Elsevier

Maturitas

Volume 57, Issue 2, 20 June 2007, Pages 210-213
Maturitas

Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: Long-term follow-up

https://doi.org/10.1016/j.maturitas.2006.12.004Get rights and content

Abstract

Objectives

Levonorgestrel (LNG), delivered locally into the uterine cavity has a profound effect on the endometrium. The aim of the study was to use a LNG intrauterine system to treat non-atypical and atypical endometrial hyperplasia in women and to evaluate the long-term cure (remission) rate.

Methods

Each of the 20 women in the study, of whom eight were diagnosed with atypical hyperplasia, received a LNG–IUS, releasing 20 μg LNG/day. The study is a non-comparative study with long-term follow-up (range 14–90 months).

Results

All women developed a normal endometrium, except one asymptomatic woman with atypical hyperplasia who still had focal residual non-atypical hyperplasia at 3 years follow-up in the presence of a thin (<4 mm) endometrium.

Conclusion

Continuous intrauterine delivery of LNG appears to be a promising alternative to hysterectomy for the treatment of endometrial hyperplasia and could enhance the success rate when compared with other routes of progestagen administration as well as intrauterine progesterone delivery.

The significant reduction of the PR expression observed during treatment with the LNG–IUS appears to be a marker for the strong antiproliferative effect of the hormone at a cellular level resulting in an inhibition of estrogen bioactivity and endometrial suppression.

Introduction

Endometrial hyperplasia is considered a precursor of cancer of the endometrium but only women presenting with atypical hyperplasia have a risk of developing endometrial carcinoma. The risk is estimated to be between 27% and 30% [1]. Consequently, the classical treatment of atypical endometrial hyperplasia has been hysterectomy. Progestagens have been used since the 1960 mainly in young women with a wish for pregnancy. The most frequently used progestagen has been medroxyprogesterone acetate (MPA) but side effects were numerous (e.g. headache, nausea) and long-term use results in metabolic changes and exposes the woman to a higher risk of thromboembolic events [2]. More recently, GnRH analogues have been proposed for the treatment of endometrial cancer and endometrial hyperplasia but hormonal side effects preclude long-term treatment [3]. An alternative route to administer potent progestagens is an intrauterine drug delivery system. Locally acting progestagens act many times stronger on the endometrium than when given systemically. Dosage can, therefore, be reduced significantly, minimizing side effects and optimizing patient compliance.

Clinical studies with a “frameless” levonorgestrel (LNG)–intrauterine system (IUS), releasing 14 μg LNG/day, and a “framed” LNG–IUS, releasing 20 μg LNG/day, suggest that both LNG delivery systems are effective to provide strong endometrial suppression which accounts for the endometrial suppressive effect observed during estrogen replacement therapy (ERT), the strong reduction in menstrual blood loss in women with excessive menstrual blood loss and menorrhagia as well as the high contraceptive action [4], [5], [6], [7], [8]. The interim results of the present study were published previously [9]. This study concluded that the LNG system, releasing 14 μg LNG/day, is an effective method for suppressing the endometrium in women with non-atypical and atypical hyperplasia and constitutes an alternative to hysterectomy on condition that women can be properly followed-up. The purpose of the present paper is to report on the long-term results in the same women using the LNG–IUS to prevent recurrence.

Section snippets

Materials and methods

The frameless, 14 μg releasing LNG–IUS (FibroPlant™, Contrel Research, Ghent, Belgium) has been described previously [9]. The IUS is implanted into the myometrium of the uterine fundus. Since the LNG–IUS has no frame, it is completely flexible, adapting to cavities of every size and shape. At expiry after 3 years of use of the FibroPlant LNG–IUS, the IUS was removed and replaced by a new T-shaped LNG–IUS (Femilis™, Contrel Research, Ghent, Belgium), releasing 20 μg LNG/day (Fig. 1) At the time of

Patients

Twenty women (16 parous and four nulliparous) were included in the study. Hypertension and diabetes was not present in any of them. Eight women developed postmenopausal bleeding as a result of unopposed estrogen stimulation (EST), after having taken the medication for at least 6 months up to approximately 2 years. One woman consulted because of abnormal bleeding during tamoxifen treatment for breast cancer. The other women had abnormal premenopausal bleeding. The histopathological diagnosis

Results

The average age of the patients at study entry was 54 years (range 41–67) and the average duration of use of the LNG–IUS is 32 months (range 14–90).

All women developed a thin endometrium (≤4 mm in thickness), as assessed by transvaginal ultrasound, except one patient. The latter patient presented with a polypoid structure of 20 mm in diameter prior to treatment which diminished gradually in size to 5 mm at the last follow-up examination, 53 months after insertion of the LNG–IUS.

At study initiation

Comments

In recent years, endometrial hyperplasia is caused most often by use of unopposed estrogen for ERT and tamoxifen for the treatment of breast cancer. Non-atypical (simple) hyperplasia is usually treated by oral administration of progestagens in sufficient dose and duration. However, if the treatment is discontinued, recurrence may occur. Locally applied delivery of levonorgestrel is much more potent than oral treatment and it is, therefore, logical that this form of treatment should be preferred

Conclusion

The results suggest that the LNG–IUS, releasing either 14 or 20 μg LNG/day, is an effective method for suppressing the endometrium in women with non-atypical and atypical hyperplasia and constitutes an alternative to hysterectomy especially in younger women who still wish to become pregnant and in women who refuse operation or are in poor health. Treatment should be long-term and women should be closely followed-up by vaginal ultrasound and preferably by repeat endometrial biopsy.

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  • Conservative management of endometrial hyperplasia or carcinoma with the levonorgestrel intrauterine system may be less effective in morbidly obese patients

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    For this reason, there is a growing need for alternative conservative therapies in these patients. Levonorgestrel-releasing intrauterine system (LNG-IUS) as well as oral progestin have been used to effectively treat EH/EHA with regression rates varying from 66% to 92% (Hubbs et al., 2013; Gallos et al., 2013; Wildemeersch et al., 2007). However, the efficacy of LNG-IUS therapy has not been looked at specifically in the obese population.

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