Continuous versus cyclic oral contraceptives after laparoscopic excision of ovarian endometriomas: a systematic review and metaanalysis

Accepted Manuscript Continuous versus Cyclic Oral Contraceptives after Laparoscopic Excision of Ovarian Endometriomas: A Systematic Review and Meta-Analysis Ludovico Muzii, MD, Chiara Di Tucci, MD, Chiara Achilli, MD, Violante Di Donato, MD, Angela Musella, MD, Innocenza Palaia, MD, Pierluigi Benedetti Panici, MD PII:

S0002-9378(15)01022-4

DOI:

10.1016/j.ajog.2015.08.074

Reference:

YMOB 10638

To appear in:

American Journal of Obstetrics and Gynecology

Received Date: 27 February 2015 Revised Date:

6 August 2015

Accepted Date: 31 August 2015

Please cite this article as: Muzii L, Di Tucci C, Achilli C, Di Donato V, Musella A, Palaia I, Benedetti Panici P, Continuous versus Cyclic Oral Contraceptives after Laparoscopic Excision of Ovarian Endometriomas: A Systematic Review and Meta-Analysis, American Journal of Obstetrics and Gynecology (2015), doi: 10.1016/j.ajog.2015.08.074. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ACCEPTED MANUSCRIPT

Continuous versus Cyclic Oral Contraceptives after Laparoscopic Excision of Ovarian Endometriomas: A

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Systematic Review and Meta-Analysis

Ludovico MUZII, MD, Chiara DI TUCCI, MD, Chiara ACHILLI, MD, Violante DI

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DONATO, MD, Angela MUSELLA, MD, Innocenza PALAIA, MD, Pierluigi BENEDETTI

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PANICI, MD

Department of Obstetrics and Gynecology, “Sapienza” University of Rome, Rome, Italy

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Conflict of Interest: The authors report no conflict of interest.

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Funding: No funding was received for this study.

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Address all correspondence and requests for reprints to: Ludovico Muzii, MD, Department of Obstetrics and Gynecology, “Sapienza” University of Rome, Viale del Policlinico 155, Rome 00161, Italy, e-mail: [email protected], Phone: 0039 06 4940550

Word count: Abstract 325 words, Full text 2928 words, Tables 1, Figures 12

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ACCEPTED MANUSCRIPT CONDENSATION A continuous oral contraceptive schedule may be preferred to a cyclic schedule after surgery

SHORT TITLE

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Continuous versus cyclic OC for endometriomas

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for endometrioma excision because of lower dysmenorrhea recurrence rates.

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ACCEPTED MANUSCRIPT ABSTRACT Objective: In the lack of evidence consistently supporting the use of continuous versus cyclic oral contraceptives after surgery for endometriosis, we conducted a systematic review and

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meta-analysis with the objective of comparing a continuous versus cyclic oral contraceptive schedule administered after surgical excision of ovarian endometriomas.

Data sources: A PubMed, MedLine and Embase search through December 2014 was

“endometrioma”,

“endometriosis”,

“oral

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conducted, with the use of a combination of keywords and text words related to contraceptives”,

estroprogestins”,

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“laparoscopy” and “surgery”.

“oral

Study eligibility criteria: Studies directly comparing a continuous versus cyclic schedule administered after surgical treatment of endometriomas were included, with pain and endometrioma recurrence rates as the primary outcomes.

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Study appraisal and synthesis methods: Three reviewers independently assessed methodology and extracted data from selected studies. The primary outcomes were considered pain

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recurrence (evaluated separately for dysmenorrhea, non-cyclic chronic pelvic pain and dyspareunia) and endometrioma recurrence evaluated at ultrasonography. Dichotomous

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outcomes from each study were express as risk ratio (RR) with 95% confidence interval (CI). Results: Three randomized clinical trials and one prospective controlled cohort study were included, for a total of 557 patients with endometriosis, 343 patients of which with ovarian endometriomas completing the assigned treatment and follow-up. Lower recurrence rates for dysmenorrhea were obtained with a continuous schedule (RR 0.24; 95% CI 0.06 to 0.91; p=0.04). Nonsignificant differences were present for chronic pelvic pain and dyspareunia. A

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ACCEPTED MANUSCRIPT continuous oral contraceptive schedule was associated with a non-significant reduction of cyst recurrence rates compared to a cyclic schedule (RR 0.54; 95% CI 0.28 to 1.05; p=0.07). Conclusions: A continuous oral contraceptive regimen, as opposed to a cyclic regimen, may

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be suggested after surgery for endometriomas because of lower dysmenorrhea recurrence rates. Due to the small number and small sample sizes of the included studies, further randomized clinical trials are needed to confirm the findings of the present systematic review.

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Also, outcomes related to patient satisfaction and quality of life should be addressed.

KEY WORDS: endometrioma, endometriosis, laparoscopy, medical treatment, oral

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contraceptives.

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ACCEPTED MANUSCRIPT INTRODUCTION Endometriosis is defined as the presence of endometrial-like tissue outside the uterus. Endometriosis may be present as peritoneal implants, adhesions, deeply infiltrating lesions, or

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ovarian endometriomas. Endometriomas are present in 17-44% of patients with endometriosis (1), and are usually associated with pelvic pain and infertility (2, 3).

Medical therapy may be considered a cost-effective treatment in case of endometriosis-

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associated pain symptoms. Oral contraceptives (OC) and progestins are considered the firstline option for medical therapy (4, 5). Surgical excision is considered the standard treatment

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when an ovarian endometrioma is present, since endometriomas do not respond to medical therapy (1, 4, 5). Surgery may be needed in particular when pain persists under medical treatment, or in case of enlarging or suspect endometriotic cysts.

In patients not currently seeking pregnancy, medical treatment is usually administered after

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surgical excision of the endometrioma, in order to reduce postoperative cyst recurrence and pain recurrence rates. Several studies have compared postoperative medical treatment versus placebo or no treatment, with conflicting results (3-6). A Cochrane meta-analysis on

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postoperative medical therapy did not report a significant reduction of pain and cyst

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recurrence rates (6). However, three recent systematic reviews (7-9) have demonstrated that postoperative OC is effective in reducing recurrence rates, particularly when administered in the long term (8).

OC may be administered either with a conventional cyclic schedule, or continuously with no pill-free interval. International guidelines on the medical treatment of endometriosis do not suggest either administration schedule as preferable. Few studies compared a cyclic versus continuous OC regimen administered after excisional surgery for endometriomas (10-13). Results of these studies are not consistent as to the efficacy of either regimen on cyst or pain

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ACCEPTED MANUSCRIPT recurrence. In light of a lack of consensus on this issue, we performed a systematic review of the pertinent medical literature.

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OBJECTIVE The objective of the present study was to conduct a systematic review and meta-analysis of

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pain and cyst recurrence after surgery for endometrioma.

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the available literature comparing the efficacy of a cyclic versus continuous OC regimen on

METHODS

Eligibility criteria and study selection

The present systematic review involved all published research articles that compared the

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efficacy of a continuous versus cyclic OC regimen after surgery for ovarian endometriomas in the prevention of endometriosis recurrence. Studies assessing endometrioma recurrence at ultrasonography and/or pain recurrence at follow-up were included. Pain symptoms were

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evaluated separately for dysmenorrhea, non-cyclic chronic pelvic pain, and dyspareunia.

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Studies evaluating only a cyclic or a continuous regimen were excluded. Studies reporting OC treatment after surgery for endometrioma recurrence were excluded. Information sources and search strategy An electronic database search was performed using PubMed, MEDLINE and Embase for the identification of articles published through December 2014, using the combination of the following search terms: “endometrioma”, “endometriosis”, “oral contraceptives”, “oral estroprogestins”, “laparoscopy” and “surgery”.

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ACCEPTED MANUSCRIPT Only articles in English were included. Only full-length articles from peer review journals were considered. Congress abstracts were excluded. Outcome measures

recurrence of pain after continuous OC compared to cyclic OC.

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The primary analyses were aimed at determining the recurrence of endometrioma and the

The recurrence of endometrioma had to be evaluated at transvaginal ultrasonography. The

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recurrence of pain, separately for dysmenorrhea, non-cyclic chronic pain and dyspareunia, had to be reported either as a dichotomous variable (symptom either present or absent), or as

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a continuous variable expressed with any validated scale (visual analog scale, VAS, for example). The pain outcome was evaluated separately for dysmenorrhea, non-cyclic chronic pelvic pain and dyspareunia. In case of studies reporting all symptoms together, the authors were contacted to obtain the data for each symptom separately.

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Secondary outcomes included discontinuation of treatment due to side effects, reoperation rates, patient satisfaction, and quality of life expressed with any validated method.

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In case of studies reporting on OC treatment after surgery for endometriosis where data from the population of patients with endometriomas were not reported separately from those of

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patients with endometriosis but without an endometrioma, the authors were contacted in order to obtain the missing data for the former population. In case the missing data could not be obtained, the studies were considered at primary analysis for the evaluation of pain recurrence and secondary outcomes; a secondary analysis after the exclusion of these studies was planned for the evaluation of endometrioma recurrence. Sensitivity analysis was planned after exclusion of nonrandomized studies and of randomized clinical trials (RCTs) at high risk of bias.

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ACCEPTED MANUSCRIPT Data collection and extraction Three investigators conducted the search independently. Following the electronic search, all articles considered pertinent on the basis of the title and abstract were retrieved, and their

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reference list searched for additional potential studies. Subsequently, the same investigators independently read the full text in order to verify the pertinence of the article to the systematic review on continuous versus cyclic OC after surgery of ovarian endometrioma. Data were extracted independently by each investigator and recorded on apposite forms. In

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case of missing data, or data expressed as diagrams, plots or rates with no absolute numbers,

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the authors were contacted in order to obtain the missing or incomplete data. Disagreements between authors were resolved by mutual discussion, or by involvement of further investigators. Assessment of risk of bias

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Risk of bias assessment for the RCTs included in this review was performed using the Cochrane risk of bias assessment tool. Six domains were evaluated: random sequence generation, allocation concealment, blinding of outcome assessor, completeness of outcome

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data reporting, selective outcome reporting, and other potential sources of bias. The

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possibility of a publication bias was assessed visually using a funnel plot for asymmetry for the primary outcomes. Data synthesis

The data were pooled using RevMan software (Review Manager version 5.1, the Cochrane Collaboration, 2011). Dichotomous outcomes from each study were express as risk ratio (RR) with 95% confidence interval (CI). Heterogeneity between studies was based on the results of the I2 and X2 statistics. A random effect model was used at meta-analysis in case of high

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ACCEPTED MANUSCRIPT heterogeneity (I2>50% or p <0.10), whereas a fixed effect model was used in case of low heterogeneity between studies. A p value less than 0.05 was considered statistically significant.

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Trial registration The systematic review was registered in the PROSPERO International Prospective Register of Systematic Reviews with the registration number CRD42015016616. The Preferred

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Reporting Item for Systematic Reviews and Meta-analysis (PRISMA) was followed.

RESULTS Study selection

The electronic search identified 13 potentially relevant papers. After removal of duplicates, 8

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records were considered (10-17). On the basis of the title and abstract, four articles were included (10-13), whereas four were excluded (14-17) (Figure 1), for the following reasons: two were review studies (15,17), and two studies did not compare a cyclic versus continuous

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OC regimen (14, 16) (Figure 1).

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After reading of the full text, four studies were included at final analysis, for a total of 557 patients evaluated. A total of 496 patients completed the assigned treatment and scheduled follow-up, 343 of which had ovarian endometriomas. Study characteristics The main characteristics of the included studies are detailed in Table 1. In all the included studies, surgical treatment was performed by laparoscopic excision of the cyst wall. In no case nonexcisional techniques or oophorectomies were performed. Three studies were RCTs

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ACCEPTED MANUSCRIPT (10-12), and one was a prospective cohort trial (13). Comparable patient characteristics and exclusion rates for the two treatment arms are reported in the four included studies. None of the three RCT was at high risk of bias (Figure 2). Funnel plots for the primary outcomes did not reveal any publication bias. Two of the RCTs were conducted by the same principal

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investigator (10, 11): the first of the two studies evaluated endometrioma recurrence at ultrasonography (10), whereas the second one evaluated the recurrence of pain in patients with ovarian endometriomas (11), with the latter study including additional patients with

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both endometrioma and pain recurrence (12, 13).

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smaller endometriomas compared with the former study. The other two studies evaluated

Two studies compared a continuous versus cyclic OC regimen (12, 13), whereas two studies included also a third group of untreated patients, which was not included in this meta-analysis (10, 11).

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Three studies evaluated endometrioma recurrence at ultrasonograpy (10, 12, 13). Three studies evaluated pelvic pain: two studies analyzed dysmenorrhea, chronic pelvic pain and dyspareunia separately (11, 13), whereas one study reported pain symptoms together (12). In

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this latter case, the authors were contacted in order to obtain data for each symptom separately: separate data were provided by the authors for dysmenorrhea and non-cyclic

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pelvic pain, whereas dyspareunia was not among the evaluated outcomes (12). In two studies (12, 13), pain recurrence was expressed as a dichotomous variable (i.e., presence or absence of pain), whereas in a third study pain was expressed both as a categorical variable and as a continuous variable expressed with a VAS scale (11). A meta-analysis was performed for the presence or absence of recurrent pain as a dichotomous variable expressed as RR with 95% CI, considering separately dysmenorrhea, chronic pelvic pain and dyspareunia. For the study reporting pain both as a dichotomous and as a continuous variable (11), only pain expressed

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ACCEPTED MANUSCRIPT as a dichotomous variable was included in the meta-analysis, for consistency with the other studies. One study (13) reported on patients with endometriosis, and, among the outcomes considered

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in the present systematic review, only the outcome of cyst recurrence was reported separately for the subgroup of patients with ovarian endometriomas. Both first author and corresponding author were contacted in order to have separate data for the endometrioma patients also for the other outcomes considered, but no response was obtained. Therefore, a secondary

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analysis was conducted, with the exclusion of this study (13). The same study is also the only

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nonrandomized study among the included studies. Therefore, the same secondary metaanalysis is valid as a sensitivity analysis performed after exclusion of nonrandomized studies. Follow up timing schedule varied between a minimum of 6 months (13) and a maximum of 24 months after surgery (10, 11). In most studies, multiple follow-up visits were planned, at

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either 6 or 12-month intervals (Table 1). For some outcomes, however, results were reported only at 12 months. For consistency, the 12-month visit data were therefore considered for all outcomes.

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As concerns the primary outcomes, recurrence of endometrioma was not significantly different after a continuous versus cyclic OC schedule (RR 0.54; 95% CI 0.28 to 1.05;

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p=0.07) (Figure 3). Heterogeneity for this comparison was low (I2=0%). At sensitivity analysis, after exclusion of the nonrandomized study (13), the endometrioma recurrence rates were still not significantly different between the two schedules (RR 0.53; 95% CI 0.22 to 1.31, p=0.17) (Figure 4). Heterogeneity for this comparison was low (I2=0%). As to pain recurrence rates, a continuous OC regimen was associated with a significantly lower RR for dysmenorrhea recurrence (RR 0.24; 95% CI 0.06 to 0.91; p=0.04) (Figure 5). Heterogeneity for this comparison was high (I2=67%). After the exclusion of the

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ACCEPTED MANUSCRIPT nonrandomized study (13), a statistically significant difference was not reached for a lower RR risk after a continuous OC schedule (RR 0.10; 95% CI 0.00 to 2.70; p=0.17) (Figure 6). Heterogeneity for this comparison was high (I2=80%).

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Non significant differences were present for chronic pelvic pain (RR 0.61; 95% CI 0.36 to 1.03; p=0.06) (Figure 7) and dyspareunia (RR 0.77; 95% CI 0.52 to 1.12; p=0.17) (Figure 8). Heterogeneity was high for the former meta-analysis (I2=51%) and low for the latter (I2=0%). Sensitivity analysis with the exclusion of the only non RCT did not change significantly the

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results for chronic pelvic pain (RR 0.78, with 95% CI 0.56 to 1.07; p=0.13, I2=0%) (Figure

only one study could be included (11).

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9), and for dyspareunia (RR 0.87, with 95% CI 0.56 to 1.35, p=0.53). In this latter analysis,

As to the secondary outcomes, discontinuation of contraception therapy was not significantly different for a continuous versus a cyclic treatment (RR 1.74; 95% CI 0.83 to 3.64; p=0.14)

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(Figure 10). Heterogeneity for this comparison was high (I2=51%). Sensitivity analysis did not significantly change the results (RR 1.47; 95% CI 0.39 to 5.59, p=0.57) (Figure 11). Heterogeneity for this comparison was high (I2=71%).

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Reoperation rates also were not significantly different between the two schedules (RR 0.53;

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95% CI 0.16 to 1.74, p=0.30) (Figure 12), with low heterogeneity (I2=0%). Patient satisfaction rates were reported only in one study (12), with non significant differences between the two schedules. No study reported on quality of life.

COMMENT Main findings

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ACCEPTED MANUSCRIPT In the present systematic review and meta-analysis, a continuous regimen of OC appears more efficacious than a cyclic regimen as to dysmenorrhea recurrence rates. The RR for dysmenorrhea recurrence after a continuous OC regimen is 0.24 (95% CI 0.06 to 0.91; p=0.04). Non significant differences between the two schedules are present for chronic pelvic

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pain and dyspareunia. There is a trend toward lower cyst recurrence rates for a continuous versus cyclic OC regimen, with a RR of 0.54 (95% CI 0.28 to 1.05), but statistical significance was not reached (p=0.07).

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Strengths and limitations

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The present study represents the first meta-analysis on the comparison of a conventional OC cyclic schedule versus a continuous schedule administered after surgery for endometrioma excision. Since no recommendation for either schedule is consistently reported in evidencebased guidelines (3-5, 18, 19), a systematic review and meta-analysis on this topic may bring

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important information to the clinician dealing with patients with endometriosis. The present meta-analysis has however several limitations. First of all, only four studies evaluated a continuous versus cyclic OC regimen after surgical excision of the endometrioma

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(10-13), with inconsistent results. Sample sizes are small for most of the studies, and the

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largest study is not a RCT (13), thus possibly introducing potential biases. Two studies included largely overlapping populations (10, 11), with one study evaluating only pain as the primary outcome (11), and the other evaluating only endometrioma recurrence (10). Therefore, for most comparisons in the present meta-analysis, only two or three studies could be included. At sensitivity analysis, only two or, for some outcome, only one study could be included. In most comparisons with low heterogeneity, only two studies were included, and the low I2 might be expected due to the low number of included studies. Comparison with existing literature

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ACCEPTED MANUSCRIPT Two recent systematic reviews on postoperative OC suggested that continuous and cyclic schedules may have comparable efficacy (7, 8), and that the choice of regimen should be modulated on patient preference (7). In both systematic reviews, however, a direct comparison of a continuous versus cyclic schedule was not among the outcomes evaluated. In

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fact, both reviews were only aimed at evaluating the effect of any postoperative OC versus no treatment.

A systematic review comparing the use of continuous versus cyclic OC after surgery was

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recently published by Zorbas et al (20). The authors of the systematic review conclude that

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the use of a continuous OC schedule may be more beneficial than a cyclic schedule. In the study by Zorbas, however, a meta-analysis was not performed, and only a descriptive analysis of the literature was provided, with inconsistent results among the selected studies. Also, one of the three available RCTs (10-12) was missed by the search performed, therefore limiting

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the validity of the systematic review.

As to the studies included in the present systematic review, three RCT and one prospective cohort trial could be identified. Seracchioli et al investigated the efficacy of a continuous

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versus cyclic 24-month OC schedule after surgical excision of endometriomas in two RCTs, one evaluating cyst recurrence (10) and a second one evaluating pain recurrence (11). The

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authors demonstrated a crude endometrioma recurrence rate of 14.7% after a cyclic schedule, versus 8.2% after a continuous schedule, a difference that was not statistically significant (10). As to associated pain, dysmenorrhea recurrence rates were significantly lower for the continuous versus cyclic schedule, whereas no difference was found for chronic pelvic pain and dyspareunia (11). Muzii et al, evaluating a continuous versus cyclic postoperative 6-month OC course in a RCT on 57 patients, reported no significant difference in cyst recurrence rates (respectively 0%

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ACCEPTED MANUSCRIPT and 4% for continuous versus cyclic regimen), and in pain recurrence rates (respectively 17% and 32%) (12). Discontinuation rates where significantly higher for the continuous schedule (41% versus 14%).

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In a prospective cohort study on 356 patients, Vlahos et al reported better results for endometrioma recurrence, dysmenorrhea and non-cyclic pelvic pain recurrence after a continuous versus cyclic postoperative schedule, whereas no difference was found for

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dyspareunia (13).

As detailed above, the currently available literature reports inconsistencies as to the

Conclusions and Implications

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preferable OC schedule to be administered after endometrioma surgery.

In conclusion, a continuous OC regimen may be suggested after surgery for endometriomas, particularly in patients in whom dysmenorrhea is the main associated symptom. A continuous

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OC schedule is in fact associated with lower dysmenorrhea recurrence rates compared to a cyclic schedule. However, the evidence from the present systematic review is not conclusive,

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due to the small number of included studies. Moreover, for other important clinical outcomes, such as endometrioma recurrence, non-cyclic pain and dyspareunia, statistical significance is

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not reached.

Further RCTs are therefore needed to confirm the findings of the present study, due to the small number and small sample sizes of the included studies, which constitute a major limitation of the present systematic review. Also, important outcomes not addressed in the included studies, such as patient satisfaction and quality of life, should be evaluated in further studies. When treatment is administered in the long term, as is the case for postoperative OC, patient compliance to therapy is very important. In this context, studies comparing different

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ACCEPTED MANUSCRIPT molecules, dosages and routes of administration, or extended-cycle schedules, should be

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conducted.

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ACCEPTED MANUSCRIPT REFERENCES 1. Chapron C, Vercellini P, Barakat H, et al. Management of ovarian endometriomas.

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Hum Reprod Update 2002;8:591–7.

2. Practice Committee of the American Society for Reproductive Medicine.

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Endometriosis and infertility: a committee opinion. Fertil Steril 2012;98:591-8.

3. Practice Committee of the American Society for Reproductive Medicine. Treatment

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of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril 2014;101:927-35.

4. Leyland N, Casper R, Laberge P, Singh SS; SOGC. Endometriosis: diagnosis and

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management. J Obstet Gynaecol Can 2010; 32: S1-S32.

5. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of

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women with endometriosis. Hum Reprod 2014;29:400-12.

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6. Furness S, Yap C, Farquhar C, Cheong YC. Pre and post operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev 2004;CD003678.

7. Seracchioli R, Mabrouk M, Manuzzi L, Vicenzi C, Frasca C, Elmakky A, Venturoli S. Post-operative use of oral contraceptive pills for prevention of anatomical relapse or symptom-recurrence after conservative surgery for endometriosis. Hum Reprod 2009;24:2729–35.

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ACCEPTED MANUSCRIPT 8. Vercellini P, DE Matteis S, Somigliana E, Buggio L, Frattaruolo MP, Fedele L. Longterm adjuvant therapy for the prevention of postoperative endometrioma recurrence: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2013;92:8-16.

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9. Wu L, Wu Q, Liu L. Oral contraceptive pills for endometriosis after conservative surgery: a systematic review and meta-analysis. Gynecol Endocrinol 2013;29:883-90.

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10. Seracchioli R, Mabrouk M, Frascà C, Manuzzi L, Montanari G, Keramyda A, Venturoli S. Long-term cyclic and continuous oral contraceptive therapy and

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endometrioma recurrence: a randomized controlled trial. Fertil Steril 2010;93:52-6.

11. Seracchioli R, Mabrouk M, Frascà C, Manuzzi L, Savelli L, Venturoli S. Long-term oral contraceptive pills and postoperative pain management after laparoscopic

2010;94:464-71.

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excision of ovarian endometrioma: a randomized controlled trial. Fertil Steril

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12. Muzii L, Maneschi F, Marana R, Porpora MG, Zupi E, Bellati F, Angioli R, Benedetti

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Panici P. Oral estroprogestins after laparoscopic surgery to excise endometriomas: continuous or cyclic administration? Results of a multicenter randomized study. J Minim Invasive Gynecol 2011;18:173-8.

13. Vlahos N, Vlachos A, Triantafyllidou O, Vitoratos N, Creatsas G. Continuous versus cyclic use of oral contraceptives after surgery for symptomatic endometriosis: a prospective cohort study. Fertil Steril 2013;100:1337-42.

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ACCEPTED MANUSCRIPT 14. Lee DY, Bae DS, Yoon BK, Choi D. Post-operative cyclic oral contraceptive use after gonadotrophin-releasing hormone agonist treatment effectively prevents endometrioma recurrence. Hum Reprod 2010;25:3050-4.

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15. Bukulmez O. Endometriosis and ovarian reserve. Journal of Endometriosis 2012;4:140-1.

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16. Cheewadhanaraks S, Choksuchat C, Dhanaworavibul K, Liabsuetrakul T. Postoperative depot medroxyprogesterone acetate versus continuous oral

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contraceptive pills in the treatment of endometriosis-associated pain: A randomized comparative trial. Gynecol Obstet Invest 2012;74:151-6.

17. Streuli I; de Ziegler D; Santulli P; Marcellin L; Borghese B; Batteux F; Chapron C. An update on the pharmacological management of endometriosis. Expert Opin

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Pharmacother 2014;15:2347-60.

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18. Gelbaya TA, Nardo LG. Evidence-based management of endometrioma. Reprod

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Biomed Online 2011;23:15-24.

19. American College of Obstetricians and Gynecologists. Practice bulletin no. 114: management of endometriosis. Obstet Gynecol. 2010;116:223-36.

20. Zorbas KA, Economopoulos KP, Vlahos NF. Continuous versus cyclic oral contraceptives for the treatment of endometriosis: a systematic review. Arch Gynecol Obstet 2015;292:37-43.

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Study design

Number of patients

Number of patients with endometrioma

Minimum cyst diameter for inclusion (cm)

Mean diameter ±SD (cm) Cyclic

RCT

57

57

>3

5.0±0.9

Seracchioli, 2010 (10)

RCT

148

148

>4

Seracchioli, 2010 (11)

RCT

187

187

NR

Prospective cohort

293

138

NR

Continuous

Cyclic

Oral contraceptive

Continuous Estrogen

Progestin

Duration of treatment (months)

Follow up (months)

NR

NR

30.3±2.9

30.6±3.1

20 µg EE

0.150 mg desogestrel

6

>6

4.9±0.8

5.1±1.1

8/75 (10.7%)

11/73 (15.1%)

29.7±2.8

28.6±2.4

20 µg EE

0.075mg gestodene

24

6-12-18-24

NR

NR

NR

NR

30.2

29.6

20 µg EE

0.075mg gestodene

24

6-12-18-24

4.5±1.4

4.8±1.7

21/84 (25.0%)

14/54 (25.9%)

27.0±2.7

28.0±2.4

30 µg EE

3mg drospirenone

>6

>6

RCT = randomized controlled trial; EE= ethinylestradiol; NR= not reported

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Cyclic

Mean Age ± SD (years)

5.1±1.0

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Vlahos, 2013 (13)

Continuous

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Muzii, 2011 (12)

Number of patients with bilateral cysts (%)

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Author, year of publication

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TABLE 1: Descriptive data of the studies included in the systematic review

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ACCEPTED MANUSCRIPT LEGENDS TO FIGURES Figure 1: Flow diagram of studies identified in the systematic review Figure 2: Risk of bias assessment for the included studies Figure 3: Forest plot for endometrioma recurrence

Figure 5: Forest plot for dysmenorrhea recurrence

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Figure 4: Forest plot of sensitivity analysis for endometrioma recurrence

Figure 7: Forest plot for chronic pelvic pain recurrence Figure 8: Forest plot for dyspareunia recurrence

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Figure 6: Forest plot of sensitivity analysis for dysmenorrhea recurrence

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Figure 9: Forest plot of sensitivity analysis for chronic pelvic pain recurrence Figure 10: Forest plot for discontinuation of treatment

Figure 11: Forest plot of sensitivity analysis for discontinuation of treatment

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Figure 12: Forest plot for reoperation

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Records identified through database searching (n = 13 )

Additional records identified through other sources (n = 0 )

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Identification

PRISMA 2009 Flow Diagram

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Records screened (n = 8 )

Records excluded (n = 4 )

Full-text articles assessed for eligibility (n = 4 )

Full-text articles excluded, with reasons (n = 0 )

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Included

Eligibility

Screening

Records after duplicates removed (n = 8 )

Studies included in qualitative synthesis (n = 4 )

Studies included in quantitative synthesis (meta-analysis) (n = 4 )

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and MetaAnalyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit www.prisma-statement.org.

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