Deep infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease

Charles Chapron1,3, Arnaud Fauconnier1,2, Jean-Bernard Dubuisson1, Habib Barakat1, Marco Vieira1 and Gérard Bréart2

1 Service de chirurgie gynécologique, Clinique universitaire Baudelocque, CHU Cochin, Saint Vincent de Paul, La Roche-Guyon, 123, bd Port-Royal 75079 Paris Cedex 14 and 2 Unité Inserm 149, recherches épidémiologiques en santé périnatale et santé des femmes, Paris, 123, bd Port-Royal 75014 Paris, France

3 To whom correspondence should be addressed. e-mail: charles.chapron{at}cch.ap-hop-paris.fr


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Little is known about the precise nature of the relationship between dysmenorrhoea (DM) and endometriosis. Our aim was to evaluate the relationship between the severity of DM in women with posterior deep infiltrating endometriosis (DIE) and indicators of the extent of their disease. METHODS: Various indicators of the extent of DIE were recorded during surgery in 209 women. The severity of their DM was assessed with a pain scale. The scale was retrospective for 155 women and prospective for 54. Correlations were sought with an ordinal logistic regression model with cumulative odds. RESULTS: On univariate analysis the following variables were related to the severity of DM: number of previous surgical procedures for endometriosis; revised American Fertility society classification; extensiveness of adnexal adhesion; Douglas obliteration; size of the posterior DIE implant; extent of the sub-peritoneal infiltration by the posterior DIE (rectal, vaginal or both versus sub-peritoneal only). Current infertility was associated with less severe DM. After multiple regression analysis, presence of a rectal or vaginal infiltration by the posterior DIE and extensiveness of adnexal adhesion were the only factors that remained related to DM severity. CONCLUSIONS: The concept of ‘very deep infiltrating endometriosis’, defined as implants invading the wall of the pelvic organ, should be tested in future classification systems specifically addressed to the prediction of endometriosis-related pain.

Key words: classification system/deep infiltrating endometriosis/dysmenorrhoea


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The association of dysmenorrhoea (DM) with endometriosis is well recognized. Although DM is very common in the general population of women (Jamieson and Steege, 1996Go), it is especially frequent among those with endometriosis (Williams and Pratt, 1977Go; Mahmood et al., 1991Go; Al-Badawi et al., 1999Go). Furthermore, one case–control study reported a trend between the risk of endometriosis and the severity of DM (Cramer et al., 1986Go), which suggests that the more extensive the disease is, the greater the severity of associated DM. Systems of endometriosis classification, such as the revised American Fertility Society classification (R-AFS) (The American Fertility Society, 1985Go), have been developed to help standardize evaluation of the extent of disease (Schenken, 1998Go). Several studies, however, have failed to correlate its extent, as measured by the AFS score, with the severity of dysmenorrhoea (Fedele et al., 1990Go; Marana et al., 1991Go; Vercellini et al., 1996Go; Porpora et al., 1999Go). Furthermore, little is known about the precise nature of the relationship between endometriosis and DM (Vercellini, 1997Go).

Deep infiltrating endometriosis (DIE) is a particular form of endometriosis that penetrates >5 mm under the peritoneal surface (Koninckx and Martin, 1994Go). These lesions are considered very active and are strongly associated with pelvic pain symptoms (Koninckx et al., 1991Go). DIE implants are located in specific locations, primarily the posterior area (Cornillie et al., 1990Go; Chapron et al., 2003Go). Posterior DIE can involve uterosacral ligaments (Chapron and Dubuisson, 1996Go), torus uterinus (retrocervical area of the uterus where the uterosacral ligaments join together (Kamina, 1984Go), the posterior vaginal wall and the anterior rectal wall (Martin and Batt, 2001Go; Chapron et al., 2003Go). DIE implants are rather poorly reflected in the R-AFS classification (Dubuisson and Chapron, 1994Go; Koninckx and Martin, 1992Go). This may explain why studies assessing disease extent with this classification have failed to observe correlations with DM severity.

Since 1992, we have conducted continuous assessment by collection of data concerning women operated on in our department for DIE. In a previous retrospective study based on the first 225 women, we made an attempt to correlate distinct painful symptoms to location and characteristics of DIE (Fauconnier et al., 2002Go). Surprisingly, we failed to correlate severe DM with any of the characteristics of the DIE implants. However, in this study DM was not evaluated in a standardized way in a questionnaire. The purpose of the present study is therefore to evaluate the relationship between indicators of disease extent and intensity of DM (using a standardized measurement) in a population of women with posterior DIE.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Population study
This study includes all the women who underwent surgery for infertility, pelvic pain symptoms (including DM, deep dyspareunia and non-menstrual pain) or adnexal masses between June, 1992 and December, 2000 and were diagnosed with posterior DIE. This determination was made during the diagnostic phase of the surgery (The American Fertility Society, 1993Go) and was based on the macroscopic appearance of the lesion, using the following criteria: (i) palpable and visible nodule or induration in the posterior area (Koninckx et al., 1996Go); (ii) dark blue nodule visible at the posterior vaginal wall at speculum examination (Vercellini et al., 1996Go). DIE was considered histologically-confirmed when endometrial glands and stroma were present at microscopic examination. We excluded those women who had previously had a DIE nodule resected and those who were no longer menstruating.

Variables
All the women assessed the severity of their DM, but the method used depended on the study period. During the ‘retrospective’ period (from June, 1992 to December, 1999) DM intensity was assessed retrospectively with an 11-point numeric scale (Garry et al., 2000Go). Two questionnaires were mailed to the women operated on—in 1997 for the women operated on between 1992 and 1996, and in 2001 for the women operated on between 1997 and 1999. During the ‘prospective’ period (from January, 2000 to December, 2000), DM intensity was assessed prospectively with a 10 cm visual analogue scale (Peveler et al., 1996Go) recorded during the month before surgery by means of a self-assessed questionnaire. Details of the questionnaire items used to assess DM for both of the study periods are given in Table V. In order to standardize the measurement of the intensity of DM, we recoded both scales into four quartiles, defined separately for each of the two study periods. Accordingly, DM severity was defined in four ordered categories, labelled mild, moderate, severe and extreme.


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Table V. Evaluation of DM during the two study periods
 
Disease extent indicators were coded onto a standardized data sheet according to the surgical report, the revised AFS scoring sheet, the anatomic drawing, the degree of the surgical procedure and the result of rectal endoscopic ultrasound (Chapron et al., 1998Go).

Disease stage was scored according to the R-AFS classification (The American Fertility Society, 1985Go), and the individual items and all subscores for implants and adhesions were also recorded. The original staging was systematically verified by the author (A.F.). Other variables recorded included size of the biggest endometrioma as well as cumulative endometrioma size, number of distinct DIE implants, size of the posterior DIE implant (defined as the maximum diameter of the lesion assessed during the diagnostic phase of the surgery) and cumulative size of all DIE implants. The extent of the sub-peritoneal infiltration by the posterior DIE was classified as follows: (i) sub-peritoneal only when the DIE implant involved only the sub-peritoneal tissue (including uterosacral ligaments, torus uterinus, or retroperitoneal tissue underlying the pouch of Douglas); (ii) rectal when the DIE implant involved the muscularis propria of the bowel either at histological examination or at rectal endoscopic ultrasound (Chapron et al., 1998Go), when the women did not have complete resection and (iii) vaginal when a partial colpectomy was required to remove the DIE (Donnez and Nisolle, 1995Go; Anaf et al., 2001Go; Chapron et al., 2001Go) or when a dark blue nodule was present in the posterior vaginal fornix at the speculum (Vercellini et al., 1996Go).

Statistical analysis
Univariate associations between DM severity and the variables considered were sought with a separate ordinal logistic regression model with cumulative odds (Ananth and Kleinbaum, 1997Go; Manor et al., 2000Go). Subsequently, variables associated with DM severity at a threshold of P = 0.20 were entered into a multiple ordinal logistic regression model. Backward stepwise selection was used to retain variables with a P-value = 0.05 in the final multiple regression model. All continuous variables were recoded into ordered categorical variables. The reference classes were those with the lowest values. The parameter values for the final model were estimated by the maximum likelihood method; the adjusted odds ratios and their 95% confidence intervals were calculated from the model’s coefficients and their standard deviations. The odds ratio represents the likelihood of being in a category of more severe dysmenorrhoea. Similar analyses were conducted for women with histologically-confirmed DIE. Because the results could vary according to the way DM was recorded, we also performed subgroup analysis on both periods of the study.

All analyses were performed with Stata Statistical Software 6.0 (Stata Corporation).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Of the 349 women eligible for the study, 140 were excluded for the following reasons: amenorrhoea, nine cases (2.6%); previous resection of DIE, 12 cases (3.4%); inadequate description of the posterior DIE, 13 cases (3.7%); and failure to respond to the questionnaire, 106 women (30.4%). The proportion of non respondents did not differ by study period (31.3% for the retrospective period, versus 27.8% for the prospective period). Accordingly, the final study population included 209 women. Their characteristics are reported in Table I. Among the 209 women with surgical diagnosis of posterior DIE, 142 (67.9%) had implants confirmed histologically, whereas 47 (22.5%) had fibrotic implants and 20 (9.6%) did not have removal of their implants. Surgery for 155 women (74.2%) took place during the retrospective period, and for 54 (25.8%) during the prospective period. During the retrospective period the median time-lapse between surgery and the questionnaire was 2.2 years (range 0.2–4.7).


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Table I. Characteristics of the 209 women in the study
 
The mean value of the numeric DM scale was 6.9 ± 3.0 for the retrospective period and was divided into four quartiles: (i) <6, mean 2.3 ± 2.4; (ii) 6 and 7, mean 6.6 ± 0.5; (iii) 8, mean 8.0 ± 0.0; and (iv) 9 and 10, mean 9.5 ± 0.5. For the prospective period, the mean value of the visual analogue DM scale was 5.8 ± 3.1: (i) <3.6, mean 1.2 ± 1.0; (ii) from 3.6 to <6.8, mean 5.5 ± 1.0; (iii) from 6.8 to <8.1, mean 7.4 ± 0.3; and (iv) = 8.2, mean 9.1 ± 0.7. Thus the final distribution of DM severity in the overall population was: (i) mild for 48 women (23.0%); (ii) moderate for 45 (21.5%); (iii) severe for 52 (24.9%); and (iv) extreme for 64 (30.6%).

On univariate analysis (Table II), the following variables were related to more severe DM: number of previous surgical procedures for endometriosis; R-AFS stage; extent of adnexal adhesion; Douglas obliteration; size of posterior DIE implant; extent of the sub-peritoneal infiltration (rectal, vaginal or both versus sub-peritoneal only). Current infertility was associated with less severe DM. After multiple regression analysis (Table III), extent of the sub-peritoneal infiltration and extensiveness of adnexal adhesion were the only factors that remained related to DM severity. The number of previous procedures for endometriosis was not included in the final model because it was strongly correlated with adnexal adhesion (P = 0.007). The final model did not change when we excluded the women without histologically-confirmed DIE (Table III). Stratified results according to the study periods are reported in Table IV. Although some associations becomes non-significant because of the lack of statistical power, the adjusted odds ratios were similar in both study periods.


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Table II. Severity of DM according to r-AFS score items and other indicators of the extent of the disease
 

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Table III. Determinants for severity of DM for all women and for women with histologically-confirmed DIE results from an ordinal multiple logistic regression analysis with cumulative odds
 

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Table IV. Determinants for severity of DM according to the study period
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
For women with posterior DIE, severity of DM was related to disease extent by two independent indicators: presence of a rectal or vaginal infiltration by the posterior DIE and the extensiveness of adnexal adhesion.

This study has two limitations. First, most of the women completed the pain questionnaire retrospectively. Because some of them received their questionnaire up to four years after operation, one may question what was really measured. Nevertheless, in studies comparing prospective and retrospective methods of pain measurement a fairly good correlation was found (Redelmeier and Kahneman, 1996Go), even after several years (Dawson et al., 2002Go). Besides, when we analysed both periods separately, the results were similar in the prospective and retrospective parts of the study.

The second limitation is that inclusion of the women was based on the surgical diagnosis of posterior DIE, regardless of histological results. At our institution, indeed, diagnosis and treatment of DIE is based on the macroscopic aspect of the lesion, a method that has been shown to be effective (Cornillie et al., 1990Go; Koninckx et al., 1996Go). However for several women histology differed from the macroscopic aspect because some forms of DIE implants may have dense fibrotic tissue instead of gland and stroma (Coronado et al., 1990Go; Brosens, 1994Go). Also, in certain cases histology was not available because women did not want extensive surgery, in particular when the posterior DIE was embedded in the rectal wall. For these women the diagnosis of rectal involvement was based on rectal endoscopic ultrasound, a method shown to have very good correlation with histological results (Chapron et al., 1998Go; Fedele et al., 1998Go). Nonetheless, two-thirds of the women in our study did have histologically-confirmed DIE, and the results did not change when we excluded the women without histological proof.

To the best of our knowledge, our study is the first to report a correlation between vaginal or rectal infiltration by DIE and DM severity. One previous study (Vercellini et al., 1996Go), on the other hand, did not find any difference in DM severity when comparing women with or without vaginal wall infiltration. One explanation is that it studied all subtypes of endometriosis, unlike ours, which considered only patients with DIE.

Neural invasion by DIE has been shown to correlate with the severity of DM (Anaf et al., 2001Go). Thus, one possible explanation of the correlation between DM and vaginal or rectal infiltration is that implants that penetrate the wall of adjacent organs will have a closer relation with nerve fibres than those which do not. A second explanation is that associated inflammatory changes in the adjacent organs, due to penetration of DIE, may also explain this association. Contrary to superficial endometriosis, DIE is usually associated with inflammatory cells (Cornillie et al., 1990Go). A third explanation is that the ratio between glandular structures and fibrosis, and also the patterns of cyclical differentiation, may differ when the DIE penetrates the wall of the adjacent organs. Indeed histological components vary according to the location of the endometriosis (Cornillie et al., 1990Go; Brosens, 1994Go; Bonte et al., 2002Go). One may hypothesize that as the depth of infiltration increases, the glandular components will become more numerous and active.

Our study, like others (Muzii et al., 1997Go; Porpora et al., 1999Go), emphasises the role of adnexal adhesion in endometriosis-related DM. Pelvic adhesions have been found to be associated with severe DM in a population of subfertile women regardless of the presence of associated endometriosis (Forman et al., 1993Go). Moreover, the treatment of severe adnexal adhesions (whatever the aetiology) has been shown to be effective in alleviating pain (Duffy and diZerega, 1996Go). The mechanism by which adnexal adhesions cause DM has not yet been explained.

Surprisingly, neither the presence nor the characteristics of endometriomas were found to correlate with the severity of DM. Our findings, similar to those from other studies, (Vercellini et al., 1996Go; Porpora et al., 1999Go;) suggest that the noteworthy association between pain and endometrioma may be explained by adnexal adhesion. In our opinion however, adhesion may not be the sole factor contributing to the relationship between DM and endometrioma. Indeed, one previous study on women with endometriomas has found that increased vascularization and high CA 125 level may be determinants for pain (Alcazar, 2001Go). Future prospective research on endometriomas is needed to clarify how they produce pain.

A classification system that correlates positively with disease prognosis is important in developing and assessing treatment. The relationship between the R-AFS stage and DM is rather inconsistent. Some studies have found such a correlation (Buttram, 1979Go; Fedele et al., 1992Go; Muzii et al., 1997Go), while many others have not (Fedele et al., 1990Go; Vercellini et al., 1996Go; Stovall et al., 1997Go; Porpora et al., 1999Go; Gruppo Italiano per lo Studio dell’Endometriosi, 2001Go). In the present study, the linear trend between R-AFS stage and DM severity was explained in part by the severity of adnexal adhesion and by obliteration of the pouch of Douglas (itself strongly related to the degree of adjacent visceral infiltration by the DIE implant). The quantification of DIE implants in the R-AFS system did not, on the other hand, appear to explain DM severity at all. This finding points out the need to improve the classification system when dealing with pain. Indeed, although DIE implants are differentiated from superficial implants, no quantification of depth is considered in the R-AFS classification (Hoeger and Guzick, 1999Go). Because depth of infiltration correlates with pain (Koninckx et al., 1991Go), proper quantification of depth is extremely important. One interesting classification includes three types of posterior DIE and is based on physiopathological mechanisms (Koninckx and Martin, 1992Go). The correlation between this classification and the severity of pain symptoms was unfortunately not studied. In the present study we aimed to quantify indirectly the depth of posterior DIE according to the presence or non-presence of the infiltration of the wall of an adjacent organ. This classification was found to correlate with the severity of DM. If our results are confirmed by others, the concept of very deep infiltrating endometriosis, defined as implants invading the wall of the pelvic organ, should be tested in future classification systems specifically addressed to the prediction of endometriosis-related pain.


    Acknowledgements
 
The authors thank Tadeka Laboratories (France) for providing their technical assistance in data collection.


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 Discussion
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Submitted on July 29, 2002; resubmitted on December 9, 2002; accepted on December 13, 2002.