Department of Obstetrics and Gynaecology, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK
1 To whom correspondence should be addressed. e-mail: jck4{at}le.ac.uk
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Abstract |
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Key words: endometriosis/levonorgestrel-releasing intrauterine system/mirena
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Introduction |
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The levonorgestrel intrauterine system (Lng-IUS) MirenaTM provides an alternative means of administering progestogens. It delivers levonorgestrel (a 19-C progestogen) into the uterine cavity at a steady rate of 20 µg/day over its 5-year lifespan. The systemic levels following such administration are less than those achieved with therapeutic oral or parenteral doses of progestogens (Nilsson et al., 1980; Luciano et al., 1988
; Du et al., 1999
; Morghissi, 1999
; Fedele et al., 2001
), hence side effects should theoretically be less severe. Its effects are predominantly localized to the endometrium where the high concentrations of levonorgestrel induce atrophy and pseudo-decidualization (Nilsson et al., 1978
; Silverberg et al., 1986
; Maruo et al., 2001
). It is this action on the endometrium that enables the Lng-IUS to be used as a highly effective intrauterine contraceptive device and has popularized its use in the management of menorrhagia (Andersson et al., 1990
; Irvine et al., 1998
). More recently, its role in protecting the endometrium has been advocated in women on estrogen-only hormone replacement therapy or tamoxifen (Gardner et al., 2000
). Its role in extrauterine pathology such as endometriosis is uncertain, as the levels of levonorgestrel reaching the peritoneal fluid to potentially affect these lesions are unknown.
In a cohort of 20 women with known endometriosis who had previously undergone conservative surgical treatment and had recurrent dysmenorrhoea, Vercellini et al. (1999) demonstrated that the Lng-IUS was associated with symptomatic relief in
70% of cases after 12 months therapy. Fedele et al. (2001
) also demonstrated a significant symptom improvement as well as radiological evidence of lesion regression in 11 women with recto-vaginal endometriosis. Neither of these studies related the changes in the symptoms to the stage or score of the disease. The aims of this pilot observational study were therefore to investigate the efficacy of the Lng-IUS in the symptomatic relief of endometriosis, and the changes in the staging of the disease induced by the Lng-IUS.
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Subjects and methods |
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At the time of recruitment in the clinic, each subject marked the severity of their pelvic pain on a 10 cm visual analogue scale (VAS) and also rated the severity of pelvic pain (dysmenorrhoea and/or non-cyclical pelvic pain) on a 4-point verbal rating scale (VRS) which has well recognized advantages and drawbacks (Karoly, 1987). Other associated symptoms were also noted. They then completed a 1 month (28 day) daily symptom diary, for pelvic pain using a 4-point VRS, and menstrual loss using a pictorial blood loss assessment chart (PBAC) (Higham et al., 1990
). The former was used to generate a monthly pain score (where each day was given a score 03 and the monthly score was the sum of the daily scores for 28 consecutive days) and the latter to generate a bleeding score (>100 suggestive of menorrhagia).
All the subjects underwent a standard two-port diagnostic laparoscopy to confirm the diagnosis of endometriosis. Where possible, peritoneal fluid was immediately aspirated from the pouch of Douglas (for a later quantification of levonorgestrel), after which the disease was then staged systematically with video documentation. A single punch biopsy of ectopic endometrium (endometriosis) was obtained where possible for future study on the effects of levonorgestrel on steroid receptor expression. The MirenaTM was then inserted following standard aseptic techniques.
Follow-up visits were at 1, 3 and 6 months after the insertion. Severity of pain was re-evaluated at these visits using the VAS and VRS. Due to irregularity of menstrual loss, these data were timed to duration of insertion of the IUS rather than day of menstrual cycle. Each subject also kept a symptom diary identical to that pre-laparoscopy; these were completed for months 1, 3 and 6 after the insertion. After 6 months, satisfaction with treatment was assessed using a 4-point VRS.
Six months after the insertion of the device, a second-look laparoscopy was performed, again with video documentation, systematic re-staging, collection of peritoneal fluid and biopsies. At this point, those who requested had the device removed.
The outcome measures included severity and frequency of pain (which was assessed by using a VAS, a VRS for dysmenorrhoea and non-cyclical pelvic pain, a monthly pain score and number of pain days per month), amount and frequency of bleeding (assessed using a monthly bleed score and number of bleeding days per month) and American Fertility Society staging and score of the disease.
Data analysis
SPSS version 11.0 was used to record and statistically analyse data. Values at the time of insertion of the IUS (i.e. time zero) were compared with those at different time points after insertion using paired t-test or Wilcoxon rank analysis as appropriate. Additionally, perception by the patient of the efficacy of the device in pain control was evaluated at 1, 3 and 6 months using a VAS, as well as overall satisfaction with treatment (taking into account the undesirable side effects) as indicated on a 4-point VRS.
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Results |
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The device was removed in five cases prior to the end of the trial period. These cases were not included in paired outcome analyses. Table I shows the indications for and the timing of all removals within and following the study period. Of the 29 women completing the 6 months, one was excluded from the pain analyses as the potent analgesics she had received during a significant part of the trial period due to her involvement in a road traffic accident were considered to have the potential to mask pains from endometriosis.
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The mean quantified menstrual loss from the PBAC chart was 204 ± 196 pre-insertion (suggestive of significant menorrhagia in most of the cases) compared with 129 ± 273 at 3 months post-insertion (P > 0.05) and 90 ± 157 at 6 months post-insertion (P < 0.001). The mean number of bleeding days per month by the end of the sixth month was not significantly different from that pre-insertion (8.7 ± 7.5 days versus 7.6 ± 3.4, P = 0.519). Tables II and III show the changes in the quantified monthly blood loss and number of bleeding days respectively, against patient satisfaction, over the study period. The blood loss in the dissatisfied and uncertain groups was more prolonged, with a smaller quantitative reduction after 6 months, when compared with those who were satisfied or very satisfied.
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Discussion |
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This modality of treatment confers several advantages over other conventional systemic forms of therapy (avoidance of the need for repeated administration, delivery of a steady amount of levonorgestrel, effective contraception and fewer systemic side effects). Although it may be expensive at the outset, the cumulative long-term costs are significantly less than those of other forms of medical therapy, such as GnRH analogues and danazol. Side effects were often transient and generally well tolerated; the side effects profile was similar to that previously described for the device (Backman et al., 2000). The PBAC scores reflect that most of the women had significant menorrhagia (defined by a score of >100) prior to therapy, which was effectively reduced after 6 months treatment. However, those experiencing prolonged and/or heavy bleeding persisting after 6 months of use were less likely to be satisfied and therefore potentially more likely to discontinue therapy, even if their symptoms improved, as is the case in those using the device as a contraceptive (Backman et al., 2000
). In our series, three of the patients discontinuing treatment (either during or after the trial period) did so for side effects (which included exacerbation of acne, weight gain and headaches), even though there was marked improvement in symptoms of pain and menorrhagia.
We found an improvement in the staging of the disease after 6 months of therapy (suggesting that whatever mechanism is involved, the lesions themselves are affected), an observation which has not been documented before. The actual significance of this in relation to symptoms is uncertain as it is widely accepted that clinical symptoms do not necessarily correlate with the extent or distribution of lesions. Staging is based on an arbitrary scoring system that was devised for prognostication of infertility rather than treatment and symptom response, and hence has a greater weighting/emphasis on the presence of adhesions rather than peritoneal endometriotic lesions. It was largely the peritoneal endometriotic lesions which appeared to respond to therapy whilst, as with all medical regimens, the presence of adhesions was not altered. Consequently, scores and hence staging may not have been drastically altered following treatment, despite a marked visible reduction in the extent of haemorrhagic and neovascular peritoneal lesions (thought to represent active disease) and a marked improvement in symptoms.
The exact mechanism by which this device is effective is uncertain, but we believe that this may be achieved via both local and systemic routes. The hypomenorrhoea which many of these patients experienced is likely to be a combination of atrophy of the endometrium (local activity) and ovarian suppression (systemic activity). It is recognized that in the first 3 months on the device, up to 85% of women have anovulatory cycles and by 12 months this figure falls to <35% (Jarvela et al., 1998). If anovulation were the only mechanism responsible for symptom relief, then we would expect a gradual recurrence and worsening of symptoms in those retaining the device after the 6 months, as ovarian activity resumes and endogenous hormone levels increase. However, both Fedele et al. (2001
) and Vercellini et al. (1999
) noted a persistent symptom improvement at 12 months. In our series (data not presented), >80% of those who elected to continue with the Lng-IUS had no significant exacerbation of symptoms after 12 months therapy, suggesting that another mechanism contributes to the efficacy of the IUS in symptom relief. This second mechanism is likely to be local. Although it may be suggested that the Lng-IUS may alter uterine perfusion and decrease pelvic congestion that may contribute to symptom relief, studies on uterine vascular resistance and impedance to flow in the presence of the Lng-IUS have failed to support this. It is suggested that decreased pelvic congestion may be mediated by systemic levels of levonorgestrel (>200 pg/ml) via receptors on uterine vasculature and, if this were the case, the effect may only last for 3 months after insertion as the systemic levels decline thereafter. Additionally, this vascular impedance is only evident in the mid-luteal phase, and no differences have been noted at menstruation (Jarvela, 1998
).
Symptom improvement may therefore be due to a combination of menstrual interruption, disruption of follicular activity and a direct effect on the endometriotic lesions. Local levels of levonorgestrel in the peritoneal fluid may facilitate this direct mechanism. Unfortunately, these peritoneal fluid levonorgestrel levels are unknown, as they have never been measured. We are currently measuring these levels in addition to studying the effects of levonorgestrel on ovarian steroid receptor expression on endometriotic lesions. If the concentration of the levonorgestrel in the peritoneal fluid is high, then it may alter the steroid receptor expression on lesions (endometriotic receptor-mediated response) in a manner similar to endometrium (Silverberg et al., 1986). Alternatively, the progestogen may affect the peritoneal fluid macrophage activity, thus altering the production of various cytokines and factors that are responsible for the maintenance of lesions and symptoms (cytokine-mediated macrophage response); this may also be receptor mediated (McLaren et al., 1996
). Finally, it may be possible that both systemic and local levonorgestrel downregulate or alter the local gene expressions associated with proliferation of lesions and progression of the disease.
Sixty-eight percent (23 out of 34) of the cases recruited into our study chose to continue with the device after the 6-month trial period. Whilst the exact mechanism of action of the Lng-IUS remains uncertain, in our trial the device appears to provide relief in a reasonable proportion of patients with symptoms of pain (mainly dysmenorrhoea) and menorrhagia associated with endometriosis (minimal to moderate). It is a convenient alternative to systemic progestogens, and if the side effects, particularly of bleeding dysfunction, which are most common within the first 3 months, can be tolerated, then it could be retained for as long as 5 years. However, further studies are now required not only to verify if this device is equally as effective as other medical options, in the form of larger, well designed, controlled trials, but also to verify whether the device retains its therapeutic effects for its full 5-year lifespan and whether it could be beneficial to women with severe/extensive disease presenting with similar symptoms to those we investigated.
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Acknowledgements |
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References |
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Submitted on January 27, 2003; resubmitted on June 2, 2003; accepted on September 16, 2003.