ORIGINAL STUDY

Management of Endometrial Hyperplasia With a

Levonorgestrel-Releasing Intrauterine System
A Korean Gynecologic-Oncology Group Study
Mi Kyoung Kim, MD,* Seok Ju Seong, MD, PhD,* Jae-Weon Kim, MD, PhD,Þ Seob Jeon, MD, PhD,þ
Ho Sun Choi, MD, PhD,§ In-Ho Lee, MD, PhD,|| Jong Hak Lee, MD, PhD,¶ Woong Ju, MD, PhD,#
Downloaded from https://journals.lww.com/ijgc by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3tjcLwhL8g9bZhhig7WeJvvseIZS3P1lGlZoXxDMN+Jhvar65q7mA3A== on 05/20/2018

Eun Seop Song, MD, PhD,** Hyun Park, MD, PhD,ÞÞ Hee-Sug Ryu, MD, PhD,þþ
Chulmin Lee, MD, PhD,§§ and Soon-Beom Kang, MD, PhD||||

Objective: The aim of the study was to evaluate the efficacy of the levonorgestrel intra-
uterine system (LNG-IUS) for treatment of endometrial hyperplasia (EH).
Methods: A prospective multicenter study was conducted from November 2010 to March
2014. Patients with histologically confirmed EH were treated with LNG-IUS. At 3, 6, and
9 months after LNG-IUS insertion, follow-up endometrial aspiration biopsies with the
LNG-IUS in the uterus were undertaken. At the 12th month of follow-up, endometrial
tissues were obtained via 2 methods: endometrial aspiration biopsy with the LNG-IUS in the
uterus, followed by dilatation and curettage (D&C) after LNG-IUS removal. The primary
outcome was the regression rate at 12 months after LNG-IUS insertion, and the secondary
outcome was the consistency of the results between the endometrial aspiration biopsy and
the D&C.
Results: The study population comprised 75 patients, including 37 with simple hyperplasia
without atypia; 3 with atypical simple hyperplasia; 23 with complex hyperplasia without
atypia, and 12 with atypical complex hyperplasia. Of these patients treated with the LNG-
IUS, 38 (50.7%) were followed up at 12 months after LNG-IUS insertion. The complete
regression rate at 12 months was 94.7% (36/38): 100% (6/6) of patients with atypical EH and
93.7% (30/32) with EH without atypia. In all of the cases (100%, 36/36), patients achieved
complete regression within 3 months of LNG-IUS insertion. A comparison of the path-
ologic results from endometrial aspiration biopsy and D&C was carried out for 15 patients.
In the histologic results by endometrial aspiration biopsy, 14 patients were diagnosed as
‘‘normal endometrium’’ and 1 as ‘‘insufficient tissue for pathologic evaluation.’’ Among
the 14 cases of normal endometrium by endometrial aspiration biopsy, 1 was diagnosed as
‘‘residual EH’’ by D&C, and the 1 case with insufficient tissue was diagnosed as normal
endometrium by D&C.

*Departments of Obstetrics and Gynecology, CHA Gangnam
Medical Center, CHA University; †Seoul National University Col-
lege of Medicine, Seoul; ‡Soonchunhyang University Cheonan
Hospital, Soonchunhyang University College of Medicine, Cheonan;
§Chonnam National University Medical School, Gwangju; ||Cheil
General Hospital and Women’s Healthcare Center, Dankook Uni-
versity College of Medicine, Seoul; ¶Gyeongsang National Uni-
versity School of Medicine, Jinju,; #Ewha Womans University
Mokdong Hospital, Ewha Womans University School of Medicine,
Copyright * 2016 by IGCS and ESGO
ISSN: 1048-891X
DOI: 10.1097/IGC.0000000000000669
Seoul; **Inha University College of Medicine, Incheon; ††CHA
Bundang Medical Center, CHA University, Bundang; ‡‡Ajou
University School of Medicine, Suwon; §§Sanggye Paik Hos-
pital, Inje University College of Medicine; and ||||Konkuk Uni-
versity Medical Center, Konkuk University School of Medicine,
Seoul, Korea.
Address correspondence and reprint requests to Seok Ju Seong, MD,
PhD, Department of Obstetrics and Gynecology, CHA
Gangnam Medical Center, CHA University, 566, Nonhyeon-ro,
Gangnam-gu, Seoul 135-081, Republic of Korea. E-mail:
sjseongcheil@naver.com.
The authors declare no conflicts of interest.
This trial was registered at ClinicalTrials.gov (NCT01234818)

International Journal of Gynecological Cancer & Volume 26, Number 4, May 2016 711

Copyright © 2016 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
Kim et al International Journal of Gynecological Cancer
Conclusions: Levonorgestrel intrauterine system is an effective and favorable method for
treatment of EH.
Key Words: Endometrial hyperplasia, Progesterone, LNG-IUS, Dilatation and curettage,
Endometrial aspiration biopsy
Received October 26, 2015.
Accepted for publication December 24, 2015.
(Int J Gynecol Cancer 2016;26: 711Y715)
E ndometrial hyperplasia (EH) is a premalignant lesion of
endometrial cancer (EC), the most common gynecological
malignancy in developed countries.1 Accurate diagnostics
and proper management of EH, therefore, are clinically sig-
nificant to the prevention of EC development.
The EH treatment modality selected depends mainly on
both the histological diagnosis and the woman’s desire to retain
fertility. For women with nonatypical EH, the risk of progres-
sion is low (G5%) but increases up to 30% for those with
atypical EH.2 In this respect, hysterectomy is recommended
for the treatment of atypical EH. However, for patients with
nonatypical EH or for young patients with atypical EH who
strongly desire to preserve their fertility, administration of oral
progestogens has become the routine conservative therapy.
Nonetheless, in atypical EH, the treatment response is unsat-
isfactory, showing a 70% regression rate.3 Furthermore, oral
progestogens are associated with systemic adverse effects
such as headache, nausea, weight gain, and thromboembolic
events, which eventually make for poor compliance and limit
overall efficacy. In addition, professional therapy guidelines
on optimal dose, treatment time, and progestational agents
have yet to be standardized.4
Recently, the levonorgestrel intrauterine system (LNG-
IUS) has been used as an alternative treatment option for EH,
and several studies have reported promising results.5Y13 Com-
pared with oral progestogens, the LNG-IUS provides a higher
endometrial progestin concentration with lower systemic side
effects and, hence, has been reported to be a more effective
EH treatment option. Unfortunately, these previous studies
have been mostly observational; they have not provided
reliable data from a large prospective study, which are in-
dispensable to the determination and recommendation of
novel treatment modalities. Furthermore, there is still no
report on the accuracy of endometrial sampling during hor-
monal treatment for EH, especially when using the LNG-
IUS. According to the literature, in cases of conservative
treatment using the LNG-IUS, the endometrial response
has been evaluated by endometrial aspiration biopsy with
the LNG-IUS in the uterus or by dilatation and curettage
(D&C) after removal of the LNG-IUS.5Y12 Notwithstanding,
there has been no reported comparison of the accuracies of
these methods.
Therefore, we set out to conduct a multicenter pro-
spective study evaluating the efficacy of the LNG-IUS for
712
Copyright © 2016 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
& Volume 26, Number 4, May 2016
treatment of EH and comparing the diagnostic accuracy of
endometrial aspiration biopsy with that of D&C in patients
treated with the LNG-IUS for EH.
MATERIALS AND METHODS
A prospective multicenter study was conducted from
November 2010 to March 2014.
Eligible subjects were women with histologically con-
firmed EH who desired to avoid hysterectomy. All of the
patients were fully informed of the study purposes and pro-
cedures, and their voluntary informed consent to partic-
ipate (as approved by the institutional review board of
each clinical trial institution) was obtained. This trial was
registered at ClinicalTrials.gov (NCT01234818) and pub-
lished in April 2011.14
The initial histologic diagnosis was made by D&C with
the patient anesthetized. For EH treatment, the LNG-IUS was
inserted into the uterus. All of the patients subsequently
underwent a regular clinic review, transvaginal ultrasonog-
raphy, and endometrial histological surveillance at 3-month
intervals. Accordingly, at 3, 6, and 9 months after LNG-IUS
insertion, the endometrial histological surveillance was per-
formed by outpatient endometrial aspiration biopsy using a
pipelle with the LNG-IUS remaining in the uterus. At 12 months
after LNG-IUS insertion, endometrial tissues were obtained
via 2 methods: endometrial aspiration biopsy using a pipelle
with the LNG-IUS in place, followed by D&C after removal
of the LNG-IUS. The histologic diagnoses of the specimens
were made by central pathologic review.
The primary outcome was the response rate. This was
determined by comparing the diagnosis of the follow-up D&C
12-month post-LNG-IUS insertion with the initial histologic
diagnosis. In assessing the histological treatment response,
complete regression (CR) was defined as endometrial atro-
phy, pseudodecidualization of stroma without evidence of
hyperplasia. During the follow-up period, if there was histo-
logical evidence of EC or progression of nonatypical EH to
atypical EH, treatment with LNG-IUS was suspended and an
alternative specific treatment option was suggested.
The secondary outcome was the consistency of the re-
sults between the endometrial aspiration biopsy and the D&C.
At 12-month post-LNG-IUS insertion, we obtained endome-
trial tissues via 2 methods, as noted previously. To evaluate the
* 2016 IGCS and ESGO
International Journal of Gynecological Cancer & Volume 26, Number 4, May 2016
FIGURE 1. Flowchart of study population.
diagnostic accuracy of the endometrial aspiration biopsy (with
the LNG-IUS in the uterus) compared with the D&C (after
removal of the LNG-IUS), the histological results of the 2
methods were compared.
RESULTS
During the study period, a total of 75 patients meeting
the inclusion criteria were enrolled, and 66 of whom were
followed up on at the third month (1 patient failed to insert
the LNG-IUS, 2 expelled the LNG-IUS, 1 removed the LNG-
IUS because of vaginal spotting, and 5 were lost to follow-up;
Fig. 1). The patients’ baseline characteristics are provided in
Table 1. The mean (SD) age of the patients was 42.67 (8.35)
years. The histological classification of EH was as follows:
simple hyperplasia (SH) without atypia, 37 (49.3%); com-
plex hyperplasia (CH) without atypia, 23 (30.7%); atypical
SH, 3 (4.0%); and atypical CH, 12 (16.0%).
Of these patients treated with the LNG-IUS, 38 (50.7%)
were followed up on 12 months after the LNG-IUS insertion.
The CR rate at 12 months was 94.7% (36/38). In the cases of
atypical EH, 6 (100%) of the 6 patients had regression, and
in the cases of EH without atypia, 30 (93.7%) of the 32
patients had regression (Table 2). In all (100%, 36/36) of the
CR cases, CR was achieved within 3 months of LNG-IUS
insertion. Of the 2 patients who did not achieve CR, 1 had
persistent CH without atypia and 1 obtained only a partial
response: specifically, CH without atypia partially regressed
to SH without atypia.
Comparison of the pathologic results from endometrial
aspiration biopsy and D&C was carried out for 15 patients
including 5 with CH without atypia, 7 with SH without atypia,
and 3 with atypical CH. The histologic results by endometrial
aspiration biopsy were ‘‘normal endometrium’’ (14 patients)
and ‘‘insufficient tissue for pathologic evaluation’’ (1 patient).
Among the 14 cases of normal endometrium by endometrial
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Management of Endometrial Hyperplasia
aspiration biopsy, 1 case was diagnosed as ‘‘residual EH’’ by
D&C. The 1 case of insufficient tissue by endometrial aspi-
ration biopsy was diagnosed as normal endometrium by D&C
(Table 3).
According to the follow-up endometrial biopsy, no
patients developed EH progression during the study period.
Treatment was generally well tolerated, and there were no
cases of serious complications. Of all the women receiving
ongoing treatment with the LNG-IUS, only 2 chose to have
the device removed because of vaginal spotting. Expulsion
of LNG-IUS occurred in only 3 patients.
DISCUSSION
In this study, we evaluated the efficacy of the LNG-IUS
for treatment of EH and compared the pathological outcome
of endometrial aspiration with that of D&C. The main finding
was that the LNG-IUS was a safe and highly effective method
for treatment of EH. At the 12th month of follow-up, a sig-
nificantly high regression rate (94.7%), with few side effects,
was noted. These findings are consistent with those of earlier
studies assessing LNG-IUS efficacy.3,5Y13 A meta-analysis of
24 observational studies including 1001 women showed that
in the treatment of nonatypical complex EH, a significantly
higher regression rate was achieved with the LNG-IUS than with
oral progestins (92% vs 66%).3 More recently, a meta-analysis
of 7 randomized controlled trials including 766 women re-
ported that in the treatment of nonatypical EH, the LNG-IUS
once again achieved a highly significant response rate rela-
tive to that for oral progestins.15 To the best of our knowledge,
ours is the first multicenter prospective study in Korea to
show the efficacy of the LNG-IUS in the treatment of EH.
However, an unresolved issue remains in respect of the
accuracy of the follow-up evaluation methods: Can aspiration
biopsy be as accurate as D&C for EH patients treated with the
LNG-IUS?
A recent study comparing the diagnostic accuracy of
pipelle biopsy with that of D&C reported almost an equal
EH-diagnostic success rate.16 These results though were
obtained for cases where the LNG-IUS was not in the uterus
and where there were no progestin effects on the endometrium.
Moreover, that study focused on the initial diagnostic accuracy,
not the follow-up evaluation, which can possibly be affected
by hormonal treatment.
Actually, there has been only 1 evaluative report on the
response of the endometrium in follow-up, particularly for the
use of the LNG-IUS combined with high-dose oral progestin
TABLE 1. Patients’ characteristics (N = 75)
Age, y 42.67 (8.35, 23Y57)
Endometrial histology
SH without atypia 37 (49.3)
CH without atypia 23 (30.7)
SH with atypia 3 (4.0)
CH with atypia 12 (16.0)
Data are presented as mean (SD, range) or n (%).
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Kim et al International Journal of Gynecological Cancer & Volume 26, Number 4, May 2016

TABLE 2. Outcomes of study according to histological data derived following treatment with LNG-IUS
RR at 3 mo RR at 6 mo RR at 9 mo RR at 12 mo
SH without atypia 93.5 (29/31) 95.5 (21/22) 90.9 (20/22) 100 (19/19)
CH without atypia 85.0 (17/20) 93.3 (14/15) 80.0 (8/10) 84.6 (11/13)
SH with atypia 100.0 (3/3) 100.0 (2/2) 100.0 (1/1) 100 (2/2)
CH with atypia 100.0 (12/12) 100.0 (10/10) 10.0 (7/7) 100 (4/4)
Total 93.9 (62/66) 95.9 (47/49) 90.0 (36/40) 94.7 (36/38)
Data are presented as % (n/n)
RR, regression rate.

in the treatment of early-stage EC.17 In that study, which
compared the accuracy of endometrial aspiration biopsy (with
the LNG-IUS in the uterus) with that of D&C (after LNG-IUS
removal), the diagnostic concordance between examinations
was only 32.1%; that is to say, the diagnostic accuracy of
endometrial aspiration biopsy with the LNG-IUS in place was
very poor.
For this reason, we planned to evaluate the diagnostic
accuracy of endometrial aspiration biopsy for EH patients
treated with LNG-IUS, by comparing the pathologic result of
aspiration biopsy with that of D&C at the 12th month of
follow-up. However, we could not find results sufficiently
satisfactory for analysis of the diagnostic concordance between
the 2 examinations, due to a small sample size (15 patients) and
a high regression rate. In almost all of these patients (14/15), the
pathologic result according to D&C was normal endometrium.
Only 1 case was diagnosed by D&C as residual EH, but the
histologic result by endometrial aspiration biopsy was nor-
mal endometrium. Another limitation of this study is the low
follow-up percentage (50.7%) at the 12th month. We think
that the relatively long follow-up duration combined with the
high relapse rate within a short period of treatment time could
be cause of these results.
In an effort to compensate for this shortcomings of
this investigation and to obtain more reliable data, a Korean
prospective multicenter study currently is underway to com-
pare the pathological outcome of endometrial aspiration with
that of D&C as well as the response rates with 3 types of
TABLE 3. Comparison of pathologic results from
endometrial aspiration biopsy and D&C
Endometrial
D&C n Aspiration Biopsy
Normal 14 Normal
Material insufficiency
CH without atypia 1 Normal
Total 15 Total
LNG-IUS is an effective and favorable method for treatment of
EH. Further study on the diagnostic accuracy of endometrial sam-
pling for follow-up evaluation of patients treated with progestational
agents is required.
progestin treatment (cyclic oral progestin, continuous oral
progestin, LNG-IUS) at 6 months (ClinicalTrials.gov Iden-
tifier NCT02412072).
In conclusion, the LNG-IUS is an effective and favor-
able treatment modality for EH. The patients observed in
the present study achieved a therapeutic effect within a short
treatment duration and tolerated the LNG-IUS effectively with
a low incidence of side effects. In addition, accurate diagnosis
and response assessment are essential to any successful hor-
monal treatment regimen. Further study on the diagnostic
accuracy of endometrial sampling for follow-up evaluation
of patients treated with progestational agents is required.
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Management of Endometrial Hyperplasia
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