Hum. Reprod. Advance Access originally published online on August 26, 2006
Human Reproduction 2007 22(1):266-271; doi:10.1093/humrep/del339
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Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients
1 First Department of Obstetrics and Gynaecology 2 Second Department of Obstetrics and Gynaecology, University of Milano and 3 Istituti Clinici di Perfezionamento, Milano, Italy
4 To whom correspondence should be addressed at: Clinica Ostetrica e Ginecologica, Istituto ‘Luigi Mangiagalli’, Università di Milano, Via Commenda, Milano 12-20122, Italy. E-mail: paolo.vercellini{at}unimi.it
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Abstract |
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BACKGROUND: The association between lesion type, disease stage and severity of pain was studied in a large group of women with endometriosis to verify whether endometrial implants at different sites determine specific complaints and to evaluate the validity of the current classification system in women with symptomatic disease. METHODS: A total of 1054 consecutive women with endometriosis undergoing first-line conservative or definitive surgery were included. Data on age at surgery, disease stage according to the revised American Fertility Society (AFS) classification, anatomical characteristics of endometriotic lesions, and type and severity of pain symptoms were collected and analysed by multiple logistic regression. RESULTS: Minimal endometriosis was present in 319 patients, mild in 139, moderate in 292 and severe in 304. A significant inverse relationship was demonstrated between age at surgery and moderate-to-severe dysmenorrhoea, dyspareunia and non-menstrual pain. A strong association was found between posterior cul-de-sac lesions and pain at intercourse [Wald
2 = 17.00, P = 0.0001; odds ratio (OR) = 2.64, 95% confidence interval (CI) = 1.68–4.24]. A correlation between endometriosis stage and severity of symptoms was observed only for dysmenorrhoea (Wald 2 = 5.14, P = 0.02) and non-menstrual pain (Wald 2 = 5.63, P = 0.018). However, the point estimates of ORs were very close to unity (respectively, 1.33, 95% CI = 1.04–1.71, and 1.01, 95% CI = 1.00–1.03). CONCLUSIONS: The association between endometriosis stage and severity of pelvic symptoms was marginal and inconsistent and could be demonstrated only with a major increase in study power.
Key words: classification/dysmenorrhoea/dyspareunia/endometriosis/pelvic pain
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Introduction |
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Pelvic pain together with infertility constitutes a major clinical problem for women with endometriosis. However, whether the type and site of lesions or the extent of disease is correlated with the frequency and severity of symptoms is far from clear (Vercellini, 1997
; Whiteside and Falcone, 2003). Several attempts have been made to disentangle this issue in recent years (Cornillie et al., 1990; Koninckx et al., 1991; Ripps and Martin, 1991; Vercellini et al., 1991; Perper et al., 1995; Muzii et al., 1997; Porpora et al., 1999; Parazzini et al., 2001; Fauconnier et al., 2002; Milingos et al., 2006), but results are inconsistent. Attention has focused specifically on the validity of the staging system (Fedele et al., 1990; Mahmood et al., 1991; Marana et al., 1991; Stout et al., 1991; Fedele et al., 1992; Matorras et al., 1996; Vercellini et al., 1996; Stovall et al., 1997; Szendei et al., 2005) designed by the former American Fertility Society (AFS, 1985), now the American Society for Reproductive Medicine (ASRM, 1997). In this scheme, different scores are attributed to various types of endometrial implants and adhesions, based on the presupposition that a gradient exists between extension of lesions and biological impact. However, this has not been confirmed with regard to infertility (Guzick et al., 1997).
Controversies on pelvic pain are not only of academic interest, because demonstration of the reliability of a classification would indirectly unravel which lesion causes which pain symptom, suggesting the underlying algogenic mechanism (Chapron et al., 2003a; Fauconnier and Chapron, 2005). Previous reports from our institution included only infertile women (Fedele et al., 1992), only symptomatic ones (Vercellini et al., 1996) or both (Fedele et al., 1990), but always with a relatively limited number of subjects.
The main objective of the present study was to analyse the association between patient characteristics, lesion type, disease stage and severity of pain symptoms in a large group of women undergoing surgery for endometriosis. Our hypothesis was that a major increase in study power together with performance of a multivariate analysis, which allows for the effect of several potential confounding factors simultaneously, would provide robust evidence on which to base a definitive evaluation of the role, if any, of the currently adopted classification for endometriosis in women with symptomatic disease.
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Materials and methods |
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We included 1054 consecutive women with endometriosis undergoing first-line conservative or definitive surgery at the First Department of Obstetrics and Gynaecology of the University of Milan during the period 1996–2002. The study population differed from those assessed previously by us (Vercellini et al., 1991
, 1996). The primary indication for surgery was chronic pain in 329 subjects, pelvic mass in 313 and infertility in 312, whereas in 100 the indications were mixed. Data were collected on age at surgery, parity, BMI, disease stage according to the revised AFS classification (1985) and detailed anatomical characteristics of endometriotic lesions. Patients with a previous clinical or endoscopic diagnosis of endometriosis or with other diseases that might cause pelvic pain (chronic pelvic inflammatory disease, pelvic varices and genital malformations) were excluded from the study. Other exclusion criteria were treatment for endometriosis other than non-steroid anti-inflammatory drugs up to 6 months before study entry, previous abdominal surgery except appendectomy, a diagnosis of gastrointestinal, urological and orthopaedic diseases with potential pain irradiation to the pelvic area and known psychiatric disturbances.
Each patient was asked to complete a questionnaire on the presence and severity of dysmenorrhoea, deep dyspareunia and non-menstrual pelvic pain graded according to a 0- to 3-point multidimensional categorical rating scale modified from the one devised by Biberoglu and Behrman (1981), which defines dysmenorrhoea according to loss of work efficiency and need for bed rest (absence of pain, 0; some loss of work efficiency, mild, 1; in bed part of 1 day, occasional loss of work, moderate, 2 and in bed for 1 or more days, incapacitation, severe, 3), non-menstrual pain according to various degrees of discomfort and use of analgesics (absence of pain, 0; occasional pelvic discomfort, mild, 1; noticeable discomfort for most of the cycle, moderate, 2; pain persisting during the cycle or requiring strong analgesics, severe, 3) and deep dyspareunia according to limitation of sexual activity (no discomfort, 0; tolerated discomfort, mild, 1; intercourse painful to the point of interruption, moderate, 2; intercourse avoided because of pain, severe, 3).
The women were also requested to grade the severity of dysmenorrhoea, non-menstrual pelvic pain and deep dyspareunia using a 100-mm visual analogue scale (VAS) the left extreme of which indicated the absence of pain and the right one pain as bad as it could be; a score of 1–50 was considered mild pain, 51–80 moderate pain and 81–100 severe pain. Threshold points defining different categories of pain were chosen based on a previous correlation analysis (Vercellini et al., 1996) with the Biberoglu and Behrman multidimensional categorical rating scale (1981). The severity of symptoms was dichotomized between pain absent (no or mild symptoms) or present (moderate or severe symptoms on both scales).
Surgeons were not blinded as to the nature of the symptoms at the time of staging. In the case of patients not personally operated on by the authors, the original staging was verified by G.A., who systematically reviewed the surgical descriptions and detailed diagrams made at the time of laparoscopy or laparotomy. The diagnosis of endometriosis was mainly visual, as biopsies were not always performed. A histological diagnosis was available in 768 subjects (72.9%).
Data management
Data were archived using Access 97 and then exported into SAS 6.12 (SAS Institute Inc., Cary, NC, USA) for analysis. To estimate simultaneously the effect of several covariates on symptoms before surgery, unconditional multiple logistic regression was used. Included in the regression equations were terms for age at surgery, BMI, revised AFS classification stage, revised AFS classification score for implants and for adhesions separately, uterine position (anteflexion and retroflexion), peritoneal lesions of the anterior or posterior cul-de-sac, diameter of right and left ovarian endometriomas and rectovaginal lesions. Age at surgery, endometriosis stage, classification score and lesion diameter were managed as continuous variables to avoid overparameterization. The significance of the main effects was tested by the Wald 2 test (two-sided). Odds ratios (ORs) were computed separately for the considered factors from data stratified for quinquennia of age, and corresponding 95% confidence intervals (95% CIs) were based on profile likelihood.
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Results |
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The clinical characteristics of the subjects recruited are reported in Table I. Minimal endometriosis was present in 319 patients, mild in 139, moderate in 292 and severe in 304. Deeply infiltrating lesions of the uterosacral ligaments and rectovaginal pouch were observed in 167 subjects (43 at stage II, 55 at stage III and 69 at stage IV). Partial or complete posterior cul-de-sac obliteration with adhesion of the rectosigmoid to the posterior cervical aspect was present in, respectively, 87 and 58 women.
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Using logistic regression analysis, a strong inverse relationship was observed between age at surgery and moderate-to-severe dysmenorrhoea (Table II) (Wald
2 = 31.64, P = 0.0001; OR = 0.93, 95% CI = 0.91–0.95), whereas the contrary was true for endometriosis stage (Wald 2 = 5.14, P = 0.02; OR = 1.33, 95% CI = 1.04–1.71). Also, the diameter of a right ovarian endometrioma was inversely related to pain at menstruation (Wald 2 = 4.70, P = 0.03; OR = 0.87, 95% CI = 0.77–0.97), whereas only a trend was observed for the diameter of a left ovarian endometriotic cyst. Assessment of dysmenorrhoea was not available or not reliable in 57 cases.
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When deep dyspareunia was considered, advancing age was associated with a reduction in the severity of the symptom (Wald
2 = 8.15, P = 0.004; OR = 0.95, 95% CI = 0.92–0.98). As expected, a strong direct relationship was observed between posterior cul-de-sac infiltrating lesions and pain at intercourse (Wald 2 = 17.00, P = 0.0001; OR = 2.64, 95% CI = 1.68–4.24). Paucity of data on lesion size impeded the evaluation of any association with pain intensity. Assessment of deep dyspareunia was not available or not reliable in 309 cases.
Increase in age was inversely related also to non-menstrual pelvic pain (Wald 2 = 26.03, P = 0.0001; OR = 0.92, 95% CI = 0.89–0.95), whereas endometriosis stage was marginally associated with severity of the symptom (Wald 2 = 5.63, P = 0.018; OR = 1.01, 95% CI = 1.00–1.03). A positive relationship was found with lesions of the posterior cul-de-sac and an inverse one with the diameter of a left ovarian endometrioma (respectively, Wald 2 = 5.88, P = 0.015; OR = 1.58, 95% CI = 1.09–2.30 and Wald 2 = 5.92, P = 0.014; OR = 0.84, 95% CI = 0.72–0.96). Assessment of non-menstrual pain was not available in 269 cases.
No other significant correlations were observed in each of the three symptom categories considered. The relationship between endometriosis and rectal pain or dyschezia was not investigated, because information on such symptoms was incomplete.
For verifying whether indication for surgery could have influenced the relationship between covariates and pain symptoms, a subgroup analysis in the populations with pelvic pain, infertility and adnexal masses was performed separately.
The negative relationship between moderate-to-severe dysmenorrhoea and age at surgery was confirmed in each of the three subpopulations (pelvic pain group, Wald 2 = 5.20, P = 0.023; OR = 0.88, 95% CI = 0.79–0.98; infertility group, Wald 2 = 14.21, P < 0.001; OR = 0.87, 95% CI = 0.82–0.94; adnexal mass group, Wald 2 = 13.91, P < 0.001; OR = 0.92, 95% CI = 0.88–0.96). The association with endometriosis stage was confirmed only in the subgroup with pelvic pain (Wald 2 = 4.71, P = 0.03; OR = 8.68, 95% CI = 1.23–61.23), whereas the diameter of a right ovarian endometrioma remained inversely related to pain at menstruation only in patients with adnexal masses (Wald 2 = 4.28, P = 0.038; OR = 0.78, 95% CI = 0.62–0.99).
With regard to dyspareunia, the only significant association observed was between posterior cul-de-sac infiltrating lesions and pain at intercourse in the pelvic pain and infertility subgroups (respectively, Wald 2 = 9.42, P = 0.002; OR = 2.70, 95% CI = 1.43–5.09 and Wald 2 = 4.04, P = 0.045; OR = 2.76, 95% CI = 1.02–7.45).
The inverse relationship between non-menstrual pelvic pain and age at surgery was confirmed only in the infertility subgroup (Wald 2 = 8.07, P = 0.005; OR = 0.86, 95% CI = 0.78–0.96). No other significant associations were identified.
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Discussion |
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The relationship between type and site of endometriotic lesions, disease stage and frequency and severity of pelvic symptoms is a matter of endless debate, as data from numerous studies on such relationships are contradictory (Whiteside and Falcone, 2003
). Dysmenorrhoea, the symptom most frequently reported by women with endometriosis, has been variably found to be associated with early, papular and atypical implants (Vercellini et al., 1991), volume and depth of lesions (Koninckx et al., 1991; Chapron et al., 2003b), advanced disease stages only (Fedele et al., 1992), total number, but not location, of ectopic implants (Perper et al., 1995) and AFS classification score but not stage (Muzii et al., 1997). However, no consistent relationship has been found in the majority of available studies (Table III).
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An unexpectedly high prevalence of endometriosis was observed in a large group of asymptomatic women undergoing laparoscopic exploration because of infertility (Matorras et al., 2001
), and in a case-control study, no specific pain symptoms significantly associated with the disease could be identified (Matorras et al., 1996). This lack of consensus suggests per se that most probably other unknown factors play a role in the genesis of menstrual pain, and to assume that only the gross characteristics of implants determine the nature of complaints may be naïve.
According to the results of several studies, mechanisms responsible for severe pelvic pain in women with endometriosis involve the growth of nerve fibres into ectopic implants (Anaf et al., 2004; Berkley et al., 2005; Remorgida et al., 2005). This could have a varied and widespread influence on the activity of neurones both locally (Tamburro et al., 2003; Bedaiwy et al., 2006) and throughout the central nervous system (Vercellini et al., 1992; Bajaj et al., 2003).
The only strong association observed by most investigators is between deep posterior cul-de-sac lesions and dyspareunia (Vercellini et al., 1996; Porpora et al., 1999; Fauconnier et al., 2002; Chapron et al., 2003b; Chopin et al., 2005; Ferrero et al., 2005). This confirms the ‘organic’ nature of the symptom, as the retrocervical area is most likely to be struck during intercourse (Vercellini et al., 1991; Vercellini, 1997; Fauconnier et al., 2002). A close histological relationship between nerves and endometriotic foci has been observed in rectovaginal nodules (Anaf et al., 2000). Moreover, deep endometriotic lesions may be neurotrophic, as they have been consistently associated with higher expression of nerve growth factor in comparison with peritoneal and ovarian implants (Anaf et al., 2002).
In the present unusually large series of women with endometriosis, relatively few associations were observed between various clinical, anatomical and pathological variables, as well as different disease stages, and the frequency and severity of pelvic pain. The generalizability of our findings may be questionable. In fact, results apply only to patients with symptomatic endometriosis who underwent visual pelvic inspection and are not necessarily valid for subjects with endometriosis-associated pain who were managed without surgical exploration or who did not even seek medical assistance.
All women undergoing first-line surgery during the study period and satisfying the selection criteria were included in the analysis. The gynaecologists who staged the disease were not blinded as to the nature and severity of patients’ symptoms. This was because surgeons must agree on the indication for the intervention and should look for even minor lesions that could cause specific types of pain. In order to avoid diagnostic and classification biases, one expert research fellow reviewed all surgical records. Only the revised AFS system (1985) was adopted, as the more recent ‘revised’ ASRM scheme (1997) is identical with regard to attributable points as well as threshold scores between stages; the only difference is the identification of different morphological lesion types (red, white and black) which, however, are not given specific scores.
The single robust finding of our analysis was the reduction of pain severity with advancing age. It cannot be excluded that the above inverse relationship is the consequence of earlier medical assistance sought by women with more severe pain.
However, the association was observed in all symptom categories as well as at subgroup analysis, which supports the consistency of the general results. This could be interpreted in terms of decreasing estrogen production with time, but other factors may well influence the results (e.g. less impetuous sexual activity and hence reduced dyspareunia). Nevertheless, the observation suggests that disease aggressiveness may spontaneously decrease over time. If further studies confirm this finding, relevant information should be included in patient’s counselling, and treatment options should be tailored accordingly.
The inverse relation between endometrioma diameter and dysmenorrhoea and non-menstrual pelvic pain is difficult to interpret. Patients with suspected large endometriomas at ultrasonography (e.g. those with advanced stages) could be more prone to undergo surgery with less severe symptoms than subjects with peritoneal only lesions, and this would bias interpretation of the results. However, the finding is in agreement with the data of Fauconnier et al. (2002), and also Parazzini et al. (2001) confirmed this observation in a large, multicentre, Italian study. This may partly explain the weak association between endometriosis stages and symptom severity. In fact, the diameter of ovarian cysts is decisive in stage attribution according to the present system (AFS, 1985; ASRM, 1997). If endometrioma diameter is not associated with pain, no relationship could reasonably be expected between the AFS classification system (1985) and pelvic symptoms. Alternatively, ovarian endometriotic lesions may be scarcely neurotrophic (Anaf et al., 2002) and consequently not significantly related to pain. In fact, Al-Fozan et al. (2004) did not find nerve fibres in endometriomas or in the endometrioma-containing ovaries.
It is possible that pelvic adhesions are more important than cyst diameter as a cause of pain, and it has been demonstrated that the size of an endometrioma does not correlate with the extent of adhesive disease (Kaya et al., 2005). However, in line with the findings of Parazzini et al. (2006), we did not observe a significant relationship between revised AFS classification score for adhesions only and pain symptoms.
In our study, disease stage was significantly associated with severity of dysmenorrhoea and non-menstrual pain. Evaluation of deep dyspareunia could have been influenced by the high number of missing values, probably because of women’s embarrassment in completing the pertinent section of the questionnaire. However, as data relative to more than 700 subjects were analysed, it is improbable that a major association went unrecognized. Indeed, we would provocatively affirm that the major drawback of our study lies in the unusually high power. In fact, the point estimate of ORs for dysmenorrhoea and non-menstrual pain is very close to unity (respectively, 1.33 and 1.01), and it cannot be excluded that corresponding CIs would have included it if just slightly fewer subjects had been recruited, as was the case for subgroup analysis. In other words, and independently of biometric considerations, we can confidently exclude major and clinically important associations between endometriosis stage and severity of pelvic symptoms. This is probably because the lesions considered in score attribution do not consistently cause the same type and/or the same amount of pain. More likely, the intensity of pain is determined not by the type and extension of implants per se but by the interaction between endometriotic lesions and sensory afferent nerve fibres (Vercellini 1997; Anaf et al., 2000), a variable that does not follow predictable patterns. It seems improbable that inclusion of active lesion type in the classification scheme (ASRM, 1997) will improve its performance, as scores for implants and adhesions were not significantly associated with symptoms when analysed separately.
The only strong association observed with regard to implant characteristics both at general and subgroup analysis was between pouch of Douglas lesions and deep dyspareunia. As the correlation between ‘deep’ disease of the posterio-uterine cul-de-sac and severe pain is consistent in almost all studies that addressed the issue (Cornillie et al., 1990; Koninckx et al., 1991; Ripps and Martin, 1991; Vercellini et al., 1996; Porpora et al., 1999; Fauconnier et al., 2002; Chapron et al., 2003a,2003b; Garry, 2004; Chopin et al., 2005), it seems reasonable to propose that future staging systems in women with symptomatic endometriosis should include specific scores for infiltration of posterior parametria, anterior rectal wall and posterior vaginal fornix. Finally, also deep anterio-uterine cul-de-sac and bladder detrusor endometriosis should be considered, as these lesions have been reported to be consistently associated with major urological symptoms (Chapron et al., 2003a; Chopin et al., 2005; Fauconnier and Chapron, 2005; Fedele et al., 2005).
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Submitted on April 4, 2006; resubmitted on June 28, 2006; accepted on July 25, 2006.
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