Buserelin acetate in the treatment of pelvic pain associated with minimal and mild endometriosis: a controlled study*

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1 .. FERTILITY AND STERILITY Copyright 99 The American Fertility Society Vol. 59, No., March 99 Printed on acid-free paper in U.S.A. Buserelin acetate in the treatment of pelvic pain associated with minimal and mild endometriosis: a controlled study* Luigi Fedele, M.D. t Stefano Bianchi, M.D. Luca Bocciolone, M.D. Giuliana Di Nola, M.D. Dorella Franchi, M.D. Istituto Ostetrico-Ginecologico "L. Mangiagalli," Universitri Milano, Italy Objective: To evaluate the changes of pain symptoms induced by buserelin acetate, a gonadotropin-releasing hormone agonist, in a group of patients with endometriosis. Design: Thirty-five infertile patients with one or more of the following symptoms (dysmenorrhea, pelvic pain, deep dyspareunia, and endometriosis stage I or II) were allocated randomly to treatment with buserelin acetate, tlg/d IN for 6 months (n = 9) or expectant management (n = 6). Pain symptoms were recorded by the women themselves using a questionnaire that included two s for pain evaluation: one analogue and one multidimensional. The treated and untreated patients were followed for a minimum of 8 and months from the time of randomization, respectively. Results: Buserelin acetate markedly reduced dysmenorrhea, pelvic pain, and dyspareunia during the treatment and also for the subsequent months. During follow-up of the expectant management group, dysmenorrhea resolved in 9% (/6) of the cases, and pelvic pain did not recur after diagnostic laparoscopy in one of the three women affected nor did deep dyspareunia in two of the five who reported the symptom before laparoscopy. Conclusion: Buserelin acetate induced a significant improvement of pain symptoms that persisted in approximately half of the patients even after withdrawal of the drug. However, symptoms associated with endometriosis showed a spontaneous remission in approximately one fifth of the untreated patients. Fertil Steril 99;59:56- Key Words: Endometriosis, pelvic pain, buserelin acetate Endometriosis is frequently associated with pain symptoms that may constitute the patient's only or main disturbance also in initial stages of the disease, In the minimal and mild stages of the revised American Fertility Society (AFS) classification () dysmenorrhea is reported in approximately 7% of the patients and intermenstrual pelvic pain and deep dyspareunia in approximately 5% (). Medical treatment has been widely used for minimal and mild endometriosis in the last decade, first with danazol, Received March 6, 99; revised and accepted November 7, 99. * Project "Studio territoriale multicentrico della malattia endometriosica" supported by Ministero della Sanita, Rome, Italy. t Reprint requests: Luigi Fedele, M.D., Istituto Ostetrico Ginecologico "L. Mangiagalli," Universita di Milano, via Commenda, Milano, Italy. then with gestrinone, and last with gonadotropinreleasing hormone agonists (GnRH-a). Numerous studies have demonstrated the efficacy of these drugs in inducing pain resolution during their administration, associated with more or less important side effects according to the agent used (for review see Metzger and Luciano []). Whether pain relief persists after the end of treatment is still uncertain. Initial observations revealed a recurrence of symptoms in a large proportion of patients (4, 5). However, the exact frequency and characteristics of symptoms recurrence are unknown, as is the evolution of pain symptoms in untreated patients. The aim of the present study was to analyze the presence and severity of pain symptoms during and after therapy with buserelin acetate, a GnRH -a, in a group of infertile patients with minimal or mild endometriosis compared with an untreated group. 56 Fedele et al. Buserelin acetate for endometriosis Fertility and Sterility

4 Patients MATERIALS AND METHODS The present series consisted of all women with one or more of the following symptoms (dysmenorrhea, pelvic pain, and deep dyspareunia) enrolled at our institute in a

2 4 Patients MATERIALS AND METHODS The present series consisted of all women with one or more of the following symptoms (dysmenorrhea, pelvic pain, and deep dyspareunia) enrolled at our institute in a multicenter randomized study that compared the efficacy of buserelin acetate with that of expectant management in the treatment of infertility associated with endometriosis stage I or II of the revised AFS classification (6). Nineteen patients were allocated to treatment with buserelin acetate, ~g/d IN for 6 months and 6 to expectant management. No therapeutic maneuver was performed at the time of the diagnostic laparoscopy, which was always combined with a dilatation and curettage (D and C). Before laparoscopy all the women completed a questionnaire on the presence and severity of dysmenorrhea and pelvic pain and the presence of deep dyspareunia (Table ). The severity of dysmenorrhea and pelvic pain was evaluated according to two s. One was multidimensional and considered any limitation of daily activities, the coexistence of systemic symptoms, and the necessity of analgesics. Scores of to, 4 to 5, and 6 to 7 defined, respectively, mild, moderate, and severe pain. In the other, a linear one, pain severity was scored from to, with indicating the absence of pain and scores of to 4, 5 to 7, and 8 to as mild, moderate, and severe pain, respectively. The same questionnaire was compiled every month for 8 months in the treated patients and months in those untreated unless pregnancy occurred or the patients were switched to another treatment. The questionnaires were evaluated every 4 months at follow-up visits. Data Analysis We calculated the cumulative proportion of women with recurrence of dysmenorrhea according to treatment allocation using the actuarial method, and the curves were compared by the log-rank test (7). The actuarial method allows comparison of women with different lengths of follow-up. Thus, the women who became pregnant during follow-up were not excluded from the data analysis. The event data used in computing the probability of presence of dysmenorrhea were, respectively, the end of GnRH-a treatment in the buserelin acetate group and the date of randomization for the expectant management group, and the date of recurrence of the pain symptom. RESULTS No significant differences were observed between the two groups in the patient's characteristics. All the patients allocated to the buserelin acetate group completed the 6 months of treatment. Amenorrhea occurred in all cases starting from the nd month. Seventeen women (89%) reported hot flushes, 6 (%) vaginal dryness, and 4 (%) spotting after months. During the treatment no patient had dysmenorrhea, all five with pelvic pain at admission reported complete resolution of the symptom, and of the three with deep dyspareunia initially, two had complete and one partial remission. Figure shows the pattern of dysmenorrhea during follow-up in the two groups. After months of follow-up, the actuarial dysmenorrhea recurrence rate in the active treatment group was significantly lower than that of the untreated patients (7% versus 8 %, P <.). This difference was maintained during the subsequent follow-up. Dysmenorrhea recurred in eight of the buserelin acetate-treated patients: in 6% (5/8) within months of treatment suspension and in the other 7% (/8) within 6 months. Modification of severity of dysmenorrhea in the individual subjects is reported in Tables and. A spontaneous, complete, and persistent resolution of dysmenorrhea was observed also in 9% of the patients given expectant management, and 9% reported a partial remission of the symptom. Except in one case the improvement started at the first menstruation after laparoscopy and D and C. The resolution of pelvic pain observed in five women of the buserelin acetate group during treatment persisted during the follow-up. In the control group, pelvic pain resolved spontaneously in one patient and persisted in two. At the end of follow-up, deep dyspareunia had not recurred in two of the affected women in the buserelin acetate group, but in the third the symptom returned to pretreatment levels. In two untreated patients with deep dyspareunia the symptom disappeared after laparoscopy. and D and C, whereas it remained unchanged in the other three. However, in the untreated patients with spontaneous resolution of deep dyspareunia this symptom was described as intermittent at study entry. DISCUSSION In our study buserelin acetate markedly reduced pain symptoms associated with endometriosis during the treatment and also for the following months. Vol. 59, No., March 99 Fedele et al. Buserelin acetate for endometriosis 57

3 I:..,liZSA." Table Pain Questionannaire Response Score Date of compilation: Date of last menstruation: A. Was your last menstrual period painful? If yes, which of the following applied?. You did not need analgesics. You took analgesics for <4 hours and pain improved. You had to take analgesics for >4 hours to improve pain 4. The analgesics taken were not efficacious 5. In addition to low abdominal pain you also had nausea, vomiting, headache, diarrhea, general malaise 6. You could carry out your normal daily activities as usual, including work 7. You found it difficult to fulfill your work and domestic commitments but succeeded in doing so nonetheless 8. You had to limit your work and domestic activities to essential tasks and eliminate the most arduous ones 9. You could not go to work and spent at least part of the day in bed Total I I Yes/no The line above represents the continuum of the opinion of the degree of pain. The left extremity of the line represents "no pain at all" and the right one "unbearable pain." Please rate the degree of your menstrual pain by making a mark on the line.* B. Have you had low, midline, or lateral abdominal ~qin other than during menstruation? Yes/no. You did not need analgesics. You took analgesics for <4 hours and pain improved. You had to take analgesics for >4 hours to improve pain 4. The analgesics taken were not efficacious 5. In addition to low abdominal pain you also had nausea, vomiting, headache, diarrhea, general malaise 6. You could carry out your normal daily activities as usual, including work 7. You found it difficult to fulfill your work and domestic commitments but succeeded in doing so nonetheless 8. You had to limit your work and domestic activities to essential tasks and eliminate the most arduous ones 9. You could not go to work and spent at least part of the day in bed I I The line above represents the continuum of the opinion of the degree of pain. The left extremity of the line represents "no pain at all" and the right one "unbearable pain." Please rate the degree of your menstrual pain by making a mark on the line. c. Have you had painful intercourses (not considering the pain at vaginal introitus)? Yes No * The length of the line is equal to cm. Scale values were obtained by measuring the distance from to the patient mark. However, conclusions can be drawn only for dysmenorrhea and not for pelvic pain and deep dyspareunia because the number of patients with the latter two symptoms was small. It must be underlined that we considered a group of patients whose main symptom was not pain but infertility. The use of this inclusion criterion, however, allowed us to recruit a homogeneous series and to design a study with a group of untreated controls. In our opinion, it would not have been ethical to propose expectant management for patients specifically requiring treatment for pain symptoms. Another characteristic of our study was that only patients with minimal or mild endometriosis were admitted, and, in fact, medical treatment is most indicated for these initial forms. Our patients themselves completed the questionnaire on pain symptoms. Because they are difficult to quantify, we used two different s to evaluate pain severity: a multidimensional one that gives greater emphasis to the social impact of pain symptoms and an analogue that expresses the subjective aspect of pain. Important differences were not observed between the two, thus demonstrating their consistency. Furthermore, the analogue has previously been described to have good reproducibility in pain measurement (8). Only deep dyspareunia was considered in this study; its severity 58 Fedele et al. Buserelin acetate for endometriosis Fertility and Sterility

4 ~i aa ~ :is 6 II 5 ~ at 4 8 months Figure Overall -month percent probability presence of dysmenorrhea in the buserelin acetate-treated patients (bottom) and in the expectant management group (top), respectively. was not evaluated because reporting of this symptom is too subjective and we do not know a reliable system to evaluate it. Our results pose two important questions. First, why is buserelin acetate treatment effective even after its suspension, although various studies have demonstrated that endometriotic lesions persist after the end of treatment (9-)? Second, why did a spontaneous remission of dysmenorrhea, partial or complete, occur after diagnostic laparoscopy in almost half of the women who did not receive any treatment? The persistent symptomatologic relief induced by buserelin acetate could be explained by the fact that atrophy of the ectopic endometrium induced by prolonged hypoestrogenism may change the architecture of endometriotic lesions and modify their relations with nerve fibers and surrounding vessels. The spontaneous resolution of dysmenorrhea in some of our untreated patients occurred immediately after laparoscopy, which suggests that this procedure, and especially the concomitant D and C, may have played a determinant role. The same mechanism might be responsible also for the remission of dysmenorrhea observed in some of the buserelin acetate group. In one of the untreated women, dysmenorrhea resolved spontaneously months after the diagnostic laparoscopy: in this case we can hypothesize a spontaneous regression of endometriosis lesions, a phenomenon already described by Thomas and Cooke (). A placebo effect has been reported to improve dysmenorrhea in ~% of patients treated; however, this improvement does not last for longer than months (). A placebo effect may have occurred in our treated patients, but this does not explain why pain relief persisted for over months after suspension of the therapy. Gonadotropin-releasing hormone agonists are considered very effective in the treatment of endometriosis-associated pelvic pain during the period they are administered, but it is not clear whether their therapeutic effect persists after the end of treatment. The authors of the first reports (9, 4-6) reported significantly different rates of recurrence (% to 75%) of pain symptoms after treatment suspension. A large multicenter study comparing the efficacy of nafarelin 8 and 4 ILg/d with that of danazol 8 mg/d reported that pain symptoms disappeared or persisted in mild form in most patients (7% versus 77% of those who had taken nafarelin 4 and 8 ILg/d, respectively) 6 months after the end of the treatment. Only % to % of the women reported severe pain symptoms (7). We compared treatment with buserelin acetate, ILg/d and danazol 6 mg/d. One year after completing the therapy, there was a recurrence of menstrual pain in 47% of the series; 7% of the pa- Table Modifications of Severity of Dysmenorrhea Evaluated According to Linear and Multidimensional Scales Months After the End of Buserelin Acetate Treatment Dysmenorrhea pretreatment Mild Moderate Severe Linear Multidimensional Linear Multidimensional Linear Multidimensional Dysmenorrhea at -month follow-up* Absent Mild Moderate Severe * When pregnancy occurred, it was considered the pattern of dysmenorrhea at last menstruation. Vol. 59, No., March 99 Fedele et al. Buserelin acetate for endometriosis 59

5 .. Table Modifications of Severity of Dysmenorrhea Evaluated According to Linear and Multidimensional Scales Months After Randomization in the Untreated Patients Dysmenorrhea pretreatment Mild Moderate Severe Linear Multidimensional Linear Multidimensional Linear Multidimensional Dysmenorrhea at -month follow-up' Absent Mild 4 9 Moderate 4 Severe When pregnancy occurred, it was considered the pattern of dysmenorrhea at last menstruation. tients reported a return of pelvic pain and deep dyspareunia (5). Franssen et al. (8) observed that 6 months after the end of treatment with buserelin acetate 9 Mg/d, 7 of the 9 women with dysmenorrhea at admission reported an improvement, whereas the symptom was unchanged in and worsened in two; in another woman it appeared ex novo. During the follow-up, pelvic pain became gradually more severe, reaching almost pretreatment levels after 4 months. In the study of Kennedy et al. (9) comparing nafarelin 4 Mg/d and danazol 6 mg/d, pain symptoms were improved in 64% of the patients who had taken nafarelin, returned to pretreatment levels in 6%, and worsened in % at 6 months offollowup. Venturini et al. () treated women with endometriosis with goserelin depot for 6 months, and in the 6 months after therapy suspension they observed a recurrence of dysmenorrhea in 5% of the patients, of deep dyspareunia in 7.5%, and of pelvic pain in.%. In a recent randomized double-blind study of the efficacy of leuprolide acetate depot versus placebo in the therapy of pelvic pain associated with endometriosis, Dlugi et al. () reported that 57% of the patients had a recurrence of dysmenorrhea at 6 months of follow-up, whereas one third continued to be free ofthe symptom at year. There was a recurrence of moderate or severe pelvic pain at pretreatment levels in 54 % of the affected patients within months of completing treatment. Regarding dyspareunia, 75% of the patients reported persistent relief after year. Definitive considerations cannot be based on an analysis of the numerous data reported in the literature because of differences in the characteristics of the patients recruited, disease stages, assessment of pain symptoms, and length of follow-up. Fur- thermore, only one study included a control group of patients not given an active treatment (). This was the only series in which the pain symptom was evaluated adequately, but the patient inclusion criteria and disease stages differed considerably from those in the present study. In conclusion, in infertile patients with minimal or mild endometriosis, buserelin acetate induces a remission of pain symptoms that persists after treatment suspension. This phenomenon is not easy to interpret; it is probable that the prolonged hypoestrogenism induced by GnRH-a has a persistent effect on the pathogenetic mechanisms underlying the pain symptoms, whether or not these are related to endometriosis. Acknowledgment. The authors thank Fabio Parazzini, M.D., Istituto di Ricerche Farmacologiche "M. Negri," Milano, Italy, for data management. REFERENCES. The American Fertility Society. Revised American Fertility Society classification of endometriosis: 985. Fertil Steril 985;4:5-.. Fedele L, Parazzini F, Bianchi S, Arcaini L, Candiani GB. Stage and localization of pelvic endometriosis and pain. Fertil Steril 99;5: Metzger DA, Luciano AA. Hormonal therapy of endometriosis. Obstet Gynecol Clin North Am 989;6: Fedele L, Bianchi S, Viezzoli T, Arcaini L, Candiani GB. Gestrinone versus danazol in the treatment of endometriosis. Fertil Steril989;5: Fedele L, Bianchi S, Arcaini L, Vercellini P, Candiani GB. Buserelin versus danazol in the treatment of endometriosis associated infertility. Am J Obstet Gynecol 989;6: Fedele L, Parazzini F, Radici E, Bocciolone L, Bianchi S, Bianchi C, et al. Buserelin acetate versus expectant management in the treatment of infertility associated with minimal or mild endometriosis: a randomized trial. Am J Obstet GynecoI99;66: Fedele et a. Buserelin acetate for endometriosis Fertility and Sterility

6 7. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 977;5: Revill SI, Robinson JO, Rosen M, Hogg MIJ. The reliability of a linear analogue for evaluating pain. Anesthesia 976;: Schriock E, Monroe SE, Henzl M, Jaffe RB. Treatment of endometriosis with a potent agonist of gonadotropin-releasing hormone (nafarelin). Fertil Steril 985;44: Steingold HA, Cedars M, Lu JKH, Randle D, Judd HL, Meldrum DR. Treatment of endometriosis with a long acting gonadotropin-releasing hormone agonist. Obstet Gynecol 987;69:4-.. Nisolle-Pochet M, Casanas-Roux F, Donnez J. Histologic study of ovarian endometriosis after hormonal therapy. Fertil Steril 988;49:4-6.. Thomas EJ, Cooke ID. Impact of gestrinone on the course of asymptomatic endometriosis. Br Med J 987;94:7-4.. Fedele L, Marchini M, Acaia B, Garagiola U, Tiengo M. Dynamics and significance of placebo response in primary dysmenorrhea. Pain 99;6: Meldrum DR, Chang RJ, Lu J, Vale W, Rivier J, Judd HL. Medical oophorectomy using a long-acting GnRH agonist: a possible new approach to the treatment of endometriosis. J Clin Endocrinol Metab 98;54: Lemay A, Maheux R, Faure N, Jean C, Fazekas ATA. Reversible hypogonadism induced by luteinizing hormone-re- leasing hormone (LH -RH) agonist (buserelin) as a new therapeutic approach for endometriosis. Fertil Steril984;4: Lemay A, Maheux R, Hout C, Blanchet J, Faure N. Efficacy of intranasal or subcutaneous luteinizing hormone-releasing hormone agonist inhibition of ovarian function in the treatment of endometriosis. Am J Obstet Gynecol 988;58: Henzl MR, Corson SL, Moghissi K, Buttram VC, Berquist C, Jacobson J. Administration of nasal nafarelin as compared with oral danazol for endometriosis. N Engl J Med 988;8: Franssen AMHW, Kauer FM, Chadha DR, Zijlstra la, Rolland R. Endometriosis: treatment with gonadotropin-releasing hormone buserelin. Fertil Steril989;5: Kennedy SH, Williams la, Brodribb J, Barlow DH, Shaw RW. A comparison of nafarelin acetate and danazol in the treatment of endometriosis. Fertil Steril99;5: Venturini PL, Fasce V, Costantini S, Anserini P, Cucuccio S, De Cecco L. Treatment of endometriosis with goserelin depot, a long-acting gonadotropin-releasing hormone agonist analog: endocrine and clinical results. Fertil Steril 99;54: -7.. Dlugi AM, Miller JD, Knittle J, Lupron Study Group. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Fertil Steril 99;54:49-7. Vol. 59, No., March 99 Fedele et ai. Buserelin acetate for endometriosis 5

Key Words: Endometriosis, GnRH-a, goserelin, Zoladex, estrogen, sex-steroid add-back therapy,

Key Words: Endometriosis, GnRH-a, goserelin, Zoladex, estrogen, sex-steroid add-back therapy, FERTLTY AND STERLTY Copyright 1995 American Society for Reproductive Medicine Vol. 64, No. 5, November 1995 Printed on acid free paper in U. S. A. Comparison of the gonadotropin-releasing hormone agonist