Levonorgestrel releasing-intrauterine system for the ... - UMF Iasi

The European Journal of Contraception and Reproductive Health Care, December 2011; 16: 480–487

Levonorgestrel releasing-intrauterine system for the treatment of menorrhagia and/or frequent irregular uterine bleeding associated with uterine leiomyoma Demetra Socolov∗, Iolanda Blidaru∗, Bogdan Tamba∗, Nora Miron∗, Lucian Boiculese† and Razvan Socolov∗ ∗Department

of Obstetrics and Gynaecology, “Gr. T. Popa” University of Medicine, Iasi, Romania; and †Department of Medical Statistics, “Gr. T. Popa” University of Medicine, Iasi, Romania

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ABSTRACT

Objective To evaluate the effectiveness of the levonorgestrel releasing-intrauterine system (LNG-IUS) in the treatment of menorrhagia and/or frequent irregular uterine bleeding in women with uterine myomas. Study design Prospective study whereby 102 women with intramural myomas (in a few cases associated with submucous or subserous myomas), suffering from menorrhagia and/or frequent irregular uterine bleeding, were evaluated by means of the Pictorial Blood Assessment Chart (PBAC; Higham score) and ultrasound, three, six and 12 months after insertion of a LNG-IUS. Results The PBAC score dropped (from a mean value of 231.7 to 17.6 at 12 months). The duration of menstrual bleeding diminished significantly (p ⬍ 0.001). Uterine volume decreased from a mean of 145 cm³ to 129 cm³ at 12 months (p ⫽ 0.01). Changes in the volume of the myomas were not statistically significant (p ⫽ 0.23). Satisfaction rate was good in 91 cases (89%), fair in four cases (4%), and poor in seven cases (7%). During the one-year period of follow-up, 11 cases of expulsion or removal of the LNG-IUS were recorded. Conclusion The LNG-IUS is effective in controlling heavy menorrhagia and/or frequent irregular uterine bleeding related to the presence of myomas, but has no significant effect on the size of the tumours.

K E Y WO R D S

Levonorgestrel releasing-intrauterine system; Uterine myoma; Menorrhagia; Higham score; Conservative treatment

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Correspondence: Iolanda Blidaru, MD, PhD, Department of Obstetrics and Gynaecology, ‘Cuza Voda’ Maternity University Hospital, 34, Cuza Voda Street, 700038 Iasi, Romania. Tel: ⫹40 232 213000. Fax: ⫹40 232 215468. E-mail: [email protected]

© 2011 The European Society of Contraception and Reproductive Health DOI: 10.3109/13625187.2011.614028

LNG-IUS for treatment of bleeding due to myoma

I N T RO D U C T I O N

In addition to its contraceptive properties, the levonorgestrel releasing-intrauterine system (LNGIUS; Mirena®, Leiras OY Turku Finland) has beneficial non-contraceptive effects, such as the reduction of excessive menstrual blood loss. Initially recommended for treatment of dysfunctional uterine bleeding, the LNG-IUS has been used in cases of leiomyomatous or adenomyomatous uteri associated with menorrhagia and/or frequent irregular uterine bleeding. The purpose of this study was to evaluate the effectiveness of the LNG-IUS in treating heavy menstrual bleeding and/or frequent irregular uterine bleeding associated with uterine fibroids, the changes in uterine and fibroid volumes, and the acceptability of the method.

M AT E R I A L S A N D M E T H O D S

Our study is an open, non comparative, nonrandomised, one-year therapeutic trial. Between 1 January 2003, and 31 December 2009, 214 LNGIUSs were inserted in a gynaecology out-patient service in Iasi, Romania. Our prospective cohort study included 102 of these cases that met the following criteria: • Patients with myoma and menorrhagia and/or frequent irregular uterine bleeding. Myomas included in the study were subserous, intramural and submucous type II (according to the European Society for Gynaecological Endoscopy [ESGE] classification1, with more than 50% intramural component), with at least one myoma having a diameter greater then 20 mm. Although usually considered an exclusion criterion, we included patients with type II submucous myomas after informing them about the higher risk of IUD expulsion. • Patients who could afford to pay for the LNG-IUS (not supported by the National Health Service). • Acceptance of entering the study, signing the informed consent form, and attending the follow-up visits at three, six and 12 months. Exclusion criteria were: the existence of submucous myomas type 0 and I (ESGE classification1), inability to buy the LNG-IUS, and medical contraindications to its use (e.g., congenital uterine anomaly, acute pelvic inflammatory disease [PID], abnormal cervical cytology, pregnancy).

Socolov et al.

At the onset of the study, a health questionnaire was completed for each patient, which gathered information concerning: • age; • pattern of the menstrual cycles during the three months that preceded LNG-IUS insertion as detailed by the Pictorial Blood Assessment Chart (PBAC) and Higham score2; • obstetric history; • medical history (regarding in particular mastodynia, adenomyosis diagnosed by ultrasound, endometrial hyperplasia, polyps, confirmed by previous endometrial biopsy, and premenstrual syndrome). All this information was obtained from medical records of the patients. An ultrasound, using a General Electric Logiq 500 MD device, with a convex abdominal 3.5 MHz probe and an endovaginal 7.5 MHz probe, was performed on each patient just prior to the insertion of the LNGIUS. Ultrasound evaluation included: • the determination of the number, the position (subserous, intramural or submucous type II according to the ESGE classification) and the volume of the leiomyomas. The latter was calculated with the ‘prolate ellipsoid volume’ formula: V ⫽ 4/3 ⫻ π ⫻ d1 ⫻ d2 ⫻ d3/8 (where d1, d2 and d3 represent three diameters of each leiomyoma measured in sagittal and transversal planes of the uterus). The total fibroid volume is the sum of the volumes of all fibroids found in a patient; • the measurement of the three uterine dimensions, namely, the length (L), measured from the fundus to the internal os of the cervix; the width (W), being the transverse diameter at the level of the cornua, and the antero-posterior diameter (AP) at the level of the cornua and perpendicular to the width, and the determination of the uterine volume, using the same ‘prolate ellipsoid’ formula: V ⫽ 4/3 ⫻ π ⫻ L/2 ⫻ W/2 ⫻ AP/2; • the evaluation of the ovaries and the identification of adenomyosis foci. Follow-up visits were scheduled at three, six and 12 months after insertion of the LNG-IUS. On these occasions we considered the changes in bleeding pattern, assessed with the Higham menstrual score

The European Journal of Contraception and Reproductive Health Care

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LNG-IUS for treatment of bleeding associated with uterine leiomyoma

(PBAC)2 and drew blood for determination of the haematocrit and the haemoglobin concentration at enrolment and at the 12-month follow-up visits. The size of the uterus, fibroids and ovaries, and the position of the LNG-IUS were assessed by ultrasound. At these follow-up visits, we also inquired about side effects, improvements in the symptoms (such as mastodynia, dysmenorrhoea, and the premenstrual syndrome) and satisfaction about the treatment. The acceptability of this treatment was assessed using two methods: (i) the discontinuation rate (patients asking for LNG-IUS removal) and cases of spontaneous IUS expulsion or displacement during the first year; (ii) the subjective degree of satisfaction reported by patients as good, fair or poor. The statistical analysis of the data was carried out with SPSS 16 software. We used the Student’s t-test, with p ⬍ 0.05 being considered statistically significant. The study protocol was approved by the Ethical Committee of the Gr. T. Popa University of Medicine and Pharmacy, Iasi, Romania. In the present study we adopted the following definitions: Menorrhagia: heavy/prolonged menstrual bleeding exceeding 80 ml, corresponding to a Higham score of over 100. Irregular menstrual bleeding: variation of more than 20 days in the onset of bleeding from one cycle to another. Frequent uterine bleeding (according to the new classification of ‘Abnormal uterine bleeding terminologies’3): duration of less than 24 days between two consecutive bleeding periods. Oligomenorrhoea: infrequent uterine bleeding, at intervals of more than 38 days. Amenorrhoea: absence of uterine bleeding for over three months. Spotting: occurrence of bleeding not requiring the use of sanitary protection4. R E S U LT S

Our study included 102 women, aged between 30 and 54 years (median age 40), with fibromyomas, associated with menorrhagia and/or frequent irregular uterine bleeding. To each patient, a Mirena™ LNGIUS was proposed. We did not record the patients 482

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who, although meeting the inclusion criteria, refused to participate in the study. The fibroids under treatment had a minimum size of 15 mm (with at least one myoma of 20 mm in diameter in the same patient) and a maximum size of 67.5 mm. Their location was intramural in 96 cases; submucous (type 2 according to the ESGE Classification1) for at least one of the myomas in four cases; and subserous for one or more myomas in two cases. Women with type 2 submucous myomas were informed about the higher risk of expulsion of the LNG-IUS, and accepted it. Initial values of and changes in the Higham scores, menstrual pattern, uterine and myoma volumes and haemoglobin/haematocrit values at enrolment and after 12 months of treatment are shown in Table 1. Our results demonstrated a statistically significant decrease in Higham score values at three, six- and 12-month follow-up visits (p ⬍ 0.001). Even if the initial Higham score could be considered elevated in some cases (up to 745), reflecting an important blood loss, the desire to avoid a surgical procedure, sometimes associated with that of preserving the uterus, determined these patients to accept the LNG-IUS as an alternative to hysterectomy. As shown in Table 1, the duration of menses diminished significantly, in addition to the decrease of the Higham score that was observed. At the first and second follow-up visits, more than 90% of our patients had either eumenorrhoea or even slighter menstrual bleeding (Table 1). After 12 months of treatment, 96% of our patients had a reduced – or even absent – menstrual flow, spotting included. Spotting was present in 3% of the cases at the one-year follow-up visit. The decrease observed at the 12-month follow-up examination was statistically significant for the uterine volume (p ⫽ 0.01). It was not significant for the total volume of the fibroids (p ⫽ 0.23), because of the great dispersion of the values. Haemoglobin/haematocrit values were abnormally low at baseline, and increased to normal range (p ⬍ 0.05) at one year of follow-up. Side effects reported by the patients at follow-up visits were: mastodynia in 20 cases (20%), headache in 12 (12%), pelvic pain in 12 (12%), weight gain over 5% from initial weight in ten (10%), bloating in four (4%), dyspareunia in two (2%), and insomnia in one (1%).



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Table 1 Patients’ characteristics.

Parameter

At enrolment N ⫽ 102

At 3 months N ⫽ 100



Higham score ⫾ SD

231.7 ⫾ 144

40.18 ⫾ 38.29

20.84 ⫾ 24.03

17.58 ⫾ 42.48

Bleeding pattern Menorrhagia *Frequent irregular uterine bleeding Oligomenorrhoea Amenorrhoea Spotting Eumenorrhoea Uterine volume (cm3) ⫾ SD Leiomyoma volume (cm3) ⫾ SD Haemoglobin (g%) ⫾ SD Haematocrit (%) ⫾ SD

88 (86%) 14 (14%) 0 0 0 0 144 ⫾ 69 20 ⫾ 28 10.34 ⫾ 1.35 30.13 ⫾ 4.24

7 (7%) 0 11 (11%) 1 (1%) 9 (9%) 72 (72%) 139 ⫾ 66 19 ⫾ 32 – –

4 (4%) 0 19 (19%) 10 (10%) 3 (3%) 63 (64%) 132 ⫾ 66 19 ⫾ 28 – –

4 (4%) 0 36 (38%) 29 (30%) 3 (3%) 24 (25%) 129 ⫾ 75 18 ⫾ 29 13 ⫾ 1.02 39.69 ⫾ 3.32

*Patients with initial Higham score under 100 had frequent irregular uterine bleeding.

Some patients reported an improvement of certain pre-existent complaints: this pertained in particular to mastodynia, in six cases (6%), and dysmenorrhoea, in 26 cases (26%). Both the initial ultrasound and those done later showed occasionally ovarian cysts, with a diameter of between 30 and 55 mm, whose evolution is summarised in Table 2. These cysts did not elicit any clinical symptom and did not require surgical treatment. Patients’ acceptance of the LNG-IUS treatment was assessed 12 months after insertion. Ninety-one women (89%) considered the treatment to be good, and four (4%) fair. In seven cases (7%) results of the treatment were considered to be poor, due to expulsion of the

LNG-IUS, in six cases, and to spotting which persisted for six months, in one case. Indeed, six patients spontaneously expelled the device during the one-year study period; two more asked for LNG-IUS removal: one because of persistent spotting at six months, and the other for pregnancy desire at five months. Of the six patients who expelled the device, two had a type 2 submucous myoma. In three cases the LNG-IUS was found to be displaced at the 12 months follow-up control. These patients asked for removal of the device, which was followed by hysterectomy. It is noteworthy that the initial Higham score was exceeding 100 in all the cases of expulsion and displacement of the LNG-IUS. Not all of the patients

Table 2 Ultrasound characteristics of ovarian cysts diagnosed in patients with a levonorgestrel releasing-intrauterine system (LNG-IUS) in situ. Characteristics Total number Ultrasound appearance

Newly appeared/persistent* cysts Min/max diameter (mm)

At baseline

At 3 months

At 6 months

At 12 months

9 8 anechogenic (follicular) ⫹ 1 endometrioma


12 7 anechogenic (follicular) ⫹ 4 corpus luteum cysts ⫹ 1 endometrioma 7 new ⫹ 5 persistent 30/45


9 30/45

15 new ⫹ 2 persistent 30/55

2 new ⫹ 4 persistent 32/45

*Since the previous ultrasound.


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Table 3 Effects of treatment with a levonorgestrel releasing-intrauterine system (LNG-IUS) on menstrual bleeding assessed by means of the Pictorial Blood Assessment Chart (PABC): data from the literature.

Study Fedele et al.5 Grigorieva et al.6 Naki7 Mercorio et al.8 Barrington et al.9 Crossignani et al.10 Istre and Trolle11 Kittelsen et al.12 Reid et al.13 Henshaw et al.14 Rauramo et al.15 Wildermeersch et al.16* Present study

Number of cases 25 67 46 19 25 35 30 30 25 20 30 32 102

Initial PBAC ⫽ Higham score

PBAC at 3 months

PBAC at 6 months

PBAC at 12 months

211 97 529.8 310 107 184.8 420 418 240 30.7 261.5 353 231.7

48 32 – 186

43 21 77.3 155 31

44 16 – 96 38.8 42 42

49

25

40.18

20.84

8.2 7 61 17.58

*In this study a different LNG-IUS (FibroPlant®), releasing daily 14 μg levonorgestrel, was used.

who expelled their LNG-IUS were dissatisfied, as two of them asked for subsequent re-insertion. DISCUSSION

Our study confirmed that using LNG-IUS for treatment of menorrhagia and/or frequent irregular uterine bleeding associated with uterine myomas significantly reduced the quantity and duration of menstrual blood loss after 12 months, as previously shown by other investigators (Table 3). Although the initial average value of the PBAC appears to vary considerably, partly due to the fact that the method relies on subjective assessment, all the aforementioned authors described an important decrease of blood loss after the first year of

treatment. Moreover, this effect was observed in almost all patients, both in cases of frequent irregular uterine bleeding and in cases of menorrhagia associated with fibroids, as shown in the studies of Grigorieva et al.6 and Mercorio et al.8. Thus, it is likely that the LNG-IUS acts by reducing bleeding originating from the endometrium, and not by interfering with fibroid proliferation. The predominant changes in the menstrual pattern observed at the end of our study were spotting, oligomenorrhoea and amenorrhoea.This is in line with the findings of other researchers (Table 4). In our study, neither the uterine volume nor the volume of the fibroids augmented during treatment with the LNGIUS. Actually we found that the uterine volume had decreased 12 months after insertion of the LNG-IUS, whereas changes in leiomyoma volume were not significant

Table 4 Menstrual pattern after 12 months of treatment with a levonorgestrel releasing-intrauterine system: Data from the literature.

Authors Romer et al.17 Crosignani et al.10 Mercorio et al.8 Nagrani et al.18 Xiao et al.19 Present study

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Menorrhagia, %

Eumenorrhoea, %

Hypomenorrhoea or spotting, %

Amenorrhoea, %

27 12 75 0 Not available 4

0 23 0 8.7 Not available 25

33 47 20 56.5 25 41

40 18 5 34.8 33 30



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(p ⫽ 0.23). These findings are in line with data from the literature, as shown in Table 5. Considering the 20–30% natural growth rate per year of fibroids, as ascertained by a prospective study4, it is possible that the LNG-IUS inhibits their growth. This might be achieved by inducing endometrial atrophy, thereby blocking the synthesis of local growth factors that stimulate myoma proliferation. Therefore, the LNG-IUS seems to be a good method for treating patients with menorrhagia associated with uterine leiomyoma, after exclusion of the cases with intracavitary fibroids, which distort the uterus, and those with a very large uterus that could expel the device. In our study, there were two expulsions due to a submucous myoma type 2, in patients who were previously counselled against insertion due to the high risk of expulsion. If menorrhagia is considered the main indication for treatment, then the percentage of patients dissatisfied with the LNG-IUS treatment is small. Indeed, the LNG-IUS reduced blood loss in all cases. The contraceptive action of the LNG-IUS in our study was only of secondary importance, as 76% of patients were over 40 years old and only 15% required both its contraceptive action and its effects on uterine bleeding. Spotting and amenorrhoea were well tolerated because our patients had been informed at enrolment that these changes might occur after insertion of the LNG-IUS. Compared to other studies in which it ranged between 50% 21 and 98% 22, the satisfaction rate among our patients was high (89%). According to the literature, side effects of the LNGIUS treatment are oedema20,headache13,20,mastodynia13,20, acne20, back pain23, vaginal discharge23, dizziness13,23,

functional ovarian cysts13, 24, abdominal pain13 and diarrhoea13. In our study, only some of these adverse effects were recorded. But we also very rarely noted some others that were not previously mentioned, such as insomnia (1%) and bloating (4%). These were not perceived as disturbing by the patients and did not affect the acceptability of the method. In view of their extremely low incidence, this observation probably lacks clinical relevance. The product presentation leaflet mentions that functional ovarian cysts may be found in 12% of patients at the follow-up visits, because of delayed follicular atresia and continued follicular development25. These enlarged follicles cannot be clinically differentiated from ovarian cysts; they are usually asymptomatic and they spontaneously disappear within a few months. In the present study, the incidence of these functional cysts decreased from 17% at three months to 6% at 12 months. In our patients, all the cysts were asymptomatic and none required treatment. The strength of our study is that it involved one of the largest numbers of patients with uterine myomas purposefully treated with a LNG-IUS, enrolled during a period of seven years – which improves the reliability of its findings. Because it offers enhanced statistical data, our study is relevant for gynaecological treatment. It might contribute to an increased use of the LNG-IUS as an alternative to hysterectomy, which is a considerably more invasive, more risky, and more costly procedure. According to a meta-analysis by Zapata et al.26, a possible weakness of our study is the lack of untreated controls with excessive bleeding due to myomas. For ethical reasons, we consider that withholding treatment is unacceptable in this instance. Another

Table 5 Changes in uterine volume and fibroid volume during treatment with the levonorgestrel releasing-intrauterine system. Uterine volume (cm3) Study Fedele et al.5 Grigorieva et al.6 Naki7 Zsigmond et al.20* Present study

Fibroid volume (cm3)

No. cases Baseline 3 months 6 months 12 months Baseline 3 months 6 months 12 months

67 46 7 102

348 138 159 57 144

161 139

320 – 159 51 132

314 122 – 53 129

30 31 7 20

34

– 38

19

19

19 – 5 18

*In that study, the authors mentioned the volume of the largest fibroid, not the added volumes of all fibroids.


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limitation may be the lack of ferritin dosage, which was due to financial constraints. We had enrolled four women with submucous myoma type 2, which partially distorts the uterine cavity; these patients had been duly informed about the higher risk of expulsion. This did indeed happen in two of the cases (at three and six months, respectively) but, interestingly, the other two women tolerated the device well. Expulsion of the LNGIUS is likely to be related to the abundance of initial blood flow, large initial uterine volume, and distortion of the uterine cavity. Regarding unanswered questions and future research, one might contemplate assessing in parallel in our country the outcomes and costs of the main treatment modalities of this pathology, namely the LNG-IUS, oral progestins and hysterectomy.

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CONCLUSION

The LNG-IUS significantly reduced the duration and amount of menstrual flow in women with menorrhagia and/or frequent irregular bleeding associated with uterine fibroids. After one year of treatment, the volume of the uterus, but not that of the fibroids, had diminished significantly (p ⬍ 0.01) as is described also in other studies.The great majority of patients expressed a favourable opinion regarding the effects of this treatment on their menstrual pattern. Side effects induced by the LNG-IUS, including functional ovarian cysts, had no influence on the acceptability of the method. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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