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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.
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