the study. Prior to the operation patients consented to participate in
the study. A standardized questionnaire elicited information from women on
the following groups of variables: age, marital status,
education, reproductive and medical history. The questionnaire was purposefully
designed to ascertain information on potential confounders, which included gravidity
(number of pregnancies regardless of outcome) and
parity (number of live births), knowledge of accompaniing pelvic disorders, concurrent
cigarette smoking and
caffein intake, since all have been reported as risk factors for endometriosis [6,7]. Further
variables were concurrently used medication including pain killers, as well
as daily habits of excersice, type of work and general
quality of life estimates including self-image. Pelvic pain
was scored using a visual analogue scale from 0 - 10.
Only patients with histologically confirmed endometriosis and with no other
pelvic/abdominal alteration or disease confirmed at laparoscopy were then eligible to
continue the study. Patients then received a 6 month GnRH
analogue therapy and were asked to fill out the same
questionnaire upon completing medical therapy. The
number of eligible patients completing both questionnaires was 81.

2.2 Operative Procedures

Laparoscopies were performed by highly trained and
experienced surgeons. Following the operations they
completed a standardized operative report to ascertaine
information on postoperative diagnosis and other pathology regardless of surgical
indication. Severity of
endometriosis was staged according to the American
Fertility Societys revised definition. In all patients endometriosis lesions were
laparoscopically removed and/
or electrocauterized and histological examination confirmed diagnosis. The affiliated
University gave Institutional Review Board approval for the conduct of this
study.

2.3. Statistical Analysis

Analysis of data was performed using Microsoft Excel
and SPSS 15 programs. We applied chi-square test,
analysis of variance (ANOVA), and Pearson-Spearmans
rank correlation test. Data are presented as percentage
values.

3. RESULTS
Mean age of participating patients was 31.2 years
(21 - 43 years, SD = 5.24). Out of them, 17.2% were

regular smokers.

3.1. Outcomes in Pain Relief

At the end of the treatment period, 53% of patients
reported the total absence of pain that they had specifically complained about at the
beginning of the study.
Only 12% of pain-free patients were smokers. This
means that slightly more than one third (36%) of all
smokers, while 57% of all non-smoker participants reported a positive outcome in the
study. This difference
proved to be significant, as calculated by Chi-Square test
(p = 0.02, Figure 1).

3.2. Outcomes in Overall Quality of Life

(Self-Image)
The correlation between smoker status and negativ quality of life outcome proved to be
significant, as calculated
by the Pearsons correlation test (2-tailed, p < 0.01, FigOverall, 74% of patients reported
improvement in ure 2).
their general quality of life, while no improvement or
even deterioration was reported by 26% of all participants. Among those with improved
quality of life only
9% were smokers, while 47% were smokers among patients reporting no change or even
worsening in their
quality of life. That means, only 36% of all smokers in
the study reported improvement in their quality of life,
while 64% of them reported no change or worsening.
Detailed analyses revealed no significant differences
in pain relief and quality of life measures at the end of
therapy with relation to marital status, level of education,
number of previous pregnancies regardless of outcome
and parity (number of live births). Furthermore, analyzing the data concerning the extent
of the disease (i.e. the
stage of endometriosis recorded at laparoscopy) and pain
scores and quality of life values at the beginning and the
Figure 1. Correlation between smoker status and absence of specific pain as a basis for
complaints after combined surgical and medical therapy of endometriosis patients. Data are
presented as percentage values. *p = 0.02; pain, specific pain is present; no pain, specific pain is
absent.
Figure 2. Ratio of smokers among endometriosis patients with regard to positive or negative
outcome in self-image at the end of combined surgical and medical therapy. Data are presented as
percentage values. **p < 0.01; pos, positive change in general quality of life; neg, no
or negative change in general quality of life.

end of the study revealed no significant correlations.

4. DISCUSSION
The currently available medical treatments for endometriosis seem to be equally
effective. It is estimated
that about 80% - 85% of patients have improvement in
their symptoms [5]. Interestingly, severity of symptoms
does not correlate well with the extent of the disease [3],
although, in a well conducted study of 63 women a
benefit from conservative surgery seemed to be greater
in those with the most severe disease [8]. Unfortunately,

there were only two participants in the group with severe

disease, so limited data might hinder us to draw firm
conclusion. In general, we know little about possible
environmental and individual factors that can negatively
influence the efficacy of different therapeutic modalities.
The present paper deals with change in pelvic pain
and quality of life outcomes during combined surgical
and medical treatment period in endometriosis patients,
in relation to certain individual factors that might influence the effectiveness of therapy.
The instrument we
used to evaluate efficacy was a detailed questionnaire
filled out twice by eligible and consenting patients.
In our study, the overall rate of improvement in quality of life was identified in almost
three quarters of the
final study cohort (73.7%), and this is in line with other
data [5]. Similarly to earlier observations [2,3], we could
not find any correlation between the revealed extent of
the disease and its impact on personal quality of life and
pain scores reported by the patients. Moreover, no significant relation could be identified
between these study
end points and sociodemographic variables, such as
marital status, level of education, number of previous
pregnancies and births.
However, we found a striking relation between smoker
status and pain relief, as well as overall improvement of
quality of life. Those who were regular smokers in our
study reported significantly less improvement in these
fields. An explanation to this finding could be provided
by a relatively new hypothesis raising, that, dioxin, the
most toxic of the organochlorines, is associated with an
observed increase in endometriosis in the developed
world [1]. Dioxins (2,3,7,8-tetrachlorodibenzo-p-dioxin;
TCDD) and dioxin-like chemicals cause a large variety
of pathologies including immune dysfunction, carcinogenesis, developmental and
reproductive abnormalities.
Most of these toxic effects are mediated by aryl hydrocarbon receptor (AhR, also called
the dioxin receptor), a
ligand-activated transcription factor [9]. Recent investigation demonstrated that
cigarette smoke contains high
levels of agonists for AhR and markedly activates the
dioxin signaling pathway [10].
The association of endometriosis with organochlorines, specifically polychlorinated
biphenyls (PCBs) that
are not dioxinlike, was first reported from Germany [11].
Also, a letter from Belgian gynecologists suggested that
the higher prevalence of endometriosis at infertility clinics in Belgium could be caused by
the relatively high
TCDD concentration in the Belgian population [12]. In
1976, an explosion in Seveso, Italy exposed the surrounding population to among the
highest levels of
TCDD recorded in humans. The Seveso Womens
Health Study addressed the relation between TCDD

exposure and endometriosis and found a doubled but

statistically nonsignificant risk for endometriosis in
women with higher serum TCDD levels [13]. In nude
mice, Bruner and coworkers demonstrated an augmenting effect of TCDD on the
development of arteficial
endometrial lesions [14]. Also, in a rat model, it was
shown that the environmental pesticide methoxychlor,
which can be metabolized to a chemical with high affinity for the estrogen receptor, had
the same ability as estrogen to promote the growth of endometrial implants
[15]. Methoxychlor is an example of synthetic organochlorines, a large and complex
group of synthetic
organic compounds containing chlorine atoms. The
presence of chlorine tends to make the chemicals more
stable. In fact, certain organochlorines, such as dioxins
are extremely persistent and bioaccumulative [1]. Although in a study by Wilson et al. it
was demonstrated
that the maximum daily exposure estimates of dioxins
deriving from mainstream cigarette smoke are below the
current WHO Tolerable Daily Intake range of 1 - 5 pg/kg
bw/day [16], because of the highly bioaccumulative
properties of the organochlorines we need to be cautious
when interpreting these data.
More is known about the mechanism of toxicity of
dioxin than of almost any other chemical. It binds to the
Ah receptor, which functions as a ligand-activated transcription factor [9]. Dioxin disturbs
homeostasis, it is a
known human carcinogen and is toxic to multiple organ
systems [17]. Dioxins are reproductive and developmental toxicants, as well as being
neurotoxic and immunotoxic [18,19]. Cytokines such as tumor necrosis
factor and interleukins (IL) 1 and 6 have also been
shown to be induced by dioxin exposure [20,21]. TCDD
has been shown to be an immune suppressant in multiple
systems and was also recently suggested to cause autoimmunity in a mouse model [22].
Moreover, TCDD suppresses T-cell-mediated B-cell responses. It also causes a
block in T-cell maturation and is associated with thymic
atrophy at high doses in all species investigated [1].
These mechanisms might all contribute to the development and maintenance of
endometriosis.
In some studies endometriosis was inversely related to
cigarette smoking, however the available data were insufficient to clarify this point [23-26]. Moreover, these
studies had different end points and they did not focus
on improvement in general condition and pain after
therapy in endometriosis patients earlier reporting pelvic
pain. Also, in the study by Matorras et al., only a trend to
a protective effect of smoking was detected [26]. Missmer et al. observed a complex
relation with cigarette
smoking [27]. The rate of endometriosis was not linearly
associated with past smoking dose. However, the relation with current smoking differed
by case-infertility
status. Among women who had never reported infertility,

cigarette smoking was directly associated with risk.

However, when cases were concurrently infertile, current smoking was associated with
reduced risk.
Based on our results, we can conclude, that regular
smoking might have a disadvantageous impact on the
success rate of combined surgical and medical therapy
for endometriosis related pelvic pain. Although there are
several studies focusing on the patomechanism of endometriosis with regard to smoking,
to our knowledge,
this is the first report dealing with a possible correlation
between therapy issues and smoking in this field. Even
though our data passed strict statistical analyses, considering their limited amount, we
consider this work as a
preliminary one to initiate specially aimed international
studies to further clarify the issue.