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Oral Estroprogestins after Laparoscopic Surgery to Excise Endometriomas: Continuous or Cyclic Administration? Results of a Multicenter Randomized Study
Original Article
Oral Estroprogestins after Laparoscopic Surgery to Excise Endometriomas: Continuous or Cyclic Administration? Results of a Multicenter Randomized Study Ludovico Muzii, MD*, Francesco Maneschi, MD, Riccardo Marana, MD, Maria Grazia Porpora, MD, Errico Zupi, MD, Filippo Bellati, MD, Roberto Angioli, MD, and Pierluigi Benedetti Panici, MD From the Departments of Obstetrics and Gynecology, Campus Bio-Medico University (Drs. Muzii and Angioli), Santa Maria Goretti Latina (Dr. Maneschi), Catholic University of the Sacred Heart (Dr. Marana), Sapienza University (Drs. Porpora, Bellati, and Benedetti Panici), and Tor Vergata University (Dr Zupi), Rome, Italy.
ABSTRACT Study Objective: To evaluate continuous (CON) compared with cyclic (CYC) administration of combined oral estroprogestins for 6 months after laparoscopic excision of ovarian endometriomas associated with pain. Design: Multicenter, prospective, randomized trial (Canadian Task Force classification I). Setting: Tertiary care university hospitals. Patients: Fifty-seven women aged 18 to 40 years with ovarian endometriomas associated with moderate to severe pelvic pain who underwent laparoscopic excision of the disease. Interventions: Patients were randomized to receive postoperative estroprogestins for 6 months, administered as either a CON or CYC regimen. Measurements and Main Results: At 3, 6, 12, and 24 months postoperatively, patients were evaluated for recurrence of endometriomas (defined as cysts .3 cm in greatest diameter) using ultrasonography, for recurrence of pain using a visual analog scale, and for patient satisfaction. After a minimum follow-up of 12 months (mean, 22 months), at intent-to-treat analysis, no endometrioma recurrence was observed in the CON group, whereas there was recurrence in 1 patient (4%) in the CYC group. Pain recurred in 5 and 9 patients, respectively (17% vs 32%; p 5 .23). Compared with pretreatment values, pain scores improved in both groups, with no significant difference between the 2 groups. Most patients in both groups were either satisfied or very satisfied, with no significant difference between treatment groups. However, compared with the CYC group, significantly more patients in the CON group experienced moderate to severe adverse effects, and therapy was discontinued (41% vs 14%; p 5 .03). Conclusions: Although both regimens were equally effective insofar as postoperative pain and recurrence of endometrioma, when compared with the CYC regimen, the CON regimen seems to be associated with significantly more adverse effects and discontinuation rates. Journal of Minimally Invasive Gynecology (2011) 18, 173–178 Ó 2011 AAGL. All rights reserved.
Endometriosis can manifest as superficial peritoneal or ovarian implants, adhesions, ovarian cysts, and deep infiltrating disease. The disease may be treated using surgery, medical therapy, or expectant management, depending on The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. Corresponding Author: Ludovico Muzii, MD, Department of Obstetrics and Gynecology, Universita Campus BioMedico, Via a del Portillo 21, 00128 Rome, Italy. E-mail: [email protected] Submitted January 29, 2010. Accepted for publication November 17, 2010. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2011 AAGL. All rights reserved. doi:10.1016/j.jmig.2010.11.004
patient desire for fertility, stage of disease, and associated symptoms. Ovarian endometriomas are one of the most frequently occurring benign ovarian neoplasms, and often are associated with pelvic pain and infertility. The treatment of choice for ovarian endometriomas should be surgical excision because endometriomas do not respond to medical therapy and expectant management yields low rates of spontaneous conception [1–3]. In addition, it would be difficult to propose expectant management to a patient with pain, whereas randomized clinical trials have demonstrated the efficacy of operative laparoscopy in patients with endometriosisassociated pain [4,5].
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In patients with pelvic pain associated with ovarian endometriomas, postoperative medical therapy has been proposed in an attempt to reduce pain recurrence after surgery. Both gonadotropin-releasing hormone analogue (GnRH-a) and low-dose combined estroprogestins have been proposed for this purpose [6–9]. However, GnRH-a can be administered for only 6 months or less because longer therapy may be associated with significant adverse effects, and data on long-term estroprogestin therapy are lacking [9]. Insofar as postoperative administration of estroprogestins, it is not clear whether the CYC or CON regimen is preferred. Guidelines for treatment of endometriosis suggest both regimens, either as postoperative adjuvant therapy or as single empiric treatment of pain associated with presumed minimal or mild disease [2,10,11]. The objective of the present randomized study was to evaluate the efficacy of CON vs CYC regimens of estroprogestins administered for 6 months after laparoscopic excision of ovarian endometriomas on pain or endometrioma recurrence at ultrasonographic follow-up. Materials and Methods From January 1, 2005, to June 30, 2006, 57 consecutive patients with a preoperative diagnosis of an endometrioma larger than 3 cm associated with pelvic pain referred to our departments of obstetrics and gynecology were considered for inclusion in the present study. All patients were informed about the study, and agreed to participate. Institutional review board approval was obtained. Inclusion criteria were age 18 to 40 years, first diagnosis of endometriosis at study entry, presence of an ovarian endometrioma larger than 3 cm at ultrasonography, moderate to severe dysmenorrhea or chronic pelvic pain (either symptom graded as R4 on a 10-point visual analog scale [VAS]), and no attempt to conceive at the time of study entry. Exclusion criteria were contraindications to the use of estroprogestins, smoking more than 15 cigarettes per day in patients older than 35 years, previous medical or surgical therapy for endometriosis (except for the use of estroprogestins, excluding the last 6 months). At hospital admission, all patients submitted a detailed general and gynecologic history, and a complete physical examination, urine pregnancy test, blood chemistry studies, and transvaginal ultrasonography were performed to confirm the presence of the endometrioma. The interval between the first and second sonograms was at least 8 weeks. Blood chemistry tests were repeated on the first postoperative day. Patients underwent laparoscopic excision of ovarian endometriomas using the stripping technique, as previously described [9]. In brief, laparoscopy was performed using a 10-mm laparoscope introduced through an umbilical incision, and three 5-mm trocars were introduced suprapubically as accessory instruments. As a first step, the pelvis, abdomen, and external surface of the cyst were inspected for possible evidence of malignant disease. Peritoneal fluid was
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aspirated for cytologic analysis. Endometriosis was staged according to the revised American Fertility Society classification [12]. If necessary, adhesiolysis was performed. When present, superficial endometriosis was treated using bipolar coagulation. The endometrioma was mobilized, with spontaneous rupture always occurring during ovarian manipulation, the cyst contents drained, and the inner cyst wall carefully inspected. After locating the cleavage plane, the cyst wall was separated from the ovarian parenchyma by means of repeated diverging traction applied with atraumatic grasping forceps. Hemostasis was achieved via bipolar coagulation. The capsule of the endometrioma was retrieved from the abdominal cavity with the use of an endoscopic specimen collecting bag introduced through a 10-mm suprapubic trocar that replaced the 5-mm trocar. Pathology reports confirmed endometriotic cysts in all patients. No intraoperative complications occurred, and the procedure was successfully concluded with the endoscopic approach in all cases. After surgery, patients were randomly allocated in a 1:1 ratio to 1 of 2 management arms, cyclic (CYC) or continuous (CON) regimen administered for 6 months, based on a computer-generated sequence. The codes were kept in opaque sealed envelopes, and were broken after randomization. Patients randomized to the CYC group received cyclic monophasic combined estroprogestins, that is, ethinyl estradiol, 0.020 mg, and desogestrel, 0.150 mg/d for 21 days, followed by a 7-day interval, for 6 months. Patients randomized to the CON group received the same monophasic combined estroprogestins daily for 6 months without any interval. Three, six, 12, and 24 months after surgery, both groups underwent clinical and ultrasound examination for possible evidence of endometrioma recurrence, and were evaluated for absence, persistence, or recurrence of pain. Additional follow-up visits were performed when indicated by the referring physician or in cases of referred pain recurrence. Cyst recurrence was defined as the presence of an ovarian cyst larger than 3 cm with sonographic characteristics suggestive of endometrioma. If an ultrasound scan suggested evidence of recurrence, ultrasonography was repeated after 2 or 3 spontaneous cycles to confirm the diagnosis. Pain recurrence was defined as severity of pain, either dysmenorrheal or chronic pain, graded 4 or higher on a 10-point VAS scale. Patient satisfaction was evaluated at each visit using a 4-grade verbal rating scale: ‘‘very satisfied,’’ ‘‘satisfied,’’ ‘‘uncertain,’’ or ‘‘dissatisfied.’’ Statistical analysis was performed using the t test and the Wilcoxon rank sum test for normally and nonnormally distributed continuous variables, respectively, and the Fisher exact test and c2 test for categorical variables. Life table analysis was performed to evaluate cumulative recurrence rates in the 2 groups, and between-group comparisons of 12- and 24-month recurrence rates were performed using the log-rank test. For life table analysis, the date of entry for each patient was the date of surgery. The end point was either the date of pain recurrence or of cyst recurrence,
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whichever occurred first, or in patients who remained asymptomatic and without clinical and sonographic evidence of endometrioma recurrence, the date of the last follow-up visit. A p value of ,.05 was considered statistically significant. Given an estimated 38% recurrence rate of either symptoms or cyst in a control group treated for endometriosis with conservative surgery only [4], the sample size of this study was selected to detect, with an 80% chance at the 5% level of significance, a difference in endometriosis recurrence between the 2 groups of approximately 33% (i.e., from 38% to 5%). Results The randomization process yielded 28 patients in the CYC and 29 in the CON treatment arm. The 2 groups of patients did not differ insofar as mean (SD; 95% CI) age (30.3 [2.9; 29.2–31.4] years in the CYC group vs 30.6 [3.1; 29.5–31.7] in the CON group), mean revised American Fertility Society classification scores (40.4 [20.1; 33.0–47.9] vs 42.1 [22.7; 33.8–50.4]), endometriotic cyst diameter (5.0 [0.9; 4.7–5.3] cm vs 5.1 [1.0; 4.7–5.5]), percentage of patients with associated superficial implants (23 of 28 vs 24 of 29), or adhesions (all patients in both groups). VAS pain scores before surgery were comparable in the 2 groups (7.1 [1.7; 6.5–7.7] in the CYC group vs 6.8 [1.7; 6.2–7.4] in the CON group). All patients completed at least 12 months of follow-up. The 2 groups were observed for a comparable time (median [range], 24 [12–48] months). An intent-to-treat analysis was performed (i.e., analysis based on the allocated intervention, not on completion of the assigned treatment), with all patients evaluable. Twelve patients allocated to the CON group did not complete the 6-month treatment for moderate to severe adverse effects, breakthrough bleeding in particular, attributable to estroprogestin therapy, compared with 4 patients allocated to the CYC group. The primary reason for discontinuation was breakthrough uterine bleeding (reported by 10 of 12 patients in the CON group and 2 of 4 in the CYC group), followed by headache (2 of 12 in the CON group and 2 of 4 in the CYC group). The difference in discontinuation rates (41% vs 14%) was statistically significant (p 5 .03). In case of noncompletion of the assigned treatment schedule, the choice of subsequent management was made by the treating physician. Crossover from one arm to the other was allowed. Of 12 patients not completing the assigned 6-month treatment in the CON group, 6 switched to the CYC regimen (after a mean duration of the allocated CON treatment of 3.0 months), and 6 were kept under observation without any further treatment (after a mean duration of the allocated CON treatment of 4.2 months). The 4 patients not completing the 6-month CYC treatment were all kept under observation, without any further treatment (after a mean duration of the allocated CYC treatment of 3.5 months).
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During follow-up, 2 patients in each group continued with cyclic estroprogestin therapy beyond the assigned 6-month treatment, according to the decision of either the referring physician or the patient. The 2 patients in the CON group had already changed to the CYC group during the 6-month treatment period because of adverse effects. At follow-up, only 1 endometrioma had recurred, at 12 months after surgery, in the 28 patients in the CYC group (3.6%), compared with no recurrence in the CON group (p 5 .49, not significant). The patient with endometrioma recurrence, after a repeated ultrasound scan confirming the diagnosis, underwent operative laparoscopy, and the endometriotic nature of the cyst was confirmed. That patient was also having pain recurrence at the time of sonographic diagnosis of recurrent endometrioma. The pain recurrence rate was 17% in the CON group (5 of 29 patients), compared with 32% (9 of 28 patients, including the patient who also had cyst recurrence) in the CYC group (p 5 .54, not significant). Compared with pretreatment values, pain scores improved in both groups, without significant difference between the 2 groups. The mean time to recurrence (endometrioma recurrence at ultrasonography or symptom recurrence) was 16 months in the CON group, compared with 12 in the CYC group (p 5 .30, not significant). Life table analysis did not demonstrate a significant difference for 12- and 24-month rates of recurrence between the 2 groups (Fig. 1). Analysis of the results in patients who completed the allocated 6-month treatment demonstrated that recurrence rates of either cyst or pain were not significantly different between the CON group (2 of 17 patients [12%]) and the CYC group (7 of 24 [29%]) (p 5 .26). Patient satisfaction was reported by most patients during follow-up. Although some patients were either ‘‘uncertain’’ or ‘‘dissatisfied’’ at the 3-month visit, because of adverse effects (4 of 29 in the CON group and 2 of 28 in the CYC group), all patients were either ‘‘very satisfied’’ or ‘‘satisfied at the 6-month visit. At 12 months, 2 patients in the CON group and 5 in the CYC group were either ‘‘uncertain’’ or ‘‘dissatisfied’’ because of pain or cyst recurrence (p 5 .25, not significant between groups). At 24 months, 5 patients in the CON group and 9 in the CYC group (p 5 .54, not significant) were either ‘‘uncertain’’ or ‘‘dissatisfied,’’ again because of pain or cyst recurrence. Discussion Surgery, either alone or in combination with medical suppression, should be the treatment of choice for ovarian endometriomas [1–3]. Operative laparoscopy should be considered the criterion standard for surgical treatment of the disease. After surgery, the gynecologist must decide whether to treat the patient medically or not. Disease recurrence after conservative surgery occurs in a significant number of patients treated by conservative surgery, and is a main concern for the gynecologist. The American College of Obstetricians and Gynecologists suggests that, although
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Fig. 1. Life table analysis comparing cumulative recurrence of pain or endometrioma according to 2 postoperative therapeutic regimens (p 5 not significant, log-rank test).
reported results of a combined medicosurgical approach are conflicting, clinical judgment supports combined therapy in certain circumstances such as postoperative treatment with oral contraceptives, GnRH-a, or danazol in fertile patients with severe pain [13]. Various studies have been published on medical treatment of endometriosis after surgery. Three recent randomized studies compared postoperative GnRH-a treatment with placebo (6,7,14), and 1 randomized study compared postoperative cyclic oral contraceptive treatment with no treatment [9]. One randomized study compared estroprogestin and GnRHa after diagnostic laparoscopy [8], one random study compared cyproterone acetate and estroprogestin for treatment of recurrent pain after conservative surgery [15], and 1 nonrandomized study evaluated continuous administration of estroprogestin, after failure of a postoperative cyclic regimen, for treatment of recurrent pain [16]. A recent nonrandomized study evaluated the use of estroprogestin, either during the entire follow-up period or discontinuously, compared with no use of estroprogestin after laparoscopic excision of endometriomas [17]. Another recent randomized study evaluated estroprogestin, administered either cyclically or continuously for 24 months, compared with no treatment after surgery for endometriomas [18]. In a randomized study by Parazzini et al [6] of 75 patients with stage III or IV endometriosis treated at laparotomy, a postoperative 3-month course of GnRH-a did not improve pelvic pain and short-term reproductive outcome, compared with no-treatment. No marked differences in pain scores were evident for the 2 different treatment arms, and pregnancy rates within 1 year after randomization were 19% in the GnRH-a group and 18% in the placebo group. In a randomized study by Hornstein et al [7], patients with endometriosis at any stage and associated pelvic pain underwent operative laparoscopy and were then randomized to either GnRH-a (49 patients) or placebo (44 patients) therapy for 6 months. The median time from surgery to initiation of alternative treatment was significantly longer in the
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GnRH-a group (.24 months) than in the placebo group (11.7 months). Both groups demonstrated a significant decrease in pain scores after surgery, at the end of postoperative treatment, and at 6 months after treatment completion. At the end of treatment, patients treated with GnRH-a demonstrated a significant decrease in pain scores, compared with placebo-treated patients. However, there was no significant difference in pain scores between the 2 groups 6 months after treatment completion. In a study by Busacca et al [14], 89 women with stage III or IV endometriosis were randomized, after laparoscopic surgery, to either 3 months of GnRH-a therapy or no treatment. No differences insofar as postoperative pregnancy rates or pain recurrence were present between the 2 groups during a mean follow-up of 19 months. In a randomized study by Muzii et al [9], it was demonstrated that a 6-month course of low-dose cyclic estroprogestin administered after operative laparoscopy for stage III or IVendometriosis, although showing a significant trend toward delay in disease recurrence, did not significantly influence long-term recurrence rates, either for symptom or endometrioma recurrence. A significant difference in pain or cyst recurrence in favor of estroprogestin treatment was evident at life table analysis at 12 months after surgery. No statistically significant differences were detectable, however, at 24 and 36 months, although a trend toward lower recurrence rates with postoperative estroprogestin therapy was still present at 24 and 36 months. In a study by Vercellini et al [8], 57 patients with endometriosis (78% with stage I or II) were randomized to a 6-month course of either cyclic estroprogestin (ethinyl estradiol, 0.020 mg, and desogestrel, 0.150 mg) or GnRHa after diagnostic laparoscopy, with no attempt at surgical treatment. A significant improvement in pain was demonstrated in both groups at the end of treatment. In particular, nonmenstrual pain diminished with no differences between the 2 groups, deep dyspareunia was significantly reduced in both groups, with GnRH-a therapy superior to estroprogestin therapy, and dysmenorrhea diminished significantly in the estroprogestin group; no between-group comparison was possible because patients in the GnRH-a group developed amenorrhea. Symptoms recurred, however, in most patients 6 months after drug withdrawal, without differences in pain severity between the 2 groups, demonstrating that pain relief with both treatments was limited in time. In a subsequent study by Vercellini et al [15], 90 women with moderate to severe pain recurrence after conservative surgery to treat symptomatic endometriosis were randomized to receive either oral cyproterone acetate or combined estroprogestins administered continuously for 6 months. At 6 months, pain was significantly reduced in both groups, with no major between-group difference. In another study by Vercellini et al [16], a CON regimen of estroprogestin was administered in 50 women who experienced recurrent pain after conservative surgery despite
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postoperative CYC estroprogestin use. After switching from CYC to CON estroprogestin therapy, the VAS score for dysmenorrhea decreased from 7.5 to 3.1, and moderate or severe adverse effects were reported by 14% of the women. Eighty percent of the women were either satisfied or very satisfied with the CON estroprogestin regimen. In a recent nonrandomized cohort study by Vercellini et al [17], 277 patients with stage III or IV endometriosis were offered cyclic estroprogestin therapy after laparoscopic excision of ovarian endometriomas. After a shared decisionmaking process, 102 patients used estroprogestin for the entire follow-up period (‘‘always users’’), 129 used estroprogestin discontinuously (‘‘ever users’’), and 46 did not use estroprogestin (‘‘never users’’). After a median follow-up of 28 months, the recurrence rates were 9% (9 of 102) in the always users and 56% (26 of 48) in the never users (p ,.001). Regular postoperative use of estroprogestin was, therefore, demonstrated to significantly reduce endometrioma recurrence. In a recent randomized study by Seracchioli et al [18], 239 patients underwent laparoscopic excision of ovarian endometriomas and were subsequently randomized into 3 management arms: expectant management, CON regimen of estroprogestin, or CYC regimen of estroprogestin, both administered for 24 months. The rate of endometrioma recurrence (defined as the presence of an ovarian cyst larger than 1.5 cm at ultrasonography with features typical of an endometrioma) at 24 months was higher in the expectant management arm (29%) compared with the CON (8%) or CYC (15%) estroprogestin groups. No information was given in this trial as to recurrence of associated pain. Evidence in the literature from randomized controlled trials shows, therefore, that postoperative medical treatment can prevent recurrence of endometriosis, at best, only during the treatment period of medium-term follow-up. GnRHa can be administered for a maximum of 6 months; longer treatment is associated with high cost and significant adverse effects that largely outweigh the possible advantage of further delay in recurrence. Add-back therapy permits longer courses of therapy. In contrast, estroprogestin can be administered for longer periods; however, although probably widely used, long-term postoperative estroprogestin therapy has, to our knowledge, been tested in only a single randomized clinical trial [18]. Usually, the decision as to which estroprogestin treatment (CON or CYC) should be administered is made after surgery, in an attempt to reduce or delay recurrence [9]. Although guidelines for the treatment of endometriosis suggest either regimen, in particular for associated pain (2,10,11), a single clinical trial [18] has compared the 2 options in a randomized study; however, pain recurrence was not evaluated as an outcome. A follow-up study of the same groups of patients, conducted during the 24 months of treatment, is under way. In the present randomized study, continuous and cyclic administration of estroprogestin administered for 6 months after operative laparoscopy because of ovarian endometriomas
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associated with moderate to severe pain was equally effective in preventing recurrence of endometriomas or pain, although adverse effects were significantly worse with the CON regimen. After a mean follow-up of 22 months, 17% of patients in the CON group experienced recurrence of pain, compared with 32% in the CYC group. The CON regimen, although associated with a nonsignificant trend compared with better outcomes in reduction of recurrences, was associated with adverse effects, breakthrough bleeding in particular, that eventually led to discontinuation of treatment in a substantial number of patients (41% in the CON group compared with 14% in the CYC group). It can be hypothesized that, balancing the higher discontinuation rate of continuous treatment because of adverse effects with the lower but nonsignificant recurrence rate, the CON and CYC regimens result in comparable patient satisfaction. Satisfaction rates were high in both treatment arms, probably because of the significant improvement in pain score due to the combined surgical-medical treatment of endometriomas. Further randomized studies, with larger sample sizes, are needed to better assess the role of postoperative cyclic compared with continuous estroprogestin administration in the management of endometriosis. A limitation of the present study is the limited sample size, particularly in the case of a negative study. The present study may be underpowered, in particular for the outcome of endometrioma recurrence, which was only 2%. Longer courses of estroprogestin treatment, both continuous and cyclic, with follow-up extending beyond the treatment period, should be tested to investigate whether a longer treatment period would prolong delay in disease recurrence observed in previous studies. Newer lower dose estroprogestin administered continuously should be used in randomized clinical trials to assess whether lower doses may be associated with lower discontinuation rates, although preserving the lower recurrence rates observed with continuous use of estroprogestin. In addition, an objective evaluation of endometriosis recurrence with second-look laparoscopy would be desirable. In the present study, as in most studies of treatment of endometriosis, only sonographic evidence of endometriomas or recurrence of pain were considered suggestive of endometriosis recurrence.
Conclusion In the present randomized study, continuous and cyclic administration of estroprogestin therapy for 6 months after operative laparoscopy to treat ovarian endometriomas associated with moderate to severe pain were equally effective in prevention of recurrence of pain or endometriomas. The continuous regimen, however, was associated with a significantly higher rate of adverse effects (breakthrough bleeding in particular), leading to discontinuation of treatment in approximately 40% of patients.
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References 1. Chapron C, Vercellini P, Barakat H, et al. Management of ovarian endometriomas. Hum Reprod Update. 2002;8:591–597. 2. Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20: 2698–2704. 3. Barton-Smith P, Ballard K, Kent ASH. Endometriosis: a general review and rationale for surgical therapy. Rev Gynecol Perinat Pract. 2006;6: 168–176. 4. Sutton CJG, Pooley AS, Ewen SP, Haines P. Follow-up report on a randomized controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal to moderate endometriosis. Fertil Steril. 1997;68:1070–1074. 5. Abbott J, Hawe J, Hunter D, et al. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril. 2004;82:878–884. 6. Parazzini F, Fedele L, Busacca M, et al. Postsurgical medical treatment of advanced endometriosis: results of a randomized clinical trial. Am J Obstet Gynecol. 1994;171:1205–1207. 7. Hornstein MD, Hemmings R, Yuzpe AA, LeRoy Heinrichs W. Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis. Fertil Steril. 1997;68:860–864. 8. Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil Steril. 1993;60:75–79. 9. Muzii L, Marana R, Caruana P, et al. Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriomas: a prospective, randomized trial. Am J Obstet Gynecol. 2000;183:588–592.
Journal of Minimally Invasive Gynecology, Vol 18, No 2, March/April 2011 10. American College of Obstetricians and Gynecologists. ACOG practice bulletin. Medical management of endometriosis. No. 11, December 1999. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet. 2000;71:183–196. 11. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis. Fertil Steril. 2006;86(suppl 4):S18–S27. 12. American Fertility Society. Revised American Fertility Society classification of endometriosis. Fertil Steril. 1985;43:351–352. 13. American College of Obstetricians and Gynecologists. Endometriosis. Technical Bulletin No. 184. Int J Gynecol Obstet. 1993;43: 221–227. 14. Busacca M, Somigliana E, Bianchi S, et al. Postoperative GnRH analogue treatment after conservative surgery for symptomatic endometriosis stage III-IV: a randomized controlled trial. Hum Reprod. 2001;16:2399–2402. 15. Vercellini P, Frontino G, Mosconi P, et al. Cyproterone acetate versus a continuous monophasic oral contraceptive in the treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis. Fertil Steril. 2002;77:52–61. 16. Vercellini P, Frontino G, De Giorni O, et al. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen. Fertil Steril. 2003;80: 560–563. 17. Vercellini P, Somigliana E, Daguati R, et al. Postoperative oral contraceptive exposure and risk of endometrioma recurrence. Am J Obstet Gynecol. 2008;198:504.e1–504.e5. 18. Seracchioli R, Mabrouk M, Frasca C, et al. Long-term cyclic and continuous oral contraceptive therapy and endometrioma recurrence: a randomized controlled trial. Fertil Steril. 2010;93:52–56.
Oral Estroprogestins after Laparoscopic Surgery to Excise Endometriomas: Continuous or Cyclic Administration? Results of a Multicenter Randomized Study Ludovico Muzii, MD*, Francesco Maneschi, MD, Riccardo Marana, MD, Maria Grazia Porpora, MD, Errico Zupi, MD, Filippo Bellati, MD, Roberto Angioli, MD, and Pierluigi Benedetti Panici, MD From the Departments of Obstetrics and Gynecology, Campus Bio-Medico University (Drs. Muzii and Angioli), Santa Maria Goretti Latina (Dr. Maneschi), Catholic University of the Sacred Heart (Dr. Marana), Sapienza University (Drs. Porpora, Bellati, and Benedetti Panici), and Tor Vergata University (Dr Zupi), Rome, Italy.
ABSTRACT Study Objective: To evaluate continuous (CON) compared with cyclic (CYC) administration of combined oral estroprogestins for 6 months after laparoscopic excision of ovarian endometriomas associated with pain. Design: Multicenter, prospective, randomized trial (Canadian Task Force classification I). Setting: Tertiary care university hospitals. Patients: Fifty-seven women aged 18 to 40 years with ovarian endometriomas associated with moderate to severe pelvic pain who underwent laparoscopic excision of the disease. Interventions: Patients were randomized to receive postoperative estroprogestins for 6 months, administered as either a CON or CYC regimen. Measurements and Main Results: At 3, 6, 12, and 24 months postoperatively, patients were evaluated for recurrence of endometriomas (defined as cysts .3 cm in greatest diameter) using ultrasonography, for recurrence of pain using a visual analog scale, and for patient satisfaction. After a minimum follow-up of 12 months (mean, 22 months), at intent-to-treat analysis, no endometrioma recurrence was observed in the CON group, whereas there was recurrence in 1 patient (4%) in the CYC group. Pain recurred in 5 and 9 patients, respectively (17% vs 32%; p 5 .23). Compared with pretreatment values, pain scores improved in both groups, with no significant difference between the 2 groups. Most patients in both groups were either satisfied or very satisfied, with no significant difference between treatment groups. However, compared with the CYC group, significantly more patients in the CON group experienced moderate to severe adverse effects, and therapy was discontinued (41% vs 14%; p 5 .03). Conclusions: Although both regimens were equally effective insofar as postoperative pain and recurrence of endometrioma, when compared with the CYC regimen, the CON regimen seems to be associated with significantly more adverse effects and discontinuation rates. Journal of Minimally Invasive Gynecology (2011) 18, 173–178 Ó 2011 AAGL. All rights reserved.
Endometriosis can manifest as superficial peritoneal or ovarian implants, adhesions, ovarian cysts, and deep infiltrating disease. The disease may be treated using surgery, medical therapy, or expectant management, depending on The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. Corresponding Author: Ludovico Muzii, MD, Department of Obstetrics and Gynecology, Universita Campus BioMedico, Via a del Portillo 21, 00128 Rome, Italy. E-mail: [email protected] Submitted January 29, 2010. Accepted for publication November 17, 2010. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2011 AAGL. All rights reserved. doi:10.1016/j.jmig.2010.11.004
patient desire for fertility, stage of disease, and associated symptoms. Ovarian endometriomas are one of the most frequently occurring benign ovarian neoplasms, and often are associated with pelvic pain and infertility. The treatment of choice for ovarian endometriomas should be surgical excision because endometriomas do not respond to medical therapy and expectant management yields low rates of spontaneous conception [1–3]. In addition, it would be difficult to propose expectant management to a patient with pain, whereas randomized clinical trials have demonstrated the efficacy of operative laparoscopy in patients with endometriosisassociated pain [4,5].
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In patients with pelvic pain associated with ovarian endometriomas, postoperative medical therapy has been proposed in an attempt to reduce pain recurrence after surgery. Both gonadotropin-releasing hormone analogue (GnRH-a) and low-dose combined estroprogestins have been proposed for this purpose [6–9]. However, GnRH-a can be administered for only 6 months or less because longer therapy may be associated with significant adverse effects, and data on long-term estroprogestin therapy are lacking [9]. Insofar as postoperative administration of estroprogestins, it is not clear whether the CYC or CON regimen is preferred. Guidelines for treatment of endometriosis suggest both regimens, either as postoperative adjuvant therapy or as single empiric treatment of pain associated with presumed minimal or mild disease [2,10,11]. The objective of the present randomized study was to evaluate the efficacy of CON vs CYC regimens of estroprogestins administered for 6 months after laparoscopic excision of ovarian endometriomas on pain or endometrioma recurrence at ultrasonographic follow-up. Materials and Methods From January 1, 2005, to June 30, 2006, 57 consecutive patients with a preoperative diagnosis of an endometrioma larger than 3 cm associated with pelvic pain referred to our departments of obstetrics and gynecology were considered for inclusion in the present study. All patients were informed about the study, and agreed to participate. Institutional review board approval was obtained. Inclusion criteria were age 18 to 40 years, first diagnosis of endometriosis at study entry, presence of an ovarian endometrioma larger than 3 cm at ultrasonography, moderate to severe dysmenorrhea or chronic pelvic pain (either symptom graded as R4 on a 10-point visual analog scale [VAS]), and no attempt to conceive at the time of study entry. Exclusion criteria were contraindications to the use of estroprogestins, smoking more than 15 cigarettes per day in patients older than 35 years, previous medical or surgical therapy for endometriosis (except for the use of estroprogestins, excluding the last 6 months). At hospital admission, all patients submitted a detailed general and gynecologic history, and a complete physical examination, urine pregnancy test, blood chemistry studies, and transvaginal ultrasonography were performed to confirm the presence of the endometrioma. The interval between the first and second sonograms was at least 8 weeks. Blood chemistry tests were repeated on the first postoperative day. Patients underwent laparoscopic excision of ovarian endometriomas using the stripping technique, as previously described [9]. In brief, laparoscopy was performed using a 10-mm laparoscope introduced through an umbilical incision, and three 5-mm trocars were introduced suprapubically as accessory instruments. As a first step, the pelvis, abdomen, and external surface of the cyst were inspected for possible evidence of malignant disease. Peritoneal fluid was
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aspirated for cytologic analysis. Endometriosis was staged according to the revised American Fertility Society classification [12]. If necessary, adhesiolysis was performed. When present, superficial endometriosis was treated using bipolar coagulation. The endometrioma was mobilized, with spontaneous rupture always occurring during ovarian manipulation, the cyst contents drained, and the inner cyst wall carefully inspected. After locating the cleavage plane, the cyst wall was separated from the ovarian parenchyma by means of repeated diverging traction applied with atraumatic grasping forceps. Hemostasis was achieved via bipolar coagulation. The capsule of the endometrioma was retrieved from the abdominal cavity with the use of an endoscopic specimen collecting bag introduced through a 10-mm suprapubic trocar that replaced the 5-mm trocar. Pathology reports confirmed endometriotic cysts in all patients. No intraoperative complications occurred, and the procedure was successfully concluded with the endoscopic approach in all cases. After surgery, patients were randomly allocated in a 1:1 ratio to 1 of 2 management arms, cyclic (CYC) or continuous (CON) regimen administered for 6 months, based on a computer-generated sequence. The codes were kept in opaque sealed envelopes, and were broken after randomization. Patients randomized to the CYC group received cyclic monophasic combined estroprogestins, that is, ethinyl estradiol, 0.020 mg, and desogestrel, 0.150 mg/d for 21 days, followed by a 7-day interval, for 6 months. Patients randomized to the CON group received the same monophasic combined estroprogestins daily for 6 months without any interval. Three, six, 12, and 24 months after surgery, both groups underwent clinical and ultrasound examination for possible evidence of endometrioma recurrence, and were evaluated for absence, persistence, or recurrence of pain. Additional follow-up visits were performed when indicated by the referring physician or in cases of referred pain recurrence. Cyst recurrence was defined as the presence of an ovarian cyst larger than 3 cm with sonographic characteristics suggestive of endometrioma. If an ultrasound scan suggested evidence of recurrence, ultrasonography was repeated after 2 or 3 spontaneous cycles to confirm the diagnosis. Pain recurrence was defined as severity of pain, either dysmenorrheal or chronic pain, graded 4 or higher on a 10-point VAS scale. Patient satisfaction was evaluated at each visit using a 4-grade verbal rating scale: ‘‘very satisfied,’’ ‘‘satisfied,’’ ‘‘uncertain,’’ or ‘‘dissatisfied.’’ Statistical analysis was performed using the t test and the Wilcoxon rank sum test for normally and nonnormally distributed continuous variables, respectively, and the Fisher exact test and c2 test for categorical variables. Life table analysis was performed to evaluate cumulative recurrence rates in the 2 groups, and between-group comparisons of 12- and 24-month recurrence rates were performed using the log-rank test. For life table analysis, the date of entry for each patient was the date of surgery. The end point was either the date of pain recurrence or of cyst recurrence,
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whichever occurred first, or in patients who remained asymptomatic and without clinical and sonographic evidence of endometrioma recurrence, the date of the last follow-up visit. A p value of ,.05 was considered statistically significant. Given an estimated 38% recurrence rate of either symptoms or cyst in a control group treated for endometriosis with conservative surgery only [4], the sample size of this study was selected to detect, with an 80% chance at the 5% level of significance, a difference in endometriosis recurrence between the 2 groups of approximately 33% (i.e., from 38% to 5%). Results The randomization process yielded 28 patients in the CYC and 29 in the CON treatment arm. The 2 groups of patients did not differ insofar as mean (SD; 95% CI) age (30.3 [2.9; 29.2–31.4] years in the CYC group vs 30.6 [3.1; 29.5–31.7] in the CON group), mean revised American Fertility Society classification scores (40.4 [20.1; 33.0–47.9] vs 42.1 [22.7; 33.8–50.4]), endometriotic cyst diameter (5.0 [0.9; 4.7–5.3] cm vs 5.1 [1.0; 4.7–5.5]), percentage of patients with associated superficial implants (23 of 28 vs 24 of 29), or adhesions (all patients in both groups). VAS pain scores before surgery were comparable in the 2 groups (7.1 [1.7; 6.5–7.7] in the CYC group vs 6.8 [1.7; 6.2–7.4] in the CON group). All patients completed at least 12 months of follow-up. The 2 groups were observed for a comparable time (median [range], 24 [12–48] months). An intent-to-treat analysis was performed (i.e., analysis based on the allocated intervention, not on completion of the assigned treatment), with all patients evaluable. Twelve patients allocated to the CON group did not complete the 6-month treatment for moderate to severe adverse effects, breakthrough bleeding in particular, attributable to estroprogestin therapy, compared with 4 patients allocated to the CYC group. The primary reason for discontinuation was breakthrough uterine bleeding (reported by 10 of 12 patients in the CON group and 2 of 4 in the CYC group), followed by headache (2 of 12 in the CON group and 2 of 4 in the CYC group). The difference in discontinuation rates (41% vs 14%) was statistically significant (p 5 .03). In case of noncompletion of the assigned treatment schedule, the choice of subsequent management was made by the treating physician. Crossover from one arm to the other was allowed. Of 12 patients not completing the assigned 6-month treatment in the CON group, 6 switched to the CYC regimen (after a mean duration of the allocated CON treatment of 3.0 months), and 6 were kept under observation without any further treatment (after a mean duration of the allocated CON treatment of 4.2 months). The 4 patients not completing the 6-month CYC treatment were all kept under observation, without any further treatment (after a mean duration of the allocated CYC treatment of 3.5 months).
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During follow-up, 2 patients in each group continued with cyclic estroprogestin therapy beyond the assigned 6-month treatment, according to the decision of either the referring physician or the patient. The 2 patients in the CON group had already changed to the CYC group during the 6-month treatment period because of adverse effects. At follow-up, only 1 endometrioma had recurred, at 12 months after surgery, in the 28 patients in the CYC group (3.6%), compared with no recurrence in the CON group (p 5 .49, not significant). The patient with endometrioma recurrence, after a repeated ultrasound scan confirming the diagnosis, underwent operative laparoscopy, and the endometriotic nature of the cyst was confirmed. That patient was also having pain recurrence at the time of sonographic diagnosis of recurrent endometrioma. The pain recurrence rate was 17% in the CON group (5 of 29 patients), compared with 32% (9 of 28 patients, including the patient who also had cyst recurrence) in the CYC group (p 5 .54, not significant). Compared with pretreatment values, pain scores improved in both groups, without significant difference between the 2 groups. The mean time to recurrence (endometrioma recurrence at ultrasonography or symptom recurrence) was 16 months in the CON group, compared with 12 in the CYC group (p 5 .30, not significant). Life table analysis did not demonstrate a significant difference for 12- and 24-month rates of recurrence between the 2 groups (Fig. 1). Analysis of the results in patients who completed the allocated 6-month treatment demonstrated that recurrence rates of either cyst or pain were not significantly different between the CON group (2 of 17 patients [12%]) and the CYC group (7 of 24 [29%]) (p 5 .26). Patient satisfaction was reported by most patients during follow-up. Although some patients were either ‘‘uncertain’’ or ‘‘dissatisfied’’ at the 3-month visit, because of adverse effects (4 of 29 in the CON group and 2 of 28 in the CYC group), all patients were either ‘‘very satisfied’’ or ‘‘satisfied at the 6-month visit. At 12 months, 2 patients in the CON group and 5 in the CYC group were either ‘‘uncertain’’ or ‘‘dissatisfied’’ because of pain or cyst recurrence (p 5 .25, not significant between groups). At 24 months, 5 patients in the CON group and 9 in the CYC group (p 5 .54, not significant) were either ‘‘uncertain’’ or ‘‘dissatisfied,’’ again because of pain or cyst recurrence. Discussion Surgery, either alone or in combination with medical suppression, should be the treatment of choice for ovarian endometriomas [1–3]. Operative laparoscopy should be considered the criterion standard for surgical treatment of the disease. After surgery, the gynecologist must decide whether to treat the patient medically or not. Disease recurrence after conservative surgery occurs in a significant number of patients treated by conservative surgery, and is a main concern for the gynecologist. The American College of Obstetricians and Gynecologists suggests that, although
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Fig. 1. Life table analysis comparing cumulative recurrence of pain or endometrioma according to 2 postoperative therapeutic regimens (p 5 not significant, log-rank test).
reported results of a combined medicosurgical approach are conflicting, clinical judgment supports combined therapy in certain circumstances such as postoperative treatment with oral contraceptives, GnRH-a, or danazol in fertile patients with severe pain [13]. Various studies have been published on medical treatment of endometriosis after surgery. Three recent randomized studies compared postoperative GnRH-a treatment with placebo (6,7,14), and 1 randomized study compared postoperative cyclic oral contraceptive treatment with no treatment [9]. One randomized study compared estroprogestin and GnRHa after diagnostic laparoscopy [8], one random study compared cyproterone acetate and estroprogestin for treatment of recurrent pain after conservative surgery [15], and 1 nonrandomized study evaluated continuous administration of estroprogestin, after failure of a postoperative cyclic regimen, for treatment of recurrent pain [16]. A recent nonrandomized study evaluated the use of estroprogestin, either during the entire follow-up period or discontinuously, compared with no use of estroprogestin after laparoscopic excision of endometriomas [17]. Another recent randomized study evaluated estroprogestin, administered either cyclically or continuously for 24 months, compared with no treatment after surgery for endometriomas [18]. In a randomized study by Parazzini et al [6] of 75 patients with stage III or IV endometriosis treated at laparotomy, a postoperative 3-month course of GnRH-a did not improve pelvic pain and short-term reproductive outcome, compared with no-treatment. No marked differences in pain scores were evident for the 2 different treatment arms, and pregnancy rates within 1 year after randomization were 19% in the GnRH-a group and 18% in the placebo group. In a randomized study by Hornstein et al [7], patients with endometriosis at any stage and associated pelvic pain underwent operative laparoscopy and were then randomized to either GnRH-a (49 patients) or placebo (44 patients) therapy for 6 months. The median time from surgery to initiation of alternative treatment was significantly longer in the
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GnRH-a group (.24 months) than in the placebo group (11.7 months). Both groups demonstrated a significant decrease in pain scores after surgery, at the end of postoperative treatment, and at 6 months after treatment completion. At the end of treatment, patients treated with GnRH-a demonstrated a significant decrease in pain scores, compared with placebo-treated patients. However, there was no significant difference in pain scores between the 2 groups 6 months after treatment completion. In a study by Busacca et al [14], 89 women with stage III or IV endometriosis were randomized, after laparoscopic surgery, to either 3 months of GnRH-a therapy or no treatment. No differences insofar as postoperative pregnancy rates or pain recurrence were present between the 2 groups during a mean follow-up of 19 months. In a randomized study by Muzii et al [9], it was demonstrated that a 6-month course of low-dose cyclic estroprogestin administered after operative laparoscopy for stage III or IVendometriosis, although showing a significant trend toward delay in disease recurrence, did not significantly influence long-term recurrence rates, either for symptom or endometrioma recurrence. A significant difference in pain or cyst recurrence in favor of estroprogestin treatment was evident at life table analysis at 12 months after surgery. No statistically significant differences were detectable, however, at 24 and 36 months, although a trend toward lower recurrence rates with postoperative estroprogestin therapy was still present at 24 and 36 months. In a study by Vercellini et al [8], 57 patients with endometriosis (78% with stage I or II) were randomized to a 6-month course of either cyclic estroprogestin (ethinyl estradiol, 0.020 mg, and desogestrel, 0.150 mg) or GnRHa after diagnostic laparoscopy, with no attempt at surgical treatment. A significant improvement in pain was demonstrated in both groups at the end of treatment. In particular, nonmenstrual pain diminished with no differences between the 2 groups, deep dyspareunia was significantly reduced in both groups, with GnRH-a therapy superior to estroprogestin therapy, and dysmenorrhea diminished significantly in the estroprogestin group; no between-group comparison was possible because patients in the GnRH-a group developed amenorrhea. Symptoms recurred, however, in most patients 6 months after drug withdrawal, without differences in pain severity between the 2 groups, demonstrating that pain relief with both treatments was limited in time. In a subsequent study by Vercellini et al [15], 90 women with moderate to severe pain recurrence after conservative surgery to treat symptomatic endometriosis were randomized to receive either oral cyproterone acetate or combined estroprogestins administered continuously for 6 months. At 6 months, pain was significantly reduced in both groups, with no major between-group difference. In another study by Vercellini et al [16], a CON regimen of estroprogestin was administered in 50 women who experienced recurrent pain after conservative surgery despite
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postoperative CYC estroprogestin use. After switching from CYC to CON estroprogestin therapy, the VAS score for dysmenorrhea decreased from 7.5 to 3.1, and moderate or severe adverse effects were reported by 14% of the women. Eighty percent of the women were either satisfied or very satisfied with the CON estroprogestin regimen. In a recent nonrandomized cohort study by Vercellini et al [17], 277 patients with stage III or IV endometriosis were offered cyclic estroprogestin therapy after laparoscopic excision of ovarian endometriomas. After a shared decisionmaking process, 102 patients used estroprogestin for the entire follow-up period (‘‘always users’’), 129 used estroprogestin discontinuously (‘‘ever users’’), and 46 did not use estroprogestin (‘‘never users’’). After a median follow-up of 28 months, the recurrence rates were 9% (9 of 102) in the always users and 56% (26 of 48) in the never users (p ,.001). Regular postoperative use of estroprogestin was, therefore, demonstrated to significantly reduce endometrioma recurrence. In a recent randomized study by Seracchioli et al [18], 239 patients underwent laparoscopic excision of ovarian endometriomas and were subsequently randomized into 3 management arms: expectant management, CON regimen of estroprogestin, or CYC regimen of estroprogestin, both administered for 24 months. The rate of endometrioma recurrence (defined as the presence of an ovarian cyst larger than 1.5 cm at ultrasonography with features typical of an endometrioma) at 24 months was higher in the expectant management arm (29%) compared with the CON (8%) or CYC (15%) estroprogestin groups. No information was given in this trial as to recurrence of associated pain. Evidence in the literature from randomized controlled trials shows, therefore, that postoperative medical treatment can prevent recurrence of endometriosis, at best, only during the treatment period of medium-term follow-up. GnRHa can be administered for a maximum of 6 months; longer treatment is associated with high cost and significant adverse effects that largely outweigh the possible advantage of further delay in recurrence. Add-back therapy permits longer courses of therapy. In contrast, estroprogestin can be administered for longer periods; however, although probably widely used, long-term postoperative estroprogestin therapy has, to our knowledge, been tested in only a single randomized clinical trial [18]. Usually, the decision as to which estroprogestin treatment (CON or CYC) should be administered is made after surgery, in an attempt to reduce or delay recurrence [9]. Although guidelines for the treatment of endometriosis suggest either regimen, in particular for associated pain (2,10,11), a single clinical trial [18] has compared the 2 options in a randomized study; however, pain recurrence was not evaluated as an outcome. A follow-up study of the same groups of patients, conducted during the 24 months of treatment, is under way. In the present randomized study, continuous and cyclic administration of estroprogestin administered for 6 months after operative laparoscopy because of ovarian endometriomas
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associated with moderate to severe pain was equally effective in preventing recurrence of endometriomas or pain, although adverse effects were significantly worse with the CON regimen. After a mean follow-up of 22 months, 17% of patients in the CON group experienced recurrence of pain, compared with 32% in the CYC group. The CON regimen, although associated with a nonsignificant trend compared with better outcomes in reduction of recurrences, was associated with adverse effects, breakthrough bleeding in particular, that eventually led to discontinuation of treatment in a substantial number of patients (41% in the CON group compared with 14% in the CYC group). It can be hypothesized that, balancing the higher discontinuation rate of continuous treatment because of adverse effects with the lower but nonsignificant recurrence rate, the CON and CYC regimens result in comparable patient satisfaction. Satisfaction rates were high in both treatment arms, probably because of the significant improvement in pain score due to the combined surgical-medical treatment of endometriomas. Further randomized studies, with larger sample sizes, are needed to better assess the role of postoperative cyclic compared with continuous estroprogestin administration in the management of endometriosis. A limitation of the present study is the limited sample size, particularly in the case of a negative study. The present study may be underpowered, in particular for the outcome of endometrioma recurrence, which was only 2%. Longer courses of estroprogestin treatment, both continuous and cyclic, with follow-up extending beyond the treatment period, should be tested to investigate whether a longer treatment period would prolong delay in disease recurrence observed in previous studies. Newer lower dose estroprogestin administered continuously should be used in randomized clinical trials to assess whether lower doses may be associated with lower discontinuation rates, although preserving the lower recurrence rates observed with continuous use of estroprogestin. In addition, an objective evaluation of endometriosis recurrence with second-look laparoscopy would be desirable. In the present study, as in most studies of treatment of endometriosis, only sonographic evidence of endometriomas or recurrence of pain were considered suggestive of endometriosis recurrence.
Conclusion In the present randomized study, continuous and cyclic administration of estroprogestin therapy for 6 months after operative laparoscopy to treat ovarian endometriomas associated with moderate to severe pain were equally effective in prevention of recurrence of pain or endometriomas. The continuous regimen, however, was associated with a significantly higher rate of adverse effects (breakthrough bleeding in particular), leading to discontinuation of treatment in approximately 40% of patients.
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