Post-operative use of oral contraceptive pills for prevention of anatomical relapse or symptomrecurrence after conservative surgery for endometriosis

Human Reproduction, Vol.24, No.11 pp. 2729 2735, 2009 Advanced Access publication on July 22, 2009 doi:10.1093/humrep/dep259 ORIGINAL ARTICLE Gynaecology Post-operative use of oral contraceptive pills for prevention of anatomical relapse or symptomrecurrence after conservative surgery for endometriosis R. Seracchioli 1, M. Mabrouk, L. Manuzzi, C. Vicenzi, C. Frascà, A. Elmakky, and S. Venturoli Minimally Invasive Gynaecological Surgery Unit, Reproductive Medicine Unit, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 1 Correspondance address. Tel: þ39-051-6363944; Fax: þ39-051-6363944, E-mail: seracchioli@aosp.bo.it background: Endometriosis recurrence after conservative surgery is not infrequent. Variable regimens of hormonal therapy have been proposed as adjuvant post-operative measures for prophylaxis against recurrence. Among these, the combined oral contraceptive pills (OCP), represents a valuable option in terms of safety and tolerability for long-term use. The objective of this review is to evaluate the effect of post-operative use of OCP in preventing symptom recurrence, and/or anatomical relapse of endometriosis. methods: A systematic search of Medline identified seven studies evaluating post-operative OCP treatment on prevention of endometriosis recurrence. results: A reduction in anatomical relapse rate was observed when oral contraceptive therapy was administered for more than 1 year after conservative surgery. Post-operative use of OCP was associated with a reduction in frequency and intensity of dysmenorrhoea recurrence. No association was found between OCP therapy and dyspareunia prevention, although the effect of OCP on chronic pelvic pain was conflicting. conclusion: Long-term OCP therapy can be a reliable adjuvant post-operative measure to prevent or reduce frequency/severity of recurrent dysmenorrhoea and anatomical relapse of endometriosis. Since both continuous and cyclic OCP administration regimens seem to have comparable effects, the choice of regimen can be modulated according to patient preferences. The protective effect seems to be related to the duration of treatment. Key words: endometrioma / pain / dysmenorrhoea / dyspareunia / chronic pelvic pain Introduction Endometriosis is a chronic gynaecological condition that affects women of reproductive age, causing infertility and pelvic pain. The pain may occur during menstrual bleeding (dysmenorrhoea), during sexual intercourse (dyspareunia) or not following any cyclical pattern (chronic pelvic pain) (Fauconnier and Chapron, 2005). If endometriosis involves the rectum or the bladder, symptoms as dyschezia or dysuria may respectively occur (Child and Tan, 2001; Milingos et al., 2003). Women affected by symptomatic endometriosis often report a significant reduction in their quality of life (Jones et al., 2004). Among the different endometriotic pelvic implants, ovarian endometrioma is the most common, affecting around 55% of patients (Liu et al., 2007). Excisional surgery is the treatment of choice, as it significantly reduces painful symptoms and improve quality of life in 67 80% of patients (Abbott et al., 2004). A frustrating aspect of conservative surgery, however, is the recurrence of endometriotic implants and painful symptoms at a long-term follow-up. It has been observed a cumulative rate of endometrioma recurrence of 12 30% after 2 5 years of follow-up (Busacca et al., 1999; Jones and Sutton, 2000; Chapron et al., 2002; Fedele et al., 2006; Guo, 2009). Recurrence & The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

2730 Figure 1 Flow-chart representing studies selection for the inclusion in the review. or worsening of pain has been observed in 7 30% of patients within 3 years of surgery, increasing to 40 50% after 5 years (Valle and Sciarra, 2003). Therefore, over recent years there has been particular interest in adjunctive post-operative hormonal therapy that reduces recurrence of endometriosis. As endometriotic tissue is hormonally sensitive, hormonal therapies could be effective in post-operative management of endometriosis (Child and Tan, 2001). It must be stressed, however, that hormones are not curative and endometriosis usually relapses at treatment suspension; therapies need therefore to be administered for long time. Oral contraceptives may be the best hormonal pharmacological choice, as they are safe, well tolerated, relatively inexpensive and can be administered for long periods (, 2008a). Oral contraceptive pills (OCP), both in cyclic and continuous regimen, have been used for years in clinical practice as adjuvant post-operative measure, even without a high-level evidence of their effectiveness (Rice, 2002; Rodgers and Falcone 2008). This review aims to evaluate the post-operative use of oral contraceptive therapy, both in cyclic and continuous administration, in preventing endometriosis recurrence. Materials and Methods Literature search criteria We performed a systematic search of Medline using the relevant medical subject heading search (MESH) with the following key words: endometriosis, pelvic pain, dysmenorrhoea, dyspareunia, endometrioma, OCP, postoperative treatment, recurrence. The studies were selected first by reading the title and the abstract and then independently screened by three authors who, after reading the full articles, selected the studies appropriate for the review. After discussion, there was a full consensus about the studies to be included in the review. The references of each selected study were also checked for other potential relevant studies. Studies evaluating OCP therapy, both in cyclic and continuous regimen, after conservative surgery for endometriosis were included in this review. Prevention or reduction of endometriosis recurrence was considered as outcome. Studies assessing anatomical and/or pain recurrence were included. Randomized controlled trials (RCTs), clinical trials (CTs), cohort and retrospective studies were included. Studies in which other hormonal therapies than oral contraceptives were administered before starting OCP therapy were excluded (Fig. 1). A validate scale (Jadad et al., 1996), evaluating randomization, double blinding and description of withdrawals or dropouts, was chosen to assess the quality of the retrieved RCTs. Results Description of the studies Seven studies that evaluated the effects of post-operative OCP on prevention of endometriosis recurrence were considered for this review. Details of the studies are summarized in Table I. Three studies assessed anatomical recurrence (Koga et al., 2006;, 2008), three focused on pain recurrence (Vercellini et al., 2003; Sesti et al., 2007;, 2009) and one considered both (Muzii et al., 2000). Among these studies, four evaluated the effect of a long-term OCP therapy (, 2003, 2008b;, 2008, 2009). Six studies were prospective trials: four were RCTs (Muzii et al., 2000; Sesti et al., 2007;, 2008, 2009), one was a self-controlled CT (, 2003) and one was a cohort study (, 2008b). One study was retrospective (Koga et al., 2006). Among RCTs, three trials (Muzii et al., 2000;, 2008, 2009) compared OCP therapy with no post-operative treatment and

OCP in prophylaxis of endometriosis recurrence 2731 Table I Design of the studies considered Study Outcome Type of study Number of patients Medical Treatment... Muzii et al. (2000) Anatomical and pain recurrence RCT 35 None 33 Cyclic OCP (2003) Pain recurrence Prospective self controlled 50 Continuous OCP Koga et al. (2006) Anatomical recurrence Retrospective 109 none 15 OCP Sesti et al. (2007) Pain recurrence RCT 110 placebo 38/39 Continuous OCP/GnRH-analogues 35 Dietary therapy (2008a, b) Anatomical recurrence Cohort study 46 None 231 Cyclic OCP (2008) Anatomical recurrence RCT 69 None 75 Cyclic OCP 73 Continuous OCP (2009) Pain recurrence RCT 87 None 92 Cyclic OCP 95 Continuous OCP RCT: randomized controlled trial; OCP: oral contraceptive pills. one (Sesti et al., 2007) analysed pain recurrence comparing the effects of hormonal therapy (OCP and GnRH-analogues), dietary therapy and placebo. The quality score of RCTs assessed by the Jadad s scale was 3/5 for all the four included studies, since an appropriate double blinding was not performed in any of the studies considered (Jadad et al., 1996). (2003) assessed the efficacy of continuous OCP administration in pain relief in women whom post-operative prophylaxis with cyclic OCP failed to prevent dysmenorrhea recurrence. The same group of authors compared the risk of endometrioma recurrence among patients who used OCP for the entire follow-up period (28 months), those who used the same therapy discontinuously (stopped therapy before 28 months) and patients who did not receive any treatment from the beginning (, 2008b). Koga et al., in their retrospective study, evaluated the independent effect of 14 variables on ovarian endometrioma recurrence after conservative surgery. One of the evaluated variables was post-operative medical therapy, including GnRH-agonist, danazol and oral contraceptives (Koga et al., 2006). Surgery performed and stage of endometriosis All the studies included patients who underwent conservative surgery for endometriosis. Laparoscopy and laparotomy for symptomatic disease were both considered in the studies of (2003; endometriosis stages I IV) and Sesti et al. (2007; endometriosis stages III IV). The remaining studies (Muzii et al.,2000; Koga et al., 2006;, 2008, 2009;, 2008b), focused on women who underwent laparoscopic of ovarian endometriosis. Medical and surgical interventions are summarized in Table II. Type of pills and regimen A low-dose monophasic oral contraceptive therapy was administered in all the considered studies. Regimens: (i) cyclic regimen was used in two studies; ethinyl estradiol (EE) 0.030 mg, gestodene (Muzii et al., 2000) and EE 0.020 mg, desogestrel 0.15 mg (, 2008b). (ii) continuous regimen was used in two studies; EE 0.020 mg, desogestrel 0.15 mg (, 2003) and EE 0.030 mg, gestodene (Sesti et al., 2007). (iii) cyclic and continuous administrations of OCP (EE 0.020 mg, gestodene ) were both evaluated in Seracchioli s trials (, 2008, 2009). Koga et al. (2006) did not specify the regimen nor the composition of the oral contraceptive administered in their study. Time of therapy and follow-up The duration of therapy and follow-up differed among the selected studies (Table II). A 6 month treatment regimen was evaluated in two studies (Muzii et al., 2000; Sesti et al., 2007); the follow-up was for 22 (range 12 48) and 12 months, respectively. In one study (Koga et al., 2006) the mean duration of post-operative therapy was 9.5 months and patients were followed up for at least 24 months. Four studies evaluated the effect of a long-term OCP therapy (, 2003;, 2008, 2009;, 2008b). Among these three (, 2003;, 2008, 2009) assessed 24-months OCP administration and follow-up. In the final study (, 2008b) the mean follow-up was of 28 months, although the length of treatment varied depending on women preferences: patients who did not withdrew the therapy took OCP for the entire follow-up period. Criteria for outcome evaluation and definition of recurrence Outcomes measured and definition of recurrence in the considered studies are summarized in Table III.

2732 Table II Surgical and medical interventions performed in the studies considered Study Surgical treatment OCP Type of pill Time of medical treatment Follow-up Regimen (months) (months)... Muzii et al. (2000) Cyclic EE 0.030 mg, gestodene 6 22 (2003) Koga et al. (2006) LPS or LPT Continuous EE 0.020 mg, desogestrel 0.15 mg Sesti et al. (2007) LPS or LPT Continuous EE 0.030 mg, gestodene (2008a, b) (2008) (2009) LPS: laparoscopy; LPT: laparotomy; EE: ethinilestradiol. 24 24 Not specified Not specified 9.5 24 Cyclic Cyclic Continuous Cyclic Continuous EE 0.020 mg, desogestrel 0.15 mg EE 0.020 mg, gestodene EE 0.020 mg, gestodene 6 12 1 28 28 24 24 24 24 In all the studies evaluating anatomical recurrence (Muzii et al., 2000; Koga et al., 2006;, 2008;, 2008b), it was defined as new appearance of endometriotic ovarian cyst, diagnosed by the detection of a cyst with all typical aspects by transvaginal ultrasonography (Exacoustos et al., 2003). In two studies (Koga et al., 2006;, 2008b) a diagnostic cut-off in cyst diameter of 2 cm was used, although (2008) considered cysts with a minimum diameter of 1.5 cm, and one study (Muzii et al., 2000) did not specify any cut-off in cyst diameter. Studies that considered painful symptoms (Muzii et al., 2000;, 2003; Sesti et al., 2007;, 2009), graded their intensity by a visual analogue scale (VAS) (Huskisson, 1983); (2003) also used a 0- to 3- point verbal rating scale (VRS). Two trials (Muzii et al., 2000;, 2009) defined pain recurrence as severity of pain graded 4 on a 10-point VAS; Muzii et al. considered pelvic pain, although evaluated dysmenorrhoea, dyspareunia and chronic pelvic pain separately. (2003) evaluated dysmenorrhoea improvement, comparing VAS and VRS scores during previous cyclic OC use and after 24 months of continuous OC use. Sesti et al. (2007) evaluated dysmenorrhoea, dyspareunia and chronic pelvic pain comparing VAS scores of the different groups. Results of the studies Results of the selected studies are described on the basis of the evaluated outcomes and duration of the administered therapy. Anatomical recurrence Short-term therapy In the trial of Muzii, the difference in endometrioma recurrence rate between patients receiving OCP (2.9%) and untreated patients (6.1%) was not significant. In life-table analysis, a lower rate of recurrence of endometrioma was observed at 12 months in the treated group whereas no significant differences were detected at 24 and 36 months (Muzii et al., 2000). Koga et al. (2006) found that post-operative medical therapy does not significantly influence longterm recurrence rate of endometrioma. Long-term therapy (2008b) observed that, at 36 months follow-up, crude recurrence rate was 9% in the group of patients treated by postoperative OCP for the entire follow-up period and 56% in the untreated group [P, 0.001; odds ratio (OR) 0.07]. Logistic regression showed that only OCP use was associated with a significant modification of the risk of recurrence. The adjusted OR for OCP use was 0.04. Furthermore, the analysis of endometrioma recurrence rate in women who used OCP discontinuously demonstrated a gradient effect with regard to duration of treatment (P, 0.001), suggesting that the protective effect of estro-progestinic therapy tends to rapidly diminish after withdrawal. (2008), at 24 months follow-up, observed an endometrioma crude recurrence rate of 29% in untreated patients versus 14.7 and 8.2% in women treated with OCP in cyclic and continuous administration, respectively. A significant difference in recurrence rate was observed between untreated patients versus women treated with OCP (P, 0.005). Furthermore, the mean diameter of endometriomas at the first observation and the increase of cysts dimensions were significantly reduced in women treated with OCP (P, 0.005) suggesting that therapy can reduce disease severity and restrain its progression. No significant differences were detected between cyclic and continuous OCP administration. New appearance of deep infiltrating endometriosis was not described in any of the studies considered. Symptoms recurrence Short-term therapy In the trial of Muzii, no significant difference in the recurrence rates of pain was observed at follow-up between patients receiving OCP

OCP in prophylaxis of endometriosis recurrence 2733 Table III Results of the studies Study Outcome Method of Definition of Patients and Results P-value measured measurement recurrence treatment... Muzii et al. Endometrioma TV US Not specified 35 no therapy Recurrence rate: ocp (2.9%) versus NS (2000) none (6.1%) pain VAS VAS. 4 33 cyclic OCP Recurrence rate: ocp (9.1%) versus NS none (17.1%) (2003) Koga et al. (2006) Sesti et al. (2007) (2008a, b) (2008) (2009) Dysmenorrhoea VAS, VRS Not specified 50 continuous OCP Reduction in mean VAS score of 45.95% after 2 years of continuous OCP therapy,0.001 Endometrioma TV US.2 cm diameter 109 no therapy OCP do not influence endometrioma NS 15 OCP recurrence (a) Dysmenorrhoea VAS Not specified 110 placebo (a) Lower VAS scores with OCP,,0.001 GnRH-analogues and dietary therapy (b) Dyspareunia 77 hormonal (b) Lower VAS scores with placebo,0.001 therapy (c) CPP 35 dietary therapy (c) Lower VAS scores with OCP,,0.001 GnRH-analogues and dietary therapy Endometrioma TV US.2 cm diameter 46 no therapy Recurrence rate: ocp (9%) versus none,0.001 231 cyclic OCP (56%) Endometrioma TV US.1.5 cm diameter 69 no therapy Recurrence rate: ocp continuous (8.2%),0.005 75 cyclic OCP and cyclic OCP (14.7%) versus none 73 continuous (29%) OCP (a) Dysmenorrhoea VAS VAS.4 87 no therapy (a) Lower recurrence rate since 6,0.001 months (continuous OCP) or 18 months (cyclic OCP) (b) Dyspareunia 92 cyclic OCP (b) OCP do not influence recurrence NS (c) CPP 95 continuous OCP (c) OCP do not influence recurrence NS CPP: chronic pelvic pain; TV US: transvaginal ultrasonography; VAS: visual analogue scale; VRS: verbal rating scale; OCP: oral contraceptive pill, NS: non-significant. (9.1%) and untreated patients (17.1%). As for the anatomical recurrence, in life-table analysis a lower rate of recurrence of symptoms was observed at 12 months in the treated group whereas no significant differences were detected at 24 and 36 months (Muzii et al., 2000). Sesti et al. observed, at 12 months follow-up, a lower VAS score for dysmenorrhoea and chronic pelvic pain in the patients treated with OCP, GnRH-analogues or dietary therapy respect to patients in the control group (P, 0.001). The placebo, otherwise, was more effective than hormonal or dietary therapy in decreasing dyspareunia intensity (P, 0.001) (Sesti et al., 2007). Long-term therapy (2009) observed a significant reduction in frequency and severity of recurrent dysmenorrhoea in patients receiving 24 months OCP therapy compared with surgery alone. Benefits of oral contraceptives were evident since the first follow-up visit, at 6 months, for the patients in continuous treatment, and after 18 months of follow-up in the women treated in cyclic regimen (P, 0.0005). No significant differences in terms of frequency and severity of dyspareunia and chronic pelvic pain were found among patients treated with OCP, both cyclic and continuous, and patients in the control group. Untreated patients, however, showed a significant worsening in dysmenorrhoea, dyspareunia and chronic pelvic pain intensity from 6 to 24 months of follow-up compared with patients in continuous OCP therapy (P, 0.001). (2003) reported a mean reduction in VAS score of 45.95% after 2 years of continuous OCP therapy (P, 0.001), showing that long-term continuous OCP can be successfully used in women with endometriosis-associated recurrent dysmenorrhoea that does not respond to cyclic OCP use after surgical treatment. Discussion Several OCP mechanisms of action can justify oral contraceptives use in the prevention of endometriosis recurrence, both anatomical and symptomatic. Oral contraceptives reduce menstrual flow and retrograde menstruation and can therefore prevent the reseeding of refluxed endometrial tissue (Busacca, 2006). Furthermore, the inhibition of ovulation induced by OCP may reduce the risk of endometrioma development; since some authors hypothesized that endometriotic cysts might develop from ovarian follicles (Jain and Dalton, 1999). It has also been demonstrated that OCP can induce atrophy of the endometriotic implants (Rodgers and Falcone, 2008), can down-regulate cell proliferation and increase apoptosis in endometrial tissue (Meresman et al., 2002). Therefore OCP therapy might prevent implant growth and reduce endometriosis-related pain, since the pain seems correlated to the cyclic micro-bleeding

2734 within the endometriotic lesions (Fauconnier and Chapron, 2005). In addition, OCP reduce the production of prostaglandins, involved in pain genesis, and can reduce the inflammatory status (Crosignani et al., 2006;, 2008a). All these mechanisms suggest that OCP can be effective in preventing endometriosis recurrence. From the analysis of the studies considered in this review, it seems that there is a growing body of evidence supporting OCP use as a reliable adjuvant post-operative measure, effective in the reduction of endometriosis recurrence. However, two of the studies included here (Koga et al., 2006; Muzii et al., 2000) report findings that contradict this statement; neither observed an association between post-operative use of OCP and longterm reduction of disease recurrence. In these studies, however, the duration of treatment should be taken into account, as it could have been responsible for the lack of long-term effects. Koga et al. retrospectively evaluated a hormonal treatment of 9.5 months and suggested that an administration longer than 1 year may be effective in preventing endometriosis recurrence. Muzii et al. reported, after a 6 months administration of OCP, a reduction in endometriosis recurrence at 12 months of follow-up. The lack of long-term effects, therefore, could be due to discontinuation of therapy more than to a real inefficacy of post-operative oral contraceptives. This hypothesis has been confirmed by the study of (2008b), who demonstrated a protective effect of OCP on current but not on previous users, showing a strong correlation between the duration of the treatment and the long-term effects. Post-operative OCP treatment, therefore, needs to be administered for years rather than months to successfully prevent endometriosis recurrence. Regarding recurrence of endometriosis-related symptoms, not all the types of pain considered seem to be equally responsive to postoperative OCP. Dysmenorrhoea, the symptom most frequently reported by women with endometriosis, can be successfully controlled by oral contraceptives. Continuous OCP can provide early reduction of dysmenorrhoea after 6 months of treatment (Sesti et al., 2007;, 2009), although cyclic OCP need to be administered for at least 18 months to be effective (Seracchioli et al., 2009). Furthermore continuous administration is a valuable treatment option for dysmenorrhoea that does not respond to cyclic use of OCP (, 2003). It is possible that the capacity of continuous OCP in preventing or reducing dysmenorrhoea could be due to inhibition of menses, rather than to a real interference with pain mechanisms. Also noteworthy is that the induced amenorrhoea could be unacceptable to some patients, mainly young women who would need to prolong therapy for years. Long-term cyclic administration may therefore be a reliable treatment option for those women who do not tolerate the absence of menstruation. Cyclic use of low-dose OCP, however, may not be sufficient to induce a complete ovarian suppression, allowing the increase of endogenous estrogens levels during the 7-days hormone-free interval (Sulak, 2008). Recently, a new regimen of OCP administration, consisting in 24 days of active combined therapy followed by 4 days of suspension (24 þ 4 regimen), has been proposed for contraception (Sulak, 2008). Theoretically, reduction in menstrual bleeding achieved with this new regimen could be effective in the prevention of endometriosis recurrence. However, further studies are necessary to assess the role of the 24 þ 4 regimen in the management of endometriosis. Only two studies in this review (Sesti et al., 2007;, 2009) evaluated endometriosis-related dyspareunia and chronic pelvic pain. Regarding dyspareunia, there is no evidence of a positive effect of post-operative OCP (Sesti et al., 2007;, 2009). Furthermore, Sesti et al. demonstrated that placebo seems to be more effective than hormonal therapy in relieving this type of pain. They explained this finding by the fact that dyspareunia perception may be influenced by psychological factors depending on woman personality, marital and psychosexual issues (Sesti et al., 2007). Regarding chronic pelvic pain, there is no agreement about the effects of post-operative OCP. (2009) did not find differences between patients treated with OCP and untreated patients in terms of chronic pelvic pain recurrence, although Sesti et al. (2007) found significant differences in favour of post-operative OCP use. The more evident benefits achieved with oral contraceptives on dysmenorrhoea in comparison with dyspareunia and chronic pelvic pain can be explained by the fact that dysmenorrhoea can be related to endometrial bleeding, that can be decreased or suppressed by OCP, although other types of pain are possibly due to different physiopathologic mechanisms. Higher concentration of activated immune cells, such as mast cell and macrophages, growth factors such as nerve growth factor, and pro-inflammatory cytokines have been observed in peritoneal fluid of women with endometriosis (Evans et al., 2007). All these factors have been shown to contribute to persistent pain (Moalem and Tracey, 2006). Some authors suggested that this inflammatory status could activate, sensitize and/or increase nociceptors present in endometrium and peritoneum (Evans et al., 2007). Furthermore, deep endometriotic implants can compress or infiltrate the subperitoneal nerves (Anaf et al., 2006), suggesting a neuropathic component in pain related to endometriosis (Evans et al., 2007). Although efficacy of OCP in prevention of dyspareunia and chronic pelvic pain has not yet been clearly defined, (2009) showed that oral contraceptives are effective in restraining aggravation of dysmenorrhoea, dyspareunia and chronic pelvic pain. Furthermore, OCP therapy can reduce dimensions and growth of recurrent endometriomas, suggesting their role in restraining disease progression (, 2008). In conclusion, long-term administration of OCP seems to be a valuable adjuvant post-operative measure in women undergoing conservative surgery for symptomatic endometriosis. Since both continuous and cyclic administrations seem similarly effective in reducing endometriosis recurrence, the choice of the regimen can be modulated according to patient preferences. 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