Levonorgestrel-Releasing Intrauterine System For
Conservative Management Of Menorrhagia In Women In
Childbearing Period
Hany Abdelhamid Elkallaf, MD
Department of Obstetrics & Gynecology, Faculty of Medicine, Benha University
Abstract
Objectives: To evaluate short-term outcome of the use of Levonorgestrelreleasing intrauterine system (LNG-IUS) for management of menorrhagia
in women in the childbearing period
Patients & Methods: The study included 53 multipara women with mean
age of 39.4±4 years presenting with menorrhagia. All women had full
history taking, clinical examination, transvaginal ultrasonography and
endometrial biopsy and cervical smear evaluation prior to LNG-IUS
insertion one day after cessation of menstrual bleeding. Patients were
evaluated at 6 and 12 months for duration and heaviness of menstrual
blood loss and for health-related quality of life was evaluated using the 5Dimensional EuroQol (EQ-5D) scoring system.
Results: Nine insertions were difficult; 7 because of pain on sounding and
2 insertions were abandoned because of the presence of cervical
adhesions. There were 3 IUS expulsions; two partial and a new IUS was
reinserted and one complete expulsion and patient was excluded of the
study. LNG-IUS significantly reduced duration and severity of blood loss
at 6 and 12 months after insertion compared to baseline data with
significant reduction at 12 months compared to at 6 months. At the end of
12 months; 7 women developed amenorrhea, 36 women had mild loss
and 7 women had moderate loss. Quality of life scoring significantly
improved at 6 and 12 months after LNG-IUS insertion compared to
baseline scores. Mood and pain sub-scores showed the significant change,
while the changes of the other sub-scores were non-significant.
Conclusion: LNG-IUS is a safe, effective and feasible therapeutic
modality for menorrhagia and is associated with significant improvement
of quality of life with special regard to mood and associated pelvic pain
and could be recommended as first line of management for women in
childbearing period wishing to retain their power to conceive in future.
Introduction
By definition, diagnosis of menorrhagia is made when the duration
of bleeding is equal to or greater than six days or blood loss is at least 80
ml and other pathological conditions have been excluded. However,
many women seek consultation for even milder bleeding episodes, due to
the associated stress, discomfort, and quality of life impairment, thus
making menorrhagia one of the most frequent reasons for gynecological
consultation. Menorrhagia is estimated to occur in 30% of women in their
childbearing years (1, 2).
Therapeutic options for menorrhagia are variant and ranging from
oral medical therapy to hysterectomy. Hysterectomy is highly effective
treatment with high satisfaction rates and improved quality of life
especially if menorrhagia was secondary to multiple and/or large fibroids.
However, the associated complications and costs may be limiting for
hysterectomy to be the sole line of treatment. Moreover, hysterectomy
could not be the line of management of women in late childbearing or
early pre-menopausal period, (3).
Hysterectomy alternatives include hysteroscopic resection which is
the standard treatment for endometrial polyps and recurrence of bleeding
is reduced by combining it with endometrial ablation. Myoma-related
menorrhagia can be treated by Gn-RH agonists for 3 months,
hysteroscopic resection for submucous myomas. Interstitial myomas can
be treated by myomectomy, myolysis, uterine artery embolisation or
occlusion, or hysterectomy. Laparoscopic myomectomy and uterine
artery embolisation are effective, well tolerated, and the best researched.
LNG-IUS is effective and well tolerated to treat adenomyosis-related
menorrhagia. The effect of other conservative treatments of the uterus
(endometrial ablation, uterine artery embolisation or occlusion) is limited,
especially in case of deep and extensive adenomyosis. Uterine artery
embolisation is the standard treatment for arteriovenous malformation, (4,
5)
.
Progesterone is a key hormone in regulating the female
reproductive system, interacting at the level of the hypothalamus, the
ovary, the uterus and the breast. Progesterone exerts effects on ovulation,
endometrial differentiation, cervical mucus, breast differentiation and
uterine contractility. Progestins and their analogs and antagonists have
many uses in gynecology including contraception, management of
miscarriage, medical abortion and treatment of conditions related to
endometrial and myometrial growth and development. Beyond providing
highly effective contraception, intrauterine delivery is safe and effective
in the management of menorrhagia, dysmenorrhea, uterine myomata, and
endometrial proliferation, (6, 7, 8).
Intrauterine delivery of progestin is an effective way to administer
local treatment and bypass systemic side effects. Intrauterine drug
delivery has the potential to treat many gynecologic conditions, but is
under utilized because clinicians lack knowledge and skills and because
the current delivery systems are unavailable or costly in many countries
(9)
.
The present prospective study aimed to evaluate short-term
outcome of the use of LNG-IUS for management of menorrhagia in
women in the childbearing period
Patients & Methods
The present prospective study was conducted at Armed Forces
Hospital, King Abdul Aziz, Airbase, Dhahran, KSA since Sep 2008 till
Jan 2010 to allow 12-month follow-up for the last enrolled case. After
obtaining written fully informed patients' and husband' consent, the study
included 53 women aged 35 to 49 years who were menstruating, had
completed their desired family size, and had menorrhagia.
Collected data included age, parity, number of deliveries, history of
previous cesarean section, and previous contraceptive methods.
Heaviness of menstrual period in the last 6 months was graduated as
light, moderate, heavy or very heavy loss and the frequency of bleeding
or spotting between cycles was reported.
Prior to LNG-IUS insertion endometrial pathology (endometrial
carcinoma and/or endometrial atypical hyperplasia) and cervical
pathology (cervical cancer and preinvasive intraepithelial lesions) were
excluded by D & C or endometrial sampling using Pipelle® (Cooper
Surgical, Trumbull, Connecticut, USA) and cervical smear, respectively.
Transvaginal ultrasonography was used to exclude possible causes of
menorrhagia, including myomas and endometrial polyps, as well as
adnexal pathology. Women with uterine or adnexal pathology as well as
women desiring preservation of fertility were excluded from the study.
Insertion of LNG-IUS was performed as an office procedure one
day after cessation of menstrual bleeding. All women must have a
negative urine pregnancy test prior to LNG-IUS insertion. The uterine
cavity length was measured using uterine sounding, followed by LNGIUS insertion. Feasibility of insertion was defined as difficult if there was
moderate or severe pain on uterine sounding or if there was need for
cervical dilatation, requirement for local anesthesia or intravenous
sedation for accomplishment of dilatation and IUD insertion. Accurate
LNG-IUS position was documented with transvaginal ultrasonography
immediately after insertion.
Health-related quality of life was evaluated using the 5Dimensional EuroQol (EQ-5D) which provides a single numeric score for
HRQL, is universally used, and has undergone validation in the Finnish
general population. TheEQ-5D consists of five subscales that indicate
dimensions of mobility, self-care, usual activities, pain, and mood each
was scored as 0 or 1 and the total EQ-5D score index was calculated;
better HRQL is indicated by higher scores (10, 11, 12). The EQ-5D scoring
was conducted prior to and 6 and 12 months after LNG-IUS insertion
Results
The study included 53 women with mean age of 39.4±4; range 3549 years. All were multipara with a mean parity of 3.6±0.7; range: 3-5.
Twenty-nine women (54.7%) had all their deliveries vaginally, while 24
women (45.3%) had previous cesarean sections. Previous contraception
was using pills (22 women; 41.5%) or cupper IUD (24 women; 45.3%); 4
women (7.5%) were acclimatized to use safe period and 3 women (5.7%)
used condom, (Table 1).
The length of menstrual cycles was varied and ranged between 23
and 32 days with a mean cycle length of 27.8±3 days. Similarly, mean
length of menstrual period was 7.4±1.1; range: 6-9 days. Also, the
heaviness of menstrual period was variable but 20 women had heavy loss,
16 had moderate, 14 had very heavy loss and only 3 women had mild
loss. Moreover, 10 women had additional spotting through the rest of the
intermenstrual period, (Table 2).
Insertion of LNG-IUS was feasible with no or mild tolerable pain
in 17 (32.1%) and 27 (50.9%) women, respectively. Nine insertions were
graded as difficult; 7 (13.2%) because of pain on sounding that required
intravenous sedation till successful accomplishment of insertion, 2
insertions (3.8%) were abandoned because of the presence of cervical
adhesions and were excluded of the study that included 51 women
(96.2%) only. The mean uterine sound measurement was 7.3±1.5; range
5–10 cm, (Table 3).
Three IUS expulsions (5.9%) occurred during the study; two partial
expulsions occurred at 2 weeks and 4 months after insertion and a new
IUS was successfully reinserted. One complete expulsion occurred
unnoticed during the first 6 months and the subject discontinued the study
and follow-up evaluation included 50 women (94.3%), (Table 3).
Considering reduction of both duration and severity of blood loss;
LNG-IUS significantly (p<0.05) reduced duration of blood loss at both 6
and 12 months after insertion compared to duration of blood loss prior to
insertion with significantly reduced duration of loss at 12 months
compared to duration of loss at 6 months, (Fig. 1). Moreover, frequency
of women with short duration of blood loss was significantly higher at
end of 12 months after insertion compared to that recorded at end of 6
months, (Table 4).
At the end of 12 months follow-up; 7 women developed
amenorrhea, 36 women had mild loss and 7 women had moderate loss,
but no women had moderate or severe loss with significant reduction
(X2=85.686, p<0.001) of frequency of women had excessive blood loss
compared to prior to LNG-IUS. On contrary, 17 women had
intermenstrual spotting with significant increase (X 2=6.113, p<0.05) of
the frequency of women had spotting at the end of 12-months compared
to prior to insertion of LNG-IUS, (Table 5).
Quality of life scoring significantly (p<0.05) improved at 6 and 12
months after LNG-IUS insertion compared to baseline scores with nonsignificantly higher scores between 6 and 12 months records. Mood and
pain sub-scores showed the significant change, while the changes of the
other sub-scores were non-significant, (Table 6, Fig. 2).
Table (1): Age and parity data of enrolled women
Data
Age (years)
Findings
Mean±SD
39.4±4 (35-49)
Strata
35-40
35 (66.1%)
>40-45
12 (22.6%)
>45-50
6 (11.3%)
Parity
Mean±SD
3.6±0.7 (3-5)
Strata
3
28 (52.7%)
4
17 (32.1%)
5
8 (15.2%)
Mode
of Vaginal
29 (54.7%)
delivery
Cesarean section
24 (45.3%)
Contraceptive Pills
22 (41.5%)
history
Cupper IUD
24 (45.3%)
Safe period
4 (7.5%)
Condom
3 (5.7%)
Data are presented as mean±SD & numbers; ranges & percentages are in
parenthesis
Table (2): Menstrual history data of enrolled women
Data
Length
(days)
menstrual cycle
Findings
27.8±3 (23-32)
5 (9.4%)
20 (37.7%)
8 (15.2%)
20 (37.7%)
7.4±1.1 (6-9)
13 (24.5%)
14 (26.4%)
16 (30.2%)
10 (18.9%)
3 (5.7%)
16 (30.2%)
20 (37.7%)
14 (26.4%)
of Mean±SD
Strata <24
24-26
27-29
30-32
Length
(days)
of Mean±SD
menstrual period
Strata 6
7
8
9
Heaviness of menstrual Mild loss
period
Moderate loss
Heavy loss
Very
heavy
loss
Spotting
throughout No
43 (81.1%)
period
Yes
10 (18.9%)
Data are presented as mean±SD & numbers; ranges & percentages are in
parenthesis
Table (3): LNG-IUS insertion and follow-up data
Data
Findings
Uterine sound Mean±SD
7.3±1.5 (5-10)
measurements Strata
5-cm
6 (11.8%)
6-cm
14 (27.5%)
7-cm
5 (9.7%)
8-cm
14 (27.5%)
9-cm
9 (17.6%)
10-cm
3 (5.9%)
Insertion
No difficulty
44 (83%)
difficulty
Difficult Pain
7 (13.2%)
insertion Cervical
2 (3.8%)*
adhesions
Insertion pain Strata
No
17 (32.1%)
Mild
27 (50.9%)
Moderate/severe
7 (13.2%)
Post-insertion No
48 (94.2%)
expulsion
Partial
2 (3.8%)
Complete
1 (2%)*
Data are presented as mean±SD & numbers; ranges & percentages are in
parenthesis
*: excluded cases
Table (4): Blood loss duration recorded throughout follow-up period
compared to baseline data
Baseline
6-m later
12-m later
Mean±SD
(days)
7.4±1.1 (6-9)
2.4±0.9 (1-5)*
1.6±1 (0-3)*†
Strata 0-day
0
0
7 (14%)
1-day
0
7 (14%)
17 (34%)
2-day
0
23 (26%)
17 (34%)
3-day
0
14 (28%)
9 (18%)
4-day
0
5 (10%)
0
5-day
0
1 (5%)
0
6-day
12 (24%)
0
0
7-day
13 (26%)
0
0
8-day
16 (32%)
0
0
9-day
9 (18%)
0
0
Data are presented as mean±SD & numbers; ranges & percentages are in
parenthesis
*: significant versus baseline data
significant versus 6-m after LNG-IUS insertion
†:
Table (5): Blood loss heaviness data recorded throughout follow-up
period compared to baseline data
Data
Heaviness
menstrual
loss
Baseline
12-m later
of No
0
7 (14%)
period Mild
3 (6%)
36 (72%)
Moderate
15 (30%)
7 (14%)
Heavy
19 (38%)
0
Very heavy
13 (26%)
0
Spotting
No
40 (80%)
33 (66%)
throughout period Yes
10 (20%)
17 (34%)
Data are presented as numbers; percentages are in parenthesis
Table (6): Quality of life scores recorded throughout follow-up
period compared to baseline scores
Baseline
3.54±0.71
1
0.86±0.35
0.94±0.24
6-m later
3.88±0.63*
1
0.88±0.33
0.96±0.20
12-m later
4.3±0.65*†
1
0.9±0.3
0.98±0.14
Total score
Strata Mobility
Self-care
Usual
activities
Pain
0.3±0.5
0.52±0.5*
0.64±0.53*†
Mood
0.44±0.71
0.52±0.5*
0.78±0.42*†
Data are presented as mean±SD & numbers; ranges & percentages are in
parenthesis
*: significant versus baseline data
†:
significant versus 6-m after LNG-IUS insertion
9
Prior
6-m later
12-m later
8
Duration of blood loss (days)
7
6
5
4
3
2
1
0
Fig. (1): Mean (+SD) duration of blood loss prior to and after
LNG-IUS insertion
6
Prior
6-m later
12-m later
Quality of life score
5
4
3
2
1
0
Fig. (2): Mean (+SD) total quality of life score determined prior
to and after LNG-IUS insertion
Discussion
The purpose of the study was to evaluate the outcome of LNG-IUS
as a therapeutic modality for menorrhagia affecting a group of women in
childbearing period who refused other lines as hysterectomy or
endometrial ablation, LNG-IUS significantly reduced duration of blood
loss and the frequency of women with prolonged duration of blood loss at
both 6 and 12 months after insertion compared to duration of blood loss
prior to insertion. Moreover, 36 women had mild loss and no women had
moderate or severe loss with significant reduction of frequency of women
had excessive blood loss compared to prior to LNG-IUS.
These data indicated the beneficial effects of LNG-IUS as a sole
therapeutic modality for menorrhagia and supported that previously
reported in literature; Wildemeersch & Rowe (13) demonstrated the
efficacy of the LNG-IUS to significantly reduce the amount of menstrual
blood loss in women with menorrhagia and concluded that the therapeutic
effect of this contraceptive method is highly desirable, particularly in
women with heavy bleeding or anemia, as other treatment modalities are
less effective, more costly, more invasive or inaccessible.
Kriplani et al., (14) reported that menorrhagia was cured in 77.7% of
their patients at 3 months and in all patients at 36 months with a
significant decrease in the mean number of bleeding days and pictorial
blood loss assessment chart score at one month, and the decrease
continued with treatment duration. Moreover, Kriplani et al., (14) reported
that the subjective blood loss reduction was considerable as well, and
endometrial thickness was significantly decreased at 12 months.
Endrikat et al., (15) compared the efficacy of LNG-IUS versus
combined oral contraceptives for treatment of menorrhagia and reported
that in both treatment groups, menstrual blood loss decreased
significantly from baseline to 12 months but the decrease was
significantly more in the LNG-IUS group, 80% of subjects had treatment
success compared with 36.8 % with oral therapy and significantly
consistently lower menorrhagia severity score in the LNG-IUS group at
all study time points. Bednarek & Jensen (16) reported that most LNGIUS users for menorrhagia experienced a dramatic reduction in menstrual
bleeding.
Quality of life scoring significantly improved at 6 and 12 months
after LNG-IUS insertion compared to baseline scores with mood and pain
sub-scores showed the significant change; the significantly improved pain
scores could be improved mood considering such pain is psychogenic in
origin in addition to the presence of some sort of pelvic congestive
symptoms that are mostly ameliorated with the use of the steady release
progesterone. The significantly improved QoL scores despite the nonsignificant change of mobility, self care and usual activity subscores also
could be attributed to improved mood while performing these activities.
Moreover, the simple design characteristics of the T-shaped LNG-IUS
could account for minimizing the occurrence of pain. These data
coincided with Bragheto et al., (17) who reported a significant decrease in
pain score at 3 and 6 months after LNG-IUS insertion. Lete et al., (18)
found LNG-IUS is an effective and well-tolerated treatment modality in
idiopathic menorrhagia with markedly improved QoL of women treated
causing high levels of patient satisfaction and concluded that LNG-IUS
can be regarded as a first-choice therapy in idiopathic menorrhagia.
Gorgen et al., (19) who measured the health-related quality of life in LNGIUS and reported significant improvement of QoL scores with significant
decrease of scores for pelvic pain, while libido and general feeling of
health were increased.
Despite these beneficial effects of LNG-IUS, at the end of 12
months follow-up; 7 women (14%) developed amenorrhea, which
undesirable for women in childbearing period. The reported figure for
amenorrhea goes in hand with Bragheto et al., (17) who reported that at 6
months after LNG-IUS insertion, oligomenorrhea was the most common
bleeding pattern observed and Kriplani et al., (14) reported amenorrhea in
28.57% of their studied menorrhagia patients treated by LNG-IUS.
Moreover, Bednarek & Jensen (16) reported that about 15% to 20% of
women become amenorrheic one-year after LNG-IUS insertion.
However, such event was explained prior to enrollment in the study
for all women and they informed that their ability to conceive could be
regained after IUD removal. Fortunately, none of these women had a
desire to get pregnant. In support of the fertility regaining, Bednarek &
Jensen (16) reported that for their amenorrheic women after removal of the
IUD, there is rapid return to fertility, with 1-year life-table pregnancy
rates of 89% for women less than 30 years of age.
Intermenstrual spotting showed significantly increased frequency
at the end of 12-months compared to prior to insertion of LNG-IUS and
was reported in 17 women (34%). The data go in hand with Kriplani et
al., (14) found Intermenstrual spotting was the most common side effect
for LNG-IUS insertion for menorrhagia treatment. Bragheto et al., (17)
who reported that at 3 months of LNG-IUS use, the most common
bleeding pattern was spotting, and at 6 months of observation,
oligomenorrhea was the most common pattern observed, although
spotting was present in one third of the women.
Multiple studies tried to explore the molecular mechanisms for
improvement and diminution of menstrual blood loss with concomitant
short menstrual period with the use of LNG-IUS; Obro et al., (20)
histological reported that progesterone receptor A and B in endometrial
glands were almost extinguished, reduced estrogen receptors with
modulation of apoptosis in glands and stroma in LNG-IUS users
compared to the oral group and concluded that the clinical effect of LNGIUS is accompanied by almost extinguished PR-receptors in glands
coinciding with modulation of apoptosis and this strongly indicate that
progestins activate non-classical initiated signaling pathways. Also,
Maruo et al., (21) demonstrated that LNG-IUS acting as progesterone
receptor modulator not only inhibits the proliferation and stimulates
apoptosis of cultured leiomyoma cells but also suppresses collagen
synthesis in a cell-type specific manner. Xu et al., (22) demonstrated that
the proliferation rate of uterine leiomyoma cells was suppressed after
treatment with LNG at a minimum concentration of 10 μg/ml and the
inhibitive effect was positively correlated with the LNG concentration
and with the incubation time. Flow cytometry showed that the apoptosis
rate was increased with the LNG concentration while the mRNA levels of
IGF-1, Bcl-2 and survivin were down-regulated significantly after
treatment with 10 mcg/mL LNG and Western blot analysis confirmed that
the expression of Bcl-2 and survivin was decreased significantly, and the
p38 phosphorylation level was increased and caspase 3 was activated
remarkably 72 h after treatment with 10 and 20 mcg/ml LNG
It could be concluded that LNG-IUS is a safe, effective and
feasible therapeutic modality for menorrhagia and is associated with
significant improvement of quality of life with special regard to mood
and associated pelvic pain and could be recommended as first line of
management for women in childbearing period wishing to retain their
power to conceive in future. However, larger scale studies with longer
duration of follow-up are mandatory for establishment of obtained results.
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