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A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study
FERTILITY AND STERILITY威 VOL. 72, NO. 3, SEPTEMBER 1999 Copyright ©1999 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
REPRODUCTIVE ENDOCRINOLOGY
A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study Paolo Vercellini, M.D., Giorgio Aimi, M.D., Stefania Panazza, M.D., Olga De Giorgi, M.D., Antonella Pesole, M.D., and Pier Giorgio Crosignani, M.D. Clinica Ostetrica e Ginecologica “Luigi Mangiagalli,” University of Milano, Milano, Italy
Received October 21, 1998; revised and accepted April 20, 1999. Presented at the 16th World Congress on Fertility and Sterility and the 54th Annual Meeting of the American Society for Reproductive Medicine, San Francisco, California, October 4 –9, 1998. Reprint requests: Paolo Vercellini, M.D., Clinica Ostetrica e Ginecologica “Luigi Mangiagalli,” Universita` di Milano, Via Commenda, 12, 20122 Milano, Italy (FAX: 390255187146; E-mail: [email protected]). 0015-0282/99/$20.00 PII S0015-0282(99)00291-5
Objective: To evaluate the efficacy and safety of an intrauterine system releasing 20 g of levonorgestrel per 24 hours in the long-term treatment of recurrent dysmenorrhea in women already operated on conservatively for endometriosis. Design: A prospective noncomparative pilot study. Setting: A tertiary care and referral academic center for patients with endometriosis. Patient(s): Twenty parous women with recurrent moderate or severe dysmenorrhea after conservative surgery for endometriosis who did not want further children. Intervention(s): A levonorgestrel-releasing intrauterine system was inserted in each woman within 7 days of the start of a menstrual cycle. Main Outcome Measure(s): Variations in severity of dysmenorrhea during treatment according to a 100-mm visual analogue scale and a 0 –3-point verbal rating scale, modification of a pictorial blood-loss assessment chart devised to evaluate the amount of menstrual flow, and degree of satisfaction after 12 months of therapy. Result(s): One woman was lost to follow-up after achieving amenorrhea and expressing satisfaction, and 1 requested system removal because of weight gain and abdominal bloating. In another subject, the levonorgestrel intrauterine system was expelled 3 months after insertion. The menstrual patterns in the remaining 17 women were characterized by amenorrhea in 4 cases, hypomenorrhea or spotting in 8, and normal flow in 5. Baseline and 12-month follow-up mean ⫾ SD blood loss scores were 111 ⫾ 36 and 27 ⫾ 26, respectively. At the same time, mean ⫾ SD visual analogue and verbal rating scale scores dropped, respectively, from 76 ⫾ 12 to 34 ⫾ 23 points and from 2.5 ⫾ 0.5 to 1.2 ⫾ 0.5 points. Four women were very satisfied with treatment, 11 were satisfied, 2 were uncertain, and 3 were dissatisfied at 12-month follow-up. Conclusion(s): Because of the amenorrhea or hypomenorrhea induced in most women, a levonorgestrel intrauterine system greatly reduced menstrual pain associated with endometriosis and achieved a high degree of patient satisfaction. (Fertil Steril威 1999;72:505– 8. ©1999 by American Society for Reproductive Medicine.) Key Words: Endometriosis, pelvic pain, dysmenorrhea, progestins, intrauterine devices
Dysmenorrhea is by far the most frequent symptom reported by women with endometriosis (1). Surgical ablation of lesions is usually effective, but postoperative pain relapse is not rare. Several successful medical therapies have been adopted that have induced symptomatic relief in patients with endometriosis, including danazol and GnRH agonists. Pain at menstruation is obviously abolished during treatment because secondary amenorrhea is achieved from anovulation and hypoestrogenism. However, because no drug used in endometriosis is
cytoreductive, dysmenorrhea frequently recurs as a result of metabolic reactivation of ectopic endometrial implants at resumption of ovulation. Unfortunately, the above hormones cause considerable side effects, are costly, and generally should be withdrawn after a few months. Consequently, the identification of safe alternatives to prolong treatment constitutes a key point in current clinical research on symptomatic endometriosis. In this regard, progestins are gradually regaining a place in the therapeu505
tic armamentarium because they cause limited untoward effects and are inexpensive (2). However, subjective tolerance to progestins is not consistent, and the possibility of aiming their therapeutic action at specific organs and thus reducing the general metabolic impact would be interesting. An intrauterine system that releases levonorgestrel, a potent 19-nortestosterone derivative progestin, could achieve amenorrhea with a different modality than standard regimens and could relieve menstrual pain. In fact, locally administered levonorgestrel has a profound effect on the endometrium, which becomes atrophic and inactive, although ovulation is usually not suppressed (3). We designed a pilot study to evaluate the tolerability and efficacy of a levonorgestrel intrauterine system in the long-term treatment of recurrent dysmenorrhea associated with endometriosis because no data are available on the potential therapeutic use of this medicated device.
disease, unwillingness to tolerate menstrual changes, and wish to conceive. After completion of the pretrial screening, a medicated device that releases levonorgestrel at 20 g/d over a period of 5 years (Mirena; Leiras Oy, Turku, Finland) was inserted into the uterine cavity within 7 days of the start of a menstrual cycle. The women underwent bimonthly follow-up visits, at which time a gynecologic examination was performed, the pattern of uterine bleeding was recorded, the pictorial blood-loss assessment chart scores were reviewed, and variations in menstrual pain intensity were recorded. At the final 12-month evaluation, the patients were requested to rate their overall degree of satisfaction with their treatment (very satisfied, satisfied, uncertain, dissatisfied). Visual analogue, verbal rating, and pictorial blood-loss scores at baseline and at the end of follow-up were compared with the Wilcoxon signed-rank test.
RESULTS
MATERIALS AND METHODS This prospective, noncomparative pilot study was conducted in a tertiary care and referral academic center for patients with endometriosis to evaluate variations in dysmenorrhea intensity and patients’ satisfaction after 1 year of therapy with a medicated intrauterine device (IUD). Institutional review board approval was obtained, and the women gave their informed consent to the study. We considered for enrollment parous patients of ⱕ40 years who were operated on conservatively for endometriosis in the previous 12 months, who did not want to undergo further surgery, and who were evaluated in our outpatient clinic for recurrent moderate to severe dysmenorrhea. Symptom intensity was assessed by use of a 100-mm visual analogue scale, the left extreme of which indicates absence of pain and the right one unbearable pain, and a 0 –3-point verbal rating scale, which grades menstrual pain according to loss of work efficiency and need for bed rest. A score of 51– 80 and 81–100 on the visual analogue scale and of 2 and 3 on the verbal rating scale, respectively, defined moderate and severe symptoms. The women were also requested to compile for two consecutive cycles the pictorial blood-loss assessment chart devised by Higham et al. (4) to evaluate menstrual flow. This monthly score has been demonstrated to correlate directly with uterine blood loss as measured by the alkaline hematin method. Details of these instruments have been described (1, 3). Subjects were eligible if they had at least moderate pain on both scales and a normal uterus and adnexa at clinical examination and transvaginal ultrasonography. Exclusion criteria were treatment for endometriosis other than nonsteroidal antiinflammatory drugs up to 3 months before study entry (6 months for GnRH agonists), the usual contraindications to progestins, history of pelvic inflammatory 506
Vercellini et al.
A total of 20 parous women, with a mean ⫾ SD age of 34 ⫾ 4 years, were recruited. Insertion of the medicated IUD was uneventful. Two women withdrew from the study (1 requested IUD removal because of weight gain and abdominal bloating; another woman expelled the medicated IUD 3 months after insertion) and 1 was lost to follow-up after she became amenorrheic and was satisfied with the treatment but before the 12-month evaluation. These subjects were included as failures in the assessment of satisfaction with treatment but were excluded from the pain and blood-loss score analyses because complete diaries were not available. The menstrual patterns in the remaining 17 women after 12 months of treatment were characterized by amenorrhea in 4 (24%), hypomenorrhea or spotting in 8 (47%), and normal flow in 5 (29%). Baseline and 12-month follow-up mean ⫾ SD pictorial blood-loss assessment chart scores were 111 ⫾ 36 and 27 ⫾ 26, respectively (mean of paired differences, 84 points; 95% confidence interval [CI], 66 –102; P⬍.0001; Fig. 1). At the same time points, mean ⫾ SD visual analogue and verbal rating scale scores dropped, respectively, from 76 ⫾ 12 to 34 ⫾ 23 points (mean of paired differences, 42 points; 95% CI, 30 –55; P⬍.0001; Fig. 1) and from 2.5 ⫾ 0.5 to 1.2 ⫾ 0.5 points (mean of paired differences, 1.3 points; 95% CI, 0.9 –1.8; P⬍.0001). The discomfort felt during irregular uterine bleeding episodes was reported as “dysmenorrhea.” Analyzing menstrual pain at 12 months on the two scales in dichotomous fashion (absent and mild versus moderate and severe), only 5 (29%) and 4 (24%) women were still considered symptomatic according to, respectively, the visual analogue and the verbal rating scales. One or more side effects were reported by 9 of the 20 patients (bloating in 7, weight gain in 5, headache in 4, breast
Levonorgestrel for dysmenorrhea in endometriosis
Vol. 72, No. 3, September 1999
endometriosis-associated dysmenorrhea, we decided first to conduct a small pilot study.
FIGURE 1 Baseline (open symbols) and 12-month follow-up (closed symbols) menstrual blood loss (A) and dysmenorrhea (B) scores in 17 women with endometriosis treated with a levonorgestrel-releasing intrauterine system according to, respectively, a pictorial chart devised by Higham et al. (4) and a 100-mm visual analogue scale. Horizontal bars are medians.
Vercellini. Levonorgestrel-releasing system. Fertil Steril 1999.
tension in 3, and pelvic pain and decreased libido in 1). Four women (20%) were very satisfied with treatment, 11 (55%) were satisfied, 2 (10%) were uncertain, and 3 (15%) were dissatisfied at 12-month follow-up. No statistically significant variations were observed in the lipid profiles throughout the study period (data not shown).
DISCUSSION In this pilot study, the application of a medicated IUD greatly reduced menstrual pain associated with endometriosis and offered a high degree of patient satisfaction. We consider that these results are mainly due to the amenorrhea or hypomenorrhea induced in most women by the local action of progestin, with a corresponding 76% mean reduction in pictorial blood-loss assessment chart scores. However, a general effect secondary to uterine absorption of levonorgestrel cannot be excluded, at least in some subjects, because most reported side effects are typical of progestins. We confirmed that women with endometriosis have a baseline mean menstrual score higher than normal according to the visual chart devised by Higham et al. (4, 5), and it is tempting to speculate that the reduction in monthly blood loss achieved with the levonorgestrel intrauterine system could be particularly advantageous in this patient population with heavy menstrual flows (5). The noncomparative study design and the limited sample size undoubtedly limit the strength of our findings. However, in view of the lack of data on the use of a medicated IUD for FERTILITY & STERILITY威
We studied patients with recurrent symptoms after previous conservative operations for endometriosis without performing a follow-up laparoscopy to determine the type and extension of the lesions present before inserting the medicated IUD, although we could confidently exclude the presence of ovarian cysts after transvaginal ultrasonography. Indeed, the women enrolled specifically requested an alternative to surgery. The available evidence supporting the efficacy of endometriosis ablation in reducing pelvic pain suggests that it may be incorrect to refrain from further surgery in the presence of a laparoscopic diagnosis with the sole aim of evaluating the effects of a medical therapy on untreated symptomatic disease. We assessed pain variation with two types of scales: a visual analogue scale that estimates the subjective perception of the symptom and a verbal rating scale that reflects also the objective consequences of dysmenorrhea. In addition, we decided to evaluate the degree of satisfaction with therapy because the traditional way of defining treatment benefits, only in terms of biomedical results, should probably be modified to include recognition of the patient’s point of view. This is particularly true when hormonal drugs are used and variations in pain scores or modification of endometriotic lesions are determined but without giving adequate weight to side effects, which may have a major impact on health-related quality of life. The medicated device was generally well tolerated, and only one subject required its removal because of side effects. The levonorgestrel intrauterine system may constitute an innovative, effective, safe, and convenient alternative for local delivery of a potent progestin in the long-term therapy of recurrent dysmenorrhea after conservative surgery for endometriosis. Further trials are needed, however, to verify whether the good results observed are maintained during the entire 5-year period of efficacy. Moreover, the levonorgestrel intrauterine system was studied in a selected population, namely, parous women who did not want to conceive, who had dysmenorrhea as the only or main symptom, and who were unwilling to undergo second-line surgery. The medicated device may not demonstrate the same analgesic activity or could be an inappropriate choice in a different clinical setting. Finally, comparative trials with other treatment options are needed to evaluate the effect on dyspareunia and nonmenstrual pelvic pain.
Acknowledgment: Some of the medicated devices used in this trial were kindly supplied by Pharmacia & Upjohn S.p.A., Milano, Italy.
507
References 1. Vercellini P, Trespidi L, De Giorgi O, Cortesi I, Parazzini F, Crosignani PG. Endometriosis and pelvic pain: relation to disease stage and localization. Fertil Steril 1996;65:299 –304. 2. Vercellini P, Cortesi I, Crosignani PG. Progestins for symptomatic endometriosis: a critical analysis of the evidence. Fertil Steril 1997;68:393– 401. 3. Crosignani PG, Vercellini P, Mosconi P, Oldani S, Cortesi I, De Giorgi O. A levonorgestrel-releasing intrauterine device versus hysteroscopic
508
Vercellini et al.
endometrial resection in the treatment of dysfunctional bleeding. Obstet Gynecol 1997;90:257– 63. 4. Higham JM, O’Brien PMS, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990;97: 734 –9. 5. Vercellini P, De Giorgi O, Aimi G, Panazza S, Uglietti A, Crosignani PG. Menstrual characteristics in women with and without endometriosis. Obstet Gynecol 1997;90:264 – 8.
Levonorgestrel for dysmenorrhea in endometriosis
Vol. 72, No. 3, September 1999
REPRODUCTIVE ENDOCRINOLOGY
A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study Paolo Vercellini, M.D., Giorgio Aimi, M.D., Stefania Panazza, M.D., Olga De Giorgi, M.D., Antonella Pesole, M.D., and Pier Giorgio Crosignani, M.D. Clinica Ostetrica e Ginecologica “Luigi Mangiagalli,” University of Milano, Milano, Italy
Received October 21, 1998; revised and accepted April 20, 1999. Presented at the 16th World Congress on Fertility and Sterility and the 54th Annual Meeting of the American Society for Reproductive Medicine, San Francisco, California, October 4 –9, 1998. Reprint requests: Paolo Vercellini, M.D., Clinica Ostetrica e Ginecologica “Luigi Mangiagalli,” Universita` di Milano, Via Commenda, 12, 20122 Milano, Italy (FAX: 390255187146; E-mail: [email protected]). 0015-0282/99/$20.00 PII S0015-0282(99)00291-5
Objective: To evaluate the efficacy and safety of an intrauterine system releasing 20 g of levonorgestrel per 24 hours in the long-term treatment of recurrent dysmenorrhea in women already operated on conservatively for endometriosis. Design: A prospective noncomparative pilot study. Setting: A tertiary care and referral academic center for patients with endometriosis. Patient(s): Twenty parous women with recurrent moderate or severe dysmenorrhea after conservative surgery for endometriosis who did not want further children. Intervention(s): A levonorgestrel-releasing intrauterine system was inserted in each woman within 7 days of the start of a menstrual cycle. Main Outcome Measure(s): Variations in severity of dysmenorrhea during treatment according to a 100-mm visual analogue scale and a 0 –3-point verbal rating scale, modification of a pictorial blood-loss assessment chart devised to evaluate the amount of menstrual flow, and degree of satisfaction after 12 months of therapy. Result(s): One woman was lost to follow-up after achieving amenorrhea and expressing satisfaction, and 1 requested system removal because of weight gain and abdominal bloating. In another subject, the levonorgestrel intrauterine system was expelled 3 months after insertion. The menstrual patterns in the remaining 17 women were characterized by amenorrhea in 4 cases, hypomenorrhea or spotting in 8, and normal flow in 5. Baseline and 12-month follow-up mean ⫾ SD blood loss scores were 111 ⫾ 36 and 27 ⫾ 26, respectively. At the same time, mean ⫾ SD visual analogue and verbal rating scale scores dropped, respectively, from 76 ⫾ 12 to 34 ⫾ 23 points and from 2.5 ⫾ 0.5 to 1.2 ⫾ 0.5 points. Four women were very satisfied with treatment, 11 were satisfied, 2 were uncertain, and 3 were dissatisfied at 12-month follow-up. Conclusion(s): Because of the amenorrhea or hypomenorrhea induced in most women, a levonorgestrel intrauterine system greatly reduced menstrual pain associated with endometriosis and achieved a high degree of patient satisfaction. (Fertil Steril威 1999;72:505– 8. ©1999 by American Society for Reproductive Medicine.) Key Words: Endometriosis, pelvic pain, dysmenorrhea, progestins, intrauterine devices
Dysmenorrhea is by far the most frequent symptom reported by women with endometriosis (1). Surgical ablation of lesions is usually effective, but postoperative pain relapse is not rare. Several successful medical therapies have been adopted that have induced symptomatic relief in patients with endometriosis, including danazol and GnRH agonists. Pain at menstruation is obviously abolished during treatment because secondary amenorrhea is achieved from anovulation and hypoestrogenism. However, because no drug used in endometriosis is
cytoreductive, dysmenorrhea frequently recurs as a result of metabolic reactivation of ectopic endometrial implants at resumption of ovulation. Unfortunately, the above hormones cause considerable side effects, are costly, and generally should be withdrawn after a few months. Consequently, the identification of safe alternatives to prolong treatment constitutes a key point in current clinical research on symptomatic endometriosis. In this regard, progestins are gradually regaining a place in the therapeu505
tic armamentarium because they cause limited untoward effects and are inexpensive (2). However, subjective tolerance to progestins is not consistent, and the possibility of aiming their therapeutic action at specific organs and thus reducing the general metabolic impact would be interesting. An intrauterine system that releases levonorgestrel, a potent 19-nortestosterone derivative progestin, could achieve amenorrhea with a different modality than standard regimens and could relieve menstrual pain. In fact, locally administered levonorgestrel has a profound effect on the endometrium, which becomes atrophic and inactive, although ovulation is usually not suppressed (3). We designed a pilot study to evaluate the tolerability and efficacy of a levonorgestrel intrauterine system in the long-term treatment of recurrent dysmenorrhea associated with endometriosis because no data are available on the potential therapeutic use of this medicated device.
disease, unwillingness to tolerate menstrual changes, and wish to conceive. After completion of the pretrial screening, a medicated device that releases levonorgestrel at 20 g/d over a period of 5 years (Mirena; Leiras Oy, Turku, Finland) was inserted into the uterine cavity within 7 days of the start of a menstrual cycle. The women underwent bimonthly follow-up visits, at which time a gynecologic examination was performed, the pattern of uterine bleeding was recorded, the pictorial blood-loss assessment chart scores were reviewed, and variations in menstrual pain intensity were recorded. At the final 12-month evaluation, the patients were requested to rate their overall degree of satisfaction with their treatment (very satisfied, satisfied, uncertain, dissatisfied). Visual analogue, verbal rating, and pictorial blood-loss scores at baseline and at the end of follow-up were compared with the Wilcoxon signed-rank test.
RESULTS
MATERIALS AND METHODS This prospective, noncomparative pilot study was conducted in a tertiary care and referral academic center for patients with endometriosis to evaluate variations in dysmenorrhea intensity and patients’ satisfaction after 1 year of therapy with a medicated intrauterine device (IUD). Institutional review board approval was obtained, and the women gave their informed consent to the study. We considered for enrollment parous patients of ⱕ40 years who were operated on conservatively for endometriosis in the previous 12 months, who did not want to undergo further surgery, and who were evaluated in our outpatient clinic for recurrent moderate to severe dysmenorrhea. Symptom intensity was assessed by use of a 100-mm visual analogue scale, the left extreme of which indicates absence of pain and the right one unbearable pain, and a 0 –3-point verbal rating scale, which grades menstrual pain according to loss of work efficiency and need for bed rest. A score of 51– 80 and 81–100 on the visual analogue scale and of 2 and 3 on the verbal rating scale, respectively, defined moderate and severe symptoms. The women were also requested to compile for two consecutive cycles the pictorial blood-loss assessment chart devised by Higham et al. (4) to evaluate menstrual flow. This monthly score has been demonstrated to correlate directly with uterine blood loss as measured by the alkaline hematin method. Details of these instruments have been described (1, 3). Subjects were eligible if they had at least moderate pain on both scales and a normal uterus and adnexa at clinical examination and transvaginal ultrasonography. Exclusion criteria were treatment for endometriosis other than nonsteroidal antiinflammatory drugs up to 3 months before study entry (6 months for GnRH agonists), the usual contraindications to progestins, history of pelvic inflammatory 506
Vercellini et al.
A total of 20 parous women, with a mean ⫾ SD age of 34 ⫾ 4 years, were recruited. Insertion of the medicated IUD was uneventful. Two women withdrew from the study (1 requested IUD removal because of weight gain and abdominal bloating; another woman expelled the medicated IUD 3 months after insertion) and 1 was lost to follow-up after she became amenorrheic and was satisfied with the treatment but before the 12-month evaluation. These subjects were included as failures in the assessment of satisfaction with treatment but were excluded from the pain and blood-loss score analyses because complete diaries were not available. The menstrual patterns in the remaining 17 women after 12 months of treatment were characterized by amenorrhea in 4 (24%), hypomenorrhea or spotting in 8 (47%), and normal flow in 5 (29%). Baseline and 12-month follow-up mean ⫾ SD pictorial blood-loss assessment chart scores were 111 ⫾ 36 and 27 ⫾ 26, respectively (mean of paired differences, 84 points; 95% confidence interval [CI], 66 –102; P⬍.0001; Fig. 1). At the same time points, mean ⫾ SD visual analogue and verbal rating scale scores dropped, respectively, from 76 ⫾ 12 to 34 ⫾ 23 points (mean of paired differences, 42 points; 95% CI, 30 –55; P⬍.0001; Fig. 1) and from 2.5 ⫾ 0.5 to 1.2 ⫾ 0.5 points (mean of paired differences, 1.3 points; 95% CI, 0.9 –1.8; P⬍.0001). The discomfort felt during irregular uterine bleeding episodes was reported as “dysmenorrhea.” Analyzing menstrual pain at 12 months on the two scales in dichotomous fashion (absent and mild versus moderate and severe), only 5 (29%) and 4 (24%) women were still considered symptomatic according to, respectively, the visual analogue and the verbal rating scales. One or more side effects were reported by 9 of the 20 patients (bloating in 7, weight gain in 5, headache in 4, breast
Levonorgestrel for dysmenorrhea in endometriosis
Vol. 72, No. 3, September 1999
endometriosis-associated dysmenorrhea, we decided first to conduct a small pilot study.
FIGURE 1 Baseline (open symbols) and 12-month follow-up (closed symbols) menstrual blood loss (A) and dysmenorrhea (B) scores in 17 women with endometriosis treated with a levonorgestrel-releasing intrauterine system according to, respectively, a pictorial chart devised by Higham et al. (4) and a 100-mm visual analogue scale. Horizontal bars are medians.
Vercellini. Levonorgestrel-releasing system. Fertil Steril 1999.
tension in 3, and pelvic pain and decreased libido in 1). Four women (20%) were very satisfied with treatment, 11 (55%) were satisfied, 2 (10%) were uncertain, and 3 (15%) were dissatisfied at 12-month follow-up. No statistically significant variations were observed in the lipid profiles throughout the study period (data not shown).
DISCUSSION In this pilot study, the application of a medicated IUD greatly reduced menstrual pain associated with endometriosis and offered a high degree of patient satisfaction. We consider that these results are mainly due to the amenorrhea or hypomenorrhea induced in most women by the local action of progestin, with a corresponding 76% mean reduction in pictorial blood-loss assessment chart scores. However, a general effect secondary to uterine absorption of levonorgestrel cannot be excluded, at least in some subjects, because most reported side effects are typical of progestins. We confirmed that women with endometriosis have a baseline mean menstrual score higher than normal according to the visual chart devised by Higham et al. (4, 5), and it is tempting to speculate that the reduction in monthly blood loss achieved with the levonorgestrel intrauterine system could be particularly advantageous in this patient population with heavy menstrual flows (5). The noncomparative study design and the limited sample size undoubtedly limit the strength of our findings. However, in view of the lack of data on the use of a medicated IUD for FERTILITY & STERILITY威
We studied patients with recurrent symptoms after previous conservative operations for endometriosis without performing a follow-up laparoscopy to determine the type and extension of the lesions present before inserting the medicated IUD, although we could confidently exclude the presence of ovarian cysts after transvaginal ultrasonography. Indeed, the women enrolled specifically requested an alternative to surgery. The available evidence supporting the efficacy of endometriosis ablation in reducing pelvic pain suggests that it may be incorrect to refrain from further surgery in the presence of a laparoscopic diagnosis with the sole aim of evaluating the effects of a medical therapy on untreated symptomatic disease. We assessed pain variation with two types of scales: a visual analogue scale that estimates the subjective perception of the symptom and a verbal rating scale that reflects also the objective consequences of dysmenorrhea. In addition, we decided to evaluate the degree of satisfaction with therapy because the traditional way of defining treatment benefits, only in terms of biomedical results, should probably be modified to include recognition of the patient’s point of view. This is particularly true when hormonal drugs are used and variations in pain scores or modification of endometriotic lesions are determined but without giving adequate weight to side effects, which may have a major impact on health-related quality of life. The medicated device was generally well tolerated, and only one subject required its removal because of side effects. The levonorgestrel intrauterine system may constitute an innovative, effective, safe, and convenient alternative for local delivery of a potent progestin in the long-term therapy of recurrent dysmenorrhea after conservative surgery for endometriosis. Further trials are needed, however, to verify whether the good results observed are maintained during the entire 5-year period of efficacy. Moreover, the levonorgestrel intrauterine system was studied in a selected population, namely, parous women who did not want to conceive, who had dysmenorrhea as the only or main symptom, and who were unwilling to undergo second-line surgery. The medicated device may not demonstrate the same analgesic activity or could be an inappropriate choice in a different clinical setting. Finally, comparative trials with other treatment options are needed to evaluate the effect on dyspareunia and nonmenstrual pelvic pain.
Acknowledgment: Some of the medicated devices used in this trial were kindly supplied by Pharmacia & Upjohn S.p.A., Milano, Italy.
507
References 1. Vercellini P, Trespidi L, De Giorgi O, Cortesi I, Parazzini F, Crosignani PG. Endometriosis and pelvic pain: relation to disease stage and localization. Fertil Steril 1996;65:299 –304. 2. Vercellini P, Cortesi I, Crosignani PG. Progestins for symptomatic endometriosis: a critical analysis of the evidence. Fertil Steril 1997;68:393– 401. 3. Crosignani PG, Vercellini P, Mosconi P, Oldani S, Cortesi I, De Giorgi O. A levonorgestrel-releasing intrauterine device versus hysteroscopic
508
Vercellini et al.
endometrial resection in the treatment of dysfunctional bleeding. Obstet Gynecol 1997;90:257– 63. 4. Higham JM, O’Brien PMS, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990;97: 734 –9. 5. Vercellini P, De Giorgi O, Aimi G, Panazza S, Uglietti A, Crosignani PG. Menstrual characteristics in women with and without endometriosis. Obstet Gynecol 1997;90:264 – 8.
Levonorgestrel for dysmenorrhea in endometriosis
Vol. 72, No. 3, September 1999