Levonorgestrel-releasing Intrauterine Device is an Efficacious Contraceptive for Women with Leiomyoma

Abstract

Objective:

To evaluate the efficacy of a levonorgestrel-releasing intrauterine device (LNG-IUD) as contraception for women with uterine leiomyoma.

Methods:

Thirty women with uterine leiomyoma requiring contraception were enrolled and had a LNG-IUD inserted. Menstrual blood volume (assessed by a pictorial blood loss assessment chart [PBAC]), haemoglobin concentration, volume of uterus and leiomyoma were determined before and after LNG-IUD insertion.

Results:

The median (range) PBAC score was 145.0 (60.0 - 232.0) before LNG-IUD insertion, which significantly decreased to 44.0 (0.0 - 99.0) and 36.0 (0.0 - 90.0) after 6 and 12 months of LNG-IUD use, respectively. Prior to LNG-IUD insertion, the median haemoglobin concentration in patients with anaemia was 100.0 (69.0 - 109.0) g/l and this increased significantly after 6 and 12 months of LNG-IUD use, to 117.5 (101.0 - 131.0) g/l and 119.5 (108.0 - 135.0) g/l, respectively. There were no significant changes in uterine or leiomyoma volumes. No patient became pregnant and there were no severe side-effects; one IUD was expulsed.

Conclusion:

The LNG-IUD may be a safe and effective contraceptive for women of reproductive age with uterine leiomyoma.

Introduction

Uterine leiomyoma is the most common benign tumour of the uterus. Although most uterine leiomyomas are asymptomatic, 20 -50% of women of reproductive age with uterine leiomyoma will have clinical symptoms. ¹ One of the most frequent and important symptoms of leiomyoma is menorrhagia, which often results in iron-deficiency anaemia and a significant deterioration in quality of life. ² Many patients with uterine leiomyoma prefer conservative treatment in order to preserve their fertility, but the choice of treatment is limited.

The levonorgestrel-releasing intrauterine device (LNG-IUD; Mirena^® Bayer Pharma AG, Berlin, Germany) has proved to be a highly effective contraceptive with few contra -indications and side-effects.^3,4 Several studies have reported the effectiveness of LNG-IUD as a therapeutic option for the treatment of menorrhagia caused by uterine leiomyoma.^3,5,6 Use of the LNG-IUD for women with leiomyoma is, however, still controversial. Changes in uterine bleeding are a common occurrence with IUD use, and there is concern that it may exacerbate uterine bleeding patterns and cause anaemia in women with leiomyoma. ⁷ In addition, women with leiomyoma often have unusually large and distorted endometrial cavities, making it likely that the IUD may not fit the shape of the patient's uterus. Significant uterine enlargement can increase the risk of IUD expulsion. ⁸ Furthermore, progestin might stimulate the proliferative potential of leiomyoma cells and downregulate the rate of leiomyoma cell apoptosis. ⁹

The present study was designed to carry out further evaluation of the efficacy of the LNG-IUD as a means of contraception for women of reproductive age with uterine leiomyoma.

Patients and methods

Study Population

Premenopausal women aged between 30 and 50 years requiring contraception and who attended the Women's Hospital, College of Medicine, Zhejiang University, Zhejiang, Hangzhou, China between January 2007 and January 2010 were enrolled in this study. Random sequence methods were used; randomization was undertaken using computational random-number generators. Consequently, not all patients who attended the hospital during the study period were included in the trial, even if they met the inclusion criteria. Each patient was examined by ultrasound and, for study inclusion, was required to have a uterus size < 12 weeks gestational age, a uterine cavity < 10 cm in length and to have at least one leiomyoma present. In addition, patients had to have no contraindications for IUD insertion and to agree to insertion of the LNG-IUD for ≤ 12 months. Patients were not eligible for study inclusion if they had current pelvic inflammatory disease, the presence of submucous leiomyoma with distortion of the uterine cavity, any malignancy of the reproductive system (e.g. cervical, vaginal or ovarian cancer), liver disease, a previous history of deep venous thrombosis, hormone therapy during the 3 months preceding the study, or if they were pregnant.

The study protocol was approved by the Ethics Committee of the Women's Hospital, College of Medicine, Zhejiang University. Each participant signed an informed consent document before enrolment.

Study Procedures

Before LNG-IUD insertion, demographic and clinical data (including the patient's height, weight, number of previous pregnancies, number of previous deliveries, menstrual blood volume, blood haemoglobin concentration, and uterine and leiomyoma volume) were obtained. The LNG-IUD was inserted into the uterine cavity during the first 3 – 5 days of a menstrual cycle, using real-time transabdominal ultrasound guidance. All participants were followed-up at the outpatient clinic, with visits scheduled at 1, 3, 6 and 12 months after LNG-IUD insertion, when preinsertion measurements were repeated. In addition, any side-effects, such as vaginal bleeding, pelvic pain or headache were recorded, as were any cases of pregnancy with the IUD in situ, or expulsion or displacement of the LNG-IUD.

Uterine and leiomyoma volumes were measured by transvaginal ultrasound (by the same investigator) and were calculated using the formula for an ellipsoid: volume = (1/2 anteroposterior diameter) × (1/2 transverse diameter) × (1/2 longitudinal diameter) × 4/3 × π. In the case of multiple leiomyomas, the volume of the largest leiomyoma was recorded.

Uterine bleeding was quantified using a pictorial blood loss assessment chart (PBAC) on which patients registered the number of sanitary pads or tampons used each day, the degree of soiling of each pad or tampon, the number and size of clots passed, and the number of episodes of flooding, to produce a score. ¹⁰ A monthly score > 100 corresponded to a blood loss volume of > 80 ml and defined menorrhagia. In addition to the PBAC chart, all patients kept a bleeding diary during the study, to record menstrual pain (using a visual analogue scale where 0 indicated no pain and 10 indicated worst possible pain) and the use of analgesics.

At all clinic visits, bleeding diaries and PBAC scores for the preceding months were collected, and a blood sample was taken from each patient for the measurement of haemoglobin; anaemia was defined as a haemoglobin level ≤ 100.0 g/l. All patients also underwent breast and gynaecological examinations at these times. Any adverse events, defined as new symptoms occurring after treatment, were recorded and classified as local (in the pelvic area) or generalized. Concomitant treatment was recorded, but no additional treatment for menorrhagia was permitted during the study period.

Statistical Analyses

The median (range) of the data were calculated and analysis was carried out using the SPSS^® statistical package, version 15.0 (SPSS Inc., Chicago, IL, USA) for Windows^®. The Kruskal-Wallis test was performed to compare the volume of menstrual blood (assessed by PBAC), the concentration of haemoglobin, and uterine and leiomyoma volume both before and after LNG-IUD insertion. A P-value < 0.05 was considered to be statistically significant.

Results

Baseline characteristics of the 30 patients who agreed to LNG-IUD insertion are shown in Table 1. The median (range) age of the patients was 41 (33 - 47) years and the median body mass index was 22.77 (19.12 -25.43) kg/m². Patients had a median of three (one to six) previous pregnancies and one (one to two) previous delivery. In total, 80% (24/30) of patients had menorrhagia and 40% (12/30) of patients had anaemia caused by menorrhagia. During the study period, one patient with menorrhagia, whose uterine volume was estimated to be 11 gestational weeks and who had a uterine cavity length of 9.5 cm because of multiple intramural leiomyomas (PBAC of 190 preinsertion and 182 at 1 month after LNG-IUD insertion), experienced spontaneous expulsion of the LNG-IUD at 3 months. A total of 29 patients were, therefore, eligible for analysis.

TABLE 1:

Baseline characteristics of the 30 premenopausal women with at least one uterine leiomyoma who received contraception by insertion of a levonorgestrel-releasing intrauterine device

Characteristic	No. of patients
Age
< 40 years	10
 40 years	20
Number of leiomyoma
Single	21
Multiple	9
With menorrhagia (PBAC score > 100.0)	24
With anaemia
Mild (100.0 ≤ haemoglobin < 110.0 g/l)	6
Moderate (70.0 ≤ haemoglobin < 100.0 g/l)	5
Severe (haemoglobin < 70.0 g/l)	1

PBAC, pictorial blood loss assessment chart.

Menstrual bleeding patterns demonstrated improvement after LNG-IUD insertion (Table 2). At 1 week following LNG-IUD insertion, the predominant bleeding pattern was spotting, which occurred in more than half (79.31%, n = 23/29) of the women in the first month. The number of patients with menorrhagia gradually decreased from 79.31% (23/29) preinsertion to 13.79% (4/29) 3 months after LNG-IUD insertion. In addition, a reduction in spotting occurred, as well as an increase in patients with amenorrhagia and oligomenorrhagia over the course of the study. A total of 55.17% (16/29) patients had oligo menorrhagia or amenorrhagia by the end of the study. Compared with baseline, the median PBAC score decreased significantly at 3, 6 and 12 months after LNG-IUD insertion (P < 0.05). Among the 12 patients with anaemia at baseline, the median haemoglobin concentration increased significantly (P < 0.05) relative to baseline at both the 6- and 12-month assessments. Compared with preinsertion values, there was no significant alteration in uterine or leiomyoma volume at 6 and 12 months after LNG-IUD insertion.

TABLE 2:

Menstrual bleeding patterns and uterine parameters of the premenopausal women with at least one uterine leiomyoma before and 3, 6 and 12 months after insertion of a levonorgestrel-releasing intrauterine device

Bleeding pattern and uterine parameter	Baseline n = 29	3 months n = 29	6 months n = 29	12 months n = 29
Spotting	0	12	4	2
Oligomenorrhagia	0	2	4	7
Amenorrhagia	0	2	8	9
Menorrhagia	23	4	0	0
Regular cycle	6	9	13	11
PBAC score, mean (range)	145.0	86.0 *	44.0 *	36.0 *
	(60.00 - 232.00)	(0.00 - 170.00)	(0.00 - 99.00)	(0.00 – 90.00)
Haemoglobin in patients with anaemia at baseline, g/l, n = 12	100.00(69.00 - 109.00)	105.00(90.00 - 118.00)	117.50 * (101.00 - 131.00)	119.50 * (108.00 - 135.00)
Uterine volume, cm3	140.35(61.23 - 334.88)	145.06(60.96 - 286.39)	145.23(60.28 - 256.67)	136.80(61.23 - 287.52)
Leiomyoma volume, cm3	5.52(0.38 - 36.76)	4.98(0.40 - 23.05)	4.83(0.52 - 30.81)	5.50(0.27 - 49.62)

Data expressed as n patients or median (range), unless stated otherwise.

*

P < 0.05 versus baseline measurement (Kruskal-Wallis test).

PBAC, pictorial blood loss assessment chart (a monthly score > 100.0, which corresponded to a blood loss volume of > 80 ml, defined menorrhagia in an individual. Anaemia was defined as a haemoglobin level ≤ 100.0 g/l).

A reduction in the incidence of bleeding disturbances at 6 and 12 months following LNG-IUD insertion was observed. Breast tenderness and pelvic pain were mostly reported in the first 3 months after LNG-IUD insertion but resolved spontaneously without treatment. The details of side-effects reported during this study are shown in Table 3. No LNG-IUD was removed during the study due to side-effects and no cases of pelvic inflammatory disease occurred. Except for one case of expulsion, no IUD displacement was found by ultrasound examination and no cases of pregnancy with IUD in situ occurred during the study.

TABLE 3:

Main side-effects in the premenopausal women with at least one uterine leiomyoma after receiving contraception by insertion of a levonorgestrel-releasing intrauterine device

Side-effect	3 months n = 29	6 months n = 29	12 months n = 29
Bleeding disturbances	12	4	2
Breast tenderness	10	3	0
Pelvic pain	7	2	1

Data expressed as n patients.

Discussion

The results of the present study suggest that use of a LNG-IUD was of benefit in women with leiomyoma-related menorrhagia, with the benefits evident soon after insertion. A significant reduction in menstrual blood loss, as assessed by the PBAC score, was observed 3 months following insertion of the LNG-IUD and the beneficial effects increased with treatment duration. Over half of the patients had oligomenorrhagia or amenorrhagia by the end of this study. Improvements in haematological indices accompanied the decreases in menstrual blood loss. Haemoglobin concentrations increased significantly 6 and 12 months after LNG-IUD insertion, in the 12 patients with anaemia at baseline. These findings are consistent with many published studies that have demonstrated the effectiveness of a LNG-IUD as a method of treating of iron-deficiency anaemia, in women with menorrhagia associated with leiomyomas. ³ -^5,11–13

The mechanisms by which the LNG-IUD promotes a reduction in bleeding are not yet clear. It has been suggested that increased bleeding in patients with uterine leiomyoma could be due to extension of the bleeding surface (after structural modification of fibres), and impairment of the myocontraction process and vascular distortion (with compression and passive congestion of the myoendometrial venous plexi). ³ In the present study, no significant reduction in uterine volume was observed during the study period, but there was also no increase in uterine volume, as might be expected during the clinical course of disease; these findings are in agreement with published results.^3,14 The LNG-IUD may act on the endometrial and uterine vasculature, reducing bleeding without directly interfering with uterine volume. According to Critchley et al., ¹⁵ the LNG-IUD releases high doses of LNG into the uterine cavity, promoting rapid decidualization of the endometrial stroma. Nevertheless, the absorption of LNG is probably minimal, producing only a localized effect.

In the present study, no statistically significant differences were found between the median volume of leiomyoma at baseline (before LNG-IUD insertion) and at 12 months, which is consistent with some previous research,^13,14,16,17 although other studies have reported that insertion of a LNG-IUD promotes significant reduction in leiomyoma volume.^5,8,18 It has been suggested that progestin might stimulate mitosis within the leiomyoma and promote its multiplication;^19,20 other research has indicated that progestin may play a dual role in regulating the growth of leiomyoma, and that high local concentrations of LNG may suppress the proliferation of uterine leiomyoma cells and promote cell apoptosis.^2,9 The LNG-IUD releases 20 μg LNG daily to the uterine cavity, which achieves a concentration in the uterus that is 1000-fold greater than that in the circulation. ²¹ Further investigation is required to determine the effects of such high local concentrations of LNG on the growth of leiomyomas.

The rate of LNG-IUD expulsion seen in the present study compared well with similar investigations on the use of IUDs in women with uterine leiomyoma, in which expulsion rates of approximately 8% (range 0 – 20%) have been reported.^{3,5,8,11–13,18,22} In the present study, the relatively low expulsion rate may be the result of using real-time transabdominal ultrasound guidance for LNG-IUD insertion and of excluding all patients presenting with distortions of the uterine cavity, including submucosal myoma and length of uterine cavity  10 cm. It is also possible that the small sample size, lack of a control group and the relatively short follow-up period in the present study may have influenced the results.

Although the LNG-IUD has been considered as a locally-acting and effective agent with minimal hormonal side-effects in the pharmacological treatment of menorrhagia associated with uterine leiomyoma,^5,22,23 menstrual spotting has been reported as one of the side-effects associated with its use that leads to removal of the device in 8.9 – 13.6% of patients by the 1-year follow-up.^4,24 A discontinuation rate of 2.7% during the first year of LNG-IUD use has been reported in the literature as mainly attributable to menstrual spotting. ²⁵ It is noteworthy that, in the present study, spotting occurred in fewer patients at 6 months after insertion of the LNG-IUD than at 3 months. These data suggest that proper counselling and the provision of detailed information prior to insertion are required for patients to accept LNG-IUD treatment and thereby reduce the rate of premature removal of the device. ²⁶

In conclusion, the present study demonstrated that the LNG-IUD may be used as an effective contraceptive for women of reproductive age with uterine leiomyoma. In addition, the treatment offers effective control of leiomyoma-related menorrhagia without significant influence on leiomyoma growth or on uterine volume. Larger-scale randomized controlled trials, of longer treatment duration, are necessary to provide further detailed assessment of the efficacy of the LNG-IUD in women with uterine leiomyoma.