Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK
To whom correspondence should be addressed.Email: jck4{at}le.ac.uk
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Abstract |
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Key words: endometriosis/levonorgestrel/3 year follow-up
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Introduction |
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The advent of the levonorgestrel intrauterine system Mirena® provides an alternative route of delivering the 19-C progestogen (levonorgestrel) directly into the uterine cavity at a steady rate of 20 mg/day over a 5-year period (Bilian et al., 1990; Andersson et al., 1994
). Since systemic levels following this route of administration are less than those achieved with oral (Nilsson et al., 1980
; Luciano et al., 1988
; Monghissi, 1999
) or depot (Du et al., 1999
) progestogens, side-effects should theoretically be less severe (Van de Hurk and O'Brien, 1999
). This has indeed been demonstrated to be the case when the device is used to treat women with menorrhagia, where it has been shown to be highly effective (Lahteenmaki et al., 1998
; Stewart et al., 2001
). Levonorgestrel delivered this way, however, has only recently been demonstrated to alleviate symptoms of pelvic endometriosis during a period of either 6 months (Lockhat et al., 2004
) or 12 months (Vercelleni et al., 1999
) and also in women with adenomyosis and rectovaginal endometriosis (Fedele et al., 2001
).
Mirena confers several advantages over the oral or depot routes of administration. Apart from the fewer side-effects, there is no need for repeated administration, thus overcoming the problem of remembering to take the tablets regularly or the depot injection every 3 months, and there is no need for contraception. Although the device, which has a life span of 5 years, has been shown to control menorrhagia for this duration, such information is unavailable for its use in endometriosis.
We recently published our pilot data from an observational study of the effectiveness of this device on symptom control over the first 6 months (Lockhat et al., 2004). We present here follow-up data on the evaluation of the efficacy of Mirena as a long-term (3 years) option for endometriosis concentrating on symptom control, side-effects and continuation rates.
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Subjects and methods |
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For the month preceding the Mirena insertion, each patient completed a diary for the generation of baseline variables, which were used for the assessment of response to treatment. Response to treatment was assessed by changes in the variables, which included the patient's perception of pelvic pain severity using a visual analogue scale (VAS), her rating of both types of pelvic pain (dysmenorrhoea and/or non-cyclical pelvic pain) on a verbal rating scale (VRS), a monthly pelvic pain and bleeding score.
The VAS was a subjective assessment of the pain on a scale of 0 (no pain) to 10 (most severe pain). It was recorded on a 10-cm ruler in the diary at each follow-up visit and reflected the severity of this symptom as perceived by the patient in the preceding month. A 4-point scale (03; where 0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain) was used to rate dysmenorrhoea and/or non-cyclical pain on a daily basis. A monthly score was then generated from the summation of the daily VRS over a 28-day period (0=no pain, 96=maximum pain). Once again, this VRSmonthly was only determined for the 28 days prior to the follow-up visit. Menstrual loss was quantified using the pictorial blood loss assessment chart (PBAC) described by Higham et al. (1990). A score of >100 was used to define menorrhagia. Only the loss in the month prior to a follow-up visit was quantified.
Follow-up visits after the Mirena insertion were initially after 1, 3 and 6 months, and thereafter every 6 months. A month before each visit, the patients completed a diary of their pain scores and menstrual loss. These were collected at the follow-up visit and new diaries given for the next visits. Each subject signed an informed consent to partake in the study, which was also approved by the local ethics committee.
Data analysis
SPS version 11.0 was used to record and statistically analyse the data. Values at the time of the insertion of the intrauterine system (i.e. time zero) were compared with those at different time points after insertion using the 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, 6, 12, 18, 24, 30 and 36 months using a VAS, as well as overall satisfaction with the 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 continuation rates and reasons for requesting for removal over the 3-year period are shown in Table I. The device was retained by 29 (85%) women at 6 months, 23 (68%) at 12 months, 21 (62%) at 24 months and 19 (56%) at 36 months. There were five discontinuations before 6 months for personal reasons (one), pelvic pain (three) and acne (one). After 6 months, six requested removal because of weight gain and acne (one), migraine headaches, weight gain and irregular periods (one), and no improvement in symptoms and irregular bleeding (four). There were only four patients who requested the device to be removed after 12 months, the reasons being bleeding problems (two), weight gain and persistent abdominal pain that was thought to be related to a functional ovarian cyst (one), and planning to start a family (one). Out of a total of 15 discontinuations, five (33%) were for unacceptable irregular bleeding (unscheduled bleeding), most of which were within the first 6 months. Pelvic pain (20.6%) and weight gain (8.8%) were the second and third most common reason for requesting for removal, respectively. There were no expulsions over the 3-year period.
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Table III demonstrates the side-effects reported by the patients during the study period. The most common was irregular vaginal bleeding. There was a single case of severe depression, which responded well to a 3-month course of antidepressants. She was not willing to discontinue the device as it had significantly improved the quality of her life. The partners of two patients complained of discomfort during sexual intercourse caused by the strings of the device. Although these were shortened, the discomfort persisted but in a mild form, hence the patients retained the device. There were three cases of simple functional ovarian cysts diagnosed at laparoscopy and confirmed on ultrasound scan. Two of these presented with one-sided abdominal pain. All cases were monitored with serial ultrasound scan only.
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Discussion |
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The main reasons for discontinuation were menstrual irregularities, persistent pelvic pain and weight gain. The menstrual problems were predominantly during the first 6 months on the device. These findings are not dissimilar to those in women on the device for contraception and the treatment of menorrhagia. In this study only two patients requested that the device be removed, for unacceptable spotting after the first 6 months. If this information is provided to patients during counselling and at follow-up visits, we would anticipate the continuation rates to remain high. Although there have been anectodal approaches to managing irregular bleeding in such women, such as the short-term use of the combined oral contraceptive pill, there are no studies on the best approach to treatment. Until this evidence is available, we would advocate a careful selection of patients, pre-insertion counselling supported by information leaflets and regular re-assuring follow-up visit during the first 6 months.
The most dramatic improvements in symptoms as determined by the VAS, VRS and quantified blood loss occurred during the first 12 months of therapy. Thereafter, there were no significant changes in the variables used to assess response to treatment over the remaining 24 months. Whether these improvements in symptoms will persist for the entire 5 years remains to be determined.
The proportion of women experiencing unacceptable unscheduled bleeding was similar to that reported by Vercellini and colleagues (Vercellini et al., 1999; 2003
). However, the proportion of those continuing with the device at 12 months was lower in our study compared with that reported previously (Vercellini et al., 1999
; 2003
; Fedele et al., 2001
). The drop-out rates between 12 and 36 months were, however, higher in patients having the device as adjunct to surgery (Vercellini et al., 2003
) compared with our study, where it was used as the only treatment modality. These differences could partly be explained by the patients enrolled in these studies: a large proportion of our patients were undergoing treatment for the first time, while those in the other studies had already had other forms of treatment and were therefore more likely to tolerate side-effects, provided the treatment resulted in an improvement in their symptoms. Additionally, the numbers in our study are small.
The precise mechanism by which this device acts in pelvic endometriosis is uncertain. Several suggestions have been proposed including systemic (Luukkainen, 2000) and local (Pakarinen et al., 1995
; Jones and Critchely, 2000
; Hurskainen et al., 2000
) actions. The systemic effects are most likely to be mediated via the suppression of ovulation. The critical systemic level of levonorgestrel required to achieve this is 200 pg/ml (Nilsson and Lukkainen, 1977
). This level is achieved in most women during the first 3 months on the device, and falls thereafter. In fact, anovulatory rates of between 71% and 85% have been reported during the first 3 months on the device. It is perhaps only during this time that this mechanism influences patient's symptoms, since the ovulatory rate remains low in a large number of women (Lahteenmaki et al., 2000
).
Various potential local mechanisms have been proposed for the action of this device in women with endometriosis, but an exact understanding of these mechanisms remains unclear. We measured serum and peritoneal fluid levonorgestrel levels in this cohort during the second-look laparoscopy and demonstrated that the peritoneal fluid levels were approximately two-thirds of the serum levels. These laboratory data and discussions about the possible mechanisms of action of the device will be published separately (Lockhat et al., 2005). A combination of a reduction in peritoneal fluid volume (Drake et al., 1980
; Khorram et al., 1993) and a low concentration of peritoneal fluid macrophages (Ramey and Archer, 1993
) and inflammatory markers (Haney and Weinberg, 1988
; Kupker et al., 1998
) may be one of the mechanisms by which this device alters the symptom of pelvic pain. Whatever the case, it is likely that the device is effective through a combination of systemic and local mechanisms. The changes in the staging we demonstrated at 6 months (Lockhat et al., 2004
) suggest that there is likely to be a local effect on the condition, although this is by no means conclusive, since systemic levonorgestrel may also induce the same changes. Whatever the exact mechanism, the local effect of the progestogen on the endometrium resulting in hypomenorrhoea or amenorrhoea significantly improves the pain of dysmenorrhoea and menorrhagia.
Although it is perhaps not unreasonable to adduce from these findings that the improvement in symptoms was primarily a result of the levonorgestrel device, the placebo effect of the diagnostic laparoscopy cannot be eliminated. The only way to answer this question will be a randomized trial where one group receives the levonorgestrel intrauterine system and another a placebo intrauterine system. Since such a placebo device is currently not available, the copper intrauterine device may be used. We are currently undertaking such a randomized controlled trial with the gold standard for the medical treatment of endometriosis.
The results presented provide the first evidence to support the long-term use of this form of therapy in women presenting with symptoms of endometriosis. A better tool for the assessment of its overall effectiveness in these patients would have been a quality of life analysis. Unfortunately this was not used in this study, but will now be used in subsequent studies. Whether the symptom control observed over the 3-year period reported here will persist for the remaining 2 years of the lifespan of the device remains unanswered. Since there are no forms of medical therapy that offer such long-term relief of symptoms, it will be difficult to undertake randomized, controlled and comparable studies. However, there is the need to gather more information on the long-term use of this device, especially in the older patient who may ultimately avoid the need for a hysterectomy.
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Acknowledgements |
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References |
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Submitted on May 20, 2004; resubmitted on July 9, 2004; accepted on October 20, 2004.