Efficacy of the Levonorgestrel-Releasing Intrauterine Device as an Alternative to Oral Progesterone in the Management of Endometrial Hyperplasia without Atypia


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Saleh, H. , Ibrahiem, M. , Kamal, E. , Mohamed, M. and El Behery, M. (2014) Efficacy of the Levonorgestrel-Releasing Intrauterine Device as an Alternative to Oral Progesterone in the Management of Endometrial Hyperplasia without Atypia. Open Journal of Obstetrics and Gynecology, 4, 349-355. doi: 10.4236/ojog.2014.47052.

1. Introduction

Endometrial cancer is the most common gynecologic cancer and the incidence is still increasing. Endometrial cancer is principally developing through preliminary stages called endometrial hyperplasia and 10 - 30 percent will develop into carcinoma when left untreated [1] . Thus, correct and optimal treatment of endometrial hyperplasia will contribute to preventing endometrial cancer development and also in the long term, to reduce the incidence of endometrial cancer. Correct treatment of endometrial hyperplasia includes operative treatment with hysterectomy of the high risk cases and conservative treatment and follow up for patients with lower risk [2] .

Endometrial hyperplasia is classified according to increasingly abnormal architectural and cytologic criteria as: simple, complex, and atypical hyperplasia. Cytological atypia is the most important prognostic factor with regard to progression to endometrial cancer. For non-atypical hyperplasia, there is a 1% - 3% chance of progression to cancer, with a 72% chance of regression after expectant management.

In contrast, for atypical hyperplasia there is an 8% - 30% chance of progression to endometrial carcinoma, with only a 54% chance of spontaneous regression with expectant management [3] . In addition, endometrial cancer can coexist with atypical hyperplasia in up to 25% of cases. Because non-atypical hyperplasia is generally considered to be low risk for progression to cancer, many patients consider hysterectomy too invasive a treatment. Though there is no consensus on the best way to treat these women, they have often been treated with oral progestins [4] .

Progestins hormones are known to have a growth regulatory effect on the uterine mucosa. However, because of the systemic nature of the treatment, there can be significant side effects that limit compliance with treatment and when the treatment is discontinued, the hyperplasia can recur. Systemic adverse effects such as headache, nausea, weight gain and thromboembolic events, may limit the overall efficacy of the drugs. Moreover, the type of progestin product, the optimal dose and the duration of treatment are not clearly established [5] .

The levonorgestrel-releasing intrauterine system (LNG-IUS) is an alternative to oral progesterone without its disadvantages. Locally-acting progesterone has an effect on the endometrium several times which is stronger than that exerted by systemic products and with less systemic effect. Therefore, the dose of progesterone can be reduced and the adverse reactions minimized. So, if the therapeutic efficacy of the LNG-IUS is similar to or greater than that of oral progesterone, the LNG-IUS could become the standard treatment for EH [6] .

The levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena®) is a T-shaped device, with a reservoir containing 52 mg of levonorgestrel. In vivo, the hormone is released at an initial rate of 20 mcg daily, which progressively declines to half this rate by 5 years [7] . It exhibits a profound progestational effect on the endometrium. The endometrial lining becomes atrophic and inactive and cervical mucus becomes thick and scant [8] .

The aim of this study is to compare the efficacy and safety of the levonorgestrel-releasing intrauterine system (LNG-IUS) to dydrogesterone (oral progesterone) applied for the same length of time in management of endometrial hyperplasia without atypia.

2. Materials and Methods

One hundred women who attended to the Outpatient Clinic in Zagazig University Hospitals were complaining about abnormal uterine bleeding (AUB) in the period from May 2011 to November 2012. All these women underwent a detailed history, clinical examination, a Pap smear, a transvaginal ultrasound and endometrial biopsy by dilatation and curettage (D & C) following inpatient admission. A written informed consent was taken from all the patients of the study. Inclusion criteria were: Those with histological confirmed non-atypical simple or complex EH, age between 30 - 50 years old, a desire to avoid hysterectomy and no contra-indications against progestin hormones. Exclusion Criteria: Uterine anomaly, women with fibroids (more than 12 weeks size or distorting the uterine cavity), malignancy, genital infection, liver disease or liver tumor (benign or malignant), thromboembolic disease, deep vein thrombosis, hypercoagulable state, a history of coronary artery disease or myocardial infarction. After randomization by using a computer-generated random numeric table, the treatment according to assigned treatment arm can be started. The study protocol was approved by the local ethical and research Committee of Zagazig University Hospitals. The subjects were divided into two groups: A and B. Each group had 50 patients. The subjects in group (A) were counselled for the insertion of LNG-IUS. The subjects in group (B) were counselled for taking oral progesterone. The LNG-IUS (Mirena, Bayer Shering Oy, Turku, Finland) was inserted in the uterine cavity during the postmenstrual phase in the outpatient department and kept in situ for 6 months. While patients in group (B) were counselled to take dydrogesterone (Duphaston, Solvay pharmaceuticals B.V., The Netherlands), 10 mg two tablets twice daily from fifth day of menstruation for 21 days for 6 months. We use that dose depending on the dose used in study of Bergeron C, Ferenczy (2001) for protection of endometrial from hyperplasia in cases of menopause using estrogen Duphaston (2.5 - 20 mg/day) that was continuously combined with 17β-oestradiol 1mg and effectively protected the endometrium against the development of endometrial hyperplasia [9] . As it was found that even in management of endometrial intraepithelial neoplasia, not only hyperplasia by oral progestin or levonorgestrel-releasing intrauterine system, it is difficult to recommend a standard treatment regimen. Treatment should be continued for 6 months or more unless progression is identified [10] . So we limited time of management to 6 months and follow-up extended to 6 months more. The patients in both groups were followed up after 1 month, 3 months, 6 months, and 9 months and at the end of 1 year. The follow-up in the form of transvaginal ultrasound to assess endometrial thickness, occurrence of side related to treatment.

Endometrial histological assessment by dilatation and curettage (D/C) with biopsy at the end of treatment (after 6 months from starting which line) and 6 months later on. Primary outcome measures: Regression of hyperplasia after 6 months of therapy. Secondary outcome measures: Occurrence of side effects related to any line of treatment and recurrence of hyperplasia during follow-up period. Data obtained were statistically analyzed using SPSS version 12.

3. Results

One hundred women were included in this study. All patients who had endometrial hyperplasia without atypia were diagnosed histopathologically after D/C biopsy. The mean age of the subjects was 41 ± 2.3 in group A and was 42 ± 1.6 in group B. Table 1 summarized the demographic characters of subjects of both groups. There were no significant differences between both groups as regarding to age, parity, body weight, body mass index or medical disorders like diabetes mellitus or hypertension.

Table 2 represents clinical presentation and histological classification of patients of both groups. Patients of both groups were represented by abnormal vaginal bleedings and their endometrial histopathology was either a simple or complex hyperplasia without atypia. And there was no significant difference between both groups.

After 6 months of management in both groups, there was good clinical response with no complaint from abnormal vaginal bleeding. By TVS, most of patients in both groups developed a thin endometrium <5 mm apart from 2 cases in group A and 10 cases in group B who were still complaining from abnormal vaginal bleeding.

After comprehensive counseling, the 12 cases with persistence of abnormal vaginal bleeding decided to do hysterectomy. Their histopathology report revealed persistence of endometrial hyperplasia without atypia. 6 months follow-up histopathology of D & C biopsy revealed a significantly higher regression rate in the LNGIUS group than in Dydrogesterone group (96% vs. 80%). (P value 0.001). Also, there were lower hysterectomy rate in group A than group B (16% vs. 38%) with P value 0.001.

Follow-up of those patients for 6 months revealed no recurrence of endometrial hyperplasia in group A even after removal of LNG-IUS, but there were recurrence in 5 patients in group B in the form of recurrence of symptoms and re-thickening of endometrium seen by TVS and Table 3. Those patients were counseled for hysterectomy. Histological reports of their hysterectomy specimens showed persistent non-atypical complex EH. Table 4 represented the most side effects in both groups, amenorrhea occurred in (6%) in group A at the end of 6 months and no patient had amenorrhea in group B with P value 0.0001. Also vaginal spotting mainly in the first three months was higher in group A (3 cases) than in group B with P value 0.01. Another three patients complained from recurrent attacks of vaginal bleeding and by TVS assessment there was thin endometrium <5 mm, trial to assure patients but they were not satisfy to continue the treatment. There was no significant difference between both group as regarding to breast pain, headache, or weight gain. Nausea in Group B was significantly higher than in group A.

Regarding patient satisfaction to continue the treatment, it was higher in group A than in group B with P value 0.0001. There were 4 patients in group B who cannot tolerate headache.

Table 1. Patients characters.

Values are presented as number (%) or mean ± SD.

Table 2. Clinical and histological presentations.

Values are presented as number (%).

Table 3. Outcomes in LNG-IUS and oral progesterone groups.

Values are presented as number (%); LNG-IUS, levonorgestrel-releasing intrauterine system. P value < 0.05 is significant.

Table 4. Side effects of both regimens.

Values are presented as number (%) or mean ± SD.

4. Discussion

Endometrial hyperplasia (EH) is a common disease affecting women of all ages. Endometrial hyperplasia (EH) represents a spectrum from an exaggerated physiologic state to carcinoma in situ, as a result of unopposed estrogen stimulation in the absence of progestin influence. Endometrial hyperplasia (EH) is important clinically because it may cause abnormal uterine bleeding, and precede or occur concurrently with endometrial carcinoma. Cytologic atypia is the most important risk factor for progression to carcinoma [11] .

Although many gynecologists proceed to have hysterectomy when hyperplasia with Cellular atypia is found on an endometrial biopsy or curettage specimen, a number of conservative therapies are particularly useful for younger patients who wish to preserve fertility, and for women who do not desire or cannot undergo hysterectomy [12] .

Because endometrial hyperplasia is estrogen dependent, progestins are often used to induce regression. Progestin appears to decrease glandular cellularity in these lesions by triggering apoptosis. Progestin is the most commonly used as the safe, uterus-preserving alternative to hysterectomy. Non-atypical (simple) hyperplasia is usually treated by oral administration of progestogens in sufficient dose and duration. However, if the treatment is discontinued, recurrence may occur [13] .

Several retrospective studies demonstrated a beneficial effect of progestin treatment of endometrial hyperplasia either with or without atypia. A trial by Randall and Kurman (1997) recommended that: Oral megestrol 80 to 120 mg daily or oral MPA 10 to 30 mg daily for approximately 6 months has been shown to cause regression to loss of atypia in 94% of patients with complex atypical hyperplasia and to normal endometriumin 81% of patients [5] . Nonetheless, systemic side effects and poor compliance were often associated with oral progesterone; clinical trials of progestin therapies for atypical endometrial hyperplasia, furthermore, have not yet established a standard regimen. Compared with oral progestin, LNG-IUS in many studies has been found to have less severe systemic side effects and higher efficacy as a treatment for endometrial hyperplasia [14] . Wildemeersch and Dhont (2003), reported on women with abnormal uterine bleeding and non-atypical and atypical endometrial hyperplasia who were treated with a “frameless” LNG-IUS, which releases 14 mcg/d of levonorgestrel. The cure rate was 100%, as confirmed by repeat endometrial biopsy at 12 months and concluded that this is an effective method for suppression of the endometrium and may be considered as an alternative to hysterectomy [6] . Vereide, et al. (2003) worked on endometrial hyperplasia and compared treatment with LNG-IUS and oral gestagen. After 3 months of treatment, all the LNG-IUS patients showed regression of hyperplasia, whereas 45% of the per-oral patients still had disease. The authors concluded that LNG-IUS was a superior treatment for endometrial hyperplasia [15] .

Gallos et al. (2010) recently published a systematic review and meta-analysis that had compared endometrial hyperplasia regression rates between oral progestin and LNG-IUS. In cases of simple hyperplasia, treatment with oral progestin showed a pooled regression rate of 89%, versus the 96% rate for LNG-IUS patients. In cases of complex hyperplasia, oral progestin patients showed a pooled regression rate of 66%, versus the 92% rate for LNG-IUS patients. Overall, the treatment outcomes for LNG-IUS were statistically more significant than those for oral progestin (P < 0.01) [16] .

Lee et al. (2010) reported on the effectiveness of LNG-IUS in management of endometrial hyperplasia. In all of the cases, complete regression of endometrial hyperplasia was achieved [17] .

Orbo et al, (2008) in a multicentre randomised trial compared low dose oral progestin therapy with LNG-IUS. At 6 months of follow-up, patients in the LNG-IUS arm had significantly higher rates of regression 100% versus 96% for the women in the continuous oral progesterone group [17] .

So, most the results of those studies were similar to results of this current study. As we found, the regression rate of LNG-IUS was significantly higher than oral progesterone on management of endometrial hyperplasia without atypia (96% vs. 80%) with P value 0.001.

Regarding the type of oral progesterone that we used in our study, many studies used medroxyprogesterone acetate (MPA), megestrol acetate, gestagen or norethisterone acetate (NET), with different doses and schedules, as the most commonly used progestin therapies. Reed et al. (2009) found that there are no differences in endometrial hyperplasia regression between the various oral progestogens [18] . But, in our study, we try to use new type of progestron which is Dydrogesterone. Why? As, it is a potent, relatively safe and well tolerated orally active progestogen indicated in a wide variety of gynaecological conditions related to progesterone deficiency. Its freedom from estrogenic, androgenic, anabolic, corticoid and other undesirable hormonal effects gives it additional benefits over most other synthetic progestogens, like medroxyprogesterone. So, it has selective progestogenic properties although its progestogenic potency is 20 times higher than that of progesterone. Furthermore, it has antiestrogenic activity [19] . It is potent one, so it is recommended in postmenopausal patient under hormonal replacement therapy in dose. At least 10 mg for 14 days is acceptable for endometrial protection [20] .

So, main reason to choose it in this study is to use one oral progestin potent with the least systemic side effects to prove even with using it, Still LNG-IUS is the best in management of endometrial hyperplasia without atypia. As systemic side effects of Dydrogesterone like nausea in those patients treated was significantly higher than those treated by LNG-IUS, p value is 0.04.

Satisfaction of patient to complete her line of management is significantly lower in oral group than in LNG-IUS with p value is 0.0001. As the diagnostic accuracy of endometrial aspiration biopsy with using oral progestin or with LNG-IUS in place was shown to be very poor, where there is insufficient tissue for pathologic evaluation due to endometrial atrophy. So, the researchers must pay more attention. That endometrial aspiration biopsy with LNG-IUS in place is less accurate than D & C after removal of LNG-IUS; and it might not be reliable for follow-up and evaluation of management of EH [21] . Also, it was found that endometrial hyperplasia diagnosed by dilation and curettage compared with Pipelle was less likely to miss cancer evident only on subsequent hysterectomy (27% compared with 46%, respectively) [22] . Mass lesions that impinge on the uterine cavity, such as polyps or uterine leiomyomas, may deflect Pipelle devices, which are flexible, preventing adequate assessment of the endometrial cavity. Endometrial sampling may be better-accessed by a rigid curet [23] . So, in this current study, we depended on D & C biopsy to decrease the incidence of error in results of histopathology which was the corner stone of study.

The progestron concentrations in the uterine mucosa when delivered through an intrauterine device, directly into the cavity are reported to exceed that of the oral treatment by several-fold. Also it is associated with higher patient’s satisfaction and, therefore patients are more likely to continue the treatment. This higher chance of patients continuing the LNG-IUS treatment results in higher compliance and better efficacy in treating endometrial hyperplasia compared with oral progestogens.

Over all, this study revealed the efficacy of progestron as conservative management of endometrial hyperplasia without atypia, either using oral or local type but although using oral one with high potency and less side systemic side effects, the local progestron in the form of LNG-IUS was effective than oral one as it had regression rate 96% vs. 80% after 6 months of treatment, also had significant low recurrence after stop treatment 0% vs. 10%, less need to operative route by hysterectomy 16% vs. 38% and had more compliance from patient to continue using it although 6% of patients used it had amenorrhea, this event did not irritate them as the main primary complain of them was vaginal bleeding, so the stoppage of bleeding was wish of them.

5. Conclusions

In management of endometrial hyperplasia (EH) without atypia, LNG-IUS achieves higher regression rates and lower hysterectomy rates than oral Progesterone and could be the first-line therapy.

Thus in selected women, treatment with LNG-IUS could be beneficial to preserve the uterus and decrease the need for hysterectomy. However a continued observation is necessary. Patients who showed a positive response could remain protected for years with a long-acting hormone-releasing intrauterine system.

Conflicts of Interest

The authors declare no conflicts of interest.


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