1 Human Reproduction Unit, Department of Obstetrics and Gynaecology, School of Medicine, Universidade Estadual de Campinas (UNICAMP), Campinas, 2 Department of Obstetrics and Gynaecology, School of Medicine, Universidade de São Paulo (FMUSP-RP), Ribeirão Preto and 3 Endometriosis Unit, Department of Obstetrics and Gynaecology, School of Medicine, Universidade de São Paulo (FMUSP-SP), São Paulo, Brazil
4 To whom correspondence should be addressed at: Caixa Postal 6181, 13084-971, Campinas, SP, Brazil. Email: cpetta{at}attglobal.net
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Abstract |
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Key words: endometriosis/GnRH analogue/intrauterine levonorgestrel/pain
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Introduction |
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The LNG-IUS releases levonorgestrel (LNG) directly into the uterine cavity at a relatively constant rate of 20 µg/day for 5 years (Luukkainen et al., 1990). Since it is a 19-nortestosterone derivative, LNG exerts strong progestational activity (Sitruk-Ware, 2004
) and induces profound effects on the endometrium, which becomes atrophic and inactive, although ovulation is usually not suppressed (Nilsson et al., 1980
; Odlind, 1996
). Depending on the methodology of evaluation of blood loss and the definition of amenorrhoea, complete inhibition of menstruation has been observed in 2060% of LNG-IUS users (Nilsson et al., 1980
; Odlind, 1996
; Hidalgo et al., 2002
). Previous studies have suggested that the LNG-IUS is able to relieve CPP and dyspareunia in women with endometriosis (Vercellini et al., 1999
, 2003
) and to alleviate dysmenorrhoea associated with adenomyosis (Fedele et al., 2001
). In addition, one observational study showed an improvement in the staging of endometriosis after 6 months of use of the LNG-IUS (Lockhat et al., 2004
) and an improvement in the control of symptoms for 3 years following insertion (Lockhat et al., 2005
). However, these studies have been either non-comparative (Vercellini et al., 1999
; Fedele et al., 2001
; Lockhat et al., 2004
) or have been compared to expectant management only (Vercellini et al., 2003
), generally with a relatively small sample size.
The aim of this randomized comparative trial was to determine the effect of LNG-IUS compared to a GnRH analogue on endometriosis-associated CPP and quality of life, during 6 months of treatment.
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Materials and methods |
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All the women had had regular menstrual periods (2535 day intervals) for 3 months before entering the study, had not used any hormonal therapy for
3 months prior to the study, and had not taken long-acting progestins or GnRH analogue therapy in the preceding 9 months. None of the women had been breastfeeding or pregnant during the 3 months preceding the study, they had no history of osteoporosis, coagulation disorders, or contraindications to LNG-IUS as defined by the World Health Organization (2004)
.
Using a computer-generated system of sealed envelopes, patients were randomized to receive either an LNG-IUS (Mirena®; Schering Oy, Finland) or GnRH analogue (Lupron depot 3.75 mg; TAP Pharmaceuticals, USA), 6 ampoules, 1 ampoule i.m. every 28±3 days. LNG-IUS was inserted or GnRH analogue treatment was initiated within the first 7 days of the menstrual cycle. No adverse events occurred during insertion of the LNG-IUS. Users of the GnRH analogue were advised to use a barrier method of contraception to prevent pregnancy during treatment. Patients were instructed to use no medication other than that provided during the study.
Follow-up visits were scheduled every 28±3 days after initiation of treatment for at least six completed visits following randomization. Women randomized to use the LNG-IUS were allowed to keep the system after completion of the study and are being followed-up regularly at the same clinic. To assess the response to treatment, we evaluated the changes in the patient's daily perception of pelvic pain, daily bleeding score, daily occurrence of vasomotor symptoms, and their quality of life. All women received a pain score diary and a bleeding diary. Pain was evaluated by comparing the mean score recorded each month with the score registered in the month prior to study initiation.
The pain score diary was based on the VAS in which patients recorded the occurrence and intensity of their pain daily (Woodforde and Merskey, 1972). VAS consists of a subjective evaluation of the pain on a scale of 10 in which 0 is no pain and 10 the most severe pain (Howard, 2003
). The score was recorded daily in the diary by marking a point somewhere along a 10 cm line. The monthly score was calculated as the result of the sum of the daily scores divided by the number of days in each observation period. Additionally, the participants were questioned about their cycle length before being admitted to the study and at every monthly follow-up visit. Bleeding patterns were assessed by the participants throughout the study on a daily basis and recorded in individual diaries. Bleeding was assessed as: 0=no bleeding; 1=spotting (light bleeding not requiring sanitary protection); 2=light bleeding (light bleeding requiring sanitary protection); 3=normal bleeding (bleeding similar to normal menstrual blood flow); and 4=heavy bleeding (bleeding exceeding normal menstrual blood flow). No bleeding was defined as 30 consecutive days with bleeding score 0 (Rodriguez et al., 1976
; World Health Organization, 1986
). The mean bleeding score was calculated by dividing the sum of the daily scores by the number of days in each observation period.
Patients were also asked specifically about the daily occurrence of vasomotor symptoms, vaginal dryness, mood changes, breast tenderness, peripheral oedema, and abdominal distension, and were requested to record the occurrence of these symptoms in the diary. At the pretreatment visit and at study completion (visit 6), volunteers answered the Psychological General Well-Being Index Questionnaire (PGWBI) (Dupuy, 1984) to evaluate their quality of life.
Sample size was estimated at a minimum of 32 women per study arm, based on a 100% improvement in clinical symptoms as observed previously by Fedele et al. (2001) and a maximum absolute difference of 20% between treatments.
was set at 0.05 and
at 0.20 (Pocock, 1987
). For quantitative variables with normal distribution, the parametric t-test was used; in the case of the other variables, the non-parametric MannWhitney test was applied. For qualitative variables,
2-test or Fisher's exact test were used (Altman, 1999
). For dependent variables with numerical scores referring to long-term measurement, multivariate analysis of variance (MANOVA) was used, with four sources of variation: stage of endometriosis (I and II versus III and IV), treatment, time (or period between visits), and interaction between treatment and time (Johnson and Wichern, 1982
). For comparison between treatment groups, in which each visit was analysed separately, the non-parametric MannWhitney test was applied.
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Results |
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Compared to pretreatment values, the PGWBI scores of LNG-IUS users increased by 8.3 (SD±15) points, whereas the scores of GnRH analogue users increased 6.8 (SD±18.2) points. This increase was not significant in either group and there was no significant difference between the groups (P=0.474). Table II presents PGWBI scores recorded during the pretreatment cycle (baseline) and at study completion visit (visit 6).
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Discussion |
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GnRH analogues have long been used to treat endometriosis-associated CPP, principally because they provoke anovulation, hypoestrogenism with amenorrhoea, and a reduction in endometriotic lesions (Prentice et al., 2000; Lockhat et al., 2004
; Schroder et al., 2004
). However, the main concerns with respect to hypoestrogenism are the induction of vasomotor symptoms and the effect on bone mineral density, including the risk of osteoporosis. For this reason, treatment with GnRH analogue alone is usually limited to a period of 6 months, although longer treatment with add-back hormone therapy is now common (Prentice et al., 2000
). In addition, GnRH analogues are an expensive medication, not readily available to women worldwide, especially in developing countries.
Endometriosis is an enigmatic disease, affecting up to 10% of women of reproductive age. There is a need, therefore, for better treatment options than the ones currently available, offering therapeutic efficacy over a longer period of time at an affordable cost, and with easy administration. Several possibilities are currently under investigation (Fedele and Berlanda, 2004). Although endometriosis is a frequent cause of infertility, not all patients with endometriosis wish to conceive and some contraceptive methods have been used to control pain, including the LNG-IUS (Vercellini et al., 1996
, 1999
, 2003
; Fedele et al., 2001
; Lockhat et al., 2004
, 2005
). Previous reports on the effect of the LNG-IUS in the control of CPP in women with endometriosis have been encouraging (Vercellini et al., 1999
, 2003
; Fedele et al., 2001
; Lockhat et al., 2004
, 2005
) but large, randomized, comparative studies are needed.
Our study provides evidence that the LNG-IUS is as effective as GnRH analogue in the control of endometriosis-associated CPP and can be used to treat patients with this symptom. Compared to previous observational studies (Lockhat et al., 2004), the present trial also included patients with more severe stages of the disease (stage IIIIV) (American Fertility Society, 1985
), although one previous study also included patients with stage IIV (Vercellini et al., 2003
). In this study, duration of treatment was limited to 6 months because this is the maximum recommended duration of GnRH use; however, the therapeutic effect of the LNG-IUS is potentially much longer since the device has been approved for 5 years of use. Release of LNG from this device is almost 20 µg per day during the first year, slowly decreasing to 11 µg/day at 5 years of use (Luukkainen et al., 1990
). Despite the small amount of LNG released by the system, amenorrhoea is achieved in
60% of women after 6 months of use and this percentage remains stable throughout the years of use (Hidalgo et al., 2002
). Therefore, based on the induced endometrial atrophy that provokes amenorrhoea, it is possible to speculate that the LNG-IUS may be effective in controlling CPP over the same period of time. It is important to note that the longer the effect on the control of pain, the more cost-effective the LNG-IUS will be. Moreover, the market cost of one LNG-IUS in Brazil is only a little higher than just one ampoule of the GnRH analogue.
Although effective in controlling CPP and reducing the stage of endometriosis (Lockhat et al., 2004), the precise mechanism of action of the LNG-IUS in endometriosis is unclear and at the present moment can only be speculated. Previous studies have shown a decrease in the extension of recto-vaginal septum lesions as evaluated by ultrasonography (Fedele et al., 2001
), and a decrease in the severity of endometriosis at laparoscopy (Vercellini et al., 2003
; Lockhat et al., 2004
). The mechanism of action of the LNG-IUS on endometriosis is apparently different from that of GnRH analogue, as the former does not inhibit ovulation in the majority of women (Barbosa et al., 1995
), does not provoke hypoestrogenism (Nilsson et al., 1980
), and the concentration of LNG outside the uterus is very low and similar to serum levels (Nilsson et al., 1982
).
The adverse effects of the LNG-IUS and GnRH analogue were expected. It is important to note that although some adverse effects occurred in both groups, no woman in either treatment group discontinued the study because of side-effects. These women have a chronic disease that has a great impact on their quality of life (Marques et al., 2004) and they are therefore presumably highly motivated to continue using the GnRH analogue or the LNG-IUS for the control of pain despite the occurrence of side-effects.
Higher bleeding scores were recorded in LNG-IUS users than in the GnRH analogue group. As observed in clinical trials on the use of the LNG-IUS for contraception (Hidalgo et al., 2002; Baldaszti et al., 2003
), LNG-IUS users experienced light, irregular bleeding during the initial months of use, which decreased after the 3rd month of use. By study completion, 70% of the women were amenorrhoeic. In comparison, all GnRH analogue users became amenorrhoeic in a shorter time.
Endometriosis is a disease that impairs women's quality of life (Marques et al., 2004). This study showed a slight increase in the PGWBI scores but no significant improvement in the psychological well-being of these women compared to pretreatment scores. It is important to note that a symptom such as pain may be part of a larger picture involving the emotional and general well-being of an individual. In addition, the PGWBI is a general measure of intra-psychic well-being and is not specific to any particular condition, which may represent a limitation of the instrument for the evaluation pursued in this study (Woodforde and Merskey, 1972
).
Many women with endometriosis and pain no longer wish to become pregnant or may wish to delay pregnancy for some time. For these women, few long-term therapeutic options are available. Our results suggest that the LNG-IUS may be a possible treatment of choice since it offers the opportunity to use the same system for 5 years and provides highly effective contraception at the same time. In addition, in Brazil, the LNG-IUS is more cost-effective than GnRH analogue for the medical treatment of endometriosis-associated CPP. Its efficacy was similar to that of GnRH analogue over short-term use (6 months), but its long-term use still needs to be evaluated. Unfortunately this study was unable to identify a subset of women who were more likely to benefit from treatment with the LNG-IUS.
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Acknowledgements |
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Submitted on October 21, 2004; resubmitted on February 15, 2005; accepted on February 23, 2005.