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ORIGINAL RESEARCH |
From the *The Finnish Medical Society Duodecim, Helsinki, Finland; Schering Oy, Research and Development, Clinical Operations, Helsinki, Finland, and Department of Obstetrics and Gynecology, Central Hospital of Hedmark County, Hamar, Norway.
Address reprint requests to: Ilkka Rauramo, MD, The Finnish Medical Society Duodecim, PO Box 713, 00101 Helsinki, Finland; e-mail: ilkka.rauramo{at}duodecim.fi.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: This study was an open, randomized 3-year trial. Patients with menorrhagia were assigned randomly to either the levonorgestrel intrauterine system (n = 30) or endometrial resection (n = 29). Pictorial blood loss assessment charts were used to measure menstrual blood loss. A pictorial blood-loss assessment chart score exceeding 75 (representing menstrual blood loss 
60 mL) was used to diagnosis the patient as having menorrhagia. Discontinuations and cases requiring repeat operations were evaluated.
RESULTS: Pictorial blood loss scores decreased from a baseline median of 261.5 (range, 60–1503) to 7 (range, 0–101; P < .001) for the levonorgestrel intrauterine system and from 311 (range, 81–2506) to 4 (range, 0–182; P < .001) for transcervical resection of the endometrium. Nineteen women of 30 using the levonorgestrel intrauterine system completed the 3-year follow-up compared with 22 of 29 for transcervical resection of the endometrium.
CONCLUSION: Both treatments efficiently reduced menstrual bleeding. The high continuation rate suggests that the levonorgestrel intrauterine system is comparable with transcervical resection of the endometrium.
LEVEL OF EVIDENCE: I
In recent years, transcervical resection of the endometrium has become a valid alternative to hysterectomy in the treatment of menorrhagia.1 Increasing experience of the surgeon reduces the number of complications.8 However, hospitalization and anesthesia are required, and the procedure is not suitable for women who want to preserve their fertility.9 Furthermore, even when complete destruction of endometrium is attempted, residual endometria may persist,9–11 and regeneration of endometrium is common.8 Consequently, transcervical resection of the endometrium does not provide contraception, and if hormone-replacement therapy is needed, the endometrium should be protected with a progestin.12
The levonorgestrel intrauterine system is an effective long-term contraceptive13 that induces atrophy of the endometrial epithelium for more than 5 years,14 thus providing a meaningful rationale for reduction of menstrual bleeding in menorrhagic women during a prolonged time period. The levonorgestrel intrauterine system has been shown to reduce menstrual blood loss by 80–96% during a period of 12 months,6,15–18 with a low rate of adverse events.6,18 Preliminary data show that menstrual blood loss remains at low levels for as many as 36 months in menorrhagic women.19 In a randomized comparative study, additional surgery because of a complication or recurrence of symptoms was needed in 9% of women who had undergone hysterectomy compared with women treated with transcervical resection of endometrium during a median follow-up time of 2 years.20 The aim of the present randomized study was to compare the effects of the levonorgestrel intrauterine system and transcervical resection of the endometrium during an extended period for the treatment of idiopathic menorrhagia.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The women represented a population who had sought medical attention for heavy menstrual bleeding and subsequently been referred to the local district hospital for surgical treatment. Eleven (36.7%) women in the levonorgestrel intrauterine system group and 13 (43.3%) women in the transcervical resection of the endometrium group were referred because of failed oral medical treatment.
The women, aged from 30 to 49 years, expressed no further desire for children, had idiopathic menorrhagia needing treatment, and exhibited a normal uterine cavity. They were not pregnant, breastfeeding, or menopausal, as evidenced by a follicle-stimulating hormone (FSH) level not exceeding 30 IU/L and a serum estradiol (E2) level less than 20 nmol/L. They did not have any of the following: subserous or intramural fibroids (myomata) with a diameter more than 40 mm or submucous fibroids confirmed by ultrasonography, current genital infection or pelvic inflammatory disease within the last 6 months, Pap test classified as cervical intraepithelial neoplasia 2 or higher, manifest endometriosis or adenomyosis, a history of or active thromboembolic disorder, undiagnosed abnormal uterine bleeding, acute liver disease or liver tumor, breast cancer, or use of injectable hormones during the preceding 12 months. Endometrial biopsy (Pipelle de Cornier, Laboratoire C.C.D., Paris, France) was performed in all patients at screening and at the 36-month visit to exclude polyps, hyperplasia, and carcinoma.
Patients were randomly allocated into 2 equal-sized groups. Randomization was performed in blocks of 6 patients using SAS/PLAN Procedure (SAS Institute Inc., Cary, NC). The sealed randomization envelopes were opened at entry in order of enrollment after eligibility had been confirmed.
Uterine bleeding was quantified using semiquantitative pictorial blood loss assessment charts.21 The patients were carefully instructed how to fill in the charts. Pictorial blood-assessment charts were completed by all patients during the course of 2 menstrual cycles before their enrollment and during all episodes of bleeding during the first 12 months after entry. Pictorial blood-assessment charts for the 24- and 36-month visits were completed for the last episode of bleeding before the visit. For determining the pictorial blood-assessment chart scores for the 12-, 24-, and 36-month visits, a time window of 45 days was used. The scoring was based on the number of sanitary towels and tampons used each day and their degree of soiling. The number and size of any clots passed were also taken into account. The pictorial blood-assessment charts were read by one of the authors and the study nurse. A score of 75 on the pictorial blood-assessment chart, corresponding to a blood loss of 60 mL or greater, was regarded as excessive bleeding.21 Standard tampons and towels were used.
The endometrial resections were performed under spinal anesthesia by the same surgeon (O.I.) who also inserted all the levonorgestrel intrauterine systems. The technique has been described in detail previously.18
All patients completed bleeding diaries during the screening period and the whole study period. Bleeding was defined as any bloody vaginal discharge that required use of sanitary protection, and spotting was defined as any vaginal discharge that required light sanitary protection, such as panty liners. Bleeding and spotting days were analyzed during 90-day reference periods using the Menstrual Diary System.22 In addition, menstrual pain and medication for menstrual pain were recorded in the bleeding diaries. Visual Analog Scales (VAS) were used at screening, 12, 18, 24, and 36 months to record hot flushes, sweating, sleeping problems, dyspareunia, vaginal dryness, urinary frequency, nervousness, depression, edema, libido, and overall genital health.
The patients were followed at the outpatient clinic, with visits scheduled at 6 weeks and at 6, 12, 18, 24, and 36 months after transcervical resection of the endometrium or insertion of the levonorgestrel intrauterine system. At the visits, the bleeding diaries and pictorial blood-assessment charts for the preceding months were collected. The patients had a gynecologic examination, and their weight was measured. Adverse events were documented using specific forms. Vaginal ultrasonography was conducted at screening and at 6, 12, 24, and 36 months to evaluate the endometrial thickness. Serum FSH, E2, blood hemoglobin, and serum ferritin levels were analyzed at screening and at 6, 12, 18, 24, and 36 months. Repeat surgery for any reason in the transcervical resection of the endometrium group and removal of the levonorgestrel intrauterine system in the levonorgestrel intrauterine system group were considered treatment failures.
The following deviations from the study protocol were found: At baseline, 1 woman in the levonorgestrel intrauterine system group had a pictorial blood-assessment chart score of 60. One woman in the levonorgestrel intrauterine system group developed postmenopausal FSH and E2 concentrations between 12 and 36 months. In the transcervical resection of the endometrium group, menopausal status was found in 1 woman between 24 and 36 months and in another woman between 6 and 12 months, when she discontinued the study at her own request. The baseline and 1-year results have been presented in a previous report.18 In this work, pictorial blood-assessment charts are presented as medians rather than the means, which we used in the previous article.
Sample size calculations were based on previous menstrual blood loss data because no pictorial blood-assessment chart data were available. Menstrual blood loss was assumed to be distributed normally, with a standard deviation of 14. A statistical power of 80% and a significance level of 5% were chosen. A sample size of 15 per group was needed to detect a 15-mL difference in menstrual bleeding between the treatment groups with a power of 80%; allowing for a dropout rate of 20% and taking into account the lack of results with the pictorial blood-assessment chart and uncertainty with the assumption of normality, the sample size was set at 30 subjects per treatment group. The following nonparametric methods were used for analysis: Wilcoxon rank-sum test to compare differences between the groups at baseline and for analyzing the treatment by time interaction; Friedman's 2-way analysis of variance for repeated measures, and Wilcoxon signed rank test for intra-group comparisons. Serum ferritin and blood hemoglobin were tested in similar manner as menstrual blood loss. The alpha level was controlled at the overall level main effects and was set at P < .05. The treatment by time interaction for menstrual blood loss was performed using multiple pairwise comparisons between the groups. The Bonferroni procedure should have been applied and, consequently, for the 3 comparisons the significance level should have been set to 0.0167. The data program used was SAS (SAS Institute Inc., Cary, NC). All analyses were based on the intent-to-treat population.
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RESULTS |
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At baseline, 26 women in the levonorgestrel intrauterine system group and 27 in the resection group had either proliferative or secretory endometrium. Three women in the levonorgestrel intrauterine system group and 1 woman in the resection group showed simple endometrial hyperplasia. One woman assigned to receive the levonorgestrel intrauterine system had signs of progestogen treatment, and 1 woman who was assigned to the resection group was menstruating. During follow-up, no hyperplasia was found in the levonorgestrel intrauterine system group compared with 1 case at 36 months in the resection group.
In the levonorgestrel intrauterine system group, 19 of 30 women (63,3%) completed the 36-month follow-up. In the resection group, the procedure was effective during the 3-year study period in 22 of 29 women (75.9%). In the resection group data, up to 36 months also are presented for the 4 patients with treatment failure. The reasons for discontinuation or repeat surgery by time are given in Figure 1. Two of 6 women who underwent repeat endometrial resection during the follow-up period required subsequent hysterectomy.
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Menstrual blood loss determined with the pictorial blood-assessment chart score decreased significantly in both groups over the course of time (P = .001; Table 2). The change in the pictorial blood loss-assessment chart score from baseline to 12, 24, and 36 months did not differ between the groups. Menstrual blood loss of less than 60 mL (ie, pictorial blood loss-assessment chart score >75) was not achieved in 3 women in the levonorgestrel intrauterine system group and in 2 women in the resection group at premature discontinuation or completion of the study. All but 5 subjects had a baseline pictorial blood loss-assessment score of more than 100, representing a menstrual blood loss of more than 80 mL. Blood hemoglobin and serum ferritin concentrations increased significantly (P = .001) in both groups without significant differences between the groups (Fig. 2).
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The median number (range) of bleeding days during the first 90-day period was 25 (range, 7–73) in the levonorgestrel intrauterine system group and 12 (range, 0–40) in the resection group. Thereafter, the median number decreased to 11.5 days at 12 months, to 1.5 days at 24 months, and to 0 days at 36 months in the levonorgestrel intrauterine system group (P = .001). In the resection group, the median number of bleeding days decreased to 0 at all time points, respectively (P < .001). In the levonorgestrel intrauterine system group, the median number of spotting days decreased from 22 to 4.5 days at 12 months, to 4.0 days at 24 months, and to 1.0 day at 36 months (P < .001) and in the resection group from 12.0 days to 2.0, 4.0 and 1.0 days (P = .001), respectively. During the first 90-day period, there was a significant difference in the number of bleeding days between the groups (P < .001), which also was present at 12 months (P = .003). Fewer spotting days in the resection group were only found during the first 90-day reference period (P = .019). During the first 90-day reference period, none of the women in the levonorgestrel intrauterine system group were amenorrheic compared with 1 woman in the resection group. After 1 year, 3 women in the levonorgestrel intrauterine system group and 7 in the resection group were amenorrheic; after 2 years, 5 and 8; and at the end of the third year, 6 and 9 women, respectively.
Menstrual pain diminished in the levonorgestrel intrauterine system users during the study, as indicated by a decrease in the number of days with mild pain (P = .001) and with moderate/severe pain (P = .001) over time when the first 90-day treatment period was compared with the subsequent periods. No such decrease was found in the resection group.
The change in the VAS score for sweating from baseline to 36 months showed a statistically significant difference (P = .034) between the groups: It decreased in the levonorgestrel intrauterine system group and remained unchanged in the resection group. The VAS score for the overall feeling of lower abdominal health showed a significant improvement over the course of time in both groups. There were no other significant changes in climacteric or general symptoms between baseline and other time points or between the groups. None of the other VAS variables measured showed any significant changes.
The median serum FSH increased from 4.2 IU/L at baseline to 5.9 IU/L at 36 months (P = .02) in the levonorgestrel intrauterine system group and from 5.0 IU/L to 5.7 IU/L (NS) in the resection group. The median E2 values remained unchanged in both groups.
There was 1 case of edema in an levonorgestrel intrauterine system user, which was classified as both significant and related to the treatment. Similarly, 1 case of endometriosis and another case of bleeding and pain resulting in repeat transcervical resection of endometrium were reported as significant and treatment-related in the resection group.
Other significant adverse events were as follows: In the levonorgestrel intrauterine system group, 3 subjects were diagnosed with endometritis and 2 with PID. Further, 1 partial expulsion occurred. The patient refused removal of the intrauterine system, and it was successfully pushed back into the uterine cavity. In the resection group, 1 woman with hypertension experienced a stroke 1.5 months after the transcervical resection of endometrium, which was not considered as related to transcervical resection of endometrium procedure. Another 3 women had pelvic inflammatory disease, 1 had adenomyosis and one had myometritis. All 3 abnormal Pap tests, 2 cases of severe dysplasia after 18 and 36 months of treatment, and 1 case of mild dysplasia were detected in the resection group.
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DISCUSSION |
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Our intention was to study a population with ovulatory dysfunctional bleeding. Regular menstrual bleeding, baseline endometrial histology, as well as exclusion of other uterine pathology by ultrasonography support this in all cases except the 4 women who had simple endometrial hyperplasia at baseline, reflecting long-term estrogenic action on the endometrium.
Hysterectomy has been considered the definitive treatment for menorrhagia. However, there is a need for effective but less-invasive and simpler techniques that decrease comorbidity and preserve fertility and the uterus, especially for women in whom no organic reason can be detected for the menorrhagia. In addition, the methods used should preferably be cost-effective and increase quality of life. We used a first-generation hysteroscopic endometrial ablation procedure that has been shown to be effective for as many as 6.5 years, with high rates of satisfaction and moderate rates of amenorrhea.1 Further surgery is needed in up to 22% of women treated with transcervical resection of endometrium within 2 years or longer.20,25 There are increasing data indicating that second-generation endometrial ablation techniques are equivalent to the more classical hysteroscopic procedures.26 In a large 1-year study comparing the levonorgestrel intrauterine system and hysterectomy in menorrhagic women, both treatments showed similar improvement of quality of life. Overall, the costs of levonorgestrel intrauterine system treatment were significantly lower.27
In our study, 67% of the levonorgestrel intrauterine system users and 76% of those treated with transcervical resection of endometrium completed the 3-year study period. This compares well with previous findings showing that 68–85% of women using the levonorgestrel intrauterine system continued treatment up to 1 year17,27 and 70% up to 3 years.19 Further surgery was needed by 17% in the resection group. This is well in accordance with the published data for transcervical resection of endometrium.20,25 In the levonorgestrel intrauterine system group, women discontinued predominantly during the first year whereas in the resection group, most of the discontinuations or treatment failures took place during the second and third years. In contrast with previous reports, none of the levonorgestrel intrauterine system users discontinued because of expulsion.17,19 Furthermore, observational data have suggested that the effect of the levonorgestrel intrauterine system for the treatment of menorrhagia is sustained for up to 5years in about 50% of the users.28
The pictorial blood loss-assessment chart method used in this study has been shown to correlate well with the gold standard alkaline hematin method,21,29 although this correlation also has been challenged.30 We used 60 mL bleeding per period as selection criterion. However, all women except 5 had baseline bleeding in excess of 80 mL. Thus, our results are well comparable with previous data.
Previous studies have shown that the number of bleeding and spotting days per cycle decreases and the amenorrhea rate increases after both levonorgestrel intrauterine system insertion and transcervical resection of endometrium.18–20,25 Our results are fully compatible with previous data. Consequently, we were able to demonstrate a statistically significant increase in hemoglobin and ferritin concentrations. This replenishment of iron stores may imply better health for menorrhagic women.
It has been shown that after transcervical resection of endometrium the risk of pain and hematometra is increased in sterilized women.31 This coincides with our findings as 5 of the 6 women who underwent repeat transcervical resection of endometrium had undergone previous sterilization and hematometra was detected in 4 of them.
Some studies have indicated that major uterine surgery such as hysterectomy and endometrial ablation may prelude an early onset of menopause.32 In this study, we saw a small increase in median FSH from 4.2 IU/L to 5.9 IU/L in the levonorgestrel intrauterine system group. However, the VAS score for sweating decreased in the levonorgestrel intrauterine system group, whereas other VAS scores for menopausal symptoms and general well-being did not change. These data indicate that no clinically significant changes indicating early onset of menopause occurred during the 3-year observation period in either the levonorgestrel intrauterine system or the resection group.
On the basis of our data and the literature, strong evidence exists to suggest that the levonorgestrel intrauterine system should be considered the first-line treatment for idiopathic menorrhagia because it is easy to insert, has a sustained effect, provides contraception, may reduce the need for surgery, and is cost-effective and well tolerated.
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Footnotes |
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Financial Disclosure Ilkka Rauramo was an employee of the sponsor (Schering Ag, Berlin, Germany) at the time of conduct of the study. Iina Elo is an employee of the sponsor of the study.
Received May 31, 2004. Received in revised form July 7, 2004. Accepted July 28, 2004.
doi:10.1097/01.AOG.0000143824.16435.91
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REFERENCES |
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