The levonorgestrel intrauterine system is an effective treatment in women with abnormal uterine bleeding and anticoagulant therapy
The Levonorgestrel Intrauterine System is an Effective Treatmentin Women with Abnormal Uterine Bleedingand Anticoagulant Therapy
George A. Vilos, , Valentin Tureanu, MD, Meivys Garcia, MD, and Basim Abu-Rafea, MDFrom St. Joseph’s Health Care, Department of Obstetrics and Gynecology, The University of Western Ontario, London, Ontario, Canada (all authors), and KingKhalid, University Hospital, King Saud University, Riyadh, Saudi Arabia (Drs. Vilos and Abu-Rafea).
Objective: To evaluate the efficacy of levonorgestrel intrauterine systems (LNG-IUS) in obese women with AUB on antico-agulant therapy. Design: Prospective observational case series (Canadian Task Force Classification II-3). Setting: University affiliated teaching hospital. Patients: Premenopausal women on Warfarin therapy. Interventions: From January 2002 through January 2007, 10 women were identified from the senior author’s clinical practice(G.A.V.). After clinical assessment, including Papanicolaou smear, endometrial biopsy, and pelvic sonography, the LNG-IUSwas placed to treat their AUB. Measurements and Main Results: The median and range of age, parity, and body mass index were 45 years (34-49), 1 (0-4),and 38 kg/m2 (26-52), respectively. All women were receiving warfarin therapy (4-12.5 mg/d) for previous venous thrombo-embolism. Some patients had additional comorbid conditions and were at high risk for traditional medical or surgical therapies. After placement of the LNG-IUS, all women reported menstrual reduction at 3 and 6 months. By 12 months, 1 woman withlarge fibroids expelled the LNG-IUS and was treated with transfemoral uterine artery embolization. Two women had amenor-rhea, and 7 had hypomenorrhea. At 2 to 5 years, 1 woman expelled the LNG-IUS and hysterectomy indicated extensiveadenomyosis in a 195-g uterus, and 1 woman had hysteroscopic endometrial ablation, 4 were menopausal, 2 had amenorrhea,and 1 had hypomenorrhea. In the 5 women with uterine fibroids measuring 4.2 to 147 cm3, the fibroids were reduced in volumeby approximately 75% in 2, were no longer detectable in 1, were subsequently shown to be adenomyoma in 1, and requireduterine artery embolization in 1. Conclusion: In properly assessed and selected obese, premenopausal women with AUB receiving warfarin therapy and at highrisk for traditional therapies, the LNG-IUS was an effective treatment in 70% of patients. Journal of Minimally InvasiveGynecology (2009) 16, 480–484 Ó 2009 AAGL. All rights reserved.
LNG- IUS; Mirena; Menorrhagia; Warfarin; Thromboprophylaxis; Anticoagulant
Abnormal uterine bleeding (AUB), defined as change in
adversely affects quality of life, and is associated with
any or a combination of frequency, duration or amount of
significant use of health care resources. The prevalence of
bleeding is experienced by approximately 20% to 30% of pre-
AUB increases with age and peaks just before menopause in
menopausal women . In general, AUB is a common de-
accordance with changes in steroidogenesis and serum sex
bilitating condition that results in reduced hemoglobin,
hormones or lack of ovulation and serum progesterone .
In general, the menstrual cycle and amount of menstrual
blood loss (MBL) are regulated by cyclic ovarian response
The authors have no commercial, proprietary, or financial interest in the
to extraovarian stimuli and production of estrogen and pro-
products or companies described in this article.
gesterone. AUB then can be modulated by partial or complete
Corresponding author: George A. Vilos, MD, Department of Obstetrics andGynecology, St. Joseph’s Health Care, 268 Grosvenor St, London, Ontario,
suppression of ovarian steroidogenesis with a variety of
agents including combined oral contraceptives, progestins,
androgens (danazol) or gonadotropin-releasing hormone ag-onists In the presence of intrauterine polyps, found in
Submitted February 20, 2009. Accepted for publication April 30, 2009. Available at and
25% to 35%, and leiomyomas, found in 15% to 30% of
1553-4650/$ - see front matter Ó 2009 AAGL. All rights reserved. doi:10.1016/j.jmig.2009.04.018
women with AUB effective treatments include hystero-
reduction of their bleeding. At 2 to 5 years, a 34-year-old
scopic surgery or hysterectomy. In the absence of intrauterine
woman expelled the LNG-IUS, and hysterectomy revealed
disease, medical therapies, levonorgestrel intrauterine sys-
extensive adenomyosis in a 195-g uterus. A 42-year-old
tems (LNG-IUS), and hysteroscopic and nonhysteroscopic
woman underwent hysteroscopic endometrial ablation for
endometrial ablation enjoy certain degrees of popularity in
unpredictable spotting, 4 women reached menopause, 2 had
accordance with personal experience, training, expertise,
amenorrhea, and 1 had hypomenorrhea.
Two women with fibroids (patients 4 and 5) reached men-
Among the general population of women with AUB, gyne-
opause, and their fibroids were reduced by approximately
cologists occasionally encounter women with morbid condi-
75% in volume. In a third woman (patient 10) the fibroid
tions and ailments that may contribute to AUB in conjunction
was no longer detectable by transvaginal sonography. One
with age and hormonal, metabolic, and body mass index
woman (patient 8) with simple endometrial hyperplasia and
(BMI) changes. Such cases may include neuromuscular or
a uterine mass of 31 cm3 had development of hypomenorrhea
bleeding disorders, cerebrovascular accidents, and thrombo-
but spontaneously expelled the LNG-IUS at 24 months. After
embolic events that may require prolonged thromboprophy-
vaginal hysterectomy, the uterus, weighing 195 g, showed
laxis with anticoagulant agents. Under such circumstances,
extensive adenomyosis and proliferative endometrium with
traditional therapies may be contraindicated, ineffective,
no evidence of leiomyoma or endometrial hyperplasia. The
refused, difficult, or quite risky to administer or perform.
fifth woman (patient 9) with large fibroid uterus had develop-
In this study we report our experience with 10 women
ment of hypomenorrhea but subsequently requested uterine
with AUB, and various comorbidities and conditions, all of
artery embolization at 12 months for unpredictable spotting.
which required continuous warfarin therapy, treated withLNG-IUS (Mirena; Bayer Shering Pharma AG, Berlin, Ger-
many). Review of these patient’s records was approved byour university ethics committee (HSREB 13849 E).
Traditionally, premenopausal healthy women with AUB
from benign causes are managed quite effectively with a vari-ety of treatments including oral, transdermal, or injectable
medications, intrauterine hormone-releasing systems, and
From January 2002 through January 2007, we identified
surgical interventions including hysteroscopic and nonhys-
10 women with AUB requiring thromboprophylaxis from
teroscopic procedures or hysterectomy However, gyne-
the senior author’s clinical practice (G.A.V.) at a univer-
cologists occasionally are faced with women experiencing
sity-affiliated teaching hospital. The median for age, parity
AUB with multiple health disorders and ailments in which
and BMI were 45 years, 1 child (range 0-4), and 38 kg/m2
most of the above traditional therapies are contraindicated
(range 26-52), respectively. All women had experienced a va-
riety of thromboembolic events including deep vein throm-
In this study, the senior author (G.A.V.) was referred 10
bosis, pulmonary embolism, or stroke and required
women with AUB, and a variety of comorbidities including
continuous thromboprophylaxis with warfarin 4 to 12.5 mg
obesity, all of whom required thromboprophylaxis for previ-
daily. In addition, patients had a variety of comorbid condi-
ous thromboembolic events. Under these conditions, estro-
tions including diabetes, nephropathy, asthma, hypertension,
gens are contraindicated because they increase the risk of
angina, gastroesophageal reflux, atrial fibrillation, and de-
thromboembolism, injectable agents cause injection site
pression. Two women with advanced multiple sclerosis
bleeding and hematomas, and surgical treatments require
were confined to wheelchairs with indwelling Foley catheter
temporary discontinuation or alteration of the anticoagulants.
and were totally incapable of caring for themselves. Their
Therefore the choices for contraception and treatment options
menstrual bleeding was a major problem for themselves
for women with AUB on anticoagulant therapy are very lim-
and their caregivers. All patients had Papanicolaou smear,
ited. Under such circumstances, oral progestins or LNG-IUS
endometrial biopsy, and sonohysterography before place-
may be the least risky choices of therapy, but data on their use
ment of the LNG-IUS. Endometrial histologic study was pro-
liferative in 6, secretory in 3, and simple hyperplasia in 1. In 5
LNG-IUS consists of a polyethylene, barium-coated
women, uterine fibroids were reported ranging in volume
frame (32 ! 32 mm) to make it radiopaque with a containing
from 4.2 to 147 cm3. The demographics, assessment and clin-
reservoir (52 mg) around its vertical stem The system ini-
ical outcomes of the 10 women are listed in the .
tially releases levonorgestrel approximately 20 mg/d via
All women were reassessed at 3, 6, and 12 months and an-
a drug-controlling membrane, decreasing to approximately
nually thereafter. At 3 months, all women reported significant
half of that by 5 years and to less than 10 mg/d from 5 to 7
menstrual reduction. At 6 to 12 months, a 45-year-old woman
years. The average release within the first 5 years is approx-
with the 2 largest fibroids measuring 75 cm3 and 147 cm3, re-
imately 14 mg/d. Interestingly, clinical observations indicate
spectively, expelled the LNG-IUS, and she was successfully
that the efficacy of the LNG-IUS may diminish after the third
treated with uterine artery embolization for unpredictable
year of placement for noncontraceptive uses (personal obser-
bleeding. Two women had amenorrhea, and 7 had further
vations). LNG is absorbed from the uterine cavity very
Ten obese premenopausal women with AUB and thromboprophylaxis treated with LNG-IUS
MS 5 Multiple sclerosis; SEH/CEH 5 simple/complex endometrial hyperplasia; DVT/PE 5 deep vein thrombosis/pulmonary embolism; HEA 5 hysteroscopic endometrial ablation; UAE 5 uterine artery em-
bolization; Fib. 5 fibroid; Ameno 5 amenorrhea; Hypomen 5 hypomenorrhea.
rapidly, reaching sustained serum levels of 150 to 200 pg/mL
was removed 7 days after placement in 1 woman because
of abdominal pain and 1 month later in the other because
The effects of LNG-IUS in women with menorrhagia has
she had development of transverse sinus thrombosis. Nine-
been reviewed from both cohort and randomized studies. In
teen of 28 (68%) women with hemostatic disorders (not on
general, after placement of the LNG-IUS in women with
anticoagulants) experienced improvement of menstrual
menorrhagia, MBL was reduced by 79% to 97%, with patient
satisfaction and continuation rates being 72% to 94% and
Finally, Lukes et al reported on 7 premenopausal
65% to 88%, respectively On the basis of the above
women with hemostatic disorders and AUB treated with
evidence and on the limited treatment options, in our group
the LNG-IUS. Four women were using anticoagulants, 3
of 10 women we elected to use the LNG-IUS after obtaining
warfarin and 2 aspirin. A reduction of BML and improved
informed consent. A literature search revealed 1 case report
quality of life was reported by 5 (71%) women .
of apparent interaction between warfarin and levonorgestrel.
Based on the above limited data, Kadir and Chi in
A 35-year-old woman was taking warfarin 7 mg daily. After
their review article concluded that the LNG-IUS is a safe
2 doses of levonorgestrel 0.75 mg given 12 hours apart for
and attractive option for women with hemostatic disorders,
emergency contraception, the woman’s international normal-
which may obviate the need for surgical interventions in
ized ratio rose from 2.1 to 8.1 in 3 days . Current evi-
these women. Their review, however, did not include any
dence suggests that the risk of thromboembolism is not
women without bleeding disorder and previous thromboem-
increased in patients using levonorgestrel containing oral
bolism requiring current anticoagulants.
contraceptives ; however, there is no evidence to support
To our knowledge, this is the first report of women with
the same in women who already had a thromboembolic event
AUB, without apparent hemostatic disorders requiring
and are currently on thromboprophylaxis.
thromboprophylaxis treated with the LNG-IUS. As the
Association of menstrual bleeding and anticoagulant ther-
indicates, all women had comorbid conditions that may or
apy has been reported in a small number of women. Van Eijke-
may not have contributed to their AUB and MBL. One pa-
ren et al measured MBL in 6 premenopausal women with
tient with insulin-dependent diabetes had multiple sclerosis
various congenital or acquired bleeding disorders and in 11
and end-stage nephropathy. After placement of LNG-IUS,
women using oral anticoagulant therapy. The mean MBL, by
the insulin requirements did not change. A randomized trial
alkaline hematin method, was 98 mL (9-239 mL) in women re-
demonstrated that the LNG-IUS had no adverse effect on glu-
ceiving anticoagulant therapy. Five (45%) had menorrhagia
cose metabolism in diabetic women at either 6 weeks or 6
(MBL . 80 mL). Of the remaining 6 women, 2 had blood los-
ses in the high normal range (60-80 mL). The authors con-
All of our patients were overweight (BMI . 25 kg/m2).
cluded that oral anticoagulants increase MBL
Eight were obese (BMI . 30 kg/m2), and 6 were morbidly
Kadir and Chi in a review article reported that 9 of 11
obese (BMI . 35 kg/m2). As a rule, obesity is associated
(82%) women with bleeding disorders on anticoagulant ther-
with many chronic diseases, as well as clinical conditions in-
apy had menorrhagia (pictorial blood loss assessment chart
cluding venous thromboembolism, diabetes, hypertension,
score . 100). Five women had development of intermenst-
and menstrual disorders including uterine neoplasia .
rual bleeding, and 6 reported adverse effects on their quality
Obesity currently is reaching epidemic proportions in the de-
of life during menstruation after the start of their anticoagu-
veloped world. In 1999 to 2002, 62% of U.S. women aged 20
lant therapy Because the prevalence of menorrhagia
years or older were overweight (BMI . 25 kg/m2), and 30%
in the general population is 20% to 30%, the above studies
were obese (BMI , 30%/m2) . Under the circumstances,
indicate that bleeding disorders and anticoagulant therapy
health care providers will encounter more and more women
significantly increase the risk of AUB up to 80%.
with similar conditions and ailments to those of our present
The efficacy and use of the LNG-IUS in anticoagulated
study. Our experience therefore with this small group of pa-
women with bleeding disorders has been reported in small
tients, indicating that 7 of 10 women (70%) were effectively
studies. Pisoni et al treated 16 women with menorrhagia
and safely treated with the LNG-IUS, may be of considerable
associated with warfarin with the LNG-IUS. The LNG-IUS
benefit and value to both patients and therapists.
treatment was associated with a reduction of MBL in 87% ofwomen, 4 (25%) of whom became amenorrheic, and 75%were very satisfied or satisfied with their treatment. In a fol-
low-up study, the same authors reported on 17 women with
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