Pelvic pain in endometriosis: is success of therapy gone in cigarette smoke?

doi:10.4236/health.2011.39098

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Vol.3, No.9, 571-576 (2

doi:10.4236/health.2011.39098

011) Health

Pelvic pain in endometriosis: is s uccess 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

1Institute of Nursing and Clinical Sciences, Faculty of Health Sciences, University of Pécs, Pécs, Hungary;

*Corresponding Aut hor: [email protected]

2Department of Obst e t r i c s and Gynecology, Faculty of Medicine, University of Pécs, Pécs, Hungary;

3Department of Pathophysiology and Gerontology, Faculty of Medicine, University of Pécs, Pécs, Hungary;

4Department of O b stetrics and Gynecology, Faculty of Medicine, University of Giessen, Giessen, Germany.

Received 17 January 2011; revised 1 June 2011; accepted 10 August 2011.

ABSTRACT

The objective of the study was to assess poten-

tial individual factors influencing the efficac y of

combined surgical and medical therapy in en-

dometriosis patients with pelvic pain. For this

purpose we performed a prospective study us-

ing a specifically design ed questionnaire among

patients suffering from persistent pelvic pain

and undergoing laparoscopy and further GnRH

analogue therapy in a university-based gyne-

cologic department. Eighty-one women of re-

productive age with histologically confirmed

endometriosis were enrolled. A questionnaire

gathered information from women on the fol-

lowing 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 gen-

eral quality of life estimates including self-im-

age. Pelvic pain was scored using a visual ana-

logue scale. Patients filled out the question-

naires before surgery and upon completing

medical therapy. Data were statistically evalu-

ated. 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 smok-

ers in the study. However, 56% of non-smoker

participants reported a positive outcome that

proved to be significantly larger than the ra tio of

pain-free smoker participants (p = 0.02). Im-

provement in q uali ty of l ife was repo rt ed by 74%

of all patients, and only 9% of them were smok-

ers. However, 47% were smokers among pa-

tients 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 pelv ic 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 exten sive

problems with fertility and loss of work time [1]. Endo-

metriosis might remain asymptomatic and discovered

accidentally. However, it may cause symptoms, which

include chronic pelvic pain, bleeding, infertility, and

increases susceptibility to development of adenocarci-

noma [2]. Signs and symptoms arise from cyclic bleed-

ing into the surrounding tissues, resulting in inflamma-

tion and formation of scarring and adhesions. It is pecu-

liar, that symptom severity does not correlate well with

the extent or progression of the lesions [3]. Minor

laparoscopic findings might come with severe com-

plaints, while extensive lesions might remain undetected

and revealed only accidentally. The exact roles of dif-

ferent factors contributing to the establishment and per-

sistence 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 surgi-

cally 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

A. Koppan et al. / Health 3 (2011) 571-576

572

by GnRH agonists, oral contraceptives and Type II pro-

gesterone receptor ligands [4]. All medical treatments

seem to be equally effective in managing endometriosis.

Although about 80% - 85% of patients have improve-

ment in their symptoms [5], many women experience

unsatisfactory results. However, little is known about

factors on patient’s side influencing the efficacy of gen-

erally 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 deter-

mine 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 patient’s 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. Stud y Population and Sample

The prospective cohort study population consisted of

patients of reproductive age complaining about persis-

tent pelvic pain and undergoing laparoscopy in our de-

partments (Department of Obstetrics and Gynecology,

Faculty of Medicine, University of Pécs, 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 endo-

metriosis were then recruited. This initial number of

recruited patients was arbitrarily set and reached in a 6

month period between June and December, 2008. Ran-

domization was based on the unpaired character of pa-

tients’ 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 pa-

tients consented to participate in the study. A standard-

ized questionnaire elicited information from women on

the following groups of variables: age, marital status,

education, reproductive and medical history. The ques-

tionnaire was purposefully designed to ascertain infor-

mation on p otential co nfounders, wh ich includ ed gravid-

ity (number of pregnancies regardless of outcome) and

parity (number of live births), knowledge of accompani-

ing pelvic disorders, concurrent cigarette smoking and

caffein intake, since all have been reported as risk fac-

tors for endometriosis [6,7]. Further variables were con-

currently 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 endometrio-

sis and with no other pelvic/abdominal alteration or dis-

ease confirmed at laparoscop y were then eligible to con-

tinue 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 question-

naires 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 pa-

thology regardless of surgical indication. Severity of

endometriosis was staged according to the American

Fertility Society’s revised definition. In all patients en-

dometriosis lesions were laparoscopically removed and/

or electrocauterized and histological examination con-

firmed diagnosis. The affiliated University gave Institu-

tional 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-Spearman’s

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 smoke r s .

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 specifi-

cally 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 re-

ported a positive outcome in the study. This difference

proved to be significant, as calculated by Chi-Square test

(p = 0.02, Figure 1).

A. Koppan et al. / Health 3 (2011) 571-576

573573

3.2. Outcomes in Overall Quality of Life

(Self-Image) The correlation between smoker status and negativ qual-

ity of life outcome proved to be significant, as calculated

by the Pearson’s correlation test (2-tailed, p < 0.01, Fig-

ure 2).

Overall, 74% of patients reported improvement in

their general quality of life, while no improvement or

even deterioration was reported by 26% of all partici-

pants. Among those with improved quality of life only

9% were smokers, while 47% were smokers among pa-

tients 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, analyz-

ing the data concerning th e 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 com-

plaints after combined surgical and medical therapy of endometriosis patients. Data are pre-

sented 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 pre-

sented as percentage values. **p < 0.01; pos, positive change in general quality of life; neg, no

or negative change in general quality of life.

Openly accessible at /HEALH

A. Koppan et al. / Health 3 (2011) 571-576

574

end of the study revealed no sig nificant correlation s.

4. DISCUSSION

The currently available medical treatments for endo-

metriosis 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 influ-

ence 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 qual-

ity 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 observatio ns [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 sig-

nificant 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, carcino-

genesis, developmental and reproductive abnormalities.

Most of these toxic effects are mediated by aryl hydro-

carbon receptor (AhR, also called th e dioxin receptor), a

ligand-activated transcription factor [9]. Recent investi-

gation demonstrated that cigarette smoke contains high

levels of agonists for AhR and markedly activates the

dioxin signali n g pat h way [1 0] .

The association of endometriosis with organochlori-

nes, specifically polychlorinated biphenyls (PCBs) that

are not dioxinlike, was firs t re p o rt ed from Germany [11].

Also, a letter from Belgian gynecologists suggested that

the higher prevalence of endometrio sis at infertility clin-

ics 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 sur-

rounding population to among the highest levels of

TCDD recorded in humans. The “Seveso Women’s

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 augment-

ing 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 affin-

ity for the estrogen receptor, had the same ability as es-

trogen to promote the growth of endometrial implants

[15]. Methoxychlor is an example of synthetic or-

ganochlorines, 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]. Al-

though 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 tran-

scription factor [9]. Dioxin disturbs homeostasis, it is a

known human carcinogen and is toxic to multiple organ

systems [17]. Dioxins are reproductive and develop-

mental toxicants, as well as being neurotoxic and im-

munotoxic [18,19]. Cytokines such as tumor necrosis

factor and interleukins (IL) 1β and 6 have also been

shown to be induced by dioxin exposure [20,21]. TCDD

has been shown to be an immune sup pressant in multiple

systems and was also recently suggested to cause auto-

immunity in a mouse model [22]. Moreover, TCDD sup-

presses 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 develop-

ment and maintenance of endometriosis.

In some studies endometriosis was inversely related to

cigarette smoking, however the available data were in-

A. Koppan et al. / Health 3 (2011) 571-576

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sufficient 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 patie nts earlier reporting pelvic

pain. Also, in the study by Mato rras et al., only a trend to

a protective effect of smoking was detected [26]. Miss-

mer et al. observed a complex relation with cigarette

smoking [27]. The rate of endometriosis was not linearly

associated with past smoking dose. However, the rela-

tion 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, cur-

rent 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 re lated pelvic pain. Although there are

several studies focusing on the patomechanism of en-

dometriosis 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, consid-

ering their limited amount, we consider this work as a

preliminary one to initiate specially aimed international

studies to further clarify the issue.

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