{"paper_id":"8377be0b-49c2-42e3-8f8a-2a5833c1cec4","body_text":"VU Research Portal\nClinical management of endometriosis\nMabrouk, M.A.A.\n2013\ndocument version\nPublisher's PDF, also known as Version of record\nLink to publication in VU Research Portal\ncitation for published version (APA)\nMabrouk, M. A. A. (2013). Clinical management of endometriosis. 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Jun. 2026\n\n \nChapter 4 \n \nCombined Oral Contraceptive Therapy in Women with \nPosterior Deep Infiltrating Endometriosis \n \n \n    \n  \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nMohamed Mabrouk \nClarissa Frascà \nElisa Geraci \nGiulia Montanari \nGiulia Ferrini \nDiego Raimondo, \nStefania Alvisi \nRoberto Paradisi \nGioia Villa \nRenato Seracchioli    J Minim Invasive Gynecol. 2011 Jul-Aug;18(4):470-4 \n\n \nABSTRACT  \nStudy Objective: To estimate the effect of combined oral contraceptives (COCs) in women with \ndeep infiltrating endometriosis (DIE). \nDesign: Retrospective study (Canadian Task Force classification II-2). \nSetting: Tertiary care university hospital. \nPatients: One hundred six women with uncomplicated posterior deep infiltrating endometriosis \nscheduled to undergo laparoscopic surgery between November 2004 and November 2009. \nInterventions: During the waiting -list time, between surgical scheduling and laparoscopic \nintervention (preoperative period), 75 patients received cyclic COCs (users), and 31 received no \nhormone therapy (COC nonusers). \nMeasurements and Main Results: Patients had undergone 2 clinical examinations, at surgical \nscheduling and immediately before surgery. Presence and intensity of dysmenorrhea, dyspareunia, \nchronic pelvic pain, and dyschezia were evaluated using a 10 -point visual analog scale (VAS ) \n(primary outcome). In both examinations, patients underwent transvaginal ultrasonography to \nevaluate localization and mean diameter of endometriotic nodules. Quality of life was evaluated \nusing the Short Form-36 (SF-36) score. Mean (SD) nodule diameter at the beginning and end of the \npreoperative period in COC users was, respectively, 24.81 (15.13) mm and 26.66 (15.5) mm ( p = \n.09), and in the nonuser group was, respectively, 23.09 (11.11) mm and 30.89 (19.1) mm (p = .007). \nIn COC users, VAS scores for dys menorrhea, dyspareunia, chronic pelvic pain, and dyschezia did \nnot vary significantly during the preoperative period (p = .90, p = .55, p = .15, and p = .17, \nrespectively). In nonusers, VAS scores for dysmenorrhea and dyspareunia were significantly higher \nat the second examination than at the first examination (p =.002 and p=.005, respectively), whereas \nscores for chronic pelvic pain and dyschezia did not vary during the preoperative period (p = .88 \nand p = .16, respectively). The Short Form -36 total score d id not vary significantly during the \npreoperative period in either the COC user group (p = .82) or the nonusers group (p = .76). \nConclusions: Combined oral contraceptive therapy can have a role in restraining the progression of \ndysmenorrhea and dyspareunia and the growth of deep endometriotic nodules. \n \n\nINTRODUCTION \nDeep infiltrating endometriosis (DIE) is usually characterized by severe pain. Endometriosis -\nassociated pain may occur during menstruation (dysmenorrhea) or sexual inter - course \n(dyspareunia) or not demonstrate any cyclic pattern (chronic pelvic pain) [1]. If deep endometriosis \ninvolves the rectum, dyschezia may occur [2, 3]. Women with symptomatic endometriosis often \nreport a significant reduction in their quality of life. Furthermore, because DI E affects young \nwomen primarily, it can possibly impair social and professional functioning [4].  Although it is \ngenerally accepted that DIE is a chronic and aggressive disease, its natural history is not completely \nunderstood. Moreover, in the current literature, there is no agreement as to whether endometriosis is \na progressive disease [5, 6]. \nThe treatment of choice for symptomatic DIE is laparoscopic surgery because endometriotic lesions \ncan be completely excised and the pelvic anatomy can be restored [ 7, 8]. Furthermore, laparoscopic \nexcisional surgery can significantly reduce pain and improve quality of life in 67% to 80% of \npatients with endometriosis [9]. \nIn the last years, it has been observed that DIE responds to hormone treatment because estrogen and \nprogesterone receptors are normally expressed in deeply infiltrating lesions [10]. Among hormones, \ncombined oral contraceptives (COCs) are considered a good pharmacologic choice be - cause they \nare safe, well tolerated, and relatively inexpensive and can be administered for long periods [11]. \nAll of these data prompted us to retrospectively evaluate whether oral contraceptive therapy \nadministered preoperatively can interfere in potential progression of DIE insofar as worsening of \nsymptoms and growth of nodules.  \n \nPATIENTS AND METHODS \nPatients with posterior DIE who were scheduled to undergo laparoscopic surgery between \nNovember 2004 and November 2009 at our tertiary referral center for treatment of endometriosis \nwere considered for inclusion in the presen t retrospective study. Patients were evaluated between \nthe surgical scheduling and the laparoscopic intervention (preoperative period) because in tertiary \nreferral centers, women with uncomplicated DIE can be wait-listed for surgery for months. \nWomen aged 20 to 40 years with an ultrasonographic diagnosis of uncomplicated DIE were \nincluded in the study. All patients reported symptoms related to posterior DIE including \ndysmenorrhea, dyspareunia, chronic pelvic pain, and dyschezia. Patients with complicated DIE with \nbowel stenosis, obstructive uropathy, or severe symptoms required urgent surgical intervention and \nwere, therefore, not included in the study. The presence of gastrointestinal or urologic disease or a \ndiagnosis of current pelvic inflammatory disease  that might have caused painful pelvic symptoms \nnot related to endometriosis were considered exclusion criteria. None of the patients included in the \n\nstudy had previously undergone any surgical treatment of endometriosis. None had received \nhormone therapy for at least 6 months before scheduling the surgical intervention. \nAfter approval by the local ethics committee, data were collected from computerized medical \nrecords. All patients were routinely asked to give informed consent to anonymously use their \nclinical data for medical research. For every patient, data collected included age, weight, height, \nbody mass index, and use of oral contraceptives to treat endometriosis during the preoperative \nperiod. Women included in the study were retrospectively divided into 2 groups: nonusers, who had \nnot received any hormone treatment, and users, who had received COCs during the entire \npreoperative period. At our center, all patients with symptomatic noncomplicated DIE who are \nscheduled to undergo nonurgent surgery are offered COC therapy. Nonusers are patients who do not \nagree or who have contraindications to hormone therapy. All users received cyclic administration of \nCOC therapy: active pills containing 3 mg drospirenone and 20 mcg ethinilestradiol for 21 days and \nno hormone therapy for 7 days.  \nAt our center, all patients with DIE and scheduled for surgery routinely undergo at least 2 clinical \nexaminations, the first at surgical scheduling and the second immediately before the intervention. In \nboth examinations, patie nts included in the study underwent transvaginal ultrasonography \nperformed by ultrasonographers (G.V.,G.M.) with extensive experience in the diagnosis of \nendometriosis. Presence, localization, and diameter of deep endometriotic nodules were reported in \ncomputerized clinical records. Mean nodule diameter was obtained by measuring the diameter in 3 \ndimensions and calculating the average. Furthermore, patients had been asked to grade the presence \nand severity of pain using a 10 -point visual analog scale (VAS),  in which a score of 1 to 3 was \nconsidered mild pain; 4 to 7, moderate pain; and 8 to 10, severe pain [12]. All of the women \nincluded in the study had aVASscore of 4 or greater for at least 1 type of pain (dysmenorrhea, \ndyspareunia, chronic pelvic pain, or dyschezia). \nAt both examinations, the women completed the Short Form -36 questionnaire (SF -36, Italian \nversion, release 1.6), a validated multipurpose health survey for evaluation of quality of life [13]. \nTotal SF-36 score was considered for evaluation of changes in quality of life in patients with DIE in \nboth study groups. The primary variables assessed were changes in VAS scores, diameter of \nendometriotic nodules, and SF -36 total score during the preoperative period in the COC user and \nnonuser groups.  \n \nStatistical Analysis \nIn the literature, treatment success at the 3 -month follow up after medical therapy was defined as \n25% reduction in the VAS score [14].With change in VAS score as a primary outcome measure, we \nretrospectively assumed that a 25% reductio n in VAS pain scores between the first and second \nexaminations in COC users was clinically significant. The study was designed to have 80% power \n\nto detect a difference of 25% in VAS scores with 2 -sided α levels of 0.05. A sample of 24 patients \nwas calculated for each group (total of 48 participants) to achieve this power. Because this was a \nretrospective study, all eligible patients who fulfilled the inclusion criteria were enrolled. \nAll continuous data are given as mean (SD). At univariable analysis, 1 -way analysis of variance \nwith the Scheffé post hoc pairwise test was performed to assess differences in the means of different \ngroups. When the Levene test for homogeneity of variances was significant (p <,.05), the \nMann-Whitney test (2 independent groups) or  the Kruskal - Wallis test (≥ 3 independent groups) \nwas used. Differences in mean values at various follow -up times were assessed using the paired t \ntest. The χ 2 test, calculated using the exact method for small samples (nondicotomic variables) or \nthe Fisher exact test (dicotomic variables) was performed to investigate the relationships between \ngrouping variables. \nStatistical analysis was performed using commercially available software (SPSS version 14.1; \nSPSS, Inc., Chicago, IL). For all tests, p <,.05 was considered significant. \n \nRESULTS \nOf 241 patients considered for the study, 135 were excluded: 102 because they received hormone \ntherapy before surgical scheduling, and 33 because of previous surgery to treat endometriosis. Thus, \n106 patients were included in the study. Of these, 75 patients were included in the COC user group, \nand 31 in the nonuser group. The 2 study groups were homogeneous insofar as mean age body mass \nindex (Table 1). \n \nVariables  \nStudy group  \np Value COC Users \n(n =75) \nCOC nonusers \n(n= 31) \nAge, yr 34.35 (5.09) 33.41 (5.38) .38 \nBody mass \nindex 21.98 (3.35) 21.39 (3.44) .56 \n \nTabel 1: Clinical features in 106 Study patients a \n COC = combined oral contraceptives     \n aData are given as mean (SD) \n \nThe mean (SD) duration of the preoperative  period, from surgical scheduling to laparoscopic \nintervention, was 5.8 (3.7) months (median, 5.5 months; 25th –75th percentile, 3.06–7.41). None of \nthe patients included in the study declined the surgical intervention. Histopathologic reports \nconfirmed DIE in all cases. \n\nPain \nMean VAS scores for the 4 types of pain considered at the first and second clinical examinations \nare given in Table 2.  \n \n  \nVAS score  \npValue First  \nexamination \nSecond  \nexamination \nSymptoms  Mean (SD) 95% CI Mean (SD) 95% CI  \nDysmenorrhea \nCOC Users 6.81 (3.38) 6.11-7.51 6.75 (3.26) 6.07-7.43 .90 \nNonusers 6.09 (3.35) 4.93-7.25 8.00 (1.95) 7.32-8.68 .002 \nChronic \npelvic pain \nCOC Users 2.24 (3.41) 1.53-2.95 2.88 (3.33) 2.19-3.57 .15 \nNonusers 3.72 (3.31) 2.57-4.87 3.63 (3.47) 2.43-4.83 .88 \nDyspareunia \nCOC Users 4.04 (3.53) 3.31-4.77 4.25 (3.47) 3.53-4.97 .55 \nNonusers 4.47 (3.14) 3.38-5.56 6.16 (2.38) 5.33-6.99 .005 \nDyschezia \nCOC Users 4.57 (3.87) 3.77-5.37 5.17 (3.88) 4.36-5.98 .17 \nNonusers 2.44 (3.81) 1.12-3.76 3.56 (3.55) 2.33-4.79 .16 \nBoldface indicates significant values \nCI = confidance interval; COC = combined oral contraceptives; VAS= Visual Analog Scale \nTabel 2: VAS scores for pain at first and second examination \n \nIn COC users, mean VAS scores for dysmenorrhea, dyspareunia, chronic pelvic pain, and dyschezia \ndid not vary significantly from the first to the second examination. In nonusers, mean VAS scores \nfor dysmenorrhea and dyspareunia were higher at the second examination (p = .002 and p = .005, \nrespectively), and VAS s cores of dyschezia and chronic pelvic pain did not vary significantly \nduring the preoperative period (Table 2). Comparison of mean VAS scores for the 2 groups \ndemonstrated that during the preoperative period, dysmenorrhea and dyspareunia scores were \nhigher in nonusers (p = .02 and p = .005, respectively), with worsening of pain intensity (Table 3). \n \n\n \nSymptoms  \nVAS score  \np Value  Δ Mean (SD)a  95% CI  \n  \n Dysmenorrhoea \nCOC Users 0.06 (4,021) -0.79- 0.9 \n.02 \nNonusers -1,91 (3,145) -3.04- -0.77 \nChronic pelvic \npain \nCOC Users -0,64 (4,195) -1.52- 0.24 \n.56 \nNonusers 0,09 (3,541) -1.18- 1.37 \nDyspareunia \nCOC Users -0,20 (3,167) -0.87- 0.46 \n.06 \nNonusers -1,69 (3,136) -2.82- -0.56 \nDyschezia \nCOC Users -0,60 (4,075) -1.45- 0.26 \n.54 \nNonusers -1,13 (4,449) -2.73- 0.48 \n \nTabel 3: Changes in VAS score during preoperative period \nBoldface indicates significant values \nCI = confidance interval; COC = combined oral contraceptives; VAS= Visual Analog Scale \na Defined as the mean difference between first and second examination VAS score  \n \nNodule Diameter \nIn COC users, mean (SD) nodule diameter at the first and second examinations was, respect ively, \n24.81 (15.13) mm and 26.66 (15.5) mm (p = .09), and in nonusers was, respectively, 23.09 (11.11) \nmm and 30.89 (19.1) mm (p = .007) (Fig. 1). In the preoperative period, mean nodule diameter \nincreased by 1.8 (10.3) mm in COC users and 7.8 (15.1) mm in nonusers (p = .02). \n \nFigure 1: Mean nodule diameter at first and second examinations in combined  oral contraceptive \n(COC) users and nonusers. \n\nQuality of Life \nIn COC users, the mean (SD) SF -36 total score at the first and second examinations was, \nrespectively, 48 (15) and 50 (21) (p = .82), and in nonusers was, respectively, 52 (17) and 50 (22) (p \n= .76). Using the Mann -Whitney test, we detected that the median variation in total SF -36 scores \nbetween the first and second examinations did not vary significantly between the 2 groups. \n \nDISCUSSION \nData from the present study demonstrate that COC therapy can have a role in restraining the \nprogression of dysmenorrheal and dyspareunia and in preventing endometriotic nodule growth in \nwomen with uncomplicated poste rior DIE. Analysis of the data demonstrated that patients who did \nnot receive COC therapy exhibited a significant increase in endometriotic nodule dimensions and \nsignificant worsening of dysmenorrhea and dyspareunia during the time considered. It seems, \ntherefore, that from the clinical point of view, untreated DIE tends to progress over time. \nThese results seem to be in contrast with those of Fedele et al [5], who affirmed that untreated \nrectovaginal endometriosis progresses in a low percentage of cases. I t must be stressed, however, \nthat none of the women included in that study had symptoms at first diagnosis of endometriosis. \nThis lack of endometriosis -related symptoms could reflect a low inflammatory status and the \npresence of an inactive form of endomet riosis. The literature, however, reports few data about the \nnatural history of endometriosis. \nIn the present study, significant variations in nodule dimensions and symptom intensity were not \nobserved in COC users, which demonstrates a potential restraining  effect of oral contraceptive \ntherapy on the hypothesized progression of DIE. Several mechanisms of action could explain the \neffect of COC on DIE. Oral contraceptive agents, through ovarian inactivation, decrease \nprostaglandin production due to endogenous estrogens and reduce the inflammatory status [11, 15]. \nIn addition, oral contraceptives can induce atrophy of the endometriotic implants [16], \ndownregulate cell proliferation, and increase apoptosis in endometrial tissue [17]. Therefore, COC \ntherapy might prevent implant growth and reduce endometriosis -related pain because pain seems to \nbe correlated with cyclic microbleeding within the endometriotic lesions [1]. \nOther authors, however, have affirmed that preoperative hormone therapy could be a risk factor for \nendometriosis recurrence because it may cause changes in the structure of endometriotic lesions, \nrendering their detection during surgery difficult [18 –20]. However, it is generally accepted that in \nthe treatment of DIE, surgical outcomes are highly op erator-dependent and that optimal results can \nbe assured in a tertiary care and referral center [21]. To assess whether, compared with nonusers, \npatients who receive preoperative COC therapy demonstrate a higher rate of recurrence of \nendometriosis after surgery is, therefore, the objective of a current prospective study at our center. \n\nThe current literature reports few data about the effect of oral contraceptive therapy on DIE. A \nreview by Vercellini et al [10] reported that in women with rectovaginal endom etriosis, medical \ntreatment is effective for pain relief, lesion reduction, and improvement in quality of life. However, \nonly 1 of the published reports included in that review evaluated oral contraceptive therapy [22]; \npain relief and lesion reduction wer e reported after 12 -months of continuous COC therapy in \nwomen with recurrent rectovaginal endometriosis. In addition, continuous postoperative hormone \ntreatment might prevent pain recurrence after surgical removal of deep infiltrating nodules [23]. \nIn the present study, intensity of symptoms, nodule dimensions, and health -related quality of life \nremained stable in COC users throughout the preoperative period (mean [SD] duration, 5.8 [3.7] \nmonths), and none of the patients declined the surgical intervention.  That longer duration of \ntreatment could possibly provide better results cannot be ruled out. It must be stressed, however, \nthat surgery is still the definitive treatment option because hormone therapy is not cytoreductive \n[24] and, therefore, is not curat ive [11]. Recently, some experienced authors adopted the concept \nthat in the treatment of DIE, it is most likely that combined medical and surgical treatments should \nbe used [25, 26]. \nThe present study has 2 possible limitations. First, it was a retrospect ive study in patients scheduled \nfor surgical interventions and included a smaller number of patients in the nonuser group. A larger \nrandomized trial will be necessary to adequately power such a study. Second, although the results of \nthis short -term study a re encouraging, longer follow -up is needed to demonstrate hypothetical \neffects in suppression of nodule growth and pain associated with endometriosis. \nIn conclusion, COCs can have a role in restraining hypothesized clinical progression of DIE and \npreventing symptom worsening and nodule growth. 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