Objective The purpose of this study was to investigate if the Results After 6 months all three treatment regimens showed
levonorgestrel-impregnated intrauterine device (LNG-IUS, significant effect when the outcome was evaluated as therapy
Mirena) is safe and effective as therapy for low-risk and response or not (P < 0.001). Responses were obtained for all the
medium-risk endometrial hyperplasia compared with oral women in the LNG-IUS group (53/53, 95% CI 0.931.0) and for
medroxyprogesterone (MPA). 96% of the women in the continuous oral group (46/48, 95% CI
0.860.99). Only 69% of the women in the cyclic oral group were
Design A multicentre randomised trial.
responders (36/52, 95% CI 0.550.81). Adverse effects were
Setting Norway. relatively common with minimal differences between therapy
groups.
Population In all, 170 women aged 3070 years with low- or
medium-risk endometrial hyperplasia who met inclusion criteria. Conclusion In the first trial of its kind, women treated with the
LNG-IUS showed histologically normal endometrium after
Methods Patients were randomly assigned to one of three
6 months of therapy for endometrial hyperplasia. Cyclical
treatment arms: LNG-IUS; oral MPA 10 mg administered for
progestogens are found to be less effective compared with
10 days per cycle, or continuous oral MPA 10 mg daily, for
continuous oral therapy and LNG-IUS and should not be used for
6 months.
this purpose.
Main outcome measures The primary outcome measure was
Keywords Endometrial hyperplasia, levonorgestrel-impregnated
normalisation or persisting hyperplasia.
intrauterine device versus oral progestin, therapy.
Please cite this paper as: rbo A, Vereide AB, Arnes M, Pettersen I, Straume B. Levonorgestrel-impregnated intrauterine device as treatment for endometrial
hyperplasia: a national multicentre randomised trial. BJOG 2014;121:477486.
2013 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of 477
Royal College of Obstetricians and Gynaecologists.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
rbo et al.
478 2013 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
Royal College of Obstetricians and Gynaecologists.
LNG-IUS versus oral progestin
Progestogen tablets and LNG-IUS were funded by the coor- Centre, University Hospital of North Norway to be stored
dinator of the study (A) and were given free to the there blinded to the main investigators (A, ABV, MA, IP
women for the entire treatment period. At inclusion, blood and BS). This information was not given to the main inves-
samples for investigation of estradiol, progesterone, folli- tigator before the study was closed. Histological slides
cle-stimulating hormone (FSH) and haemoglobin were obtained during therapy were kept in the treatment data-
routinely taken. In the present study we finally chose to base in the Department of Clinical Pathology, University
define menopausal status according to serum levels of Hospital North Norway. On investigation of the endome-
estradiol and FSH as follows: women with normal estradiol trial biopsies the pathologists and the engineers were always
and normal FSH were defined as not menopausal, women blinded to which treatment group the woman belonged.
with increased FSH but estradiol within normal limits were Treatment effect, i.e. presence of hyperplasia or not, was
defined as perimenopausal, and women with low estradiol obtained after consensus between two different pathologists
and high FSH level were defined as postmenopausal. Before (A, who is a gynaecological pathologist, and one routine
the start of the study the women were also informed that pathologist).
all therapy was stopped after 6 months.
Statistical methods
Additional interventions The sample size estimation was based on a pilot study
A third and fourth clinical consultation including endome- reporting that 50% of women given oral progestin were
trial biopsy was undertaken by the gynaecologist after 3 responders whereas all women treated by LNG-IUS were
and 6 months, respectively, the last at cessation of therapy. cured.23 The intended study population in the present
Occurrence and degree of adverse effects comprising irreg- study was estimated to 200 with an a-value of 0.05 and a
ular vaginal bleeding, nausea and headache were reported b-value of 0.20, according to a difference in effect of 20%
after 3 and 6 months. Ultrasound-estimated endometrial and a drop out frequency of 10%. For analyses of primary
thickness was registered at each consultation. The gynaecol- outcome of the present study the histological material of
ogist at each consultation completed a separate form the endometrial specimens was analysed according the
reporting this information during the study and copies principle of intention to treat.
were sent to the Clinical Research Centre, University Hos- Main hypotheses were answered by comparing number
pital of North Norway for electronic reading. The endome- of women with regressed hyperplasia in each of the three
trial biopsies taken at each consultation (including index treatment groups at the end of therapy using simple uni-
biopsy and biopsies taken after 3 and 6 months) were variate statistics.
immediately soaked in a separate 10-ml glass with 10%
formaldehyde (glasses labelled with womans name and Additional methods
date of birth). All biopsies were sent for investigation by Light microscopy. The histological material obtained from
light microscopy based on modified WHO941,28 classifica- endometrial biopsies was sent to the Department of Pathol-
tion followed by the D-score assessment at the Department ogy, University Hospital of North Norway for routine
of Clinical Pathology, University Hospital of North Nor- assessment by the modified WHO94 classification, which is
way. still considered the reference standard for evaluation of
endometrial hyperplasia.1,3,28 All endometrial biopsies
Outcome measures showing hyperplasia were divided into one of three groups,
The primary efficacy outcome after 6 months of therapy simple hyperplasia, complex hyperplasia or atypical com-
was endometrial hyperplasia or not, assessed by light plex hyperplasia according to the modified WHO94 classifi-
microscopy. Regular proliferative endometrium or exagger- cation.1,3,28
ated progestogen effect with atrophic glands and pseudode-
cidualised stroma was considered as a therapy effect. Morphometric analysis D-score. As reproducibility of the
Secondary outcomes included reported adverse effects expe- WHO classification is considered rather poor we have
rienced during therapy with focus on nausea (only some- introduced the morphometric image analyses algorithm
times and trivial versus often and annoying), pain (only D-score to improve the selection of risk groups. The
sometimes and trivial versus often and annoying), vaginal D-score method represents an objective and highly repro-
bleeding (more or <10 days per month). No changes to ducible procedure that has been implemented as routine
outcomes were made after the trial commenced. analysis in our health region.2932 Hence all women with
D-score >0 are considered to have medium- and low-risk
Blinding procedures hyperplasia (recommendation is progestin therapy and fol-
All clinical information (study form copies) from the study low up), and women with D-score <0 are considered at
was sent by the gynaecologists to the Clinical Research high risk of co-existent or future carcinoma (recommenda-
2013 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of 479
Royal College of Obstetricians and Gynaecologists.
rbo et al.
tion is hysterectomy).2932 After investigation by light the slow inclusion rate, the study was closed when the
microscopy by pathologists, the D-score analyses were per- lowest desired number of included women was attained
formed by trained engineers (IP, KH, KL). In the original (November 2011). After randomisation, 17 withdrawals
computerised morphometric analysis study on endometrial were reported from the total group, five in the cyclic oral
hyperplasia, a total of ten nuclear features and 12 architec- group, nine in the continuous oral group, and three in
tural features were analysed. Using a linear stepwise regres- the LNG-IUS group, respectively. The number of with-
sion analysis and discriminant analysis, three of these drawals was most frequent in the continuous oral group.
quantitative features were selected as having significant The main reasons for withdrawal from the study were
independent prognostic value and were combined into the reported to be irregular bleeding, two in cyclic oral group,
formula called D-score, as follows: D-score = 0.6229 + three in the continuous oral group, and one in the
(0.0439 9 [volume percentage stroma]) (3.9934 9 LNG-IUS group. One woman in the cyclic oral group
Ln [standard deviation shortest nuclear axis]) (0.1592 9 dropped out due to depression. Withdrawal without
[outer surface density glands]), Where Ln stands for natural reporting any specific reason occurred in all three groups,
logarithm. The measurements were performed with a two in the cyclic oral, six in the continuous oral, and two
Q-PRODIT image analysis system (version 6.1; Leica, in the LNG-IUS group (Figure 1). A simple sensitivity
Cambridge, UK). The method describing the performance analysis was performed to ensure that withdrawals from
of the D-score method is described in detail in previous the study were not influencing the main conclusions of
studies.29,31,33 D-score measurements for hyperplasia have the study (data not shown).
been implemented as routine investigations in our health
region and include routines for follow up. The group with Clinical and laboratory data
D-score <0 are recommended hysterectomy according to the The three therapy groups seemed well balanced according
established routine in our health region. Hence, only the to demographic data including age, parity, body mass index
women with D-score 01 or D-score >1 were eligible for (BMI), menopausal status, hormones and haemoglobin
the study. (Table 1). The final results revealed that the majority of
women with endometrial hyperplasia were between 45 and
51 years of age when included in the study (Table 1). Ther-
Results
apy response seemed independent of age group. More than
Between January 2005 and November 2011, 170 women 50% of the women included were overweight when BMI
with endometrial hyperplasia were enrolled and randomly was considered with no difference between treatment
assigned to one of the three treatment regimens; the last groups (Table 1); however, BMI showed no influence on
included woman completed therapy in May 2012. Due to therapy response or not. The majority of women in all
480 2013 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
Royal College of Obstetricians and Gynaecologists.
LNG-IUS versus oral progestin
Table 2. Fraction of regression of hyperplasia and the confidence intervals (95% CI) in each category of endometrial hyperplasia in the three
therapy groups
Intervention SH Fraction of regress. (95% CI) CH Fraction of regress. (95% CI) ACH Fraction of regress. (95% CI)
LNG-IUS 6/6 = 1.0 (0.541.0) 41/41 = 1.0 (0.911.0) 6/6 = 1.0 (0.541.0)
Oral continuous 6/6 = 1.0 (0.541.0) 33/34 = 0.97 (0.841.0) 7/8 = 0.88 (0.471.0)
Oral cyclic 7/11 = 0.64 (0.310.89) 26/36 = 0.72 (0.550.86) 3/5 = 0.6 (0.140.95)
Total 19/30 = 0.64 (0.440.80) 100/111 = 0.90 (0.830.95) 16/19 = 0.84 (0.600.97)
SH, simple hyperplasia; CH, complex hyperplasia; ACH, atypical complex hyperplasia.1,28
2013 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of 481
Royal College of Obstetricians and Gynaecologists.
rbo et al.
Table 3. The incidence and frequency of irregular vaginal bleedings Table 5. Incidence and grade of nausea in the three treatment
were registered during the treatment period in all three therapy groups during therapy and related to therapy response
groups and related to therapy response
No adverse Grade 1, Grade 2, Total,
No adverse Grade 1, Grade 2, Total, effects, n (%) n (%) n (%) n (%)
effects, n (%) n (%) n (%)
n (%)
Therapy/sickness*
Cyclic MPA 26 (26.8) 21 (43.7) 5 (62.5) 52 (33.9)
Therapy/irregular bleeding* Continuous 33 (34.0) 12 (25.0) 3 (37.5) 48 (31.4)
Cyclic MPA 16 (48.5) 25 (37.3) 11 (20.75) 52 MPA
Continuous 11 (33.3) 19 (28.4) 18 (33.9) 48 LNG-IUS 38 (39.2) 15 (31.3) 0 (0.00) 53 (34.6)
MPA Total 97 (100.0) 48 (100.0) 8 (100.0) 153 (100.0)
LNG-IUS 6 (18.2) 23 (34.3) 24 (45.3) 53 Therapy response/sickness**
Total 33 (100.0) 67 (100.0) 53 (100.0) 153 (100.0) Normal 89 (91.8) 40 (83.3) 6 (75.0) 135 (88.2)
Therapy response/irregular bleeding** Persisting 8 (8.3) 8 (16.7) 2 (25.0) 18 (11.8)
Normal 27 (81.8) 58 (86.6) 50 (94.3) 135 hyperplasia
Persisting 6 (18.2) 9 (13.4) 3 (5.7) 18 Total 97 (100.0) 48 (100.0) 8 (100.0) 153 (100.0)
hyperplasia
Total 33 (100.0) 67 (100.0) 53 (100.0) 153 (100.0) *Grade 1 and 2 correspond to more or <10 days per month.
Pearson chi-square 9.17.
*Vaginal bleeding grade 1 and 2 correspond to observed bleedings **Grade 1 and 2 correspond to more or <10 days per month.
lasting more or <10 days per month. Pearson chi-square = 9.65. Pearson chi-square 3.62.
**Vaginal irregular bleeding grade 1 and 2 correspond to observed
bleedings lasting more or <10 days per month. Pearson
chi-square = 3.39.
Therapy response related to the modified WHO
classification and D-score
In Table 6 different classification systems for endometrial
hyperplasia are compared for the three treatment groups
Table 4. Incidence and grade of pain during therapy in the
treatment groups and related to therapy response before therapy. Most cases with simple and complex hyper-
plasia correspond to the D-score group >1.
No adverse Grade 1, Grade 2, Total, Of the 23 women with simple hyperplasia and D-score
effects, n (%) n (%) n (%) n (%) >1 before therapy, four of 11 in the cyclic group were non-
responders. All women in the continuous oral group and
Therapy/pain* all in the LNG-IUS group responded. No women with sim-
Cyclic MPA 24 (28.6) 21 (36.2) 7 (63.6) 52 (100.0)
ple hyperplasia had D-score 01. Among women with com-
Continuous 28 (33.3) 19 (32.8) 1 (9.1) 48 (100.0)
plex hyperplasia and D-score >1, all women responded to
MPA
LNG-IUS 32 (38.1) 18 (31.0) 3 (27.3) 53 (100.0) therapy in the continuous oral (n = 31) and in the
Total 84 (100.0) 58 (100.0) 11 (100.0) 153 (100.0) LNG-IUS (n = 40) groups, respectively. In the cyclic oral
Therapy response/pain** group nine of 30 women with complex hyperplasia and
Normal 75 (89.3) 53 (91.4) 7 (63.6) 135 (88.2) D-score >1 were non-responders. For women with complex
Persisting 9 (10.7) 5 (8.6) 4 (36.4) 18 (11.8) hyperplasia and D-score 01, one of six lacked a response
hyperplasia
in the cyclic oral group and one of three in the continuous
Total 126 (100.0) 21 (100.0) 11 (100.0) 153 (100.0)
oral group. Only one woman with atypical hyperplasia had
*Pain grade 1 corresponds to only sometimes and trivial. Pain grade D-score >1. This woman had continuous therapy and
2 corresponds to frequent and/or annoying. Pearson responded. For women with atypical hyperplasia and
chi-square = 6.61. D-score 01, two of five in the oral group and one of seven
**Pain grade 1 corresponds to only sometimes and trivial. Pain
in the continuous group were non-responders. All six
grade 2 corresponds to frequent and/or annoying. Pearson
chi-square = 7.05. women with atypical hyperplasia who had LNG-IUS
responded.
Discussion
symptoms were not actively asked about by the gynaecolo-
gist but were occasionally reported by the woman such as Main findings
weight gain, altered appetite, altered libido and sleep Our study is the first randomised multicentre trial to
disturbances (data not shown). show that the LNG-IUS is safe and efficient as therapy
482 2013 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
Royal College of Obstetricians and Gynaecologists.
LNG-IUS versus oral progestin
Table 6. The table shows modified WHO94 diagnoses and categories of D-score for the therapy groups before treatment
SH 0 11 0 6 0 6 23
CH 6 30 3 31 1 40 111
ACH 5 0 7 1 6 0 19
Total 11 41 10 38 7 46 153
SH, simple hyperplasia; CH, complex hyperplasia; ACH, atypical complex hyperplasia.1,28
D-score >1 means low risk of coexistent or future carcinoma. D-score 01 means slightly increased risk of coexistent or future carcinoma. See
Methods.
for simple, complex and atypical hyperplasia. Although was performed after WHO classification to ensure objective
continuous oral therapy was nearly as effective as intra- stratification into low- and medium-risk categories. In pre-
uterine treatment, the cyclic oral dose was significantly vious studies the morphometric prognostic index for endo-
less efficient compared with LNG-IUS and the continuous metrial hyperplasia has proved capable of predicting more
regimen. Adverse effects were common and reported in accurately the outcome of endometrial hyperplasia and has
all three therapy groups independent of treatment regi- given reliable recommendations for treatment.30,31,33,3540
men; however, vaginal bleeding was found to be more Hence, the present results showed that women with simple,
annoying for LNG-IUS users compared with those on oral complex and atypical hyperplasia could safely choose the
therapy. Hence, adverse effects could hardly be decisive LNG-IUS but also continuous progestogen as therapy for
for choice of therapy in the treatment of endometrial this disease. Patients with D-score below zero were not
hyperplasia. included in the study.
One main weakness of the study was the long inclusion
Strengths and limitations period of the women lasting for nearly 6 years, partly
A main strength of the study is the design, which repre- through the strict inclusion criteria. As shown in Figure 1,
sents the first investigation to meet the mandatory criteria many women were not eligible for the study, most often
of a multicentre RCT comparing LNG-IUS with oral pro- because of the poor quality of endometrial biopsy material
gestin regimens. The study is also performed according to unsuitable for light microscopy or morphometry. The high
the standards of the CONSORT criteria. The three treat- number of participating centres recruiting women may
ment groups were equally sized and well balanced and the have caused differences in questioning of the women and
investigated variables were evenly distributed among the reporting routines of adverse effects, although, the study
participants. Blinding of treatment to the investigators was procedures were described in detail in the protocol. It may
performed during the study. It was also consistently accom- be open to discussion if such variations might have
plished during the randomisation procedure. When cases impaired the validity of the results. Age distribution is
with endometrial hyperplasia were evaluated for eligibility another limitation of the study. The data demonstrate that
for the study, the quality of endometrial biopsies was care- a proportionally low fraction of the women were older
fully considered. Therefore, specimens with fragmentation, than 52 years or postmenopausal and differences in
those lacking preserved tissue architecture, and specimens response due to hormonal status are not considered. No
with scant material were not included. High quality was interim analyses were performed during the inclusion per-
also ensured when the two same trained pathologists, iod to avoid bias, as the first included women had com-
blinded to treatment group, independently investigated all pleted treatment before the last were included. Optimal
endometrial samples in the study in the same laboratory. procedures for the comparison between therapy regimens
The WHO classification system for endometrial hyper- should have included placebo therapy but procedures
plasia, still regarded and used as a gold standard, was used including placebo medication were not performed in the
as a primary criterion for tissue selection. As the WHO present study. Participating gynaecologists as well as
classification at present is heavily debated because of low women in all three therapy groups might have been biased
reproducibility and lack of objectivity in diagnostics,34 the as blinding of the therapy was not performed. Although
D-score was used as an additional procedure to compensate the possibility was evaluated before study start, it was con-
for this limitation. For all the women included, a D-score cluded that the intrauterine and oral therapy were so prin-
2013 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of 483
Royal College of Obstetricians and Gynaecologists.
rbo et al.
cipally different that placebo medication would have been tively common with minimal differences between therapy
difficult to implement. Construction of an intrauterine pla- groups and should be excluded as an argument for choice
cebo device was considered a possible alternative; however, of therapy. Other characteristics such as BMI and meno-
this was not within reach from an economical view. Of pausal status had no influence on response to therapy.
great importance is the fact that when dealing with prema-
lignant diseases, treatment with placebo might be consid- Disclosure of interests
ered unethical. A has received fees from Bayer for invited lectures in sci-
entific seminars for gynaecologists. For contributing
Interpretations authors ABV, MA, IP and BS no disclosure of interest
In a previous study we showed that nearly 50% of the exists.
women had persisting hyperplasia after therapy with 10 mg
MPA 10 days per cycle for 3 months.23 Comparably, the Contributions to authorship
percentage of women with therapy failure in the present All the authors were involved in the planning and design
study had been reduced to 31% after 6 months of treat- of the study. All authors contributed to the writing of the
ment. Hence, the low-dosed therapy seemed more effective report and can confirm the accuracy and completeness of
when continued for 6 months compared with withdrawal the data reported. After the completion of the study all
after 3 months.23 A direct dose-dependent effect was also authors had full access to all of the results.
demonstrated for the continuous oral therapy, which was
shown to be significantly superior to the cyclic oral treat- Details of ethics approval
ment. Treatment time no <6 months to accurately assess The trial was conducted in accordance with national law
response, was also recommended by Gunderson and col- and local regulations. Permission from The Regional Com-
leagues 41 in a recent review of women receiving progestin mittee for Medical Research Ethics (P REK NORD 25/
therapy for atypical endometrial hyperplasia. However, 2004). Permission from the Medicines Agency (Statens
when meta-analyses of studies are evaluated the results are Legemiddelverk, SLV) was granted on 13th of May 2005.
less comparable because of variation in type, dose, regimen Permission from the National Privacy Protection Commit-
and duration of oral treatment.1,79,1215,23,25,42 tee was granted on 18th of March 2004. The Norwegian
Only women with simple, complex and atypical hyper- System of Compensation to Patients also insured each par-
plasia have been included in the present study. However, ticipating woman.
successful treatment of women with complex atypical
hyperplasia or highly differentiated endometrial carcinoma Funding
in stage I with LNG-IUS has been performed in a few stud- We are grateful to the institutions financing the present
ies.7,42,43 Permission to include cases with severe endome- study. From 2005 to 2011 a research grant given by the
trial changes suspicious of endometrial carcinoma would Norwegian Cancer Association, the Regional Research
be hard to obtain from the Committee of Ethics as these Board of Northern Norway (Helse Nord), and the Bank of
women are most often chosen for surgery. However, safe North Norway funded the study. Annual funding is also
conservative therapy is important for women who want to granted from the University of Troms.
preserve their fertility and for women who are inoperable
due to serious illness. A study with sufficient power includ- Acknowledgements
ing only the mentioned categories would take too long as We are grateful to all the gynaecologists contributing to
such women are few and difficult to recruit. include women in this study: Senior resident Christine
Hancke, MD, Department of Gynaecology and Obstetrics
University Hospital North Norway, Troms, N-9038
Conclusions
Troms, Norway; Chief physician Hans Krogstad MD,
The current randomised multicentre study is the first ever Department of Gynaecology and Obstetrics, University
to prove that the LNG-IUS can be used as therapy for Hospital North Norway, Harstad, N-9400 Norway; Chief
endometrial hyperplasia and that the LNG-IUS is com- Physician Kristen Olav Lind, MD, Department of Gynae-
pletely safe used in simple, complex and atypical hyperpla- cology and Obstetrics, Hospital of Nordland, Stokmarknes
sia. Continuous oral therapy proved to be nearly as Hospital, Stokmarknes, N-8451, Norway; Chief Physician
effective as the LNG-IUS and can be used as an alternative Kevin Sunde Oppegaard, MD, Department of Gynaecology
for women who do not tolerate the LNG-IUS. Only 69% and Obstetrics, Hospital of Finnmark, Hammerfest, N-9600
of the women obtained response after cyclic oral treatment, Hammerfest, Norway; Chief Physician Hemma Hegnauer,
proving that this regimen cannot be recommended as treat- MD, Department of Gynaecology and Obstetrics, Hospital
ment for endometrial hyperplasia. Adverse effects were rela- of Nordland, N- 8000 Bod, Norway; Researcher Louise
484 2013 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
Royal College of Obstetricians and Gynaecologists.
LNG-IUS versus oral progestin
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