REPRODUCTIVE ENDOCRINOLOGY

REPRODUCTIVE ENDOCRINOLOGY FERTILITY AND STERILITY VOL. 76, NO. 2, AUGUST 2001 Copyright 2001 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Treatment of menorrhagia with the levonorgestrel intrauterine system versus endometrial resection Olav Istre, M.D., Ph.D., a and Birgitta Trolle, M.D. b Department of Obstetrics and Gynecology, Central Hospital of Hedmark County, Hamar, Norway Received July 3, 2000; revised and accepted February 12, 2001. Supported by Leiras Oy, Turku, Finland. Presented at the XV World Congress of Gynecology and Obstetrics, Washington, DC, September 3 8, 2000. Reprint requests: Olav Istre, M.D., Ph.D., Department of Obstetrics and Gynecology, Ullevaal Hospital, University of Oslo, N-0407 Oslo, Norway (FAX: 47-23 015840; E- mail:oistre@c2i.net). a Current address: Department of Obstetrics and Gynecology, Ullevaal Hospital, University of Oslo, Oslo, Norway. b Current address: Department of Obstetrics and Gynecology, Holstebro Central Hospital, Holstebro, Denmark. 0015-0282/01/$20.00 PII S0015-0282(01)01909-4 Objective: Treatment of menorrhagia with levonorgestrel intrauterine system (LNG IUS) and transcervical resection. Design: An open, therapeutic, randomized study. Setting: Central county hospital specializing in hysteroscopy. Patient(s): Two parallel groups of 30 subjects each. Intervention(s): Thirty patients had a LNG IUS inserted within the first 7 days of menses; 29 patients underwent endometrial resection. Main Outcome Measure(s): A 12-month follow-up of menstrual blood loss and adverse events were evaluated. Result(s): LNG IUS group: 13 patients reported one or more pelvic adverse events, bleeding disorders (n 6), abdominal pain (n 4), breast tenderness (n 3), headache, acne (n 2), and mood changes (n 1). Six patients discontinued treatment because of irregular bleeding (n 3), pain (n 2), and acne (n 1). In both groups, general feeling of genital health increased with Visual Analogue Scale score. Nine patients reported adverse events. This included pelvic pain indicating inflammation (n 4), bleeding (n 3), vaginitis (n 1), and ulceration (n 1). Treatment success at 12 months was achieved in 20 (67%) of the 30 patients in the LNG IUS group and in 26 (90%) of the 29 patients in the transcervical resection group. Adverse events were more often reported in the LNG IUS group. Conclusion(s): Both treatments effectively reduced the menstrual blood loss. Furthermore, the LNG IUS treatment is reversible and has no operative hazards. (Fertil Steril 2001;76:304 9. 2001 by American Society for Reproductive Medicine.) Key Words: Levonorgestrel intrauterine system, transcervical endometrial resection, menorrhaghia, hysteroscopy The levonorgestrel intrauterine system (LNG IUS, Mirena) is one of the most effective contraceptive methods available, as well as the hormonal contraceptive with the lowest hormonal dose (1). In addition, the LNG IUS significantly reduces menstrual blood loss. The reduction has been reported to exceed 80% in women with confirmed menorrhagia (2). Because the contraceptive effect of the IUS lasts for 5 years, it would seem to offer a simple long-term therapy for menorrhagia and alleviate the need for surgical treatment in a significant number of cases. In recent years, transcervical endometrial resection (TCRE) has become a valid alternative to hysterectomy in the treatment of uterine bleeding disorders. In experienced hands, there are few complications, and promising clinical results have been reported (3). But the operation requires hospitalization, and it is not a suitable technique for women who want to preserve their fertility (4). Some of the concerns connected to the treatment of menorrhagia with the LNG IUS have been the incidence of side effects. The most common complaints resulting in discontinuation of therapy are irregular bleeding and hormonal side effects, such as breast tension, mood changes, and acne (5). The aim of this randomized study was to compare the effect of surgical and hormonal treatment of menorrhagia and the incidence and adverse events. 304

MATERIALS AND METHODS The local Institutional Review Board and the Norwegian Medicines Control Authority approved the study after changes in patient information. The Norwegian Medicines Control Authority was to be informed expeditiously of all protocol amendments and all serious unexpected adverse reactions. The patients were recruited from the outpatient clinic, and informed consent was obtained from all women. The study was designed as an open, therapeutic, randomized, comparative study with an LNG IUS group and a TCRE group, each including 30 patients. The patients were assigned to one of the groups in order of their enrollment. Randomizations were done with random permuted blocks (blocks of six subjects). Their general practitioner had referred the women after failed attempts at conservative medical treatment in 40% of the women. The therapy included sequential progestagen and tranexamic acid tablets for 6 months in most of these patients. The other 60% of the patients refused conservative surgery or entered the study directly without previous medication. The waiting list for surgery in the hospital was 6 months or more. Uterine bleeding was quantified by the semiquantitative pictorial blood loss assessment score (PBAC), completed by all subjects over a screening period of 2 months before enrollment (6). The score is recorded on a chart on which the patient registers the number of sanitary pads or tampons used each day, the degree of soiling on each pad or tampon, the number and size of clots passed, and episodes of flooding. A monthly score of 75 on this chart, corresponding to a blood loss of 60 ml, was regarded as excessive bleeding. All tampons and towels used by the patients through the study were Ob Fleur and Saba Normal from Saba.Moelnlycke. All women were premenopausal (serum FSH level of 30 IU/L and 17- E 2 level of 0.2 nanomol/l). Inclusion criteria also included age between 30 and 49 years, a regular uterine cavity 10 cm in length as measured by ultrasound, and no wish for further pregnancy. The evaluation of the uterus was done with transvaginal ultrasound; when the ultrasound findings were in doubt, saline infusion ultrasongraphy or hysteroscopy of the cavity was performed to exclude intrauterine pathology. Exclusion criteria were breast feeding, presence of subserous myoma of 40 mm, current or recent pelvic inflammatory disease, abnormal Papanicolau smear, known endometriosis, breast cancer, a previous history of deep venous thrombosis, thromboembolism or liver disease, and hormone therapy during the last 3 months preceding the study. An endometrial biopsy was performed in all cases. No pretreatment to suppress the endometrium was given. The resection was performed without simultaneous laparoscopy. The cervical canal was dilated to Hegar 11 and a Stortz rigid resectoscope (Ch. 26, model 27040 SL; Stortz, Tuttlingen, Germany) equipped with a Hopkins 27005 B 30 optic (Stortz) was passed into the uterine cavity. Glycine 1.5% (Baxter, Thetgord, UK) was infused for irrigation. A mixed diathermal current of 120 W (80% cutting/20% coagulation) supplied by a Valleylab Force 2 diathermia unit was routinely used for resection of both fibroids and endometrium. For haemostasis, coagulation current of 80 W was applied. In addition to the PBAC form, all patients also kept a bleeding diary during the screening period. The purpose of this was to register menstrual pain and use of analgesics. All patients also completed a Visual Analogue Scale (VAS) form regarding climacteric symptoms and general feeling of genital health. Pain was registered as number of days that the patient felt mild, moderate, or severe pain. The patients were followed at the outpatient clinic with visits scheduled at 6 weeks, 6 months, and 12 months after the operation or the insertion of the IUD. At all visits, the bleeding diaries and PBAC chart for the preceding months were collected. The patients had a breast and gynecological examination, and their weight and blood pressure was controlled. Any adverse events, defined as new symptoms occurring after treatment, were recorded and classified as local (in the urogenital area) or generalized. Concomitant treatment was recorded, and FSH and E 2 levels were analyzed. Climacteric symptoms were recorded on the VAS scale. No additional treatment for menorrhagia was allowed during the study period. In the TCRE group, only barrier methods were allowed if contraception was needed, and in case the patient could not accept this, a tubal occlusion was performed. Treatment success was defined as a PBAC score of 75 at 12 months. Treatment failure was defined as a PBAC score of 75, resurgery for any reason in the TCRE group, and removal of the intrauterine device in the LNG IUS group. Statistics For the analyses of numerical efficacy and demography variable, the ANOVA or repeated measures ANOVA was used. The continuous variables were tested with two-sample t test or Wilcoxon rank sum test. Categorical variables were tested with Fisher s exact test. The time effect within treatment group was tested with Freedman s test in both groups separately. The level of significance was set at P.05. The data program used was SAS (SAS Institute Inc., Cary, NC). RESULTS LNG IUS Group No complications occurred during the insertions of the IUSs. Dilatation of the cervix was needed in two cases. FERTILITY & STERILITY 305

TABLE 1 Pictorial blood loss assessment chart score. Group Visit Mean (SD) Minimum Maximum LNG IUS Baseline 420 (352) 88 1,498 12 mo 42 (99) 0 463 TCRE Baseline 404 (480) 81 2,519 12 mo 7 (15) 0 61 Thirteen patients reported one or more local pelvic adverse events, most frequently bleeding disorders (n 6) but also pelvic pain and vaginal discharge. Ten patients reported generalized symptoms, including abdominal pain (n 4), breast tenderness (n 3), headache (n 2), acne (n 2), and mood changes (n 1). Six patients discontinued treatment during the follow-up period: three because of irregular or prolonged bleeding or spotting for 6 months after insertion, two because of pain, and one because of acne and greasy skin. Twenty (83%) of the 24 patients still keeping the LNG IUS after 12 months had a significant reduction in monthly blood loss (MBL; from 420 to 42) measured with PBAC (Table 1), and treatment success was thus achieved in 67% of patients treated. The 6 patients who discontinued treatment underwent a successful endometrial resection, and during the follow-up period of 1 year, none of these patients underwent additional treatment. As indicated in Figure 1, the median VAS score for sleeping problems decreased from baseline to 12-month follow-up, and the overall feeling of genital health increased (P.004). There was no other significant change in climacteric or general symptoms after 12 months of treatment (Fig. 2) and no significant change in serum E 2 level during the study period. Weight and blood pressure did not change. TCRE Group One patient regretted her consent after randomization because she had recently gotten engaged and was considering a pregnancy. Transcervical endometrial resection was thus performed in 29 patients, and all operations were uneventful. Two patients were excluded when analysis of the data was performed because they did not meet the inclusion criteria: one because of PBAC score of 75, the other, because all baseline results were obtained 365 days earlier. Nine patients reported one or more local pelvic adverse FIGURE 1 Median values for VAS (mm). Open bars, baseline for LNG IUS; hatched bars, 12-month follow-up for LNG IUS; filled bars, baseline TCRE; shaded bars, 12-month follow-up for TCRE. 306 Istre and Trolle Treatment of menorrhagia Vol. 76, No. 2, August 2001

FIGURE 2 Median values for VAS (mm). Abd abdomen. Open bars, baseline for LNG IUS; hatched bars, 12-month follow-up for LNG IUS; filled bars, baseline TCRE; shaded bars, 12-month follow-up for TCRE. events: pelvic pain and local tenderness indicating inflammation (n 4), bleeding (n 3), vaginitis (n 1), and genital ulceration (n 1). One patient reported abdominal pain, and a total of nine single complaints were recorded. Two patients had a repeat TCRE: one because of pelvic pain and one because of hematometra. This treatment was successful, with no recurrence of symptoms during the study follow-up. Twenty-five (93%) of the 27 patients had a significant reduction of monthly blood loss 12 months after the operation, and average monthly blood loss was reduced from 378 to 7 ml. The median VAS score for sleeping problems also decreased in this group, and the general feeling of genital health increased significantly (P.001). There was no other significant change in climacteric or general symptom or serum E 2. Weight and blood pressure remained stable. Comparison of Groups There was no difference between the groups with regard to baseline variables (Table 2). Blood Loss Treatment success at 12 months was achieved in 20 (67%) of the 30 patients in the LNG IUS group and in 26 (90%) of the patients in the TCRE group. The difference is statistically significant (P.005). There were more frequent reports of adverse events in the LNG IUS group (P.045). Menstrual Pain The number of pain days each month was recorded during the follow-up. A total of 17 patients in the LNG IUS group and 19 in the TCRE group reported mild pain, but there was a significant reduction in pain over time in both groups (P.001 and P.012, respectively). When the number of pain days was compared separately at each of the periods, there was no difference between the groups. TABLE 2 Demographic data by treatment group. Variable LNG IUS TCRE P Age (y) 41.4 (3.8) 41.9 (3.8) 0.63 Sound measure in mm, mean (SD) 7.5 (1.1) 7.7 (1.1) 0.37 Parity (median) 2 (0 5) 2 (1 5) 0.46 Length cycle (d) 28 (21 35) 28 (21 31) 0.39 Duration flow 6.5 (4 10) 7 (4 21) 0.17 FERTILITY & STERILITY 307

Climacteric Symptoms The results of the VAS assessment of climacteric symptoms at baseline and 12 months are presented in Figure 2. The median VAS score for sleeping problems decreased in the LNG IUS group and increased in the TCRE group, and this difference reached statistical significance (P.042). There was no difference between the groups in feeling of genital health. Serum E 2 levels fell in both groups during the study period, but the change was not statistically significant. Serum FSH levels rose slightly in both groups, and there was no difference between the groups. Weight or blood pressure did not change in either group during the follow-up period. DISCUSSION The sample size (n 30 in both groups) required to indicate a 15-mL mean difference in MBL was estimated using standard power technique. The method of assessing the amount of blood lost during periods was evaluated in the study by Highham et al. (6). The visual analogue scale is a generally accepted and widely used method of measuring subjective symptoms. There was a dramatic decrease in blood loss in both groups, although this was more pronounced in the TCRE group, as described elsewhere (7). Levonorgestrel administered locally has a profound effect on the endometrium, which becomes atrophic and inactive. This method of treatment has the major advantage of reversibility, in contrast to the methods involving resection or destruction, and it is easier to apply than the surgical methods requiring hysteroscopy. However, the TCRE represents the method of choice in patients with fibroids, at least in the near future (3). But in the absence of fibroids, the LNG IUS is an important alternative to oral medication and surgical methods (1, 2). In the VAS assessment of subjective symptoms and in the bleeding diaries, there was no difference between the groups, except that sleeping problems slightly increased in the TCRE group and decreased in the LNG IUS group. Menstrual pain decreased over time in both groups. This is in concordance with results of other studies examining the effect of local treatment of the endometrium on menstrual pain (8). There is evidence to suggest that hysterectomy may adversely affect the function of conserved ovaries (9). In a retrospective study, this did not seem to be the case after TCRE (10), but it is difficult to eliminate all sources of bias in a retrospective study. In our study, serum FSH tended to increase in both groups, which is not surprising in women approaching the menopause. Two patients in the TCRE group and one in the LNG IUS group had serum FSH levels of 30 IU/L at 6 or 12 months after the inclusion. There was no significant differences between the groups with regard to gonadotropin levels during the follow up period, so if TCRE has an adverse effect on ovarian function, the same seems to be the case for the LNG IUS. One of the most important differences between the two treatment methods is the reversibility of the LNG IUS, which is easily removed, and the nonreversibility of the TCRE. If the subjects in the TCRE group suffered intolerable side effects of the operation, the only possible treatment was a new operation, such as re-tcre or hysterectomy. This can probably explain part of the difference in dropout rate between the groups. Also, the women may have found the hormonal adverse events, such as breast tension, mood changes, and acne, unacceptable. In this study, there were six reports of these symptoms. The hormonal symptoms are most common at the beginning of the treatment, and their incidence is low, probably because of a low steroidal dose (11). The low systemic hormonal impact of the LNG IUS was also demonstrated by the fact that we could not find any difference in body weight between the groups at the 12- month examination. The adverse events found in the present study, such as abdominal pain, acne, and spotting, have also been demonstrated by others (12). In general, the noncontraceptive benefits of the LNG IUS are substantial and far outweigh the negative effects, which are usually mild and transient in nature and can often be managed satisfactorily by counseling (13, 14). A better understanding of these effects, both beneficial and harmful, should lead to more effective patient counseling. This, in turn, should improve user quality of life, minimize unnecessary removals, and maximize continuation of use. The results found in the present study imply that the LNG IUS might primarily treat 60% 70% of patients now scheduled for operative procedures. The result of this study has clearly demonstrated that both LNG IUS and TCRE clearly reduce menstrual blood loss. Although TCRE seems to be even more effective in reducing MBL than LNG IUS, TCRE is an invasive procedure needing operative equipment and theatre. The LNG IUS in the treatment of menorrhagia can be carried out in the outpatient department. This is in line with other studies that found that 64% of 28 women scheduled for hysterectomy due to bleeding problems could cancel their decision to undergo hysterectomy, compared with 14% in the control group (15). Another aspect is the reversibility of the treatment and potential return of fertility associated with LNG IUS. To conclude, the LNG IUS is a contraceptive that has a dramatic effect in lowering bleeding intensity in menorrhagic patients. It is further characterized by reversibility and may be the first-line treatment in younger women with menorrhagia, and because of its low systemic steroidal dose, the adverse events are mild and few. However, TCRE is even more effective in reducing blood loss but implies use of operation facilities, is irreversible, and often requires a new operation if treatment fails. Overall, the tolerability of both treatments is good. 308 Istre and Trolle Treatment of menorrhagia Vol. 76, No. 2, August 2001

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