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Efficacy of the levonorgestrel-releasing intrauterine system in uterine leiomyoma
International Journal of Gynecology and Obstetrics 116 (2012) 35–38
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CLINICAL ARTICLE
Efficacy of the levonorgestrel-releasing intrauterine system in uterine leiomyoma Alka Kriplani, Divya Awasthi, Vidushi Kulshrestha, Nutan Agarwal ⁎ Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India
a r t i c l e
i n f o
Article history: Received 21 February 2011 Received in revised form 23 July 2011 Accepted 1 September 2011 Keywords: Leiomyoma Leiomyoma-related abnormal uterine bleeding Levonorgestrel-releasing intrauterine system Menstrual blood loss Menorrhagia
a b s t r a c t Objective: To evaluate the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) in reducing menstrual blood loss (MBL) in myoma-related menorrhagia and to assess the effect of the LNG-IUS on uterine and leiomyoma volume. Methods: A prospective comparative study investigated the effect of LNG-IUS use in women with myoma-related menorrhagia (n = 54) and women with idiopathic menorrhagia (n = 50). The outcome was assessed in terms of reductions in MBL and in myoma and uterine volume. Results: Within 1 month of LNG-IUS insertion, the Pictorial Blood Loss Assessment Chart score in the myoma group fell by 86.8% (P b 0.0001). At 3, 12, 24, 36, and 48 months, the MBL was reduced by 92.1%, 97.4%, 97.4%, 99.5%, and 99.5%, respectively, similar to the effect seen in the idiopathic menorrhagia group. The mean uterine volume was significantly reduced in both groups, but the reduction was greater in the group with leiomyomas (idiopathic menorrhagia, P = 0.038; myoma-related menorrhagia, P = 0.012). There was no statistically significant reduction in the myoma volume (P = 0.409). Conclusion: Use of the LNG-IUS appears to lead to a significant reduction in the uterine volume of women with menorrhagia, as well as reducing the MBL in women with uterine leiomyomas. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Uterine leiomyoma is the most common benign smooth muscle cell tumor of the myometrium, occurring in as many as 30% of women aged over 35 years [1]. Treatment is required only in the presence of symptoms (menorrhagia, pain, and/or pressure). Hysterectomy is a common form of treatment in perimenopausal patients. Younger patients who wish to preserve their fertility can opt for a myomectomy. In the past decade, many alternatives to hysterectomy have emerged, including gonadotropin-releasing hormone (GnRH) analogs and the levonorgestrel-releasing intrauterine system (LNGIUS). However, GnRH analogs cannot be used for extended treatment; the LNG-IUS does not have this limitation [2]. The LNG-IUS (Mirena) was launched as a contraceptive by Schering (Turku, Finland) in 1990 and was subsequently found to be efficacious in the treatment of heavy menstrual blood loss (MBL) [3–6]. Use of the LNG-IUS leads to a reduction in MBL shortly after insertion because of its antiproliferative action on the endometrium [7]. Previous studies have shown a reduction in MBL and a significant improvement in anemia in users of the LNG-IUS, particularly in cases of anemia caused by menorrhagia [3,8–11]. Therefore, this system is now used in the treatment of idiopathic menorrhagia [11–13]. Only a few prospective studies have examined use of the LNG-IUS specifically for the treatment of fibroid-related menorrhagia, which is ⁎ Corresponding author at: 55, New Campus, I.I.T., Hauz Khas, New Delhi 110029, India. Tel.: + 91 11 26864284/26510320; fax: + 91 11 26588641/26588663. E-mail address: [email protected] (N. Agarwal).
classified by the International Federation of Gynecology and Obstetrics (FIGO) as leiomyoma-related abnormal uterine bleeding (AUBL) [14]). Grigorieva et al. [13] reported that, in addition to reducing MBL, insertion of the LNG-IUS in women with myomas resulted in a reduction in myoma volume and in total uterine volume. However, Maruo et al. [15] concluded that the use of levonorgestrel does not always lead to a reduction in the volume of leiomyomas and may even stimulate the proliferative activity of leiomyoma cells. In view of the controversy surrounding this subject, the present study was designed to compare the efficacy of the LNG-IUS in reducing the MBL in AUB-L with its efficacy in reducing the MBL in idiopathic menorrhagia, and to assess the effect of the LNG-IUS on the uterine and leiomyoma volume in women with AUB-L who have opted to use the LNG-IUS for the treatment of menorrhagia. 2. Materials and methods The present prospective comparative study was conducted in the Department of Obstetrics and Gynecology at the All India Institute of Medical Sciences, New Delhi, India, from May 1, 2005, to May 31, 2009. The Ethical Committee of the study institution approved the trial protocol and all participants provided written informed consent. In total, 104 women of reproductive age (25–45 years) who complained of menorrhagia and wished to preserve their reproductive function were considered eligible for the study. The study included 2 groups. Group I comprised women with menorrhagia who had at least 1 myoma (FIGO category AUB-L). Exclusion criteria were active pelvic inflammatory disease, type 0 or type I submucous myoma (European
0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2011.07.031
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A. Kriplani et al. / International Journal of Gynecology and Obstetrics 116 (2012) 35–38
Society of Hysteroscopy classification), adenomyosis, congenital or acquired uterine malformation, and premalignant or malignant uterine disease. Group II (the control group) included age-matched women with idiopathic menorrhagia, which comprised the FIGO abnormal uterine bleeding categories AUB-O (ovulatory dysfunction), AUB-E (endometrial), and AUB-N (not yet classified) [14]. Women with atypical changes on endometrial aspiration were excluded. The MBL was semi-quantitatively assessed with the Pictorial Blood Loss Assessment Chart (PBAC), which takes into account the number of sanitary pads used and the degree to which they are soiled with blood [16]. A PBAC score of 100 or more was considered to be diagnostic of menorrhagia. This cutoff value has sensitivity and specificity values of more than 80% [16]. The participants received clear instructions on how to fill in the charts daily during their menstrual flow and were advised to use similar kinds of sanitary napkins. Before LNG-IUS insertion, all women underwent a detailed history interview, complete physical examination, routine laboratory evaluation (hemoglobin, total leukocyte count, platelet count, thyroid profile, and fasting and postprandial blood sugar), transvaginal sonography, endometrial aspiration with a 4-mm Karman cannula, cervical smear, and hysteroscopy to evaluate the uterine cavity and the submucosal component. According to the Wamsteker classification, which has been adopted by the European Society of Hysteroscopy, myomas that had all their volume in the cavity, attached with a stalk, were classified as type 0 (pedunculated intracavitary), myomas that had more than 50% of their volume in the cavity were classified as type I, and myomas that had less than 50% of their volume in the cavity were classified as type II. A type II myoma is principally an intramural myoma with a submucosal component. After the complete work-up, the LNG-IUS (currently marketed as Mirena by Bayer Oy Pharmaceuticals, Turku, Finland) was inserted. The patients were called for follow-up at 1 month, 3 months, 12 months, 2 years, 3 years, and 4 years after insertion of the LNGIUS. The primary outcome measures were reductions in MBL and in myoma and uterine volume. The PBAC score was noted before LNG-
IUS insertion and at each follow-up. The size of the uterine myoma was assessed before insertion and at 2 years. Secondary outcome measures were patient satisfaction (premature removal of the LNGIUS) and the 12-month rate of hysterectomies performed because of insufficient symptom relief. A repeated-measures analysis was used to evaluate changes over time, followed by post-hoc comparison by the least-square deviation method, using SPSS version 15 (SPSS, Chicago, IL, USA). Pb0.05 was considered statistically significant. 3. Results In total, 54 women with myoma-related menorrhagia were recruited into group I and 50 age-matched women with idiopathic menorrhagia were recruited into group II (Fig. 1). The median age of the patients in group I was 38 years (mean 38.75 ± 5.16, range 30–50 years). The median age in group II was 41 years (mean 40.5± 6.23, range 29–52 years). In group I, 45 (83.3%) women were multiparas, 5 (9.3%) were primiparas, and 4 (7.4%) were nulliparas. In group II, 42 (84.0%) women were multiparas, 6 (12.0%) were primiparas, and 2 (4.0%) were nulliparas. No clinically significant differences were evident between the 2 groups with regard to medical history, obstetric history, concomitant diseases, concomitant medication, physical examination, systolic/diastolic blood pressure, or body mass index. In group I, the median duration of menorrhagia was 28 months (range 3–192 months). The median number of bleeding days was 8 and the median PBAC score was 380 (mean 464.2 ± 258.3, range 120–1300). Forty-two (77.8%) patients had dysmenorrhea. By comparison, the median duration of menorrhagia in group II was 24 months (range 6–160 months). The median number of bleeding days was 12 and the median PBAC score was 460 (mean, 538.8 ± 56.1; range, 220–1800). In group I, 13 (24.1%) women had a submucosal myoma (type II), 38 (70.4%) had an intramural myoma, and 3 (5.6%) had a subserosal myoma as the main component; 17 (31.5%) women had multiple myomas. All 3 patients with a subserosal myoma (FIGO class O6) had
Group I (n=54)
Group II (n=50)
Premature removal (n=3) because of pain (at 6 and12months) (n=2) because of menorrhagia (at 12 months) (n=1)
. .
Lost to follow-up (n=3) Complete expulsion (n=4) . after 2 months (n=1) . after 6 months (n=1)
. . . .
after 12 months (n=1) after 15 months (n=1)
Premature removal (n=2) because of dysmenorrhea (at 1 month) (n=1) because of menorrhagia (at 2 months) (n=1)
Partial expulsion after 2 months (n=1) reinserted continued therapy
Lost to follow-up (n=2)
Complete expulsion after 6 months (n=1)
. .
Hysterectomy (n=4) after expulsion (n=1) because of lack of response (n=3)
. .
Partial expulsion after 1 month (n=1) reinserted continued therapy
Hysterectomy (n=3) after expulsion (n=1) because of lack of response (n=2)
. .
Continued therapy (n=40)
Continued therapy (n=42) Fig. 1. Flow of participants.
A. Kriplani et al. / International Journal of Gynecology and Obstetrics 116 (2012) 35–38
multiple myomas and were included because they presented with heavy MBL [14]. The median fibroid size was 3.5 cm (mean 3.6 ±1.6 cm, range 1.0–7.9 cm). The size of the uterus ranged from 6 weeks to 16 weeks in group I and from 6 weeks to 12 weeks in group II. The most common adverse effect of the LNG-IUS was prolonged intermenstrual bleeding/spotting during the first 3 months following insertion (observed in 31/46 [67.3%]) among patients in group I. However, the spotting in group I decreased progressively in subsequent months, and by the end of 12 months 9/41 (21.9%) patients had become amenorrheic and 21/41 (51.2%) continued to have spotting. In group II, 23/39 (58.9%) patients experienced intermenstrual bleeding/spotting at 3 months, which decreased gradually, and 11/33 (33.3%) patients became amenorrheic and 14/33 (42.4%) had spotting at 12 months. Other adverse effects in group I were weight gain (10 [18.5%], with the mean weight gain being 4.37 ± 3.21 kg), backache (14 [25.9%]), leg pain (4 [7.4%]), amenorrhea at 1 year (9/41 [21.9%]), vaginal discharge (6 [11.1%]), headache (5 [9.3%]), body swelling (7 [13.0%]), breast tenderness (3 [5.6%]), sleeping problems (5 [9.3%]), mood changes (1 [1.9%]), hot flushes (3 [5.6%]), chloasma (1 [1.9%]), ovarian cysts (2 [3.7%]), and acne (1 [1.9%]). The adverse effects in group II were weight gain (12.0 [24%]), amenorrhea at 1 year (17 [34.0%]), backache (10 [20.0%]), vaginal discharge (7 [14.0%]), breast tenderness (5 [10.0%]), body swelling (3 [6.0%]), and hot flushes (1 [2.0%]). None of the patients discontinued the LNG-IUS because of adverse effects. The MBL was markedly reduced in both groups after device insertion (Table 1). After the first month, the PBAC score was reduced by 86.6% in group I and by 73.9% in group II. At subsequent time points, the extent of the decrease in the 2 groups was comparable. The uterine volume differed significantly between the 2 groups and at different time points (Fig. 2). The mean uterine volume was reduced by 63.6 ± 19.0 cm 3 in group I (P = 0.012; Table 2) and by 43.4 ± 15.3 cm 3 in group II (P = 0.038). With respect to the mean leiomyoma volume, a small reduction of 6.1 ± 3.1 cm 3 was seen after 2 years of LNG-IUS use (Table 2); however, this difference was not statistically significant (P = 0.4099). The device was expelled spontaneously in 5/51 (9.8%) women in group I, 1 of whom eventually underwent a hysterectomy because her symptoms worsened (Fig. 1). One of the 5 women experienced a partial expulsion (the lower end of the device's vertical stem protruded from the external cervical os) at 2 months. The device was reinserted with all precautions taken. Expulsion of the device was more common among patients with a submucosal fibroid (2/13 [15.4%]) than among those with other fibroid types (3/38 [7.9%]) and among those with idiopathic menorrhagia (2/48 [4.2%]). In group I, 3/51 (5.9%) women opted for LNG-IUS removal within 12 months of insertion and underwent a hysterectomy—2 because of persisting pain and 1 because of persisting menorrhagia (Fig. 1). A fourth woman had a hysterectomy after expulsion of the device. The
37
fibroid uterus 180
idiopathic menorrhagia
160 140 120 100 80 60 40 20 0
baseline
3 mths
12 mths
24mths
Fig. 2. Effect of the levonorgestrel-releasing intrauterine system on mean uterine volume (cm3).
overall hysterectomy rate in group I was therefore 7.8%. In group II, 2/48 (4.2%) women discontinued the LNG-IUS because they had no symptomatic relief. Three (6.3%) women, including those who discontinued the LNG-IUS, had a hysterectomy in this group. 4. Discussion The present study provides the longest follow-up to date of uterine leiomyoma cases managed with the LNG-IUS and has compared the effectiveness of the LNG-IUS in patients who had AUB-L with that in patients who had idiopathic menorrhagia (AUB-E, AUB-O, AUB-N). The LNG-IUS proved to be significantly effective in reducing PBAC scores in women with a fibroid uterus and menorrhagia. The LNG-IUS was as effective in AUB-L as in idiopathic menorrhagia; in fact, during the early follow-up period its effect was greater in the myoma cases. At 4 years, the effect was similar in both groups. The reduction in MBL achieved in women with AUB-L was excellent (86.8% after 1 month, 97.4% after 1 year, and 99.5% after 4 years). This result is extremely good compared with most other studies. Grigorieva et al. [13] reported 83.5% reduction in PBAC after 12 months of LNG-IUS insertion, whereas we found 97.4% reduction at 12 months. However, when the 9 patients with amenorrhea and the 11 patients with spotting were excluded from the analysis, the MBL at 1 year was reduced by 92.8%, which is comparable to the results from other studies [10]. The incidences of amenorrhea and spotting in the present study were high despite the presence of myomas. This might be attributable to ethnic factors. The most common and bothering adverse effect was intermenstrual bleeding or spotting. This was more prevalent in the leiomyoma
Table 1 Effect of LNG-IUS use on menstrual blood loss. Parameter
Pre-insertion
1 month
3 months
12 months
24 months
36 months
48 months
Uterine leiomyoma PBAC score Median Range Mean ± SD Reduction of median PBAC score, % Idiopathic menorrhagia PBAC score Median Range Mean ± SD Reduction of median PBAC score, %
n = 54
n = 49
n = 46
n = 41
n = 30
n = 19
n = 11
380 120–1300 464.2 ± 258.3 — n = 50
50 10–660 92.6 ± 121.2 86.8 n = 41
30 0–600 59.5 ± 112.4 92.1 n = 39
10 0–210 25.6 ± 45.6 97.4 n = 33
10 0–100 13.02 ± 21.5 97.4 n = 28
2 0–86 9.12 ± 18.16 99.5 n = 18
2 0–28 4.28 ± 6.3 99.5% n = 13
460 220–1800 538.8 ± 56.13 —
120 0–810 139.5 ± 174.3 73.9
36 0–1260 113.6 ± 183.5 92.1
10 0–88 38.7 ± 42.5 97.8
2 0–28 5.2 ± 6.8 99.6
2 0–25 4.9 ± 6.7 99.6
2 0–12 3.2 ± 2.3 99.6%
Abbreviations: LNG-IUS, levonorgestrel-releasing intrauterine system; PBAC, Pictorial Blood Loss Assessment Chart.
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A. Kriplani et al. / International Journal of Gynecology and Obstetrics 116 (2012) 35–38
Parameter
Baseline (n = 54)
3 months (n = 46)
12 months (n = 41)
24 months (n = 30)
these therapeutic benefits to the already proven benefit of being a highly safe and effective contraceptive method. Advantages of the LNG-IUS include not only the prevention but also the delay of surgery. Because LNG-IUS insertion causes a reduction in uterine size, it makes surgery easier and reduces the risk of complications.
Uterine volume, mL Uterine leiomyoma volume, mL
154.6 ± 70.1 27.8 ± 21.3
132.5 ± 65.4 26.7 ± 20.7
119.4 ± 66.1 23.5 ± 15.2
91 ± 72.3 a 21.1 ± 11.1 b
Conflict of interest
Table 2 Effect of the levonorgestrel-releasing intrauterine system on uterine and leiomyoma volume in group I.
a b
P = 0.012 for the comparison with baseline. P = 0.4099 for the comparison with baseline.
The authors have no conflicts of interest. References
group than in the idiopathic menorrhagia group (67.3% versus 58.9%). Intermenstrual bleeding improved over time, and many affected women subsequently became amenorrheic. After 1 year, 21.9% of the women with AUB-L had become amenorrheic, compared with 34.0% in the idiopathic menorrhagia group. The expulsion rate of the LNG-IUS has previously been reported to be 4.2% [17]. A higher rate of 9.8% was observed in the present study. The expulsion rate was even higher in patients with a submucosal fibroid (15.4%), compared with a rate of 7.9% among women with another uterine fibroid type and a rate of 4.2% among women with idiopathic menorrhagia. Most expulsions occurred during the first year of LNG-IUS use. The present study included patients with at least 1 type II myoma (European Society of Hysteroscopy criteria). For both copper-containing intrauterine devices and the LNG-IUS, the WHO stipulates in its 2010 edition of the Medical Eligibility Criteria for Contraceptive Use that “there are no restrictions in women with uterine fibroids without distortion of the cavity. However, for women in whom cavity distortion is present, the WHO indicates that insertion of either device would present an unacceptable health risk” [18]. It should be recognized that the WHO criteria apply only to women who use the devices for contraceptive purposes and not to women considering their use for non-contraceptive indications. The present study found a statistically significant reduction in uterine volume after LNG-IUS insertion. This reduction was particularly high among women with uterine fibroids (P = 0.012), which may be expected because these women have a larger uterus. However, the leiomyoma volume was not significantly reduced. It is possible that the LNG-IUS acts differently on myometrial tissue than on the fibromuscular tissue of leiomyoma but this requires further study. This can also be attributed to the probability of greater inhibition of insulin-like growth factor-I (IGF-I) by IGF-binding protein 1 in the normal myometrial tissue of a larger uterus compared with its effect on a leiomyoma, which is made up of mainly fibrous tissue and minimal myometrial tissue rich in protein [19]. Magalhães et al. [20] found a mean reduction of 64 cm 3 (40.6%) in uterine volume and of 5.2 cm 3 (40%) in leiomyoma volume at 3 years with the LNG-IUS. In the present study, the uterine volume was reduced by 63.6 cm 3 (41.1%) and the leiomyoma volume by 6.1 cm 3 (21.8%) after 2 years of LNG-IUS use. The effect of LNG-IUS insertion on uterine volume is comparable in the 2 studies, but the reduction in leiomyoma volume differs. Although LNG-IUS insertion uniformly causes atrophic changes of the endometrium that are associated with decreased proliferation and increased apoptosis [21], Maruo et al. [22] noted after LNG-IUS insertion that leiomyoma size was increased in onethird of cases, remained the same in one-third, and was decreased in one-third. The rate of premature LNG-IUS removal was 5.9% in the myoma group and 4.2% in the idiopathic menorrhea group, compared with a rate of 2.7% quoted by Andersson et al. [23]. The hysterectomy rate was also higher in the myoma group (7.8% versus 6.3%). In conclusion, use of the LNG-IUS appears to lead to a significant reduction in the uterine volume among women with menorrhagia (more so among women with uterine myoma than among those with idiopathic menorrhagia), as well as resulting in high rates of menorrhagia control among women with uterine leiomyomas, adding
[1] Vollenhoven BJ, Lawrence AS, Healy DL. Uterine fibroids: a clinical review. Br J Obstet Gynaecol 1990;97(4):285–98. [2] ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. Surgical alternatives to hysterectomy in the management of leiomyomas. Number 16, May 2000 (replaces educational bulletin number 192, May 1994). Int J Gynecol Obstet 2001;73(3):285–93. [3] Hubacher D, Grimes DA. Noncontraceptive health benefits of intrauterine devices: a systematic review. Obstet Gynecol Surv 2002;57(2):120–8. [4] Barrington JW, Arunkalaivanan AS, Abdel-Fattah M. Comparison between the levonorgestrel intrauterine system (LNG-IUS) and thermal balloon ablation in the treatment of menorrhagia. Eur J Obstet Gynecol Reprod Biol 2003;108(1): 72–4. [5] Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivelä A, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 2004;291(12):1456–63. [6] Rauramo I, Elo I, Istre O. Long-term treatment of menorrhagia with levonorgestrel intrauterine system versus endometrial resection. Obstet Gynecol 2004;104(6): 1314–21. [7] Luukkainen T. The levonorgestrel intrauterine system: therapeutic aspects. Steroids 2000;65(10–11):699–702. [8] Faúndes A, Alvarez F, Díaz J. A Latin American experience with levonorgestrel IUD. Ann Med 1993;25(2):149–53. [9] Monteiro I, Bahamondes L, Diaz J, Perrotti M, Petta C. Therapeutic use of levonorgestrel-releasing intrauterine system in women with menorrhagia: a pilot study(1). Contraception 2002;65(5):325–8. [10] Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2005;4 CD002126. [11] Rosa e Silva JC, de Sá Rosa e Silva AC, Cândido dos Reis FJ, Manetta LA, Ferriani RA, Nogueira AA. Use of a levonorgestrel-releasing intrauterine device for the symptomatic treatment of uterine myomas. J Reprod Med 2005;50(8):613–7. [12] Singer A, Ikomi A. Successful treatment of fibroids using intrauterine progesterone device (abstract); 1994. Montreal, Canada. [13] Grigorieva V, Chen-Mok M, Tarasova M, Mikhailov A. Use of a levonorgestrelreleasing intrauterine system to treat bleeding related to uterine leiomyomas. Fertil Steril 2003;79(5):1194–8. [14] Munro MG, Critchley HO, Broder MS, Fraser IS, FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynecol Obstet 2011;113(1):3–13. [15] Maruo T, Matsuo H, Samoto T, Shimomura Y, Kurachi O, Gao Z, et al. Effects of progesterone on uterine leiomyoma growth and apoptosis. Steroids 2000;65(10– 11):585–92. [16] Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990;97(8):734–9. [17] Sivin I, Stern J, Coutinho E, Mattos CE, el Mahgoub S, Diaz S, et al. Prolonged intrauterine contraception: a seven-year randomized study of the levonorgestrel 20 mcg/day (LNg 20) and the Copper T380 Ag IUDS. Contraception 1991;44(5): 473–80. [18] WHO. Medical Eligibility Criteria for Contraception Use. 4th edition. WHO; 2010. [19] Giudice LC, Irwin JC, Dsupin BA, Pannier EM, Jin IH, Vu TH. Insulin-like growth factor (IGF), IGF binding protein (IGFBP), and IGF receptor gene expression and IGFBP synthesis in human uterine leiomyomata. Hum Reprod 1993;8(11): 1796–806. [20] Magalhães J, Aldrighi JM, de Lima GR. Uterine volume and menstrual patterns in users of the levonorgestrel-releasing intrauterine system with idiopathic menorrhagia or menorrhagia due to leiomyomas. Contraception 2007;75(3):193–8. [21] Maruo T, Laoag-Fernandez JB, Pakarinen P, Murakoshi H, Spitz IM, Johansson E. Effects of the levonorgestrel-releasing intrauterine system on proliferation and apoptosis in the endometrium. Hum Reprod 2001;16(10):2103–8. [22] Maruo T, Laoag-Fernandez JB, Matsuo H, Samoto T, Kurachi O, Takeuchi S, et al. Effects of levonorgestrel-releasing intrauterine system on the endometrium and the relevance to the management of menorrhagia caused by uterine myoma and adenomyosis. In: Maruo ET, Barlow D, Mardon H, Kennedy S, editors. Cell and Molecular Biology of Endometrium in Health and Disease. Osaka, Japan: Osaka Soeisha; 2001. p. 193–207. [23] Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49(1):56–72.
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International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Efficacy of the levonorgestrel-releasing intrauterine system in uterine leiomyoma Alka Kriplani, Divya Awasthi, Vidushi Kulshrestha, Nutan Agarwal ⁎ Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India
a r t i c l e
i n f o
Article history: Received 21 February 2011 Received in revised form 23 July 2011 Accepted 1 September 2011 Keywords: Leiomyoma Leiomyoma-related abnormal uterine bleeding Levonorgestrel-releasing intrauterine system Menstrual blood loss Menorrhagia
a b s t r a c t Objective: To evaluate the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) in reducing menstrual blood loss (MBL) in myoma-related menorrhagia and to assess the effect of the LNG-IUS on uterine and leiomyoma volume. Methods: A prospective comparative study investigated the effect of LNG-IUS use in women with myoma-related menorrhagia (n = 54) and women with idiopathic menorrhagia (n = 50). The outcome was assessed in terms of reductions in MBL and in myoma and uterine volume. Results: Within 1 month of LNG-IUS insertion, the Pictorial Blood Loss Assessment Chart score in the myoma group fell by 86.8% (P b 0.0001). At 3, 12, 24, 36, and 48 months, the MBL was reduced by 92.1%, 97.4%, 97.4%, 99.5%, and 99.5%, respectively, similar to the effect seen in the idiopathic menorrhagia group. The mean uterine volume was significantly reduced in both groups, but the reduction was greater in the group with leiomyomas (idiopathic menorrhagia, P = 0.038; myoma-related menorrhagia, P = 0.012). There was no statistically significant reduction in the myoma volume (P = 0.409). Conclusion: Use of the LNG-IUS appears to lead to a significant reduction in the uterine volume of women with menorrhagia, as well as reducing the MBL in women with uterine leiomyomas. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Uterine leiomyoma is the most common benign smooth muscle cell tumor of the myometrium, occurring in as many as 30% of women aged over 35 years [1]. Treatment is required only in the presence of symptoms (menorrhagia, pain, and/or pressure). Hysterectomy is a common form of treatment in perimenopausal patients. Younger patients who wish to preserve their fertility can opt for a myomectomy. In the past decade, many alternatives to hysterectomy have emerged, including gonadotropin-releasing hormone (GnRH) analogs and the levonorgestrel-releasing intrauterine system (LNGIUS). However, GnRH analogs cannot be used for extended treatment; the LNG-IUS does not have this limitation [2]. The LNG-IUS (Mirena) was launched as a contraceptive by Schering (Turku, Finland) in 1990 and was subsequently found to be efficacious in the treatment of heavy menstrual blood loss (MBL) [3–6]. Use of the LNG-IUS leads to a reduction in MBL shortly after insertion because of its antiproliferative action on the endometrium [7]. Previous studies have shown a reduction in MBL and a significant improvement in anemia in users of the LNG-IUS, particularly in cases of anemia caused by menorrhagia [3,8–11]. Therefore, this system is now used in the treatment of idiopathic menorrhagia [11–13]. Only a few prospective studies have examined use of the LNG-IUS specifically for the treatment of fibroid-related menorrhagia, which is ⁎ Corresponding author at: 55, New Campus, I.I.T., Hauz Khas, New Delhi 110029, India. Tel.: + 91 11 26864284/26510320; fax: + 91 11 26588641/26588663. E-mail address: [email protected] (N. Agarwal).
classified by the International Federation of Gynecology and Obstetrics (FIGO) as leiomyoma-related abnormal uterine bleeding (AUBL) [14]). Grigorieva et al. [13] reported that, in addition to reducing MBL, insertion of the LNG-IUS in women with myomas resulted in a reduction in myoma volume and in total uterine volume. However, Maruo et al. [15] concluded that the use of levonorgestrel does not always lead to a reduction in the volume of leiomyomas and may even stimulate the proliferative activity of leiomyoma cells. In view of the controversy surrounding this subject, the present study was designed to compare the efficacy of the LNG-IUS in reducing the MBL in AUB-L with its efficacy in reducing the MBL in idiopathic menorrhagia, and to assess the effect of the LNG-IUS on the uterine and leiomyoma volume in women with AUB-L who have opted to use the LNG-IUS for the treatment of menorrhagia. 2. Materials and methods The present prospective comparative study was conducted in the Department of Obstetrics and Gynecology at the All India Institute of Medical Sciences, New Delhi, India, from May 1, 2005, to May 31, 2009. The Ethical Committee of the study institution approved the trial protocol and all participants provided written informed consent. In total, 104 women of reproductive age (25–45 years) who complained of menorrhagia and wished to preserve their reproductive function were considered eligible for the study. The study included 2 groups. Group I comprised women with menorrhagia who had at least 1 myoma (FIGO category AUB-L). Exclusion criteria were active pelvic inflammatory disease, type 0 or type I submucous myoma (European
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Society of Hysteroscopy classification), adenomyosis, congenital or acquired uterine malformation, and premalignant or malignant uterine disease. Group II (the control group) included age-matched women with idiopathic menorrhagia, which comprised the FIGO abnormal uterine bleeding categories AUB-O (ovulatory dysfunction), AUB-E (endometrial), and AUB-N (not yet classified) [14]. Women with atypical changes on endometrial aspiration were excluded. The MBL was semi-quantitatively assessed with the Pictorial Blood Loss Assessment Chart (PBAC), which takes into account the number of sanitary pads used and the degree to which they are soiled with blood [16]. A PBAC score of 100 or more was considered to be diagnostic of menorrhagia. This cutoff value has sensitivity and specificity values of more than 80% [16]. The participants received clear instructions on how to fill in the charts daily during their menstrual flow and were advised to use similar kinds of sanitary napkins. Before LNG-IUS insertion, all women underwent a detailed history interview, complete physical examination, routine laboratory evaluation (hemoglobin, total leukocyte count, platelet count, thyroid profile, and fasting and postprandial blood sugar), transvaginal sonography, endometrial aspiration with a 4-mm Karman cannula, cervical smear, and hysteroscopy to evaluate the uterine cavity and the submucosal component. According to the Wamsteker classification, which has been adopted by the European Society of Hysteroscopy, myomas that had all their volume in the cavity, attached with a stalk, were classified as type 0 (pedunculated intracavitary), myomas that had more than 50% of their volume in the cavity were classified as type I, and myomas that had less than 50% of their volume in the cavity were classified as type II. A type II myoma is principally an intramural myoma with a submucosal component. After the complete work-up, the LNG-IUS (currently marketed as Mirena by Bayer Oy Pharmaceuticals, Turku, Finland) was inserted. The patients were called for follow-up at 1 month, 3 months, 12 months, 2 years, 3 years, and 4 years after insertion of the LNGIUS. The primary outcome measures were reductions in MBL and in myoma and uterine volume. The PBAC score was noted before LNG-
IUS insertion and at each follow-up. The size of the uterine myoma was assessed before insertion and at 2 years. Secondary outcome measures were patient satisfaction (premature removal of the LNGIUS) and the 12-month rate of hysterectomies performed because of insufficient symptom relief. A repeated-measures analysis was used to evaluate changes over time, followed by post-hoc comparison by the least-square deviation method, using SPSS version 15 (SPSS, Chicago, IL, USA). Pb0.05 was considered statistically significant. 3. Results In total, 54 women with myoma-related menorrhagia were recruited into group I and 50 age-matched women with idiopathic menorrhagia were recruited into group II (Fig. 1). The median age of the patients in group I was 38 years (mean 38.75 ± 5.16, range 30–50 years). The median age in group II was 41 years (mean 40.5± 6.23, range 29–52 years). In group I, 45 (83.3%) women were multiparas, 5 (9.3%) were primiparas, and 4 (7.4%) were nulliparas. In group II, 42 (84.0%) women were multiparas, 6 (12.0%) were primiparas, and 2 (4.0%) were nulliparas. No clinically significant differences were evident between the 2 groups with regard to medical history, obstetric history, concomitant diseases, concomitant medication, physical examination, systolic/diastolic blood pressure, or body mass index. In group I, the median duration of menorrhagia was 28 months (range 3–192 months). The median number of bleeding days was 8 and the median PBAC score was 380 (mean 464.2 ± 258.3, range 120–1300). Forty-two (77.8%) patients had dysmenorrhea. By comparison, the median duration of menorrhagia in group II was 24 months (range 6–160 months). The median number of bleeding days was 12 and the median PBAC score was 460 (mean, 538.8 ± 56.1; range, 220–1800). In group I, 13 (24.1%) women had a submucosal myoma (type II), 38 (70.4%) had an intramural myoma, and 3 (5.6%) had a subserosal myoma as the main component; 17 (31.5%) women had multiple myomas. All 3 patients with a subserosal myoma (FIGO class O6) had
Group I (n=54)
Group II (n=50)
Premature removal (n=3) because of pain (at 6 and12months) (n=2) because of menorrhagia (at 12 months) (n=1)
. .
Lost to follow-up (n=3) Complete expulsion (n=4) . after 2 months (n=1) . after 6 months (n=1)
. . . .
after 12 months (n=1) after 15 months (n=1)
Premature removal (n=2) because of dysmenorrhea (at 1 month) (n=1) because of menorrhagia (at 2 months) (n=1)
Partial expulsion after 2 months (n=1) reinserted continued therapy
Lost to follow-up (n=2)
Complete expulsion after 6 months (n=1)
. .
Hysterectomy (n=4) after expulsion (n=1) because of lack of response (n=3)
. .
Partial expulsion after 1 month (n=1) reinserted continued therapy
Hysterectomy (n=3) after expulsion (n=1) because of lack of response (n=2)
. .
Continued therapy (n=40)
Continued therapy (n=42) Fig. 1. Flow of participants.
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multiple myomas and were included because they presented with heavy MBL [14]. The median fibroid size was 3.5 cm (mean 3.6 ±1.6 cm, range 1.0–7.9 cm). The size of the uterus ranged from 6 weeks to 16 weeks in group I and from 6 weeks to 12 weeks in group II. The most common adverse effect of the LNG-IUS was prolonged intermenstrual bleeding/spotting during the first 3 months following insertion (observed in 31/46 [67.3%]) among patients in group I. However, the spotting in group I decreased progressively in subsequent months, and by the end of 12 months 9/41 (21.9%) patients had become amenorrheic and 21/41 (51.2%) continued to have spotting. In group II, 23/39 (58.9%) patients experienced intermenstrual bleeding/spotting at 3 months, which decreased gradually, and 11/33 (33.3%) patients became amenorrheic and 14/33 (42.4%) had spotting at 12 months. Other adverse effects in group I were weight gain (10 [18.5%], with the mean weight gain being 4.37 ± 3.21 kg), backache (14 [25.9%]), leg pain (4 [7.4%]), amenorrhea at 1 year (9/41 [21.9%]), vaginal discharge (6 [11.1%]), headache (5 [9.3%]), body swelling (7 [13.0%]), breast tenderness (3 [5.6%]), sleeping problems (5 [9.3%]), mood changes (1 [1.9%]), hot flushes (3 [5.6%]), chloasma (1 [1.9%]), ovarian cysts (2 [3.7%]), and acne (1 [1.9%]). The adverse effects in group II were weight gain (12.0 [24%]), amenorrhea at 1 year (17 [34.0%]), backache (10 [20.0%]), vaginal discharge (7 [14.0%]), breast tenderness (5 [10.0%]), body swelling (3 [6.0%]), and hot flushes (1 [2.0%]). None of the patients discontinued the LNG-IUS because of adverse effects. The MBL was markedly reduced in both groups after device insertion (Table 1). After the first month, the PBAC score was reduced by 86.6% in group I and by 73.9% in group II. At subsequent time points, the extent of the decrease in the 2 groups was comparable. The uterine volume differed significantly between the 2 groups and at different time points (Fig. 2). The mean uterine volume was reduced by 63.6 ± 19.0 cm 3 in group I (P = 0.012; Table 2) and by 43.4 ± 15.3 cm 3 in group II (P = 0.038). With respect to the mean leiomyoma volume, a small reduction of 6.1 ± 3.1 cm 3 was seen after 2 years of LNG-IUS use (Table 2); however, this difference was not statistically significant (P = 0.4099). The device was expelled spontaneously in 5/51 (9.8%) women in group I, 1 of whom eventually underwent a hysterectomy because her symptoms worsened (Fig. 1). One of the 5 women experienced a partial expulsion (the lower end of the device's vertical stem protruded from the external cervical os) at 2 months. The device was reinserted with all precautions taken. Expulsion of the device was more common among patients with a submucosal fibroid (2/13 [15.4%]) than among those with other fibroid types (3/38 [7.9%]) and among those with idiopathic menorrhagia (2/48 [4.2%]). In group I, 3/51 (5.9%) women opted for LNG-IUS removal within 12 months of insertion and underwent a hysterectomy—2 because of persisting pain and 1 because of persisting menorrhagia (Fig. 1). A fourth woman had a hysterectomy after expulsion of the device. The
37
fibroid uterus 180
idiopathic menorrhagia
160 140 120 100 80 60 40 20 0
baseline
3 mths
12 mths
24mths
Fig. 2. Effect of the levonorgestrel-releasing intrauterine system on mean uterine volume (cm3).
overall hysterectomy rate in group I was therefore 7.8%. In group II, 2/48 (4.2%) women discontinued the LNG-IUS because they had no symptomatic relief. Three (6.3%) women, including those who discontinued the LNG-IUS, had a hysterectomy in this group. 4. Discussion The present study provides the longest follow-up to date of uterine leiomyoma cases managed with the LNG-IUS and has compared the effectiveness of the LNG-IUS in patients who had AUB-L with that in patients who had idiopathic menorrhagia (AUB-E, AUB-O, AUB-N). The LNG-IUS proved to be significantly effective in reducing PBAC scores in women with a fibroid uterus and menorrhagia. The LNG-IUS was as effective in AUB-L as in idiopathic menorrhagia; in fact, during the early follow-up period its effect was greater in the myoma cases. At 4 years, the effect was similar in both groups. The reduction in MBL achieved in women with AUB-L was excellent (86.8% after 1 month, 97.4% after 1 year, and 99.5% after 4 years). This result is extremely good compared with most other studies. Grigorieva et al. [13] reported 83.5% reduction in PBAC after 12 months of LNG-IUS insertion, whereas we found 97.4% reduction at 12 months. However, when the 9 patients with amenorrhea and the 11 patients with spotting were excluded from the analysis, the MBL at 1 year was reduced by 92.8%, which is comparable to the results from other studies [10]. The incidences of amenorrhea and spotting in the present study were high despite the presence of myomas. This might be attributable to ethnic factors. The most common and bothering adverse effect was intermenstrual bleeding or spotting. This was more prevalent in the leiomyoma
Table 1 Effect of LNG-IUS use on menstrual blood loss. Parameter
Pre-insertion
1 month
3 months
12 months
24 months
36 months
48 months
Uterine leiomyoma PBAC score Median Range Mean ± SD Reduction of median PBAC score, % Idiopathic menorrhagia PBAC score Median Range Mean ± SD Reduction of median PBAC score, %
n = 54
n = 49
n = 46
n = 41
n = 30
n = 19
n = 11
380 120–1300 464.2 ± 258.3 — n = 50
50 10–660 92.6 ± 121.2 86.8 n = 41
30 0–600 59.5 ± 112.4 92.1 n = 39
10 0–210 25.6 ± 45.6 97.4 n = 33
10 0–100 13.02 ± 21.5 97.4 n = 28
2 0–86 9.12 ± 18.16 99.5 n = 18
2 0–28 4.28 ± 6.3 99.5% n = 13
460 220–1800 538.8 ± 56.13 —
120 0–810 139.5 ± 174.3 73.9
36 0–1260 113.6 ± 183.5 92.1
10 0–88 38.7 ± 42.5 97.8
2 0–28 5.2 ± 6.8 99.6
2 0–25 4.9 ± 6.7 99.6
2 0–12 3.2 ± 2.3 99.6%
Abbreviations: LNG-IUS, levonorgestrel-releasing intrauterine system; PBAC, Pictorial Blood Loss Assessment Chart.
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A. Kriplani et al. / International Journal of Gynecology and Obstetrics 116 (2012) 35–38
Parameter
Baseline (n = 54)
3 months (n = 46)
12 months (n = 41)
24 months (n = 30)
these therapeutic benefits to the already proven benefit of being a highly safe and effective contraceptive method. Advantages of the LNG-IUS include not only the prevention but also the delay of surgery. Because LNG-IUS insertion causes a reduction in uterine size, it makes surgery easier and reduces the risk of complications.
Uterine volume, mL Uterine leiomyoma volume, mL
154.6 ± 70.1 27.8 ± 21.3
132.5 ± 65.4 26.7 ± 20.7
119.4 ± 66.1 23.5 ± 15.2
91 ± 72.3 a 21.1 ± 11.1 b
Conflict of interest
Table 2 Effect of the levonorgestrel-releasing intrauterine system on uterine and leiomyoma volume in group I.
a b
P = 0.012 for the comparison with baseline. P = 0.4099 for the comparison with baseline.
The authors have no conflicts of interest. References
group than in the idiopathic menorrhagia group (67.3% versus 58.9%). Intermenstrual bleeding improved over time, and many affected women subsequently became amenorrheic. After 1 year, 21.9% of the women with AUB-L had become amenorrheic, compared with 34.0% in the idiopathic menorrhagia group. The expulsion rate of the LNG-IUS has previously been reported to be 4.2% [17]. A higher rate of 9.8% was observed in the present study. The expulsion rate was even higher in patients with a submucosal fibroid (15.4%), compared with a rate of 7.9% among women with another uterine fibroid type and a rate of 4.2% among women with idiopathic menorrhagia. Most expulsions occurred during the first year of LNG-IUS use. The present study included patients with at least 1 type II myoma (European Society of Hysteroscopy criteria). For both copper-containing intrauterine devices and the LNG-IUS, the WHO stipulates in its 2010 edition of the Medical Eligibility Criteria for Contraceptive Use that “there are no restrictions in women with uterine fibroids without distortion of the cavity. However, for women in whom cavity distortion is present, the WHO indicates that insertion of either device would present an unacceptable health risk” [18]. It should be recognized that the WHO criteria apply only to women who use the devices for contraceptive purposes and not to women considering their use for non-contraceptive indications. The present study found a statistically significant reduction in uterine volume after LNG-IUS insertion. This reduction was particularly high among women with uterine fibroids (P = 0.012), which may be expected because these women have a larger uterus. However, the leiomyoma volume was not significantly reduced. It is possible that the LNG-IUS acts differently on myometrial tissue than on the fibromuscular tissue of leiomyoma but this requires further study. This can also be attributed to the probability of greater inhibition of insulin-like growth factor-I (IGF-I) by IGF-binding protein 1 in the normal myometrial tissue of a larger uterus compared with its effect on a leiomyoma, which is made up of mainly fibrous tissue and minimal myometrial tissue rich in protein [19]. Magalhães et al. [20] found a mean reduction of 64 cm 3 (40.6%) in uterine volume and of 5.2 cm 3 (40%) in leiomyoma volume at 3 years with the LNG-IUS. In the present study, the uterine volume was reduced by 63.6 cm 3 (41.1%) and the leiomyoma volume by 6.1 cm 3 (21.8%) after 2 years of LNG-IUS use. The effect of LNG-IUS insertion on uterine volume is comparable in the 2 studies, but the reduction in leiomyoma volume differs. Although LNG-IUS insertion uniformly causes atrophic changes of the endometrium that are associated with decreased proliferation and increased apoptosis [21], Maruo et al. [22] noted after LNG-IUS insertion that leiomyoma size was increased in onethird of cases, remained the same in one-third, and was decreased in one-third. The rate of premature LNG-IUS removal was 5.9% in the myoma group and 4.2% in the idiopathic menorrhea group, compared with a rate of 2.7% quoted by Andersson et al. [23]. The hysterectomy rate was also higher in the myoma group (7.8% versus 6.3%). In conclusion, use of the LNG-IUS appears to lead to a significant reduction in the uterine volume among women with menorrhagia (more so among women with uterine myoma than among those with idiopathic menorrhagia), as well as resulting in high rates of menorrhagia control among women with uterine leiomyomas, adding
[1] Vollenhoven BJ, Lawrence AS, Healy DL. Uterine fibroids: a clinical review. Br J Obstet Gynaecol 1990;97(4):285–98. [2] ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. Surgical alternatives to hysterectomy in the management of leiomyomas. Number 16, May 2000 (replaces educational bulletin number 192, May 1994). Int J Gynecol Obstet 2001;73(3):285–93. [3] Hubacher D, Grimes DA. Noncontraceptive health benefits of intrauterine devices: a systematic review. Obstet Gynecol Surv 2002;57(2):120–8. [4] Barrington JW, Arunkalaivanan AS, Abdel-Fattah M. Comparison between the levonorgestrel intrauterine system (LNG-IUS) and thermal balloon ablation in the treatment of menorrhagia. Eur J Obstet Gynecol Reprod Biol 2003;108(1): 72–4. [5] Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivelä A, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 2004;291(12):1456–63. [6] Rauramo I, Elo I, Istre O. Long-term treatment of menorrhagia with levonorgestrel intrauterine system versus endometrial resection. Obstet Gynecol 2004;104(6): 1314–21. [7] Luukkainen T. The levonorgestrel intrauterine system: therapeutic aspects. Steroids 2000;65(10–11):699–702. [8] Faúndes A, Alvarez F, Díaz J. A Latin American experience with levonorgestrel IUD. Ann Med 1993;25(2):149–53. [9] Monteiro I, Bahamondes L, Diaz J, Perrotti M, Petta C. Therapeutic use of levonorgestrel-releasing intrauterine system in women with menorrhagia: a pilot study(1). Contraception 2002;65(5):325–8. [10] Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2005;4 CD002126. [11] Rosa e Silva JC, de Sá Rosa e Silva AC, Cândido dos Reis FJ, Manetta LA, Ferriani RA, Nogueira AA. Use of a levonorgestrel-releasing intrauterine device for the symptomatic treatment of uterine myomas. J Reprod Med 2005;50(8):613–7. [12] Singer A, Ikomi A. Successful treatment of fibroids using intrauterine progesterone device (abstract); 1994. Montreal, Canada. [13] Grigorieva V, Chen-Mok M, Tarasova M, Mikhailov A. Use of a levonorgestrelreleasing intrauterine system to treat bleeding related to uterine leiomyomas. Fertil Steril 2003;79(5):1194–8. [14] Munro MG, Critchley HO, Broder MS, Fraser IS, FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynecol Obstet 2011;113(1):3–13. [15] Maruo T, Matsuo H, Samoto T, Shimomura Y, Kurachi O, Gao Z, et al. Effects of progesterone on uterine leiomyoma growth and apoptosis. Steroids 2000;65(10– 11):585–92. [16] Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990;97(8):734–9. [17] Sivin I, Stern J, Coutinho E, Mattos CE, el Mahgoub S, Diaz S, et al. Prolonged intrauterine contraception: a seven-year randomized study of the levonorgestrel 20 mcg/day (LNg 20) and the Copper T380 Ag IUDS. Contraception 1991;44(5): 473–80. [18] WHO. Medical Eligibility Criteria for Contraception Use. 4th edition. WHO; 2010. [19] Giudice LC, Irwin JC, Dsupin BA, Pannier EM, Jin IH, Vu TH. Insulin-like growth factor (IGF), IGF binding protein (IGFBP), and IGF receptor gene expression and IGFBP synthesis in human uterine leiomyomata. Hum Reprod 1993;8(11): 1796–806. [20] Magalhães J, Aldrighi JM, de Lima GR. Uterine volume and menstrual patterns in users of the levonorgestrel-releasing intrauterine system with idiopathic menorrhagia or menorrhagia due to leiomyomas. Contraception 2007;75(3):193–8. [21] Maruo T, Laoag-Fernandez JB, Pakarinen P, Murakoshi H, Spitz IM, Johansson E. Effects of the levonorgestrel-releasing intrauterine system on proliferation and apoptosis in the endometrium. Hum Reprod 2001;16(10):2103–8. [22] Maruo T, Laoag-Fernandez JB, Matsuo H, Samoto T, Kurachi O, Takeuchi S, et al. Effects of levonorgestrel-releasing intrauterine system on the endometrium and the relevance to the management of menorrhagia caused by uterine myoma and adenomyosis. In: Maruo ET, Barlow D, Mardon H, Kennedy S, editors. Cell and Molecular Biology of Endometrium in Health and Disease. Osaka, Japan: Osaka Soeisha; 2001. p. 193–207. [23] Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49(1):56–72.