Medical management of heavy menstrual
bleeding: a comprehensive review of the
literature
Johannes Bitzer, MD, PhD,1 Oskari Heikinheimo, MD, PhD,2 Anita L. Nelson,
MD,3 Joaquin Calaf-Alsina, MD, PhD,4 Ian S. Fraser, MD, DSc 5
1
Department of Obstetrics and Gynecology, University Hospital of Basel, Basel,
Switzerland; 2Department of Obstetrics and Gynaecology, Kätilöopisto Hospital,
University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland;
3
Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center,
Torrance, CA USA; 4Department of Obstetrics and Gynaecology, Hospital de la
Santa Creu i Sant Pau, Universitat Autónoma, Barcelona, Spain; 5University of
Sydney, Sydney, New South Wales, Australia
Corresponding author: Ian Fraser, Department of Obstetrics and Gynaecology,
Central Clinical School, D02–QEII Research Institute for Mothers and Infants, The
University of Sydney, Sydney, NSW 2006, Australia. Phone: +61 2 9351 2478; Fax:
+61 2 9351 4560; E-mail: ian.fraser@sydney.edu.au
1
Supplemental tables
Table 1: Characteristics and outcomes of trials that assessed the levonorgestrel-releasing intrauterine system (initial release rate of 20 µg
LNG/24 hours after placement; LNG-IUS) for the treatment of heavy menstrual bleeding (HMB). Data shown for the LNG-IUS group only.
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Randomized controlled trial in women with AUB-E (or those described having HMB without further definition)
Crosignani et al
LNG-IUS (n=35)
Randomized Women aged 38 years or older PBAC
12 months’ treatment
1997(1)
open-label
referred for hysterectomy for
Endometrial resection
79% mean PBAC score
HMB. Inclusion criteria
Italy
(n=35)
reduction at 6 and 12
included uterine volume
months (6 month data
equivalent to an 8-week
estimated from graph)
pregnancy or less, a negative
cervical smear in the last 12
Recurrent HMB
months, no evidence of
(defined as PBAC 100
atypical hyperplasia, no
or higher) was
adnexal tumors, and normal
observed in 4/34 (12%)
uterine cavity as determined
at 12 months
by hysteroscopy. Exclusions
included desire for future
childbearing, congenital or
acquired uterine anomalies,
pelvic inflammatory disease,
or intramural or subserous
myomas of more than 3 cm in
diameter, as shown by
transvaginal ultrasound
Irvine et al
LNG-IUS (n=22)
Randomized
Healthy women 18–45 years
with a regular menstrual cycle,
Alkaline
3 cycles’ treatment
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
Adverse events were
reported by 19/34 (n=10,
bloating; n=8, weight
gain; n=6, breast pain;
n=4, headache; n=2 for
pelvic pain, decreased
libido, hair loss, acne,
and anxiety-depression;
n= 1 for hypertension
and leg pain)
Only 1 (3%)
subject did not
complete study
(lost to follow up)
1 (3%) women
scheduled for
surgical treatment
2 (2/34; 5.9%) partial
expulsions occurred.
No perforations reported
No difference in adverse
events (headaches, acne,
20 (91%)
completed 3
2
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
1998(2)
Norethisterone (5 mg
TID from day 5 to 26;
n=22)
open-label
hematin
88% and 99% median
reduction in MBL at
cycle 1 and 3 cycles of
treatment:
abdominal or back pain,
nausea, oedema, weight
gain, decreased libido,
sweating, hair loss or
greasy hair and increase
in body hair) at baseline
and over 3 months.
Intermenstrual bleeding,
breast tenderness and
mood swings appeared to
decrease relative to
baseline.
months
UK
a normal pelvic examination
with a uterine sound < 10 cm,
negative cervical cytology and
MBL >80 mL (objectively
confirmed during 1 pretreatment cycle)
17 (77%) elected
to continue with
the treatment
<<Surgery
avoided or
required not
reported>>
1/22 (5%) had LNG-IUS
expulsion
No perforations reported
Hurskainen et al.,
2001(3)
Finland
LNG-IUS (n=119)
Hysterectomy (n=117)
Randomized
open label
Women aged 35–49 year
referred for HMB and who
had completed their family
and eligible for hysterectomy.
Exclusion criteria included
submucous fibroids;
endometrial polyps; ovarian
tumours or cysts (>5 cm);
cervical disease; urinary and
bowel symptoms or pain due
to large fibroids; history of
cancer; menopause; severe
depression; metrorrhagia as a
main complaint; severe acne;
Alkaline
hematin
12 months follow-up
MBL was measured in
only 25 subjects at 12
months.
Mean MBL decreased
from 130 mL to 13mL
at 12 months (MBL
only measure in 25
women at 1 year). One
subject had HMB
(MBL >80 mL). The
remaining subjects had
amenorrhoea or
Adverse events not
reported
1 (1%) expulsion of
LNG-IUS occurred
No perforations reported.
81 (68%) had the
LNG-IUS in situ
at 12 months,
24 (20%) had
undergone
hysterectomy
3
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
uterine malformation
Soysal et al
2002(4)
Turkey
Barrington et al
2003(5)
UK
Rauramo et al
2004‡ (6)
Finland/Norway
LNG-IUS (n=36)
Endometrial ablation
(n=36)
LNG-IUS (n=25)
Endometrial ablation
(n=25)
LNG-IUS (n=30)
Endometrial resection
(n=29)
Randomized
open-label
Randomized
open-label
Randomized
open-label
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
Adverse events reported
by 21/36 subjects (n=
6,spotting; n= 5,
mastalgia; n=10, weight
gain; n=2, mood swings;
n=8, bloating; n=7, acnegreasy skin; n=4, nausea;
n=1, headache )
All patients were
followed for 12
months
negligible bleeding (not
defined)
Women aged over 40 years
with no further desire for
childbearing complaining of
HMB. Exclusion criteria
included: congenital and
acquired uterine anomalies,
pelvic inflammatory disease,
uterine volume greater than
8week pregnancy, intramural
and subserous myomas greater
than 2 cm in diameter in high
resolution transvaginal
ultrasonography and any
abnormalities in hysteroscopy
PBAC
Women with HMB refractory
to medical therapy. Exclusion
criteria included uterine cavity
length >12 cm or subserous
fibroids, and any malignant or
pre-malignant pathology
PBAC
Women aged 30 to 49 years,
with no further desire for
children, and idiopathic HMB
needing treatment, and with a
normal uterine cavity.
PBAC
12 months’ treatment
95% mean PBAC score
reduction at 12 months
77% treatment success
(PBAC≤100) at 12
months
1 (3%) subject lost LNGIUS
No perforations reported
6 months’ treatment
AEs not reported.
71% mean PBAC score
reduction
No LNG-IUS expulsions
reported
71% median PBAC
score reduction
No perforations reported
Study initially planned
for 1 year, but extended
to 3-years treatment
In the LNG-IUS group, 3
subjects were diagnosed
with endometritis, 2 with
pelvic inflammatory
disease, and 1 edema.
Reduction in median
PBAC scores: 95%,
97% and 97% at 1, 2
1 (3%) partial expulsion
21 (84%)
completed 6
months
3 (12%)
underwent
surgical treatment
24 (80%)
completed 12
months
Of the 22 subject
who consented to
participate in
4
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
and 3 years,
respectively
occurred.
extension phase
19 (86%
completed 3
years)
No perforations reported
No women
underwent
subsequent
surgical treatment
Reid and
Virtanen-Kari
2005(7)
UK
Malak and Shawki
2006(8)
Egypt
LNG-IUS (n=25)
Mefenamic acid (500 mg
TID from days 1-4;
n=26)
LNG-IUS (n=30)
Endometrial resection
(n=30)
Randomized
open-label
Randomized
open-label
Women aged 18–47 years
with regular ovulatory,
menstrual cycles of 21–35
days and objective HMB
(MBL ≥80 mL objectively
confirmed in one pretreatment cycle). Exclusions
included anovulatory cycle,
submucous fibroids or fibroids
with a total volume of >5 cm3,
a uterine sound of >10 cm or
abnormal cervical cytology.
Alkaline
hematin,
PBAC and
total
menstrual
fluid
Women aged 40–50 years
with spontaneous cycles
scheduled to undergo
hysterectomy for HMB.
Exclusion criteria included:
cavity ≥10 cm, one fibroid
PBAC
6 cycles’ treatment
Reduction in median
MBL: 90%, and 96%
in cycles 3 and 6,
respectively
Reduction in median
PBAC scores: 80% and
89% in cycles 3 and 6,
respectively
Reduction in median
total menstrual fluid
loss: 71% and 85% in
cycles 3 and 6,
respectively
12 months’ treatment
87% mean PBAC score
reduction at 12 months
87% median PBAC
Common AEs with
LNG-IUS included:
headache (n=10; 40%);
abdominal pain (n=8;
32%); ovarian cysts
(n=6; 24%); breast pain
(n=6; 24%); nausea
(n=4; 16%); and upper
respiratory infection
(n=5; 20%). No
perforations reported
21 (84%)
completed study
<<Surgery
avoided or
required not
reported>>
4/25 (16%) partial or
complete expulsions (all
discontinued)
Adverse events reported
by 7/30 subjects (n=2,
metrorrhagia; n=3, pelvic
pain; n=4, vaginal
discharge; n=5,
abdominal pain; n=3,
87% completed
12 months
treatment
4 (13%)
underwent
5
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
>3cm of more than three
fibroids, pelvic inflammatory
disease
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
score reduction at 12
months
breast tenderness; n=2,
headache; n=2, acne;
n=1, mood change)
surgical treatment
77% treatment success
(PBAC <75)
No LNG-IUS expulsions
reported
No perforations reported
Busfield et al
2006 (9)
New Zealand
Shaw et al
2007(10)
UK
LNG-IUS (n=40)
Endometrial ablation
(n=39)
LNG-IUS (n=33)
Endometrial ablation
(n=33)
Randomized
open-label
Randomized
open-label
Women aged 25–50 years
with regular cycles, selfdescribed HMB and
completed their families.
Exclusion criteria included
ultrasound abnormalities
(submucousal fibroids,
intramural fibroids greater
than 3 cm in diameter, large
subserosal fibroids,
endometrial polyps),
intermenstrual bleeding,
chronic pelvic pain.
PBAC
Women aged 25–49 years who
had completed their families
and with HMB (PBAC >120
in two control cycles) that
failed first-line oral therapy.
Exclusion criteria included:
submucus fibroid (>2.5 cm)
identified on scan or
hysteroscopy, Uterine cavity
less than 7 cm or greater than
PBAC
24 months’ treatment
74%, 85%, 92%, and
96% mean PBAC score
reduction at 3, 6, 12
and 24 months,
respectively
AEs not reported in
detail ( 1 subject had
actinomycoses).
31 (78%)
completed 12
months treatment
4 (10%) subjects had
LNG-IUS expulsion.
26 (65%)
completed 24
months treatment
No perforations reported
6 (15%) subjected were
treatment failures
(defined as a major
change in treatment)
7 (18%)
underwent
surgical treatment
12 months’ treatment
AEs not reported.
62%, 72%, 93%, and
94% median PBAC
score reduction at 3, 6,
9 and 12 months,
respectively
2 (6%) subjects had
LNG-IUS expulsion.
No perforations reported
23 (70%)
completed 12
months treatment
20 (61%)
continued with
the LNG-IUS to
24 months
8 (24%) had listed
for or undergone
6
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
11 cm.
Kucuk and Ertan
2008(11)
Assumed to be
Turkey and/or
Germany (not
clear)
Endrikat et al
2009(12)
Canada.
LNG-IUS (n=44)
Oral MPA (5 mg daily;
n=44)
Randomized
open-label
Depot MPA (n=44);
Perimenopausal women (aged
>40 years) who were smokers.
Those with organic pathology
and nonsmokers were
excluded.
surgery
PBAC
2 cycles’ treatment
73% mean PBAC score
reduction by cycle 2
HMB confirmed using PBAC
and hemogram (duration for
confirmation not stated).
LNG-IUS (n=20)
NETA/EE (1mg/20µg;
n=19)
Randomized
open-label
Healthy women >30 years
with idiopathic HMB (PBAC
score ≥100 confirmed during 2
consecutive pre-treatment
cycles) and a normal or only
slightly enlarged uterus
Continuation
rates (for LNGIUS)
Common adverse effects
included intermenstrual
bleeding (n=6; 14%) and
breast tenderness (n=6;
14%)
No LNG-IUS expulsions
reported
No perforations reported
PBAC
12 months’ treatment
Reduction in median
MBL (estimated from
graph):
 77%, 95%, 94% and
94% during 3, 6, 9
and 12 months,
respectively
One (5%) patient
reported an inguinal
hernia
No LNG-IUS expulsions
reported
No perforations reported
Proportion
completing study
not reported
38 (86%) willing
to continue
<<Surgery
avoided or
required not
reported>>
19 (95%)
completed 12
months
<<Surgery
avoided or
required not
reported>>
83% mean reduction in
PBAC score at 12
months
de Sousa et al
2010(13)
Brazil
LNG-IUS (n=30)
Endometrial ablation
(n=28)
Randomized
open-label
Women with HMB
determined using PBAC.
Inclusion criteria included
PBAC
12 months’ treatment
AEs not reported.
84%, 93% and 92%
mean PBAC score
No LNG-IUS expulsions
reported
Continuation rate
not reported
1 (3%) opted for
7
Author
(year)/Country
Kaunitz et al
2010(14)
United States,
Canada, and
Brazil
Comparators
LNG-IUS (n=82)
MPA (10 mg daily from
16 to 25; n= 83)
Study design Inclusion/Exclusion criteria
Randomized
open-label
HMB refractory to medical
treatment age 35 years or
older, and no intracavitary
abnormalities, pelvic
inflammatory disease,
suspected endometrial
pathology, abnormal
endometrial histology,
abnormal cervical, large
myomas or any ovarian
disease for which
hysterectomy would be more
appropriate. In addition, all
women had to have
completed their families.
Parous women aged ≥18 years
with idiopathic HMB (MBL
≥80 mL objectively confirmed
during 2–3 pre-treatment
cycle), desiring intrauterine
contraception and willing to
use barrier contraception if
required.
Exclusions included fibroids
(if they distorted the uterine
cavity or cervical canal);
history of organic causes of
abnormal uterine bleeding.
MBL
assessment
method
Alkaline
hematin
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
reduction at 1, 6 and 12
months, respectively
(estimated from graph)
No perforations reported
hysterectomy
6 cycles’ treatment
Headache (n=13;
16.3%), ovarian cysts
(n=10; 12.5%), bacterial
vaginitis (n=9; 11.3%),
urinary tract infection
(n=6; 7.5%), acne (n=5;
6.3%), hypertension
(n=5; 6.3%), sinusitis
(n=5; 6.3%), upper
respiratory tract infection
(n=5; 6.3%), breast
tenderness (n=4; 5%),
fatigue (n=4; 5%), pelvic
pain (n=4; 5%),
increased weight (n=4;
5%), lower abdominal
73 (89%)
completed 6
cycles
83% and 95% median
MBL reduction at cycle
3 and 6
62% and 71% mean
MBL reduction at cycle
3 and 6
LNG-IUS successfully
treated 67 (85%) of
women (defined as
proportion with MBL
<80 mL at end of study
and ≥50% reduction in
MBL from baseline).
<<Surgery
avoided or
required not
reported>>
8
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
pain (n=3; 3.8%)
4/80 discontinued due to
AEs
4/80 had partial or
complete expulsion.
No perforations
occurred
Ghazizadeh et al
2011(15)
Iran
LNG-IUS (n=52)
Endometrial resection
(n=52)
Randomized
open-label
Women aged 35–45 years
with HMB ((PBAC score >
100) and with no medical
treatment in last 6 months.
Exclusion included uncertain
about future wish for
pregnancy, abnormal
endometrial histology, or any
other pathology such as
uterine prolapse or large
myomas. Patients who were
uncertain about their future
wish for pregnancy were also
excluded.
PBAC
12 months’ treatment
90%, and 89% mean
PBAC score reduction
at 6 and 12 months,
respectively
9 (17%) had no
response to treatment
Adverse events with
LNG-IUS were cramps
and pains in four (8.2%),
spotting in 19 (38.8%),
breast tenderness in ten
(20.4%), headaches in
nine (18.4%), acne in
two (4.1%), mood
changes in four (8.2%),
weight gain in one (2%)
and ovarian cyst in one
(2%) patient
30 (58%)
completed 12
months treatment.
No women
underwent
subsequent
surgical treatment
in LNG-IUS
group
9 (17%) subjects had
LNG-IUS expulsion
No uterine perforations
occurred
Shabaan et al
2011(16)
Egypt
LNG-IUS (n=56)
LNG 150 µg/EE 30 µg;
n= 56)
Randomized
open-label
Women aged 20–50 years
with self-defined HMB and
requesting contraception.
Exclusions included previous
Alkaline
hematin and
PBAC
12 months’ treatment
AEs not reported.
87% mean MBL
reduction at12 months
1 (2%) expulsion of
LNG-IUS occurred
48 (86%)
completed 12
months
9
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
ectopic pregnancy, ultrasound
abnormalities including
fibroids (any size), previous
endometrial ablation.
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
90% and 87%
reduction in mean
PBAC scores at 6 and
12 months
No perforations reported
5/56 underwent
surgical treatment
due to treatment
failure
12 months’ treatment
AEs not reported.
96%, 94%, >99% and
94% mean PBAC score
reduction at 3, 6, 12
and 24 months,
respectively
No LNG-IUS expulsions
reported
Continuation rates
not reported.
6 of 56(11%) failed
treatment (defined as
initiation of a different
treatment).
Sesti et al
2012(17)
Italy
LNG-IUS (n=36)
Laparoscopic
Supracervical
Hysterectomy (n=36)
Randomized
open-label
Women aged 35–50 years who
had completed their families
and with confirmed HMB
(PBAC score ≥ 100 average of
two consecutive
cycles).unresponsive to
medical treatment were
eligible for the study.
PBAC
No perforations reported
<<Surgery
avoided or
required not
reported>>
Exclusion criteria included:
any uterine pathology on scan
or hysteroscopy
Non-randomized studies in women with AUB-E (or those described as having HMB without further definition)
Andersson and
LNG-IUS (n=20)
NonParous women aged ≤45 years Alkaline
12 months’ treatment
Rybo, 1990 (18)
randomized, with HMB not planning
hematin
86% 91%, and 97%
prospective
pregnancy were considered.
Sweden
median MBL reduction
Inclusion criteria included
at 3, 6 and 12 months,
were: regular periods, no
respectively
intermenstrual bleedings or
spottings; normal sized or only
slightly enlarged uterus and no
AEs not reported (one
subject discontinued
because of acne, weightgain (2,5 kg), mood
changes and
intermenstrual spotting).
17 (85%)
continuation rate
at 12 months
2 (10%) of the
subject had
hysterectomies
1 (5%) subject had LNG-
10
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
sign of pelvic pathology;
confirmed HMB (80 mL or
more during two consecutive
cycles).
Milsom et al.,1991
(19)
Sweden
Tang et al 1995
(21)
LNG-IUS (n=20)
Flurbiprofen and
tranexamic acid data
previously presented as
Andersch et al 1988(20)
LNG-IUS (n=10)
Hong Kong
Nonrandomized
study with
LNG-IUS
Nonrandomized,
prospective
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
IUS expulsion
Women with confirmed HMB
(>80 mL) pretreatment with a
normal-sized or only slightly
enlarged uterus and no signs
of pelvic pathologies on
gynecologic examination were
recruited. Exclusion criteria
included pelvic pathologic
conditions, e.g., palpable
fibroids diagnosed by
gynecologic examination.
Alkaline
hematin
Parous women aged ≥35 years
with HMB were considered.
Endometrial pathology was
ruled out and uterine size less
than an 8 week pregnancy.
Alkaline
hematin
12 months with the
LNG-IUS
Adverse events not
reported for all women
83%, 88% and 96%
reduction in mean
MBL at 3, 6 and 12
months with the LNGIUS
1(5%) subject had LNGIUS expulsion,
Up to 22 months’
follow up
AEs not reported.
51% 75%, and 88%
mean MBL reduction
at 1, 3 and 6 months,
respectively.
No perforations reported
2 (20%) subjects had
LNG-IUS expulsion
16 (80%)
completed 12
months
1(5%) subject had
hysterectomy
Continuation rates
over 12 months
not reported
2 (20%) subjects
had hysterectomy
54% 87%, and 95%
median MBL
reduction at 1, 3 and 6
months, respectively.
Barrington et al
1997 (22)
LNG-IUS (n=50)
Nonrandomized,
Women aged 28 to 53 years
with HMB who had failed
previous medical therapy and
PBAC
Up to 9 months followup of treatment
AEs not reported.
6 (12%)subjects had
8 (16%) of
women
withdrawn at 3
11
Author
(year)/Country
Comparators
UK
Xiao et al.,
2003(23)
Study design Inclusion/Exclusion criteria
prospective
LNG-IUS (n=34)
China
Nonrandomized,
prospective
MBL
assessment
method
awaiting surgical treatment
were recruited. Those
recruited underwent
endometrial sampling to
exclude those with
malignancy or premalignant
change.
Women aged 27–43 years who
experienced regular and heavy
menstrual bleeding with a
normal sized or slightly
enlarged uterus were recruited.
Exclusion criteria included:
deformity of the uterine cavity
or cervical canal, undiagnosed
abnormal bleeding, or any
other systemic diseases.
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
74% mean PBAC
score reduction at 3
months
LNG-IUS expulsion
months
No perforations reported
2 (4%) opted for
surgical treatment
Common adverse events
reported included
abdominal pain (n=5)
and weight gain (n=6)
12 month
continuation rate
not reported
75% reduction in
median PBAC score
Alkaline
hematin
36 months follow-up
79%, 84%, 98% and
85% reduction in mean
MBL at 6, 12, 24 and
36 months, respectively
4(12%) subject had
LNG-IUS expulsion,
24 (71%)
completed 36
months.
<<Surgery
avoided or
required not
Insignificant or small fibroids,
detected by ultrasound, were
acceptable.
Gupta et al., 2006
(24)
India
LNG-IUS (n=25)
Endometrial resection
(n=25)
Nonrandomized,
comparative
Women with no desire for
another pregnancy and HMB
unresponsive to oral or
injectable hormonal and
nonhormonal treatment.
Exclusion criteria included
pelvic disease; active genital
tract infection; use of an
intrauterine contraceptive
PBAC
12 months follow-up
87%, 94%, 88% and
97% reduction in mean
PBAC score at 3, 6, 9
and 12 months,
respectively
Common AEs with
LNG-IUS included:
irregular spotting (n =
11); abdominal pain (n =
9); and backache (n = 6).
2 (8%) subjects had
LNG-IUS expulsion
No perforations reported
17 (68%) attended
12 month followup
No women
underwent
hysterectomy n
the LNG-IUS
group
12
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
PBAC
Up to 4 years follow-up
of treatment
Prolonged intermenstrual
bleeding/spotting
reported by 45 (71.4%)
subjects during the first 3
months. Other common
adverse events reported
included: increased
vaginal discharge (n=20
[33.3%]), weight gain
(n=18 [30.5%]),
backache (n=23
[38.3%]), leg pain (n=12
[2.0%]), amenorrhea
(n=17 [26.9%]),
headache (n=8 [13.3%]),
body swelling (n=7
[11.7%]), breast
tenderness (n=6 [1.0%]),
sleeping problems (n=5
[8.3%]), mood changes
(n=5 [8.3%]), hot flushes
(n=4 [6.7%]), cholasma
(n=3 [5.0%]), weakness
(n=3 [5.0%]).
12 month
continuation rate
not reported
device in the last 2 months;
and atypical hyperplasia of the
endometrium.
Kriplani et al 2007
(25)
India
LNG-IUS (n=63)
Nonrandomized,
prospective
Women with HMB aged 29–
52 years were recruited.
Exclusion criteria included
endometrial carcinoma,
endometrial hyperplasia with
atypia, uterine size greater
than that of a 12-weekpregnant uterus, uterocervical
length greater than 10 cm, or
an endocrinopathy or systemic
illness causing menorrhagia
71%, 78%, 90%, 98%,
99%, 99% and 99%
mean PBAC score
reduction at ,1 3, 6, 12,
24, 36 and 48 months,
respectively
70%, 80%, 90%, 95%,
95%, 95% and 97%
median PBAC score
reduction at ,1 3, 6, 12,
24, 36 and 48 months,
respectively
45 (71.4%)
continued over 4
years
10 (16%)
underwent
hysterectomy
8 (13%) subjects had
LNG-IUS expulsion
13
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
No perforations reported
Gorgen et al,
2009(26)
LNG-IUS (n=66)
Turkey
Chattopdhyay et al
2011 (27)
LNG-IUS (n=42)
India
Nonrandomized,
prospective
Nonrandomized,
prospective
Women aged 26–55 years
with HMB that failed
conservative medical therapy.
The women had normal
uterine cavity with
histological benign
endometrium. Those with
PBAC score ≥75 points were
eligible for the study. Women
with intracavitary
abnormalities were excluded.
PBAC
Women aged 35 to 55 years
with idiopathic HMB with or
without irregular cycle.
PBAC
74% reduction in mean
PBAC score at 6
months
LNG-IUS (patients with
Nonrandomized,
Women aged 25 to 45 years
with HMB and desire to
Common adverse events
reported include:
spotting (17%); pelvic
pain (13%); bloating
(5%) and weight gain
(5%)
60 (91%)
completed 6
months
2 (3%) women
underwent
hysterectomy
No LNG-IUS expulsions
reported
No perforations reported
Up to 36 months
follow-up of treatment
83%, 92%, 96%, 96%
and 98% median
PBAC score reduction
at 3, 6, 12, 24 and 36
months, respectively
Exclusion criteria included
any organic pelvic pathology
(uterine fibroids >2 cm in
size), endometrial carcinoma,
atypical endometrial
hyperplasia, uterine cervical
length more than10 cm
presence of any hematological
disorder like platelet disorders,
bleeding diathesis,
coagulopathy, endocrinopathy
or diabetes mellitus.
Kriplani et al
6 months follow-up
Adverse event reported
with irregular bleeding
(29%) and pelvic pain
(5%)
1 (2%) subjects had
LNG-IUS expulsion
No perforations occurred
PBAC
Up to 4 years follow-up
Most common adverse
effects in group I was
100%, 90% ,
88%, 88% and
64% completed
3, 6, 12, 24 and
36 months follow
up, respectively
<<Surgery
avoided or
required not
reported>>
12 month
continuation rate
14
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
2012(28)
no pathologies; n=50)
prospective
India
LNG-IUS (leiomyoma
patients; n=54)
preserve fertility. Two groups
of women sort, group 1 had at
least one myoma and group 2
were aged matched women
with HMB of no obvious
cause.
Exclusion criteria included
active pelvic inflammatory
disease or type 0 or 1
submucous myoma,
adenomyosis, congenital or
acquired uterine
malformation.
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
Group 1 (leiomyoma
group)
 87%, 92%, 97%,
97%, 100%, and
100% median
PBAC reduction at
1, 3, 12, 24. 36 and
48 months
prolonged
bleeding/spotting 31/46
[67.3%]) in first 3
months. Other adverse
events included:
not reported
 80%, 87%, 94%,
97%, 98% and 99%
mean PBAC
reduction at 1, 3,
12, 24. 36 and 48
months
Group 2 (HMB with
no obvious cause)
 74%, 92%, 98%,
100%, 100%, and
100% median
PBAC reduction at
1, 3, 12, 24. 36 and
48 months
 74%, 79%, 93%,
99%, 99% and 99%
mean PBAC
reduction at 1, 3,
12, 24. 36 and 48
months
weight gain (10 [18.5%],
backache (14 [25.9%]),
leg pain (4 [7.4%]),
amenorrhea at 1 year
(9/41 [21.9%]), vaginal
discharge (6 [11.1%]),
headache (5 [9.3%]),
body swelling (7
[13.0%]), breast
tenderness (3 [5.6%]),
sleeping problems (5
[9.3%]), hot flushes (3
[5.6%]), an ovarian
cysts (2 [3.7%])
40 (75%)
continued therapy
to 4 years in
group 1 and 42
(84%) in group 2
Group 1
(leiomyoma): 4
(7%) underwent
hysterectomy
Group 2 (no
obvious
pathology): 5
(10%) underwent
hysterectomy
Most common adverse
effects in group I was
prolonged
bleeding/spotting 23/39
(58.9%) in first 3
months. Other adverse
events: weight gain (12
[24%]), amenorrhea at 1
year (17 [34.0%]),
backache (10 [20.0%]),
vaginal discharge (7
15
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Significant reduction
in uterine volume, but
not leiomyoma volume
[14.0%]), breast
tenderness (5 [10.0%]),
and body swelling (3
[6.0%])
Continuation
rates (for LNGIUS)
6 (11%) expulsion of
LNG-IUS occurred in
group 1
3 (6%) expulsion of
LNG-IUS occurred in
group 1
Studies in women with HMB secondary to uterine structural pathology or coagulopathy
Kingman et al
LNG-IUS (n=16)
NonWillebrand’s disease
2004 (29)
randomized,
Women aged 15 to 50 years
prospective
UK
with HMB and von
Willebrand’s disease were
recruited. Inclusion criteria
included no symptoms of
pelvic and previous failed
medical treatment. Exclusion
criteria included planning
pregnancy within the next year
or significant pelvic pathology
on transvaginal ultrasound
such as uterine fibroids.
PBAC
Up to 9 months followup of treatment
78% reduction in
median PBAC score at
9 months
AEs not reported.
No LNG-IUS expulsions
reported
No perforations reported
Continuation rates
not reported
<<Surgery
avoided or
required not
16
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
Choudry et al
2009 (30)
LNG-IUS (n=24)
Nonrandomized,
prospective
PBAC
Up to 12 months
follow-up of treatment
AEs not reported.
22 (92%)
continued over 12
months treatment.
Pakistan
Kilic et al
2009(31)
Turkey
Grigorieva et
al.,2003 (32)
Russia
LNG-IUS (n=20)
No treatment controls
(n=20)
LNG-IUS (n=69)
(26 women had HMB,
PBAC score >100 at
baseline)
Randomized
open-label.
Nonrandomized,
prospective
Bleeding disorders
HMB without pelvic
pathology but underlying
bleeding disorder or use of
oral anticoagulants.
Anticoagulant therapy
61%, 75% and 84%
reduction in median
PBAC score at 3, 6 and
12 months, respectively
PBAC
Women who had undergone
cardiac valve replacement
procedures and on
anticoagulant therapy with a
PBAC score > 185 were
eligible for the study.
Leiomyomas
Women aged 20-45 years with
uterine leiomyomas who
chose the LNG IUS as their
method of contraception
(strictly not a HMB study but
included for completeness).
Inclusion criteria included:
least one leiomyoma ≥2.5 cm
in diameter; multiple
leiomyomas, at least one of
which ≥1.5 cm on ultrasound.
PBAC
1 (4%) subjects had
LNG-IUS spontaneously
expelled
No perforations reported
<<Surgery
avoided or
required not
reported>>
6 months’ treatment
AEs not reported.
13% and 35% mean
MBL reduction at 3
and 6 months,
respectively
No LNG-IUS expulsions
reported
12 months follow-up
Most common AEs were
spotting and breast
tenderness
61 (88%)
completed 12
months
2(3%) discontinued due
to AEs
<<Surgery
avoided or
required not
reported>>
67%, 77% and 84%
reduction in mean
PBAC score at 3, 6 and
12 months, respectively
Significant reduction in
the uterine and
leiomyoma volume
No perforations reported
4 (6%) expulsion of
LNG-IUS occurred
All women
completed the
study
<<Surgery
avoided or
required not
No perforations reported
Exclusion criteria included;
17
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
PBAC
12 months follow-up
AEs not reported.
40%, 50%, 65% and
69% reduction in
median PBAC score at
3, 6, 9 and 12 months,
respectively
4 (13%) expulsion of
LNG-IUS occurred
19 (59%)
completed 12
months
distortion of the uterine cavity.
Mercorio et al.
2003 (33)
LNG-IUS (n=32)
Italy
Nonrandomized,
prospective
Leiomyomas
Women referred for
hysterectomy because of
myoma-related HMB. Those
who wished to retain their
uterus were invited to
participate.
No perforations reported
7(22%) scheduled
for hysterectomy
Persistent HMB
(PBAC score >100)
remained in 14 women
at 12 months
Inclusion criteria included:
HMB of at least 3 months; a
wish to retain their uterus; a
uterine volume equivalent to
8–10 week pregnancy; PBAC
score >100.
Effect on leiomyomas
not reported
Exclusion criteria included:
uterine abnormalities;
submucous fibroids; uterine
cavity >12 week pregnancy.
Soysal et al 2005
(34)
Turkey
LNG-IUS (n=32)
Endometrial ablation
(n=32; historical cohort)
Nonrandomized,
historical
cohort
comparison
Leiomyomas
Women aged >40 years with a
desire to retain their fertility
and HMB were considered
eligible for the study.
Inclusion criteria included:
PBAC score >15; iron
deficiency; myomatous uterus
as determined by transvaginal
ultrasound; presence of at least
PBAC
12 months’ follow up
AEs not reported.
85% 88%, and 90%
mean MBL reduction
at 3, 6 and 12 months,
respectively.
No LNG-IUS expulsions
occurred
Effect on leiomyomas
not reported
No perforations reported
28 (88%)
completed 12
months
4 (13%)
underwent
hysterectomy
18
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
PBAC
6 months follow-up
AEs not reported.
85% mean PBAC
reduction at 6 months
No LNG-IUS expulsions
reported
Continuation rates
not reported
No reduction of uterine
or leiomyoma volumes
No perforations reported
12 months follow-up
Common adverse events
included: Ovarian cysts
(n=11; 16%), weight
gain (n=6; 9%), pelvic
pain (n=4; 6%), bloating
(n=3; 5%) and headache
(n=3; 5%)
one type II myoma; individual
myomas < 5 cm in diameter.
Exclusion included active
pelvic disease, premalignant
and malignant uterine and
breast diseases.
Murat Naki et al.,
2010 (35)
LNG-IUS (n=46)
Turkey
Nonrandomized,
prospective
Leiomyomas
Women with HMB and
leiomyoma uteri were
considered.
Exclusion criteria included:
uterine size >12 pregnancy
weeks at pelvic examination;
history of PID; history or risk
for STD; submucous
leiomyomas; endometrial
polyps.
Shawki et al
2009(36)
Egypt
LNG-IUS (n=68)
Nonrandomized,
prospective
Leiomyomas
Women aged 35 to 50 years
with HMB over the last 6
months and ultrasound-proven
submucous uterine leiomyoma
were eligible.
Exclusion criteria included:
current or recent pelvic
inflammatory disease,
abnormal pap smear;
endometriosis; breast cancer;
PBAC
83% and 88%
reduction in median
PBAC score at 6 and
12 months, respectively
No significant effect on
fibroid or uterine
volume
<<Surgery
avoided or
required not
reported>>
50 (74%)
completed 12
months
7 (10%) had a
hysterectomy
No LNG-IUS expulsions
reported
19
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
Alkaline
hematin and
PBAC
12 months’ treatment
AEs not reported.
91% mean MBL
reduction at12 months
3 (10%) expulsion of
LNG-IUS occurred
23 (79%)
completed 12
months
92% and 88%
reduction in mean
PBAC scores at 6 and
12 months
No perforations reported
history of venous
thromboembolism or liver
disease.
Sayed et al 2011
(37)
LNG-IUS (n=29)
COC (Microvlar; n=29)
Randomized
, open-label.
Egypt
Socolov et al
2011(38)
Romania
LNG-IUS (n=102)
Nonrandomized,
prospective
Leiomyomas
Women aged between 20 and
50 years requesting
contraception and with HMB
and fibroids with recruited.
Exclusion criteria included
pelvic inflammatory disease,
defective coagulation,
abnormalities on ultrasound,
including submucous fibroids
of any size if they distort the
uterine cavity or intramural or
subserous fibroids >5 cm in
diameter, history of
malignancy or evidence of
hyperplasia in the endometrial
biopsy, incidental adnexal or
abnormality on ultrasound .
Leiomyomas
Women with myoma and
HMB and/or frequent irregular
bleeding were eligible for the
study. Myomas included
3(10%)
underwent
surgical treatment
due to treatment
failure
6 of 29 (23.1%) failed
treatment (defined as
initiation of a different
treatment, or the
confirmed expulsion or
removal of LNG-IUS).
Significant reduction in
uterine weight but not
diameter of
leiomyomas
PBAC
12 months follow-up
83, 91% and 92%
reduction in mean
PBAC score at 3, 6 and
12 months, respectively
Adverse effects included:
mastodynia (n= 20;
20%), headache (n=12;
12%), pelvic pain (n=12;
12%), weight gain over
5% from initial
Continuation rates
not reported
3 (3%) had a
hysterectomy
20
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
subserous, intramural and
submucous type II, with at
least one myoma having a
diameter greater than 20 mm.
Exclusion criteria included:
submucous myomas type 0.
Jindabanjerd &
Taneepanichskul
2006(39)
LNG-IUS (n=22)
Nonrandomized,
prospective
Thailand
Xie et al 2012(40)
LNG-IUS (n=30)
China
(24 with HMB; PBAC
score >100 at baseline)
Nonrandomized,
prospective
Leiomyomas
PBAC
Women aged 20 to 45 years
and uterus less than 12 week
pregnancy and at least one
myoma ultrasound
examination. Exclusion
criteria included sub-mucous
myoma with distortion of
cavity and history of pelvic
inflammatory disease.
Leiomyomas
Women aged 30 to 50 years
and uterus less than 12 week
pregnancy and at least one
myoma ultrasound
examination. Exclusion
criteria included sub-mucous
myoma with distortion of
cavity, malignancy of the
reproductive system and
history of pelvic inflammatory
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
No significant change
in leiomyoma volume.
Significant reduction in
uterine volume
observed
weight(n=10; 10%),
bloating in (n=4; 4%),
dyspareunia (n=2; 2%)
6 months’ treatment
Adverse events reported
included in women who
completed study (n=16):
bleeding disorders
(n=11; 69%);
amenorrhea (n=6; 38%);
irregular bleeding (n=5;
31%); breast tenderness
(n=5; 31%).
80% and 97%
reduction in median
PBAC score at 3 and 6
months, respectively
Significant reduction in
myoma and uterine
volume at 6 months
Continuation
rates (for LNGIUS)
6 (6%) expulsion of
LNG-IUS occurred
16 (73%)
completed study
3 (14%)
underwent
hysterectomy
1 (5%) expulsion of
LNG-IUS occurred
PBAC
12 months’ treatment
40%, 70% and 75%
reduction in mean
PBAC score at 3, 6 and
12 months, respectively
No significant
reduction in myoma or
uterine volume up 12
months
Adverse events reported
at three months included
bleeding disturbance
(n=12; 40%); breast
tenderness (n=10; 33%)
and pelvic pain (n=7;
23%)
29 (97%)
completed 12
months
<<Surgery
avoided or
required not
reported>>
1 (3%) expulsion of
LNG-IUS occurred
21
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
PBAC
Up to 4 years follow-up
Most common adverse
effects in group I was
prolonged
bleeding/spotting 31/46
[67.3%]) in first 3
months. Other adverse
events included:
12 month
continuation rate
not reported
disease.
Kriplani et al
2012(28)
LNG-IUS (leiomyoma
patients; n=54)
India
LNG-IUS (patients with
no pathologies; n=50)
Nonrandomized,
prospective
Leiomyomas
Women aged 25 to 45 years
with HMB and desire to
preserve fertility. Two groups
of women sort, group 1 had at
least one myoma and group 2
were aged matched women
with HMB of no obvious
cause.
Group 1 (leiomyoma
group)
 87%, 92%, 97%,
97%, 100%, and
100% median
PBAC reduction at
1, 3, 12, 24. 36 and
48 months
Exclusion criteria included
active pelvic inflammatory
disease or type 0 or 1
submucous myoma,
adenomyosis, congenital or
acquired uterine
malformation.
 80%, 87%, 94%,
97%, 98% and 99%
mean PBAC
reduction at 1, 3,
12, 24. 36 and 48
months
Group 2 (HMB with
no obvious cause)
 74%, 92%, 98%,
100%, 100%, and
100% median
PBAC reduction at
1, 3, 12, 24. 36 and
48 months
 74%, 79%, 93%,
99%, 99% and 99%
mean PBAC
reduction at 1, 3,
weight gain (10 [18.5%],
backache (14 [25.9%]),
leg pain (4 [7.4%]),
amenorrhea at 1 year
(9/41 [21.9%]), vaginal
discharge (6 [11.1%]),
headache (5 [9.3%]),
body swelling (7
[13.0%]), breast
tenderness (3 [5.6%]),
sleeping problems (5
[9.3%]), hot flushes (3
[5.6%]), an ovarian
cysts (2 [3.7%])
40 (75%)
continued therapy
to 4 years in
group 1 and 42
(84%) in group 2
Group 1
(leiomyoma): 4
(7%) underwent
hysterectomy
Group 2 (no
obvious
pathology): 5
(10%) underwent
hysterectomy
Most common adverse
effects in group I was
prolonged
bleeding/spotting 23/39
(58.9%) in first 3
months. Other adverse
events: weight gain (12
22
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
12, 24. 36 and 48
months
Significant reduction
in uterine volume, but
not leiomyoma volume
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
[24%]), amenorrhea at 1
year (17 [34.0%]),
backache (10 [20.0%]),
vaginal discharge (7
[14.0%]), breast
tenderness (5 [10.0%]),
and body swelling (3
[6.0%])
6 (11%) expulsion of
LNG-IUS occurred in
group 1
3 (6%) expulsion of
LNG-IUS occurred in
group 1
Fedele et al 1997
(41)
Italy
LNG-IUS (n=25)
Nonrandomized,
prospective
Adenomyosis
PBAC
12 months follow-up
Women aged 38 to 45 years
with recurrent HMB
associated with adenomyosis
were eligible
77, 80% and 80%
reduction in mean
PBAC score at 3, 6 and
12 months, respectively
Exclusion criteria included:
endometrial disorders, uterine
myomas, or adnexal disease,
cardiovascular disease or
documented lipid metabolism
disorders.
Significant decrease in
endometrial thickness
Adverse event reported
included: headache (n=6;
24%); breast tenderness
(n=3; 16%); seborrhea
greasy hair, or acne (n=6;
24%); and weight gain
>1kg (n= 7; 28%)
23 (92%)
completed 12
months
1 (4%) had a
hysterectomy
1 (4%) expulsion of
LNG-IUS occurred
No perforations reported
23
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for LNGIUS)
Adverse effects (for
LNG-IUS)
Continuation
rates (for LNGIUS)
Cho et al 2008(42)
LNG-IUS (n=47)
Nonrandomized,
prospective
PBAC
36 months follow-up
AEs not reported.
95%, 95%, 95% and
89% reduction in mean
PBAC score at 6, 12,
24 and 36 months,
respectively
2 (4%) expulsion of
LNG-IUS occurred
45 (96%)
completed 12
months
South Korea
Adenomyosis
Women aged 31 to 45 years
with HMB and dysmenorrhea
for at least 6 months, and
diagnosed with adenomyosis
by transvaginal ultrasound.
PBAC of 75 corresponds to
≥60 mL HMB.
Significant decrease in
uterine volume
32 (68%)
completed 36
months
<<Surgery
avoided or
required not
reported>>
‡Same
study as Istre and Trolle (43) and Kittelesen and Istre 1998 (44)
AE, adverse events; EE, ethinylestradiol; HMB, heavy menstrual bleeding; LNG-IUS, levonorgestrel-releasing intrauterine system; LNG,
levonorgestrel; MBL, menstrual blood loss; MPA, medroxyprogesterone acetate; NETA, norethindrone acetate (norethisterone acetate); PBAC,
pictorial blood assessment chart;
24
Table 2: Characteristics and outcomes of trials that assessed combined hormonal contraceptives for the treatment of heavy menstrual bleeding
(HMB). Data shown for the combined hormonal contraceptive group only.
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome
Adverse effects
Continuation
rates (for
combined oral
contraceptives)
Adverse events not
reported
Not reported by
drug (cross-over
design)
Randomized controlled trial in women with AUB-E (or those described as having HMB without further definition)
Fraser and
McCarron
1991(45)
Australia
LNG 150µg/EE 30 µg
(n=12)
Randomized
cross-over
Danazol (200 mg daily
from day 5, continuously;
n =12).
Naproxen (500 mg at
onset of menses followed
by 250 mg TID until 24
hours after the usual
duration of menses, max
5 days; n=14)
History of HMB and regular
periods. Pelvic and systemic
causes of HMB were
excluded. Most had undergone
diagnostic dilatation and
curettage and/or hysteroscopy
within the previous year.
Alkaline
hematin
Healthy women >30 years
with idiopathic HMB (PBAC
score ≥100 confirmed during
2 consecutive pre-treatment
cycles) and a normal or only
slightly enlarged uterus
PBAC
2 cycles’ treatment
Mean MBL reduction
during treatment, 43%
<<Surgery
avoided or
required not
reported>>
Mefenamic acid (500mg
TID from onset of
menses until 24 hours
after the usual duration
of menses, max 5 days;
n=38)
Endrikat et al
2009 (12)
NETA 1mg/EE 20µg;
(n=19)
Canada
LNG-IUS (n=20)
Randomized
open-label
12 months’ treatment
Reduction in median
MBL (estimated from
graph):
 78%, 77%, 80% and
75% during 3, 6, 9
Most frequent reasons
for study discontinuation
were intermenstrual
bleeding, menstrual
disorder, and headache
14 (74%)
completed 12
months
<<Surgery
avoided or
required not
25
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome
Adverse effects
and 12 months,
respectively
Continuation
rates (for
combined oral
contraceptives)
reported>>
68% mean reduction in
PBAC score at 12
months
Fraser et al
2011(46)
Phasic E2V/DNG#
(n=149)
Australia and
Europe (Czech
Republic, Finland,
Germany,
Hungary, the
Netherlands,
Poland, Sweden,
the UK and
Ukraine)
Placebo (n=82)
Randomized
double-blind
Women had to be aged ≥18
years with heavy, prolonged
and/or frequent menstrual
bleeding. Those with organic
pathology (including chronic
endometritis, adenomyosis,
endometriosis, endometrial
polyps, leiomyomas or
uterine, malignancy) were
excluded.
Alkaline
hematin
Phasic E2V/DNG#
(n=120)
United States and
Placebo (n=70)
Randomized
double-blind
Women had to be aged ≥18
years with heavy, prolonged
and/or frequent menstrual
bleeding. Those with organic
79% median MBL
reduction in cycle 7 (vs
7% median reduction
with placebo)
Reduction in median
MBL for OC
(estimated from graph):
11%, 72%, 74%, 79%,
83%, 85% and 89%
during cycle 1 to 7,
respectively
Reduction in median
MBL for placebo
(estimated from
graph):1%, 6%, 5%,
12%, 3%, –5%, and
13% during cycle 1 to
7, respectively
Patients underwent 90-days
run-in phase to objectively
confirm HMB (MBL ≥80
mL).
Jensen et al
2011(47)
7 cycles’ treatment
Alkaline
hematin
7 cycles’ treatment
71% median MBL
reduction in cycle 7 (vs
Adverse events occurring
in >5% of patient
included: breast pain
(n=8; 6%); headache
(n=21; 15%);
metrorrhagia’(n=8; 6%);
nasopharyngitis (n=12;
8%). Serious adverse
events were reported by
two women (chronic
cholecystitis, breast
cancer).
109 (73%)
completed 7
cycles
(62 [76%]
completed 7
cycles with
placebo)
<<Surgery
avoided or
required not
reported>>
Adverse events occurring
in >5% of patient in
placebo group: headache
(n=12; 14.8%);
nausea/vomiting (6;
7.4%)
Adverse events occurring
in >5% of patient
included: acne (n=6;
5%); metrorrhagia (n=6;
84 (70%)
completed 7
cycles
26
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
Canada
MBL
assessment
method
pathology (including chronic
endometritis, adenomyosis,
endometriosis, endometrial
polyps, leiomyomas or
uterine, malignancy) were
excluded.
LNG150 µg/ EE30 µg
(n= 56)
Egypt
LNG-IUS (n=56)
Randomized
open-label
Women aged 20–50 years
with self-defined HMB.
Exclusions included previous
ectopic pregnancy, ultrasound
abnormalities including
fibroids (any size), previous
endometrial ablation.
Adverse effects
Continuation
rates (for
combined oral
contraceptives)
19% median reduction
with placebo)
5%);
nasopharyngitis(n=9;
8%); nausea (n=6; 5%);
vaginitis bacterial (n=6;
5%)
(51 [73%]
completed 7
cycles with
placebo)
Reduction in median
MBL for OC
(estimated from graph):
20%, 76%, 80%, 78%,
76%, 78% and 87%
during cycle 1 to 7,
respectively
Reduction in median
MBL for placebo
(estimated from
graph):23%, 16%,
27%, 28%, 24%, 35%,
and 31% during cycle 1
to 7, respectively
Patients underwent 90-days
run-in phase to objectively
confirm HMB (MBL ≥80
mL).
Shabaan et al
2011(16)
Duration of
treatment/MBL
outcome
Alkaline
haematin
and PBAC
12 months treatment
35% mean MBL
reduction at12 months
Adverse events occurring
in >5% of patient in
placebo group: anemia
(n=4; 6%); headache
(n=9; 14%);
nasopharyngitis(n=6;
9%); nausea (n=5; 8%);
vaginitis bacterial (n=4;
6%)
Adverse events not
reported.
42% or 3% reduction in
mean PBAC score at 6
and 12 months
Vaginal ring (NuvaRing;
Randomized
Parous women aged 20–35
PBAC
3 cycles’ treatment
47 (84%)
completed 12
months
<<Surgery
avoided or
required not
reported>>
18 of 56(32%) failed
treatment (defined as
initiation of a different
treatment).
Abu Hashim et al
<<Surgery
avoided or
required not
reported>>
Breakthrough
All participants
27
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
2012(48)
n=48)
open-label
Egypt
Norethisterone (5 mg
TID form days 5 to 26;
n=47)
MBL
assessment
method
years requiring
contraception and had HMB
(mean PBAC score > 185
over two control cycles).
Other inclusion criteria
included regular menstrual
cycles, no pelvic pathology,
uterine sound measurement
<10 cm. Exclusion criteria
included obesity (BMI >30
kg/m2), smoking, hormone
therapy or medication that
may interfere with MBL,
injectable hormone
contraception in last 12
months.
Duration of
treatment/MBL
outcome
Mean reduction in
PBAC score: 25%,
53% and 69% in
cycles 1, 2 and 3
(cycle 1 and 2 data
estimated from
graph)
Non-randomized studies in women with AUB-E (or those described as having HMB without further definition)
Larsson et al
DSG 150 µg/EE 30 µg
NonOtherwise healthy women and Alkaline
6 months’ treatment
1992(49)
(n= 5)
randomized , no history or evidence of
hematin
32% or 45% reduction
prospective
pelvic pathology.
Sweden
(only women with MBL
in mean MBL at 3 and
>80 mL summarized
6 months
here)
Studies in women with HMB secondary to uterine structural pathology or coagulopathy
Sayed et al 2011
LNG 150 µg/ EE 30 µg
Randomised, Leiomyomas
(37)
(n=29)
open-label.
Women aged between 20 and
Alkaline
hematin
12 months’ treatment
13% mean MBL
Adverse effects
Continuation
rates (for
combined oral
contraceptives)
bleeding/spotting (4.2%),
breast tenderness (4.2%),
headache (6.3%),
leukorrhea (10.4%),
vaginal discomfort
(4.2%), vaginitis (8.3%),
ring-related events
(6.3%)
completed three
cycles
Adverse events not
reported.
All women with
HMB completed
treatment
<<Surgery
avoided or
required not
reported>>
<<Surgery
avoided or
required not
reported>>
Adverse events not
reported.
21 (72%)
completed 12
28
Author
(year)/Country
Comparators
Egypt,
LNG-IUS (n=29)
#E
Study design Inclusion/Exclusion criteria
50 years requesting
contraception and with HMB
and fibroids with recruited.
Exclusion criteria included
pelvic inflammatory disease,
defective coagulation,
abnormalities on ultrasound,
including submucous fibroids
of any size if they distort the
uterine cavity or intramural or
subserous fibroids >5 cm in
diameter, history of
malignancy or evidence of
hyperplasia in the endometrial
biopsy, incidental adnexal or
abnormality on ultrasound.
MBL
assessment
method
Duration of
treatment/MBL
outcome
Adverse effects
Continuation
rates (for
combined oral
contraceptives)
and PBAC
reduction at12 months
months
75% and 54%
reduction in mean
PBAC scores at 6 and
12 months
<<Surgery
avoided or
required not
reported>>
11 of 29 (38%) failed
treatment (defined as
initiation of a different
treatment).
2V
3 mg on days 1 and 2, E2V 2 mg/DNG 2 mg on days 3–7, E2V 2 mg/DNG 3 mg on days 8–24, E2V 1 mg on days 25 and 26 and placebo on
days 27 and 28.
AE, adverse events; DSG, desogestrel; E2V, estradiol valerate; EE, ethinylestradiol; HMB, heavy menstrual bleeding; LNG, levonorgestrel;
LNG-IUS, levonorgestrel-releasing intrauterine system; MBL, menstrual blood loss; MPA, medroxyprogesterone acetate; NETA, norethindrone
acetate (norethisterone acetate); PBAC, pictorial blood assessment chart
29
Table 3: Characteristics and outcomes of trials that assessed tranexamic acid for the treatment of heavy menstrual bleeding (HMB). Data shown
for tranexamic acid group only.
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for
tranexamic acid)
Randomized controlled studies in women with AUB-E (or those described as having HMB without further definition)
Nilsson & Rybo
Tranexamic acid (0.25g
Assumed to
Patients aged 15–49 years
Alkaline
1 cycle of treatment
1967(50)
six times daily on days 1
be a
referred for suspected
hematin
Mean MBL reduction
Sweden
to 4; n=6)
randomized
HMB. Bleeding determined to
(calculated from data
double-blind be ovulatory in 22/36 women
provided):
Tranexamic acid (0.5g
cross-over
(not determined in the others).
 Tranexamic acid
six times daily on days 1
study
(0.25g group): 34%
to 4; n=26)
 Tranexamic acid
Tranexamic acid (1g six
(0.5g group): 41%
times daily on days 1 to
 Tranexamic acid
4; n=20)
(1g group): 55%

Placebo: 15%
Placebo (n=31)
Adverse effects (for
tranexamic acid)
Continuation
rates (for
tranexamic acid)
Tranexamic acid (0.5g
group): abdominal pain
(n=4); nausea (n=3)
No patient
reported to
discontinue study
Tranexamic acid (1g
group): abdominal pain
(n=3); diarrhoea (n=6)
Placebo: nausea (n=3);
headache (n=2)
(excluding those with
fibroids)
Andersch et al
1988(20)
Sweden
Tranexamic acid (1.5 g
TID for days 1 to 3 and 1
g BID on days 4 and 5;
n=15)
Flurbiprofen (100 mg
BID for 5 days; n=15)
Randomized
cross-over
Women seeking help for
idiopathic HMB (MBL > 80
mL objectively confirmed
during two pre-treatment
periods). All women has
regular menstrual cycles and
no evidence of pelvic
pathology.
Alkaline
hematin
2 cycles’ treatment
47% and 47% mean
reduction during
cycles 1 and 2.
47% mean reduction
in MBL during
treatment
Adverse event reported
in 7 (46%) women
during tranexamic acid
treatment included
nausea, dizziness,
numbness, “restless
legs”, headache and in 3
women vomiting and
No patients
discontinued
therapy
<<Surgery
avoided or
required not
30
Author
(year)/Country
Edlund et al
1995(51)a
Sweden
Comparators
Kabi 2161 (tranexamic
acid prodrug, 600 mg
BID from days 1 to 5;
n=26)
Study design Inclusion/Exclusion criteria
Randomized
, double
blind
Kabi 2161 (600 mg four
times daily; n=28)
Placebo (n=14)
Preston et al
1995(52)
UK
Tranexamic acid (1 g
QID on days 1 to 4;
n=25)
Randomized
double-blind
Norethisterone (5 mg
BID on days 19 to 26;
n=21)
Bonnar and
Sheppard
Tranexamic acid (1 g
QID from days 1 to 5;
Randomized
(blinding not
stated but
MBL
assessment
method
Women aged ≥18 years with
regular menstrual cycles,
menorrhagia (defined as MBL
> 80 mL confirmed
objectively during two run-in
cycles) and a normal-sized
uterus. Exclusion criteria
included pelvic pathology,
CIN in cervical smear,
thromboembolic disease,
hemorrhagic or fibrinolytic
disorder.
Alkaline
hematin
Women aged ≥18 years
complaining of heavy regular
cycles (average MBL >80 mL
objectively confirmed during
two placebo cycles).
Exclusions included any
previous hormonal use in the
last three months,
abnormalities during pelvic
examination and positive
cervical cytology.
Alkaline
hematin
Patients 35-46 years with
regular HMB (MBL >80 mL
objectively confirm during 3
Alkaline
hematin
Duration of
treatment/MBL
outcome (for
tranexamic acid)
3 cycles’ treatment
Mean MBL reduction
during treatment:
Adverse effects (for
tranexamic acid)
Continuation
rates (for
tranexamic acid)
difficulty in swallowing.
reported>>
8 women reported
adverse events such as
nausea and diarrhoea
(not stated by group)
23 women did not
complete study
(not stated by
group)
Kabi 2161 (BID),
39%
<<Surgery
avoided or
required not
reported>>
Kabi 2161 (four
times daily), 31%
Placebo, no reduction
(4% increase)
2 cycles’ treatment
Mean MBL
reduction:
 55% and 34%
MBL reduction
with tranexamic
acid during cycles
1 and 2
Dysmenorrhoea (80%),
headache (32%),
gastrointestinal
(including diarrhea,
nausea, vomiting, and
dyspepsia; 12%)
2 patients did not
complete both
cycles
Not specifically
described for tranexamic
22 (85%)
completed 3
<<Surgery
avoided or
required not
reported>>
 Mean overall
reduction during
treatment, 45%.
3 cycles’ treatment
Tranexamic acid:
31
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
1996(53)
n=26)
Ireland
Ethamsylate (500 mg
QID from days 1 to 5;
n=27)
assumed to
randomised
open-label)
Mefenamic acid (500 mg
TID from days 1 to 5; n=
23)
Kriplani et al
2006(54)
India
Tranexamic acid (500 mg
QID form day 1 to 5;
n=49)
MPA (10 mg BID from
day 5 to 25; n=45)
Lukes et al
2010(55)
USA
Tranexamic acid (1.3 g
TID on days 1 to 5;
n=123)*
Placebo (n=73)
MBL
assessment
method
pre-treatment cycles). Those
with organic causes of HMB
excluded by gynaecological
investigation, including
hysteroscopy, endometrial
biopsy, and a cervical smear.
Duration of
treatment/MBL
outcome (for
tranexamic acid)
Adverse effects (for
tranexamic acid)
Continuation
rates (for
tranexamic acid)
55%, 56%, 54%
MBL reduction
during cycles 1, 2 and
3
acid
cycles.
20 (77%) taking
tranexamic acid
wished to
continue the
treatment
54% MBL reduction
(average treatment
effect over 3
treatment cycles vs
baseline)
Randomized
(blinding not
stated but
assumed to
randomised
open-label)
PBAC score >100 (confirmed
during pre-treatment cycle).
General and gynaecological
examinations to rule out any
pelvic pathology and to
measure endometrial
thickness.
PBAC
Randomized
double-blind
Women age 18–49 years
with HMB (objectively
confirmed during two pretreatment cycles; average ≥
80 mL with lowest MBL
assessed ≥ 60 mL) and
normal findings on pelvic
Alkaline
hematin
3 cycles’ treatment.
Mean PBAC score
reduction with
tranexamic acid:
58%, 61%, 60%
during cycles 1, 2 and
3
6 cycles’ treatment
Mean MBL reduction
(data estimated from
graphs):
 43%, 40%, 37%
and 39% MBL
<<Surgery
avoided or
required not
reported>>
Eight (16.3%) cases
reported adverse events
with tranexamic acid
including: allergic
reaction (n=1; 2%);
headaches (n=3; 6%);
gastrointestinal upsets
(n=3; 6%); giddiness
(n=1; 2%)
47 (96%)
completed 3
months
Treatment-emergent
adverse events occurring
in ≥5% of patient
included: menstrual
discomfort/cramps
(n=72; 62%); headache
(n=65; 56%); back pain
94 (76%)
completed 6
cycles (vs 74% on
placebo)
2 (4%) out of the
49 recruited into
the tranexamic
acid group
underwent
hysterectomy
<<Surgery
32
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
examination, no clinically
important cervical cytology
abnormalities, and no
clinically important uterine
pathologic findings by
transvaginal ultrasonography.
Leiomyomas not considered
an abnormal finding unless
sufficient in number and
size to warrant surgery.
MBL
assessment
method
Duration of
treatment/MBL
outcome (for
tranexamic acid)
reduction with
tranexamic acid
during cycles 1, 2,
3 and 6
 5%, 7%, 10% and
12% MBL
reduction with
placebo during
cycles 1, 2, 3 and 6
Adverse effects (for
tranexamic acid)
Continuation
rates (for
tranexamic acid)
(n=28; 24%); nausea
(n=17; 15%); anemia;
arthralgia (n=11; 9%);
(n=12; 10%), upper viral
tract infection (n=9; 8%),
allergies (n=10; 9%);
abdominal discomfort
(n=8; 7%), cough (n=7;
6%), insomnia (n=6;
5%); fatigue (n=8; 7%);
muscle cramps (n=8;
7%); migraine (n=7;
6%); sinus headache
(n=9; 8%)
avoided or
required not
reported>>
Treatment-emergent
adverse events occurring
in ≥5% of patient on
placebo included:
menstrual
discomfort/cramps
(n=36; 50%); headache
(n=36; 50%); back pain
(n14; 19%); nausea
(n=11; 15%); anemia
(n=4; 6%); arthralgia
(n=5; 7%); viral upper
tract infection (n=7;
10%); allergies (n=5;
7%); abdominal
discomfort (n=6; 8%);
33
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for
tranexamic acid)
Adverse effects (for
tranexamic acid)
Continuation
rates (for
tranexamic acid)
cough (n=5; 7%);
insomnia (n=6; 8%);
dyspepsia (n=8; 11%)
and migraine (n=4; 6%)
Najam et al
2010(56)
India
Tranexamic acid (500 mg
TID from days 1 to 5;
n=55)
Randomized
single-blind
Tranexamic acid (500 mg
TID) plus mefenamic
acid (250 mg TID) from
days 1 to 5; n=55)
Women aged 12-45 years with
heavy regular cycles (PBAC
>100 confirmed during pretreatments cycle). Exclusions
included any pelvic pathology,
organic disease, recent IUD or
hormonal therapy, anovulatory
or irregular cycles.
PBAC
6 months’ treatment
Mean PBAC score
reduction (data
estimated from
graphs):
Nausea and
gastrointestinal
disturbances in 9 cases
and leg cramps in 7 cases
Not reported
Treatment-emergent
adverse events occurring
in >5% of TA–treated
women and 2-fold that in
placebo group:
Tranexamic acid
doses 0.65mg TID
(91% completed
study)
 Mean 26%, 37%,
50% PBAC score
reduction with
tranexamic acid
during cycles 1, 3
and 6
<<Surgery
avoided or
required not
reported>>
 Mean 38%, 51%,
59% PBAC score
reduction with
Tranexamic acid
plus mefenamic
acid during cycles
1, 3 and 6
Freeman et al
2011(57)
USA
Tranexamic acid doses
0.65g TID form days 1-5;
n=117)
Tranexamic acid doses
1.3 g TID from days 1-5;
Randomized
double-blind
Women aged 18-49 years with
a history of cyclic HMB
(MBL ≥80 mL objectively
confirmed during two pretreatment cycles). Exclusions
included pelvic pathology
Alkaline
hematin
3 cycles’ treatment
Mean MBL reduction
(data estimated from
graphs):
 Tranexamic acid
doses 0.65mg TID
Placebo; upper
Tranexamic acid
doses 1.3 mg TID
34
Author
(year)/Country
Comparators
n=118)
Placebo (n=69)
Study design Inclusion/Exclusion criteria
(women with fibroids were
not excluded automatically
unless they required surgical
management), abnormal
cervical cytology,
coagulopathy.
MBL
assessment
method
Duration of
treatment/MBL
outcome (for
tranexamic acid)
(27%, 27% and
31% during cycles
1, 2 and 3; mean
overall reduction
during treatment
26%)
 Tranexamic acid
doses 1.3 mg TID
(39%, 38% and
38% during cycles
1, 2 and 3; mean
overall reduction
during treatment
39%)
 Placebo (4%
increase, 6% and
4% during cycles 1,
2 and 3; mean
overall reduction
during treatment
2%)
Adverse effects (for
tranexamic acid)
Continuation
rates (for
tranexamic acid)
respiratory viral tract
infection (4.5%), fatigue
(4.5%), musculoskeltal
pain (3.0%), arthralgia
(1.5%), myalgia (0%)
nasal congestion (0%),
sinusitis (1.5%), allergies
(0%), throat irritation
(3.0%) anemia (1.5%)
(87% completed
study)
Tranexamic acid doses
0.65 mg TID; upper
respiratory viral tract
infection (10.4%),
fatigue (11.3%),
musculoskeltal pain
(8.7%), arthralgia
(6.1%), myalgia (4.4%)
nasal congestion (7.0%),
sinusitis (6.1%), allergies
(5.2%), throat irritation
(6.1%) anemia (5.2%)
Placebo (90%
completed study)
<<Surgery
avoided or
required not
reported>>
Tranexamic acid doses
1.3 mg TID; upper
respiratory viral tract
infection (7%), fatigue
(3.5%), musculoskeltal
pain (5.2%), arthralgia
(4.4%), myalgia (5.2%),
nasal congestion (2.6%),
sinusitis (2.6%), allergies
35
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for
tranexamic acid)
Adverse effects (for
tranexamic acid)
Continuation
rates (for
tranexamic acid)
(3.5%), anemia (0.8%)
Non-randomized trials in women with AUB-E (or those described as having HMB without further definition)
Gleeson et al 1994 Tranexamic acid (500 mg NonWomen with regular HMB
Alkaline
3 cycles’ treatment
(58)
QID on days 1 to 5 of
randomized, and no endocrine dysfunction
hematin
55%, 64% and 52%
menses; n=15)
prospective
or bleeding diathesis were
Ireland
median MBL
recruited. Exclusion criteria
(MBL reported for 15
reduction at 1, 2 and
included pelvic abnormalities,
women)
3 cycles of treatment,
endometrial pathology. All
respectively
women undertook 3 cycles of
(estimated from
observation.
graph)
Adverse events not
reported separately for
those with HMB
Discontinuations
not reported
None of the patients
reported adverse events
100%
continuation (no
patient
discontinued)
Not reported separately
for this group
No patient
reported to
discontinue study
58% reduction in
median MBL across
all 3 treatment cycles
vs baseline
Srinil et al
2005(59)
Thailand
Tranexamic acid (1 g
TID on days 1 to 5 of
menses; n=40)
Nonrandomized,
prospective
Women aged 18 to 45 years
with HMB and no systemic
disease related to HMB were
eligible. Women with pelvic
pathologies were excluded
through pelvic examination
and transvaginal
ultrasonography.
Studies in women with HMB secondary to uterine structural pathology or coagulopathy
Nilsson & Rybo
Tranexamic acid (0.5g
Assumed to
Leiomyoma
1967(50)
six times daily on days 1
be a
Sweden
to 4; n=5)
randomized
Patients aged 15–49 years
double-blind referred for suspected
PBAC
2 cycles’ treatment
26% and 49%
reduction in mean
MBL in cycles 1 and
2, respectively
Alkaline
hematin
1 cycle of treatment
Mean MBL reduction
(calculated from data
provided):
36
Author
(year)/Country
Kouides et al
2009(60)
USA
Comparators
Study design Inclusion/Exclusion criteria
Tranexamic acid (1g six
times daily on days 1 to
4; n=5)
cross-over
study
HMB. Bleeding determined to
be ovulatory in 22/36 women
(not determined in the others).
Tranexamic acid (1 g
four times each day for
the first 5 day of menses)
Randomized,
cross-over
Bleeding disorder
Desmopressin (nasal
spray at 300 µg per
nostril on days 2 days
and 3 of cycle)
Desmopressin/
tranexamic acid sequence
(n=49)
Tranexamic acid
Desmopressin/sequence
(n=67)
Women aged 18–50 years
referred for HMB to a
hemophilia treatment centre,
bleeding disorder clinic, or
gynaecology care centre.
Inclusion criteria included
negative pelvic examination
(fibroids were allowed if the
uterus was <12 weeks
gestational size), a negative
Papanikolaou smear, PBAC
score ≥100, and detectable
bleeding disorder.
MBL
assessment
method
PBAC
Duration of
treatment/MBL
outcome (for
tranexamic acid)
 Tranexamic acid
(0.5g group): 18%
 Tranexamic acid
(1g group): 36%
2 cycles per treatment
period (data shown
for tranexamic acid
period only)
Desmopressin/
tranexamic acid
sequence:


47% and 52%
mean reduction in
cycles 1 and 2 of
tranexamic acid
(vs baseline)
38% and 42%
median reduction
in cycles 1 and 2
of tranexamic
acid (vs baseline)
Adverse effects (for
tranexamic acid)
Continuation
rates (for
tranexamic acid)
Of the 90 patients who
used either study
medication for at least
one cycle, 13 (14%) had
adverse events; seven
patients with
desmopressin and six
with tranexamic acid.
Discontinuation
rates were 43%
for the nasal
desmopressintranexamic acid
sequence and
33% for
tranexamic acid –
desmopressin
sequence
<<Surgery
avoided or
required not
reported>>
Tranexamic acid/
desmopressin
sequence:

31% and 43%
mean reduction in
cycles 1 and 2 of
desmopressin (vs
37
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for
tranexamic acid)
Adverse effects (for
tranexamic acid)
Continuation
rates (for
tranexamic acid)
baseline)

38% and 42%
median reduction
in cycles 1 and 2
of desmopressin
(vs baseline)
a
Kabi (tranexamic acid prodrug)
*New oral formulation of tranexamic acid (LYSTEDA) designed minimizing gastrointestinal adverse effects but with higher per-tablet dose and
increases drug absorption
BID, twice daily; HMB, heavy menstrual bleeding; LNG-IUS; levonorgestrel-releasing intrauterine system; MBL, menstrual blood loss; MPA,
medroxyprogesterone acetate; PBAC, pictorial blood assessment chart; TID, three times a day; QID, four times daily
38
Table 4: Characteristics and outcomes of trials that assessed danazol for the treatment of heavy menstrual bleeding (HMB). Data shown for the
danazol group only
Author
(year)/Country
Comparators and
number randomized
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for
danazol)
Adverse effects (for
danazol)
Continuation
rates (for
danazol)
Adverse effects reported
include:
Not reported
Randomized controlled studies in women with AUB-E (or those described as having HMB without further definition)
Chimbira et al
1980(61)
Danazol (200 mg daily;
n=16)
UK
Danazol (100 mg daily;
n=16)
Randomized
(blinding not
stated)
Women with regular cycles
and HMB (MBL >60 mL
objectively confirmed in two
pre-treatment cycle).
Exclusion criteria included
detectable pelvic pathology
such as fibroids, polyps or
malignancy.
Alkaline
hematin
3 cycles’ treatment
Mean MBL reduction
Danazol (200 mg
daily): 22%, 79% and
86% reduction during
cycles 1, 2 and 3,
respectively.
Danazol (100 mg
daily; (data estimated
from graphs): 30%,
55% and 61%
reduction during
cycles 1, 2 and 3,
respectively.
Cameron et al
1987(62)
Danazol (200 mg daily;
n=6)
UK
Norethisterone (5 mg
BID from day 15-25;
Randomized
(blinding not
stated but
assumed to
Ovulatory cycles and mean
monthly blood loss >50 mL
(objectively confirmed during
two pre-treatment cycles).
Alkaline
hematin
2 cycles’ treatment
Reduction in median
MBL during
Danazol (200 mg daily):
tiredness/sleepiness(n=5)
, musculoskeletal pain
(n=4), skin rash (n=3),
headaches (n=6),
irritability (n=3),
vaginitis (n=3)
<<Surgery
avoided or
required not
reported>>
Danazol (100 mg daily):
tiredness/sleepiness(n=6)
, musculoskeletal pain
(n=2), skin rash (n=2),
headaches (n=5),
irritability (n=1),
vaginitis (n=2)
Not reported
Not reported
<<Surgery
39
Author
(year)/Country
Comparators and
number randomized
Study design Inclusion/Exclusion criteria
n=8)
randomized
open-label)
Progesterone IUS (65 mg
progesterone daily; n =
8)
MBL
assessment
method
Duration of
treatment/MBL
outcome (for
danazol)
Adverse effects (for
danazol)
treatment, 75%
Continuation
rates (for
danazol)
avoided or
required not
reported>>
Mefenamic acid (500 mg
TID during menses; n =
8)
Dockeray et al
1989(63)
Danazol (100 mg BID;
n=20)
Ireland
Mefenamic acid (500 mg
TID for 3 to 5 days;
n=20)
Fraser and
McCarron
1991(45)
Danazol (200 mg daily
from day 5, continuously;
n =12).
Australia
Naproxen (500 mg at
onset of menses followed
by 250 mg TID until 24
hours after the usual
Randomized
open-label
Randomised
open-label
cross-over
Otherwise health parous
women with a HMB (MBL
>80mL objectively confirmed
during two pre-treatment
cycles) and clinically normal
pelvic organs and the absence
of any endometrial pathology
at diagnostic curettage.
Alkaline
hematin
History of HMB and regular
periods. Pelvic and systemic
causes of HMB were
excluded. Most had undergone
diagnostic dilatation and
curettage and/or hysteroscopy
within the previous year.
Alkaline
hematin
2 cycles’ treatment
Mean MBL
reduction: 46% and
76% MBL during
cycles 1 and 2 of
treatment (60%
overall reduction
during treatment)
2 cycles’ treatment
13% and 86% mean
MBL reduction at
cycles 1 and 2,
respectively.
Mean MBL reduction
Adverse effects reported
(by ≥2 patients) include:
Breast atrophy (n=3),
acne (n=3),
irritability/aggression
(n=3), headache (n=8),
nausea/vomiting (n=6),
musculoskeletal pain
(n=5), breast pain (n=2),
flushes (n=2), depression
(n=2), dizziness (n=2),
backache (n=2), tiredness
(n=2), off-color (n=2)
Adverse events not
reported
Ten patients
refused to
continue
treatment after
study
<<Surgery
avoided or
required not
reported>>
Not report by
drug (cross-over
design)
<<Surgery
avoided or
required not
40
Author
(year)/Country
Comparators and
number randomized
Study design Inclusion/Exclusion criteria
MBL
assessment
method
duration of menses, max
5 days; n=14)
Duration of
treatment/MBL
outcome (for
danazol)
Adverse effects (for
danazol)
during treatment,
49%
Continuation
rates (for
danazol)
reported>>
Mefenamic acid (500mg
TID from onset of
menses until 24 hours
after the usual duration
of menses, max 5 days;
n=38)
Low-dose COC (n=12)
Higham and Shaw
1993(64)
Danazol (recommended
dose 200 mg daily; n=19)
UK
Danazol (reduced dose
200, 100, and 50 mg
daily in cycles, 1, 2 and
3, respectively; n=19)
Norethindrone (5 mg
TID from days 19 to 26;
n= 19)
Randomized
single-blind
Women aged 20–50 years
with objectively proven HMB
(MBL >80 mL objectively
confirmed during two pretreatment cycles). Those with
underlying organic
pathologies were excluded.
Alkaline
hematin
3 cycles’ treatment
Change in median
MBL (estimated
using the two
baseline values):
 Danazol (200 mg):
40% decrease in
cycle 3
 Danazol (reduced
dose): 28%
decrease in cycle 3
Adverse events reported
in ≥2 patients include:
Danazol (200 mg):
headache/migraine
(n=7), abdominal
bloating (n=3), weight
gain (n=5), muscle
cramps (n=5),
intermenstrual bleeding
(n=4), acne (n=2),
depression (n=2),
dizziness (n=2), edema
(n=2), dysmenorrhea
(n=2), nausea/vomiting
(n=2)
Danazol (200
mg): 3 patients
discontinued
treatment phase
Danazol (reduced
dose): 5 patients
discontinued
treatment phase
<<Surgery
avoided or
required not
reported>>
Danazol (reduced dose):
headache/migraine
(n=8), abdominal
bloating (n=5), weight
41
Author
(year)/Country
Comparators and
number randomized
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for
danazol)
Adverse effects (for
danazol)
Continuation
rates (for
danazol)
gain (n=4), muscle
cramps (n=4),
intermenstrual bleeding
(n=3), acne (n=2),
depression (n=2),
dizziness (n=2),
dysmenorrhea (n=2)
Dunphy et al
1998(65)
Danazol (200 mg daily;
n=12)
Canada
MPA (10 mg daily from
days 16 to 25; n=11)
Randomized
double-blind
Women aged ≥ 18 years with
HMB (MBL> 80 mL during
one pre-treatment cycle).
Dysfunctional bleeding was
diagnosed by exclusion using
hysteroscopy with endometrial
biopsy or curettage
PBAC
3 cycles’ treatment
Mean PBAC score
reduction: 66%, 77%,
88% during cycle 1, 2
and 3 cycles,
respectively
Non-randomized trials in women with AUB-E (or those described as having HMB without further definition)
Women aged between 25 to
Chimbira et al
Danazol (400 mg daily
NonAlkaline
3 months’ treatment
50 years with HMB (>80 mL
1979(66)
starting during
randomized
hematin
Mean MBL
confirmed pretreatment) and
menstruation; n=18)
prospective
UK
reduction: 42%, 91%,
no detectable pelvic pathology
99% during cycle 1, 2
and desire to avoid
and 3, respectively
hysterectomy were recruited.
Chimbira et al
1980(67)
UK
Danazol (400 mg daily
starting immediately
after menstruation; n=13)
Nonrandomized
prospective
Women with regular
(ovulatory) cycles and HMB
(MBL >80 mL objectively
confirmed) and no detectable
pelvic pathology on
Alkaline
hematin
3 cycles’ treatment
52%, 91% and 96%
mean MBL reduction
at 1st, 2nd and 3rd
Adverse events reported
in eight of nine patients
(not specified)
2 patients withdrew due
to adverse events
9 (75%)
completed study
<<Surgery
avoided or
required not
reported>>
Adverse events included:
tiredness/sleepiness
(n=7; 39%); musculoskeletal pain (n=7; 39%);
skin rash (n=6; 33%);
headache (n=5; 28%);
irritability (n=4; 22%);
hot flushes (n=3; 17%)
Not reported
Adverse events not
reported
Not reported
<<Surgery
avoided or
required not
reported
<<Surgery
avoided or
42
Author
(year)/Country
Comparators and
number randomized
Study design Inclusion/Exclusion criteria
MBL
assessment
method
examination and uterine
curettage.
Chimbira et al
1980(61)
Danazol (200 mg daily;
n=8)
UK
Placebo (n=8)
Nonrandomized,
single-blind,
prospective
Women with regular cycles
and HMB (MBL >60 mL
objectively confirmed in two
pre-treatment cycle).
Exclusion criteria included
detectable pelvic pathology
such as fibroids, polyps or
malignancy.
Duration of
treatment/MBL
outcome (for
danazol)
Adverse effects (for
danazol)
episodes of bleeding
Alkaline
hematin
3 months’ treatment
(2 cycles placebo
run-in)
Continuation
rates (for
danazol)
required not
reported>>
Adverse events not
reported
Not reported
<<Surgery
avoided or
required not
reported>>
Mean MBL reduction
(vs baseline): 58%,
92%, 90% during
cycle 1, 2 and 3,
respectively
Mean MBL reduction
with placebo: 1%
(mean over two
placebo cycles)
Chimbira et al
1980(61)†
UK
Danazol (600 mg daily
from days 1-7 of each
cycle; n=11)
Nonrandomized,
prospective
Women with regular cycles
and HMB (MBL >60 mL
objectively confirmed in two
pre-treatment cycle).
Exclusion criteria included
detectable pelvic pathology
such as fibroids, polyps or
malignancy.
Alkaline
hematin
3 months’ treatment
(2 cycles placebo
run-in)
Mean MBL
reduction: 2% and
40% in cycles 2 and
3, respectively
Adverse events not
reported
Not reported
<<Surgery
avoided or
required not
reported>>
†
Report appears to include data from at least two studies
BID, twice daily; HMB, heavy menstrual bleeding; IUS, intrauterine system; MBL, menstrual blood loss; MPA, medroxyprogesterone acetate;
PBAC, pictorial blood assessment chart; TID, three times daily
43
Table 5: Characteristics and outcomes of trials that assessed oral progestogens for the treatment of heavy menstrual bleeding (HMB). Data
shown for the oral progestogens group only
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for oral
progestin)
Adverse effects (for
oral progestin)
Continuation
rates (for oral
progestin)
Not reported
Not reported
Randomized controlled studies in women with AUB-E (or those described as having HMB without further definition)
Short course
Cameron et al
1987(62)
UK
Norethisterone (5 mg
BID from day 15-25;
n=8)
Progesterone IUS (65 mg
progesterone daily; n =
8)
Not stated
(assumed to
randomized
open-label)
Ovulatory cycles and mean
monthly blood loss>50 mL
(objectively confirmed during
two pre-treatment cycles).
Alkaline
hematin
2 cycles’ treatment
Not stated
(assumed to
randomized
open-label)
Women with subjective HMB
and no organic pathology.
HMB objectively confirmed in
two pre-treatment cycles (only
those with >80 mL included).
Alkaline
hematin
2 cycles’ treatment
Reduction in median
MBL during
treatment, 30%
<<Surgery
avoided or
required not
reported>>
Mefenamic acid (500 mg
TID during menses; n =
8)
Danazol (200 mg daily;
n=6)
Cameron et al
1990(68)
UK
Norethisterone (5 mg
BID from day 19-26,
n=15)
Mefenamic acid (500 mg
TID during menses,
n=17)
Median 20%
reduction in MBL
during treatment
Adverse events reported
included:
Headache (33%)
Abdominal pain (20%),
Nausea (7%)
1 patient
discontinued
treatment in third
cycle
<<Surgery
avoided or
required not
reported>>
44
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for oral
progestin)
Adverse effects (for
oral progestin)
Continuation
rates (for oral
progestin)
Higham and Shaw
1993(64)
Norethindrone (5mg TID
from days 19 to 26; n=
19)
Randomized
single-blind
Women aged 20–50 years
with objectively proven HMB
(MBL >80 mL objectively
confirmed during two pretreatment cycles). Those with
underlying organic
pathologies were excluded.
Alkaline
hematin
3 cycles’ treatment
Adverse events reported
in ≥2 patients include:
2 patients
discontinued
treatment phase
Women aged ≥18 years
complaining of heavy regular
cycles (average MBL >80 mL
objectively confirmed during
two placebo cycles).
Exclusions included any
previous hormonal use in the
last three months,
abnormalities during pelvic
examination and positive
cervical cytology.
Alkaline
hematin
Women aged ≥ 18 years with
HMB (MBL> 80 mL during
one pre-treatment cycle).
Dysfunctional bleeding was
diagnosed by exclusion using
hysteroscopy with endometrial
PBAC
UK
Danazol (recommended
dose 200 mg daily; n=19)
Danazol (reduced dose
200, 100, and 50 mg
daily in cycles, 1, 2 and
3, respectively; n=19)
Preston et al 1995
(52)
UK
Norethisterone (5 mg
BID on days 19 to 26;
n=21)
Randomized
double-blind
Tranexamic acid (1 g
four times daily on days
1 to 4; n=25)
Dunphy et al
1998(65)
MPA (10 mg daily from
days 16 to 25; n=11)
Canada
Danazol (200 mg daily;
n=12)
Randomized
double-blind
Change in median
MBL (estimated
using the two
baseline values):
4% decrease in cycle
3
2 cycles’ treatment
Mean MBL
increased:
muscle cramps (n=4),
dysmenorrhea (n=3),
depression (n=3);
headache/migraine
(n=2); breast discomfort
(n=2); premenstrual
tension (n=2)
Dysmenorrhoea (85%),
headache (48%),
gastrointestinal (33%)
<<Surgery
avoided or
required not
reported>>
2 patients did not
complete both
cycles
<<Surgery
avoided or
required not
reported>>
 13% and 27%
MBL with
norethisterone
during cycles 1 and
2
 MBL increased by
20% during
treatment
3 cycles’ treatment
Mean PBAC score
reduction: 25% and
41% during cycle 1
and 2 cycles, but 12%
increase in score
Adverse events reported
in 2 of 7 patients (not
specified)
1 patient withdrew due to
adverse events
9 (82%)
completed study
<<Surgery
avoided or
required not
45
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
biopsy or curettage.
Kaunitz et al
2010(14)
MPA (10 mg daily from
16 to 25; n= 83)
United States,
Canada, and
Brazil
LNG-IUS (n=82)
Randomized
open-label
Parous women aged ≥18 years
with idiopathic HMB (me≥80
mL per cycle). Exclusions
included fibroids (if they
distorted the uterine cavity or
cervical canal); history of
organic causes of abnormal
uterine bleeding.
Duration of
treatment/MBL
outcome (for oral
progestin)
Adverse effects (for
oral progestin)
observed in cycle 3.
Alkaline
hematin
6 cycles’ treatment
2% and 13% median
MBL reduction at
cycle 3 and 6
11% and 22% mean
MBL reduction at
cycle 3 and 6
MPA successfully
treated 18 (22%) of
women (defined as
proportion with MBL
<80 mL at end of
study and ≥50%
reduction in MBL
from baseline).
Continuation
rates (for oral
progestin)
reported>>
Adverse effects reported
in more than patient
included: headache
(11%); acne (6.1%;
weight gain (6.1%),
lower abdominal pain
(6.1%); breast tenderness
(3.7%), bacterial
vaginitis (3.7%); urinary
tract infection 3.7%;
sinusitis (3.7%); fatigue
(2.4%), ovarian cysts
(2.4%), pelvic pain
(2.4%)
72 (87%)
completed 6
cycles
<<Surgery
avoided or
required not
reported>>
2/82 discontinued due to
AEs
Long course
Irvine et al
1998(2)
UK
Norethisterone (5 mg
TID from day 5 to 26;
n=22)
LNG-IUS (n=22)
Randomized
open-label
Healthy women 18–45 years
with a regular menstrual cycle,
a normal pelvic examination
with a uterine sound < 10 cm,
negative cervical cytology and
MBL >80 mL.
Alkaline
hematin
3 cycles’ treatment
63% and 78% median
reduction in MBL at
cycle 1 and 3 of
treatment
No difference in adverse
events (headaches, acne,
abdominal or back pain,
nausea, oedema, weight
gain, decreased libido,
sweating, hair loss or
greasy hair and increase
in body hair) at baseline
and over 3 months.
Intermenstrual bleeding,
16 (73%)
completed 3
months
4 (22%) elected to
continue with the
treatment.
46
Author
(year)/Country
Comparators
Kriplani et al
2006(54)
MPA (10 mg BID from
day 5 to 25; n=45)
India
Tranexamic acid (500 mg
four times daily form day
1 to 5; n=49)
Kucuk and Ertan
2008(11)
Oral MPA (5 mg daily;
n=44)
Assumed to be
Turkey and
Germany (not
clear)
Depot MPA (n=44);
Shravage et al
2011(69)
MPA (10 mg for 21 days
starting from day 2 to 5;
n =42)
Study design Inclusion/Exclusion criteria
Randomized
open-label
Randomized
open-label
LNG-IUS (n=44)
MBL
assessment
method
PBAC score >100 (confirmed
during pre-treatment cycle).
General and gynaecological
examinations to rule out any
pelvic pathology and to
measure endometrial
thickness.
PBAC
Perimenopausal women (aged
>40 years) who were smokers.
Those with organic pathology
and nonsmokers were
excluded.
PBAC
Duration of
treatment/MBL
outcome (for oral
progestin)
3 cycles’ treatment
Mean PBAC score
reduction with MPA:
55%, 52%, 58%
during cycles 1, 2 and
3
2 cycles’ treatment
Oral MPA: 33%
mean PBAC score
reduction by cycle 2
Adverse effects (for
oral progestin)
Continuation
rates (for oral
progestin)
breast tenderness and
mood swings appeared to
decrease relative to
baseline.
<<Surgery
avoided or
required not
reported>>
15 (33.3%) cases
reported adverse events
with MPA including:
intermenstrual bleeding
(n=5; 11%); tiredness
(n=3; 7%); headaches
(n=2, 4%); breast
tenderness (n=2; 4%);
gastrointestinal upsets
(n=2; 4%); mood
changes (n=1; 2%)
33 (73%)
completed 3
months
Common adverse effects
included intermenstrual
bleeding (n=12; 27%)
and breast
tenderness(n=12; 27%)
Proportion
completing study
not reported
Depot MPA: 49%
mean PBAC score
reduction by cycle 2
Randomized
double-blind
Women aged 35 to 50 years
with HMB. Exclusion criteria
include pelvic pathology,
PBAC
3 months’ treatment
8 (17.8%) out of
the 45 patients
recruited
underwent
hysterectomy
19 (43%) willing
to continue
<<Surgery
avoided or
required not
reported>>
Not reported
Not reported
Mean reduction in
PBAC score with
47
Author
(year)/Country
Comparators
India
Ormeloxifene (60 mg
taken two days a week at
an interval of 3 day;
n=42)
Abu Hashim et al
2012(48)
Norethisterone (5 mg
TID form days 5 to 26;
n=47)
Egypt
Vaginal ring (NuvaRing;
n=48)
Study design Inclusion/Exclusion criteria
MBL
assessment
method
systemic disorders, severe
anemia, chronic cervicitis and
cervical dysplasia.
Randomized
open-label
Parous women aged 20–35
years requiring contraception
and had HMB (mean PBAC
score > 185 over two control
cycles). Other inclusion
criteria included regular
menstrual cycles, no pelvic
pathology, uterine sound
measurement <10 cm.
Exclusion criteria included
obesity (BMI >30 kg/m2),
smoking, hormone therapy or
medication that may interfere
with MBL, injectable hormone
contraception in last 12
months.
Duration of
treatment/MBL
outcome (for oral
progestin)
Adverse effects (for
oral progestin)
Continuation
rates (for oral
progestin)
Breakthrough
bleeding/spotting
(12.8%), breast
tenderness (6.4%),
nausea (4.2%), headache
(4.2%)
All participants
completed three
cycles
Adverse event reported
included weight gain
(n=2), abdominal
bloating (n=3), minor
acne (n=2), mild nausea
(n=2), headache (n=2)
All participants
completed
treatment cycles
MPA: 41%, 55% and
60% during cycle 1, 2
and 3
PBAC
3 cycles’ treatment
Mean reduction in
PBAC score: 26%,
51% and 70% in
cycles 1, 2 and 3
(cycle 1 and 2 data
estimated from
graph)
Non-randomized trials in women with AUB-E (or those described as having HMB without further definition)
Fraser 1990(70)
Cyclic oral progesterone
NonStudy included six women
Alkaline
2 cycles of treatment
(norethisterone or
randomized, with anovulatory HMB (>80
hematin
Australia
Anovulatory HMB
medroxyprogesterone
prospective
mL confirmed in pretreatment
 39% and 51%
acetate)
cycles) and no obvious pelvic
mean MBL
pathology or systemic disease.
Anovulatory HMB (NET
reduction during
Ten women with ovulatory
5mg TID or MPA 10mg
cycles 1 and 2
HMB and no obvious pelvic
TID from day 12 to 25
pathology or systemic disease.
<<Surgery
avoided or
required not
reported>>
48
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome (for oral
progestin)
Adverse effects (for
oral progestin)
Continuation
rates (for oral
progestin)
Ovulatory HMB
(overall for both
MPA- and NETtreated patients):
See above
See above
inclusive; n=6)
Non-randomized trials in women with AUB-O
Fraser 1990(70)
Ovulatory HMB
Australia
MPA (10 TID for 21
days from day 5 to 25
inclusive; n=5)
NET (5mg TID for 21
days from day 5 to 25
inclusive; n=5)

32% and 36%
mean MBL
reduction during
cycles 1 and 2
Ovulatory HMB
(MPA):

32% and 37%
mean MBL
reduction during
cycles 1 and 2
Ovulatory HMB
(NET):

32% and 36%
mean MBL
reduction during
cycles 1 and 2
BID, twice daily; BMI, body mass index; HMB, heavy menstrual bleeding; IUS, intrauterine system; LNG-IUS, levonorgestrel-releasing
intrauterine system; MBL, menstrual blood loss; MPA, medroxyprogesterone acetate; NETA, norethisterone acetate; PBAC, pictorial blood
assessment chart; TID, three times daily
49
Table 6: Characteristics and outcomes of trials that assessed non-steroidal anti-inflammatory drugs for the treatment of heavy menstrual bleeding
(HMB). Data shown for the non-steroidal anti-inflammatory drugs group only.
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration/MBL
outcome
Adverse effects
Continuation
rates (for nonsteroidal antiinflammatory
drugs)
No significant increase in
number of days with
adverse effects reported
with mefenamic acid
relative to placebo
Not applicable.
Randomized controlled studies in women with AUB-E (or those described as having HMB without further definition)
Fraser et al
1981(71)
Australia
Fraser et al
1983(72) (Fraser
1981)[longer-term
follow-up of
Fraser et al 1981]
Mefenamic acid (500mg
TID from onset of
menses until end; n=30)
(data presented for
women with MLB >80
mL)
Randomized
double blind,
placebocontrolled,
cross-over
36 women continued
with mefenamic acid
after completion of
randomized double blind,
cross-over trail (includes
women with subjective
HMB)
Follow-on
Convincing history of HMB.
Only those classified with
HMB (i.e. HMB with mean
MBL >80 mL during two
placebo cycles) are
summarized here.
Alkaline
hematin
2 cycles’ treatment
Mean MBL reduction
during treatment,
30% (vs placebo)
Mean reduction vs
placebo cycles:
 31% during 2
cycles in the
double blind,
cross-over phase
<<Surgery
avoided or
required not
reported>>
Few women complained
of adverse effects. Only
2 women discontinued
because of dyspepsia
 25% during 6 to 9
months
 35% during 12 to
15 months
Muggeridge and
Elder 1983(73)
Mefenamic acid (500 mg
TID; n=15)
UK
Placebo (n=15)
Randomized
doubleblind, crossover
Women with regular, proven
HMB (≥75mL during to
control cycles) were recruited
Women with pelvic pathology
on diagnostic curettage were
excluded.
Alkaline
hematin
2 months treatment
mean MBL reduction
over 2 cycle:
 30% with
mefenamic acid
Adverse events
occurred at <10% for
nausea, headaches, and
dizziness and similar to
placebo cycles
No
discontinuations
reported
<<Surgery
avoided or
required not
50
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration/MBL
outcome
Adverse effects
 12% with placebo
Makarainen,
1986(74)
Finland
Ibuprofen (600 mg/day
from day one until end of
bleeding or for a
maximum of 10 days;
n=13)
Ibuprofen (200 mg/day
from day one until end of
bleeding or for a
maximum of 10 days;
n=13)
Ylikorkala et al
1986 (75)
Finland
Naproxen (500 mg at
onset of menses followed
by repeated 3-5 hrs later,
then 500 mg in morning
and evening for 5 days;
n=14)
Randomized
doubleblind,
placebocontrolled
cross-over
Women with primary HMB
(MBL >70mL).
Alkaline
hematin
1 cycle’ treatment for
each drug (over 3
consecutive cycles)
Continuation
rates (for nonsteroidal antiinflammatory
drugs)
reported>>
Not specifically
described in women with
primary HMB
Reduction in median
MBL (vs placebo):
Not specifically
described in
women with
primary HMB
<<Surgery
avoided or
required not
reported>>
 Ibuprofen 200 mg,
25%
 600 mg, 16%
Assumed to
be a
randomized
double-blind
cross-over
Placebo (n=14)
Patients with regular cycles
and HMB (>80mL) confirmed
during two run-in cycles. The
women had normal pelvic
finding s during in
gynecological and ultrasound
examinations.
Alkaline
hematin
Two treatment
cycles.
Mean MBL reduction
during treatment (vs
baseline):
No adverse effects
occurred during
naproxen use.
Not reported
Adverse events not
reported
Not reported
<<Surgery
avoided or
required not
reported>>
Naproxen, 29%
Placebo, 11%
increase
Cameron et al
1987(62)
UK
Mefenamic acid (500 mg
TID during menses; n =
8)
Not stated
(assumed to
randomized
Ovulatory cycles and mean
monthly blood loss>50 mL
(objectively confirmed during
Alkaline
hematin
2 cycles’ treatment
Reduction in median
MBL during
<<Surgery
avoided or
51
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
Norethisterone (5 mg
BID from day 15-25;
n=8)
open-label)
two pre-treatment cycles).
Randomized
double blind,
cross-over
Women aged ≥18years with
HMB and no pelvic
inflammation, fibroids or other
local disease. MBL ≥80 ml
objectively confirmed during
two initial control cycles.
MBL
assessment
method
Duration/MBL
outcome
Adverse effects
treatment, 45%
Continuation
rates (for nonsteroidal antiinflammatory
drugs)
required not
reported>>
Progesterone IUS (65 mg
progesterone daily; n =
8)
Danazol (200 mg daily;
n=6)
Hall et al
1987(76)
UK
Mefenamic acid (SO0
mg was taken every 8 htotal dose 1500 mg; first,
n=34)
Naproxen (initial loading
dose of 550 mg followed
by 275 mg every h for 5
days; first, n=35)
Tsang et al 1987
(77)
Canada
Mefenamic acid (500 mg
at the onset of menses
followed by 250 mg
every 6 hrs for 3 to 5
Alkaline
hematin
2 cycles’ treatment
MBL reduction
during treatment:
 Mefenamic acid:
Median 47%
 Naproxen: Median
46%
Randomized
double-blind
cross-over
Women (aged 26-47) with
regular menstrual cycles with
a mean ML ≥80 mL per cycle
or a history of prolonged or
profuse menses that warranted
Alkaline
hematin
Two cycles of
treatment
Reduction in median
MBL vs placebo
Gastro-intestinal and
central nervous system
symptoms were
experienced 6, and 5
patients, respectively,
with mefenamic acid.
Not reported
<<Surgery
avoided or
required not
reported>>
Gastro-intestinal and
central nervous system
symptoms were
experience 13 and 6
patients, respectively,
with naproxen.
Adverse events not
reported
Of 14 women
who started only
10 completed the
study. 1 woman
had a
52
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
days; n=10)
medical and (or) surgical
intervention.
Placebo (n=10)
Vargyas et al
1987(78)
USA
Meclofenamate sodium
(100 mg TID from onset
on menses for 6 days or
until the cessation of
menses; n=29)
Placebo (n=29)
Andersch et al
1988(20)
Flurbiprofen (100 mg
BID for 5 days; n=15)
Sweden
Tranexamic acid (1.5 g
TID for days 1 to 3 and 1
g BID on days 4 and 5;
n=15)
MBL
assessment
method
Randomized
double-blind
cross-over
(twotreatment
four-period
cross-over)
Randomized
cross-over
Women aged 16 to 42 years
old with a history of HMB.
(>60 mL during at least one
observation cycle).
Adverse effects
(estimated from
graph): mean 10%
reduction vs placebo
Alkaline
hematin
2 cycles’ treatment
Mean MBL reduction
during treatment:
Meclofenamate
sodium, 51%
Patients were excluded from
the study if they had
anovulatory cycles, histologic
evidence of pathologic
changes in the endometrium,
an extrauterine disease or
underlying organic disease.
Women seeking help for
idiopathic HMB. All women
has regular menstrual cycles
and no evidence of pelvic
pathology.
Duration/MBL
outcome
Placebo, 4%
Alkaline
hematin
2 cycles’ treatment
32% and 17% mean
MBL reduction in
cycles 1 and 2,
respectively
Continuation
rates (for nonsteroidal antiinflammatory
drugs)
hysterectomy
(histopathology
revealed that she
had adenomyosis
and intramural
leiomyomas),
5 patients experienced
side effects with
meclofenamate sodium:
4 had episodes of nausea
and vomiting that may
have been related to the
drug or prostaglandin
release at the onset of
menses and 1 patient had
epigastric distress after
ingestion of the
medication on an empty
stomach
One patient
discontinued the
study because of
gastric distress
after one cycle of
meclofenamate
sodium.
Adverse event reported
during flurbiprofen use
included tiredness,
stomach pains and
nausea.
No patients
discontinued
therapy
<<Surgery
avoided or
required not
reported>>
24% mean reduction
in MBL during
53
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration/MBL
outcome
Adverse effects
Continuation
rates (for nonsteroidal antiinflammatory
drugs)
Adverse effects reported
were: nausea/vomiting
(n=4), abdominal
discomfort (n=2),
headache (n=2); diarrhea
(n=1), dizziness (n=1),
fluid retention (n=1)
Nine patients
refused to
continue
treatment after
study
Adverse events reported
included:
1 patient
discontinued
treatment in third
cycle
treatment
Dockeray et al
1989(63)
Ireland
Mefenamic acid (500 mg
TID for 3 to 5 days;
n=20)
Randomized
open-label
Danazol (100 mg BID;
n=20)
Cameron et al
1990(68)
UK
Mefenamic acid (500 mg
TID during menses, n =
17)
Norethisterone (5 mg
BID from day 19-26, n =
15)
Chamberlain et al
1991 (79)
UK
Mefenamic acid (500 mg
TID from days 1 to 5;
n=22)
Ethamsylate (500 mg
four times daily from
days 1 to 5; n=22)
Not stated
(assumed to
randomized
open-label)
Otherwise health parous
women with a HMB (MBL
>80mL objectively confirmed
during two pre-treatment
cycles) and clinically normal
pelvic organs and the absence
of any endometrial pathology
at diagnostic curettage.
Alkaline
hematin
Women with subjective HMB
and no organic pathology.
HMB objectively confirmed in
two pre-treatment cycles (only
those with >80 mL included).
Alkaline
hematin
2 cycles’ treatment
Mean MBL
reduction: 27% and
13% MBL during
cycles 1 and 2 of
treatment (20%
overall reduction
during treatment)
2cycles’ treatment
Median 24%
reduction in MBL
during treatment
Headache (24%)
Abdominal pain (18%),
Nausea (12%)
Doubleblind,
allocated
treatment by
minimizatio
n (nonrandomized)
Women aged 18-55 with
confirmed HMB (MBL >80
mL, during 2 pre-treatment
cycles) and regular cycles.
Exclusion criteria included
inflammatory bowel disease or
endocrine disorders, anemia or
notable uterine enlargement
Alkaline
hematin
3 cycles’ treatment
Mean MBL
reduction: 31%, 21%
and 20% in cycles 1,
2 and 3, respectively
(data estimated from
graph)
10 of 18 (56%) who
completed study reported
adverse effects:
abdominal discomfort
(n=4), headache (n=4),
tiredness (n=1) and
swollen ankles (n=1)
<<Surgery
avoided or
required not
reported>>
<<Surgery
avoided or
required not
reported>>
18 (82%) women
completed
treatment
<<Surgery
avoided or
required not
reported>>
54
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration/MBL
outcome
Adverse effects
Continuation
rates (for nonsteroidal antiinflammatory
drugs)
Alkaline
hematin
2 cycles’ treatment
Adverse events not
reported
Not report by
drug (cross-over
design)
due to fibroids.
Fraser and
McCarron
1991(45)
Australia
Naproxen (500 mg at
onset of menses followed
Naproxen 250 mg TID
until 24 hours after the
usual duration of menses,
max 5 days; n=14)
Randomized
open-label,
cross-over
Mefenamic acid (500mg
TID from onset of
menses until 24 hours
after the usual duration
of menses, max 5 days;
n=38)
History of HMB and regular
periods. Pelvic and systemic
causes of HMB were
excluded. Most had undergone
diagnostic dilatation and
curettage and/or hysteroscopy
within the previous year.
Mean MBL reduction
during treatment:
<<Surgery
avoided or
required not
reported>>
 Naproxen, 12%
 Mefenamic acid,
20%–39%
Low-dose COC (n=12)
Danazol (200 mg daily
from day 5, continuously;
n =12).
van Eijkeren et al
1992 (80)
The Netherlands
Mefenamic acid (500 mg
TID, treatment started 5
days before expected
menstruation until
bleeding stopped; n= 6)
Placebo (n = 5)
Randomized
double-blind
Patients scheduled for
hysterectomy because of
subjective HMB. Inclusion
criteria included: age
<45years; objectively
confirmed MBL >80 ml;
regular menstrual cycle;
normal-sized uteri as assessed
by bimanual palpation.
Alkaline
hematin
One treatment cycle
Reduction in mean
MBL vs baseline:
Mefenamic acid; 40%
Placebo; 25%
increase
Three patient reported
adverse events in
mefenamic group:
stomach pains and
itching
Two patients in placebo
group reported headache
and itching, respectively.
Not specifically
reported by group
<<Surgery
avoided or
required not
reported for
separate
groups>>
55
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration/MBL
outcome
Adverse effects
Continuation
rates (for nonsteroidal antiinflammatory
drugs)
Bonnar and
Sheppard
1996(53)
Mefenamic acid (500 mg
TID from days 1 to 5; n=
23)
Alkaline
hematin
3 cycles’ treatment
Not specifically
described for mefenamic
acid
20 (87%)
completed 3
cycles.
Ireland
Tranexamic acid (1 g
four time daily from days
1 to 5; n=26)
Randomized
(blinding not
stated but
assumed to
randomised
open-label)
Ethamsylate (500 mg
four times daily from
days 1 to 5; n=27)
Reid and
Virtanen-Kari
2005(7)
Mefenamic acid (500 mg
TID from days 1-4;
n=26)
UK
LNG-IUS (n=25)
Randomized
open-label
Patients 35-46 years with
regular HMB (MBL >80 mL
objectively confirm during 3
pre-treatment cycles).. Those
with organic causes of HMB
excluded by gynaecological
investigation, including
hysteroscopy, endometrial
biopsy, and a cervical smear.
Women aged 18–47 years
with regular ovulatory,
menstrual cycles of 21–35
days and objective HMB
(MBL ≥80 mL objectively
confirmed in one pretreatment cycle). Exclusions
included anovulatory cycle,
submucous fibroids or fibroids
with a total volume of >5 cm3,
a uterine sound of >10 cm or
abnormal cervical cytology.
Mefenamic acid:
26%, 24%, 10%
MBL reduction
during cycles 1, 2 and
3
17 (74%) patients
taking mefenamic
acid wished to
continue
treatment
20% MBL reduction
(average treatment
effect over 3
treatment cycles vs
baseline)
Alkaline
hematin,
PBAC and
total
menstrual
fluid loss
6 cycles of treatment
Reduction in median
MBL: 22%, and 17%
in cycles 3 and 6,
respectively
Reduction in median
PBAC scores: 31%
and 32% in cycles 3
and 6, respectively
Reduction in median
total menstrual fluid
<<Surgery
avoided or
required not
reported>>
Common AEs with
mefenamic acid
included: headache
(n=10; 38%); abdominal
pain (n=2; 8%); ovarian
cysts (n=3; 12%); breast
pain (n=2; 8%); nausea
(n=4, 15%); diarrhoea
(n=4; 15%); and upper
respiratory infection
(n=5; 19%)
21 (81%)
completed study
<<Surgery
avoided or
required not
reported>>
56
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Duration/MBL
outcome
loss: 28% and 26% in
cycles 3 and 6,
respectively
Non-randomized studies in women with AUB-E (or those described as having HMB without further definition)
Anderson et al
Women with HMB (>80 mL
Alkaline
3 cycles of treatment
Mefenamic acid (500 mg Non1976(81)
hematin
TID during menstruation; randomized, during 3 successive control
37% mean MBL
prospective
cycles) who had undergone
n=5)
UK
reduction during
dilatation and curettage.
treatment
Haynes et al
1980(82)
UK
Mefenamic acid (500 mg
four time daily for first 3
days of menses; n=23)
Nonrandomized,
prospective
Women aged 16 to 50 years
with HMB (>80 mL during at
least 1 control cycle) who had
undergone examination and
curettage to exclude pelvic
pathologies.
Alkaline
hematin
2 cycles of treatment
Median 45% reduction
in MBL across the 4
treatment cycles vs
baseline
Adverse effects
Continuation
rates (for nonsteroidal antiinflammatory
drugs)
4/26 (15%) discontinued
mefenamic acid
Adverse events not
reported
Discontinuations
not reported
<<Surgery
avoided or
required not
reported>>
Adverse events not
reported
1 (4%) woman
discontinued
<<Surgery
avoided or
required not
reported>>
Studies in women with HMB secondary to uterine structural pathology or coagulopathy
Makarainen,
1986(74)
Finland
Ibuprofen (600 mg/day
from day one until end of
bleeding or for a
maximum of 10 days;
n=10)
Ibuprofen (200 mg/day
Randomized
doubleblind,
placebocontrolled
cross-over
Women with myomaassociated HMB (MBL
>70mL).
Alkaline
hematin
1 cycle’ treatment for
each drug (over 3
consecutive cycles)
Reduction in median
MBL (vs placebo):
Not specifically
described in women with
myoma-associated HMB
Not specifically
described in
women with
primary HMB
<<Surgery
avoided or
57
Author
(year)/Country
Comparators
Study design Inclusion/Exclusion criteria
MBL
assessment
method
Finland
Placebo (n=11)
Continuation
rates (for nonsteroidal antiinflammatory
drugs)
required not
reported>>
 600 mg, 7%
n=10)
Naproxen (500 mg at
onset of menses followed
by repeated 3-5 hrs later,
then 500 mg in morning
and evening for 5 days;
n=11)
Adverse effects
 Ibuprofen 200 mg,
11%
from day one until end of
bleeding or for a
maximum of 10 days;
Ylikorkala et al
1986 (75)
Duration/MBL
outcome
Assumed to
be a
randomized
double-blind
cross-over
Women with HMB caused by
fibromyomas (as determined
by pelvic examination and/or
ultrasound, or on
hysterectomy on completion
of study).
Alkaline
hematin
Two treatment
cycles.
Mean MBL reduction
during treatment (vs
baseline):
No adverse effects
occurred during
naproxen use.
Not reported
8 (73%) women
underwent
hysterectomy
after end of study
Naproxen, 18%
Placebo, 8% increase
BID, twice daily; HMB, heavy menstrual bleeding; LNG-IUS, levonorgestrel-releasing intrauterine system; MBL, menstrual blood loss; TID,
three times daily;
58
Table 7: Characteristics and outcomes of trials that assessed “additional potential therapies” for the treatment of heavy menstrual bleeding
(HMB). Data shown for the “other medical therapies” group only.
Author
(year)/Country
Comparators
Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome
Randomized controlled studies in women with AUB-E (or those described as having HMB without further definition)
Nilson and Rybo
Epsilon aminocaproicRandomized,
Women aged 17 to 50 years
Alkaline
1 months treatment
1965(83)
acid (18 g daily for first
placebowith suspected HMB and
hematin
In women with HMB
three days followed by
controlled,
anemia. Curettage undertaken
(MBL >60 mL)
12, 9, 6 and 3 g for the
double-blind
to prove bleeding was
next four days,
principle
ovulatory.
63% mean reduction
respectively; n=26)
(cross-over)
vs placebo
(data presented for
women with HMB; MBL
> 60 mL)
Harrison and
Cambell 1976(84)
UK
Ethamsylate (250mg four
times a day starting 5
days before expected
menses and continuing
for 10 days; n=9)
Placebo (n=9)
(here we focus on those
women with “primary
Adverse effects
Continuation
rates (for “other
medical
therapies”)
Adverse events with
esilon aminocaproicacid (in women with
HMB, >60mL) were
nausea (n=2); meteorism
(n=1); diarrhea (n=1);
orthostatism (n=1);
dizziness (n=1)
No
discontinuations
reported
<<Surgery
avoided or
required not
reported>>
Adverse events with
placebo were: abdominal
pain (n=3), nausea (n=2
diarrhea (n=1), fainting
(n=1), slight orthostatism
(n=2)
Randomized
double-blind
crossover
Women aged between 18 to
49 years with primary
menorrhagia (complaint of
excessive menstrual loss, a
regular menstrual cycle, and
no evidence of organic
disease).
Iron atomic
absorption
(after
alkaline
extraction)
2 cycles’ treatment
Ethamsylate period:
mean 46% MBL
reduction relative to
pre-treatment
Placebo period: mean
1% MBL increase
relative to pre-
Not reported specifically
for patients with primary
menorrhagia
Not reported
specifically for
patients with
primary
menorrhagia
<<Surgery
avoided or
59
Author
(year)/Country
Comparators
Inclusion/Exclusion criteria
MBL
assessment
method
menorrhagia”)
Bonnar and
Sheppard
1996(53)
Ethamsylate (500 mg
four times daily from
days 1 to 5; n=27)
Ireland.
Mefenamic acid (500 mg
TID from days 1 to 5; n=
23)
India
Ormeloxifene [SERM]
(60 mg two days a week
at an interval of 3 days;
n=42)
MPA (10mg daily for 21
days starting from day2–
5 of cycle; n=42)
Adverse effects
Continuation
rates (for “other
medical
therapies”)
required not
reported>>
Not specifically
described for
ethamsylate
16 (59%)
completed 3
cycles.
treatment
Randomized
(blinding not
stated but
assumed to
randomised
open-label)
Tranexamic acid (1 g
four time daily from days
1 to 5; n=26)
Shravage et al.
2011 (69)
Duration of
treatment/MBL
outcome
Randomized
double-blind,
Patients 35-46 years with
regular HMB (MBL >80 mL
objectively confirm during 3
pre-treatment cycles). Those
with organic causes of HMB
excluded by gynaecological
investigation, including
hysteroscopy, endometrial
biopsy, and a cervical smear.
Women age 35–50 years with
HMB (PBAC score >100
during two pre-treatment
cycles). Those with pelvic
pathology, systemic disorders,
severe anemia, chronic
cervicitis and cervical
dysplasia were excluded.
Alkaline
hematin
3 cycles’ treatment
Ethamsylate:
5%, -9% (increase),
1% MBL reduction
during cycles 1, 2 and
3
18 (67%) taking
tranexamic acid
did not wish to
continue the
treatment (poor
efficacy the
reason for 9
patients)
3% increase in MBL
(average treatment
effect over 3
treatment cycles vs
baseline)
PBAC
3 cycles’ treatment
Mean PBAC score
reduced with
ormeloxifene by
46%, 77% and 88%
at 1. 2 and 3 months
respectively.
Non-randomized studies in women with AUB-E (or those described as having HMB without further definition)
Turnbull and Rees Gestrinone (2.5 mg twice NonWomen aged 37 to 46 years
Alkaline
3months’ treatment
<<Surgery
avoided or
required not
reported>>
9.5% amenorrhea with
Ormeloxifen. Other
adverse events not
reported.
Study completion
not stated by
group
Adverse events included:
Discontinuations
<<Surgery
avoided or
required not
reported>>
60
Author
(year)/Country
Comparators
1990(85)
weekly from first day of
menstruation; n=19)
UK
Chamberlain et al
1991 (79)
UK
Ethamsylate (500 mg
four times daily from
days 1 to 5; n=22)
Mefenamic acid (500 mg
TID from days 1 to 5;
n=22)
Kriplani et al
2009(86)
India
Ormeloxifene [SERM]
(60 mg twice a week for
3 months and then once a
week for 1 month; n=42)
Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome
Adverse effects
randomized,
single-blind,
placebo
controlled
and regular HMB (>80mL
confirmed during two control
cycles) and no pelvic
abnormalities on pelvic
examination and endometrial
biopsy were recruited.
hematin
23% increase in
median MBL at first
menstruation
headaches,
dizziness/giddiness and
tiredness reported by
one-third of women
Double-blind,
allocated
treatment by
minimization
(nonrandomized)
Women aged 18-55 with
confirmed HMB (MBL >80
mL, during 2 pre-treatment
cycles) and regular cycles.
Exclusion criteria included
inflammatory bowel disease or
endocrine disorders, anemia or
notable uterine enlargement
due to fibroids.
Alkaline
hematin
Nonrandomized,
prospective
Women with confirmed HMB
(PBAC score >100).
PBAC
Exclusion criteria included:
uterine size >8 weeks
pregnancy, submucus fibroids,
fibroids >3 cm detected by
ultrasound, polyps, adnexal
mass, history of breast
malignancy, suspected
65%, 60, 36% and
71% median MBL
decrease in 2nd, 3rd,
4th and 5th
menstruation,
respectively (data
estimated from
graphs)
3 cycles’ treatment
13%, 25% and 22%
mean MBL
reduction: in cycles
1, 2 and 3,
respectively (data
estimated from
graph)
Women followed up
at 2 and 4 months of
therapy, then at 3 and
6 months after
treatment was
stopped
79% and 97% median
reduction at 2 and 4
months’ treatment,
Continuation
rates (for “other
medical
therapies”)
not reported
9 (47%)
underwent
hysterectomy
5 of 16 (31%) who
completed study reported
adverse effects:
abdominal discomfort
(n=2), headache (n=2)
and backache (n=1)
16 (73%) women
completed
treatment
Adverse effects included
ovarian cyst (n=3; 7.1%),
cervical erosion and
discharge (n=3; 7.1%),
gastric upset (n=3;
7.1%), vague abdominal
pain (n=2 ; 4.8%) and
headache (n=2; 4.8%).
3 (7.1%) women
discontinued
treatment
<<Surgery
avoided or
required not
reported>>
9 (21.4%)
underwent
hysterectomy
during the whole
study
61
Author
(year)/Country
Comparators
Inclusion/Exclusion criteria
MBL
assessment
method
adenomyosis, current genital
infection and endometrial
hyperplasia with atypia,
abnormal coagulation profile,
endocrinopathy or other
systemic diseases causing
menorrhagia.
Duration of
treatment/MBL
outcome
Adverse effects
Continuation
rates (for “other
medical
therapies”)
20 (47.6%) had
surgery 1 year
after completing
study period
8 adverse events
occurred during
desmopressin treatment
vs 10 with placebo
treatment. No specific
details provided.
No reported
24 (83%) of women
experienced at least one
adverse event during
study. Adverse events
were primarily headache,
facial flushing and
weight gain. Headache
was reported by 6(23%)
1 (3%) who
started treatment
did not complete
study
respectively.
Studies in women with HMB secondary to uterine structural pathology or coagulopathy
Edlund et al.
2002(87)
Sweden.
Desmopressin (nasal
spray at 300 µg per
inhalation BID on first 2
days of cycle; n=20)
Randomized
double-blind,
cross-over
Placebo (n=20)
All patients received
desmopressin plus
tranexamic acid, 1.5 g
TID on first 2 days of
third cycle (data
presented for randomised
section of study)
Kadir et al
2002(88)
UK
Desmopressin (nasal
spray at 150 µg per
nostril twice daily on
days 1 and 2 of cycle;
n=29)
Placebo (n=29)
Randomized,
double-blind
crossover
Prolonged bleeding time
Women age ≥18 years with
regular cycles and HMB
(MBL >80 mL objectively
confirmed during 1 pretreatment cycle), prolonged
bleeding time (>570 s) not due
to known cause.
Bleeding disorder
Women aged 18–50 years
with bleeding disorders,
including von Willebrand
disease, heterozygote factor
XI deficiency, hemophilia and
objectively confirmed HMB
(PBAC score > 100) were
Alkaline
hematin
1 cycle’ treatment
Desmopressin: mean
17% reduction in
MBL relative to
baseline
<<Surgery
avoided or
required not
reported>>
Placebo: mean 7%
reduction in MBL
relative to baseline
PBAC
2 months per
treatment period
Placebo/
desmopressin
sequence:
 60% median
reduction with
Two women
withdrew for
surgery before
receiving any
62
Author
(year)/Country
Comparators
Inclusion/Exclusion criteria
MBL
assessment
method
eligible.
Duration of
treatment/MBL
outcome
placebo
 67% median
reduction with
desmopressin
Exclusion criteria included:
type 2B von Willebrand
disease, a history of renal and
hepatic impairment, endocrine
disorders, thromboembolic
disease and nasal pathology
interfering with absorption of
the spray, including rhinitis,
nasal polyp or significantly
deviated septum .
Time effect observed
with lower PBAC
score in the second
treatment phase
irrespective of
treatment.
Adverse effects
and 7 (24%) of women
during desmopressin and
placebo, respectively.
Weight gain was
reported in 3 (12%) of
women during
desmopressin, and none
during the placebo
treatment
Continuation
rates (for “other
medical
therapies”)
medication
No significant
difference with
placebo
Rose et al 2008
(89)
USA
Bagaria et al
2009(90)
Desmopressin (nasal
spray at 150 µg per
nostril on days 1 and 2 of
cycle; n=11)
Nonrandomized,
prospective
Mifepristone (10 mg
daily; n=20)
Randomized,
double-blind
placebo-
Platelet dysfunction
PBAC
Women aged 18 to 45 years
with HMB (PBAC score ≥
100) and platelet dysfunction
were eligible. Other inclusion
criteria included negative
pelvic examination and uterine
size ≤12 week pregnancy.
Exclusion criteria included
history of thromboembolism,
anticoagulation therapy or
vascular disease.
Leiomyoma
Women with symptomatic
2 consecutive cycles
of treatment
Adverse events not
reported
42% median PBAC
reduction over 2
cycles
PBAC
3 months treatment
Mifepristone
Discontinuations
not reported
<<Surgery
avoided or
required not
reported>>
No adverse events
occurred in either group
Only 1 woman
lost to follow-up
in mifepristone
63
Author
(year)/Country
Comparators
India
Placebo (n=20)
Inclusion/Exclusion criteria
controlled
MBL
assessment
method
Duration of
treatment/MBL
outcome
Adverse effects
Continuation
rates (for “other
medical
therapies”)
group
Of the 90 patients who
used either study
medication for at least
one cycle, 13 (14%) had
adverse events; seven
patients with
desmopressin and six
with tranexamic acid.
Discontinuation
rates were 43%
for the nasal
desmopressintranexamic acid
sequence and
33% for
tranexamic acid –
desmopressin
 71, 88% and 95%
leiomyoma were eligible.
Exclusion criteria included
pelvic inflammatory disease or
other adnexal pathology,
surgical intervention for
leiomyoma.
mean PBAC
reduction at 1, 2
and 3 months’
treatment,
respectively.
Placebo
 No reduction
occurred
 7% and 6% mean
PBAC increase at
1 and 2 months,
and <1%
decrease at 3
months
Significant reduction
in uterine and
leiomyoma volume
vs. baseline
Kouides et al
2009(60)
USA
Desmopressin (nasal
spray at 300 µg per
nostril on days 2 days
and 3 of cycle)
Tranexamic acid (1 g
four times each day for
the first 5 day of menses)
Desmopressin/
tranexamic acid sequence
Randomized,
cross-over
Bleeding disorder
Women aged 18–50 years
referred for HMB to a
hemophilia treatment centre,
bleeding disorder clinic, or
gynaecology care centre.
Inclusion criteria included
negative pelvic examination
(fibroids were allowed if the
PBAC
2 cycles per treatment
period (data shown
for desmopressin
period only)
Desmopressin/
tranexamic acid
sequence:

13% and 21%
mean reduction in
64
Author
(year)/Country
Comparators
Inclusion/Exclusion criteria
(n=49)
uterus was <12 weeks
gestational size), a negative
Papanikolaou smear, PBAC
score ≥100, and detectable
bleeding disorder.
Tranexamic acid
Desmopressin/sequence
(n=67)
MBL
assessment
method
Duration of
treatment/MBL
outcome
Adverse effects
cycles 1 and 2 of
desmopressin (vs
baseline)

Continuation
rates (for “other
medical
therapies”)
sequence
<<Surgery
avoided or
required not
reported>>
21% and 24%
median reduction
in cycles 1 and 2
of desmopressin
(vs baseline)
Tranexamic acid/
desmopressin
sequence:
Ragni et al
2011(91)
USA
Interlukin-11
(recombinant human
interlukin-11
25 μg/kg/day by
subcutaneous selfinjection for up to seven
days during each of six
Nonrandomized,
prospective
von Willebrand disease
Women age 18–45 years with
mild von Willebrand disease,
and menorrhagia,
unresponsive to or intolerant
of hemostatic or hormonal
PBAC

31% and 25%
mean reduction in
cycles 1 and 2 of
desmopressin (vs
baseline)

31% and 32%
median reduction
in cycles 1 and 2
of desmopressin
(vs baseline)
6 months treatment
71% and 70% mean
reduction at 2 and 6
months, respectively
Drug well tolerated.
Grade 1 or less toxicity,
include conjunctival
erythema (n=7), mild
fluid retention (n=6),
injection site bruising
(n=6), flushing (n=3),
Discontinuations
not reported
<<Surgery
avoided or
required not
65
Author
(year)/Country
Donnez et al. 2012
(Pearl I) (92)
Czech Republic,
Hungary, India,
Romania, Russian
Federation,
Ukarine
Comparators
Inclusion/Exclusion criteria
consecutive menstrual
cycles; n=7)
agents.
Placebo daily (n=48)
5 mg of ulipristal acetate
daily (n=95)
10 mg ulipristal acetate
daily (n=94)
Randomized
double-blind
Leiomyoma
Women aged 18–50 years
with heavy uterine bleeding
(PBAC score >100) caused by
fibroids; fibroid-related
anaemia, at least one myoma
measuring ≥3 cm in diameter
(but no myoma measuring >10
cm), and a uterine size
equivalent to that of a
pregnancy of no more than16
weeks of gestation, and
eligible for surgery.
MBL
assessment
method
Duration of
treatment/MBL
outcome
Adverse effects
thrombocytosis,
484,000/μl (n=1),
hypokalaemia, 3.4 mEq/l
(n=1), and diastolic
hypertension, 93 mmHg
(n=1).
PBAC
13 weeks of
treatment (after
which patients could
have surgery)
Median reduction in
PBAC score from
baseline to wk 9–13:
 Placebo, 11%
 5 mg of ulipristal
acetate daily,
100%
 10 mg ulipristal
acetate daily,
100%
Headache: 4%, 4% and
10%, respectively
Breast pain/tenderness/
discomfort: 0%, 2%, 6%
Abdominal pain: 4%,
2%, 3%
Continuation
rates (for “other
medical
therapies”)
reported>>
Completed study:
98%, 96%, and
94%, respectively
Underwent
surgery: 40%,
43%, and 50%
Pyrexia: 4%, 3%, and
2%
Hypercholesterolemia:
2%, 3% and 2%
Hypothyroidism: 2%,
3%, and 2%
Constipation: 2%, 4%
and 0%
Hypertriglyceridemia:
2%, 3% and 1%
Influenza: 2%, 1%, and
3%
Dizziness: 0%, 1% and
66
Author
(year)/Country
Comparators
Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome
Adverse effects
Continuation
rates (for “other
medical
therapies”)
3%
Nasopharygitis: 0%, 3%,
and 0%
Dysmenorrhea: 4%, 0%
and 0%
Donnez et al. 2012
(Pearl II)(93)
Austria, Belgium,
France, Germany,
Israel, Italy,
Netherlands,
Poland, and Spain
Intramuscular leuprolide
acetate 3.75 mg once
monthly (n=101)
5 mg oral ulipristal
acetate daily (n=97)
10 mg oral ulipristal
acetate daily (n=103)
Randomized
double-blind
Leiomyoma
Premenopausal women aged
18–50 years with heavy
uterine bleeding (PBAC score
>100) caused by fibroids, at
least one myoma measuring
≥3 cm in diameter (but no
myoma measuring >10 cm),
and a uterine size equivalent
to that of a pregnancy of no
more than16 weeks of
gestation, and eligible for
surgery.
PBAC
13 weeks of
treatment (after
which patients could
have surgery)
intramuscular
leuprolide acetate
group; 92% median
reduction at 13 weeks
5 mg oral ulipristal
acetate group; 94%
median reduction at
13 weeks
10 mg oral ulipristal
acetate group; 99%
median reduction at
13 weeks
Moderate-to-severe hot
flashes occurred in 11%,
10% and 40% of women,
in the three groups
respectively.
Hot flush: 65%, 26%,
and 24% respectively
Completed study:
94%, 98%, and
97%, respectively.
Underwent
surgery: 51%,
52%, and 53%
Headache: 29%, 26%,
and 18%
Procedural pain: 9%, 9%,
and 15%,
Abdominal pain:14%,
6% and 11%
Nausea: 6%, 6%, and 7%
Fatigue: 3%,4%, and 7%
Anaemia: 5%, 5%, and
3%
Breast pain/tenderness:
2%, 5%, and 3%
Influenza: 5%, 2%, and
67
Author
(year)/Country
Comparators
Inclusion/Exclusion criteria
MBL
assessment
method
Duration of
treatment/MBL
outcome
Adverse effects
Continuation
rates (for “other
medical
therapies”)
2%
Insomnia: 5%, 2%, and
2%
Pharyngitis:2%, 5%, and
0%
BID, twice daily; MPA, medroxyprogesterone acetate; PBAC, pictorial blood assessment chart; SERM, selective estrogen receptor modulator;
TID, three times daily
68
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