OBJECTIVE: To compare the efficacy and safety of the levonorgestrel-releasing intrauterine system and oral medroxyprogesterone acetate in the treatment of idiopathic heavy menstrual bleeding.
METHODS: In this multicenter, randomized, controlled study, women aged 18 years or older with heavy menstrual bleeding (menstrual blood loss 80 mL or more per cycle) were randomly assigned to six cycles of treatment with either levonorgestrel-releasing intrauterine system or oral medroxyprogesterone acetate (10 mg daily for 10 days beginning on day 16 of each cycle). The primary efficacy variables were the absolute change in menstrual blood loss from baseline to end of study and the proportion of women with successful treatment (defined as menstrual blood loss less than 80 mL and a 50% or greater reduction in menstrual blood loss from baseline).
RESULTS: Of 807 women screened, 165 were randomly assigned to treatment (levonorgestrel-releasing intrauterine system n=82, oral medroxyprogesterone acetate n=83). At the end of the study, the absolute reduction in median menstrual blood loss was significantly greater in the levonorgestrel-releasing intrauterine system group (−128.8 mL, range −393.6 to +1242.2 mL) than in the medroxyprogesterone acetate arm (−17.8 mL, range −271.5 to +78.6 mL, P < .001), and the proportion of women with successful treatment was significantly higher for the levonorgestrel-releasing intrauterine system (84.8%) than for medroxyprogesterone acetate (22.2%, P < .001).
CONCLUSION: In women with idiopathic heavy menstrual bleeding, the levonorgestrel-releasing intrauterine system reduces menstrual blood loss more effectively and has a higher likelihood of treatment success than oral medroxyprogesterone acetate.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00360490.
LEVEL OF EVIDENCE: I
The levonorgestrel-releasing intrauterine system is more effective in reducing menstrual blood loss and alleviating heavy menstrual bleeding than oral medroxyprogesterone acetate.
From the Department of Obstetrics and Gynecology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida; Department of Obstetrics and Gynecology, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada; Human Reproduction Unit, Department of Obstetrics and Gynecology, School of Medicine, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil; Bayer Schering Pharma Oy, Espoo, Finland; Bayer Schering Pharma AG, Berlin, Germany; Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, Oregon.
Funded by Bayer Schering Pharma AG.
Presented at the Association of Reproductive Health Professionals' 2009 annual clinical meeting October 1–3, 2009, Los Angeles, California.
The authors thank Richard Glover of InScience Communications, a Wolters Kluwer Business, for medical writing assistance in the preparation of this article, with the financial support of Bayer Schering Pharma AG.
Corresponding author: Andrew M. Kaunitz, 653-1 West 8th Street, Jacksonville, FL 32209-6561; e-mail: Andrew.firstname.lastname@example.org.
Financial Disclosure Dr. Kaunitz serves on scientific advisory boards and as a consultant for Bayer Schering Pharma AG. The Department of Obstetrics and Gynecology of the University of Florida College of Medicine-Jacksonville receives financial support from Bayer Schering Pharma AG for conducting clinical trials. Dr. Lukkari-Lax and Mr. Muysers are employed by Bayer Schering Pharma Oy/AG. Dr. Jensen has received payments for consulting, scientific advisory boards, and for giving talks for Bayer Healthcare. He also receives research financial support from Bayer Healthcare and Bayer Schering Pharma AG. Drs. Bissonnette and Monteiro did not report any potential conflicts of interest.
In the United States, more than 600,000 hysterectomies are performed annually.1,2 Approximately 90% of these were for benign diseases including menstrual disorders (approximately 17% of the total number of hysterectomies) such as heavy menstrual bleeding.1 Heavy menstrual bleeding, defined objectively as blood loss 80 mL or more per menstrual cycle, is an important cause of iron-deficiency anemia and adversely affects health-related quality of life.3 An analysis of the 1999 National Health Interview Survey4 showed a 7% reduction in “employment” attributed to heavy menstrual bleeding, translating into an average loss of 3.6 work weeks (or US $1,692 in wages) per year.
Although hysterectomy or endometrial ablation provides effective surgical options for heavy menstrual bleeding, both approaches are associated with perioperative and long-term surgical risks.5–8 Algorithms for heavy menstrual bleeding emphasize the use of medical treatment before resorting to surgical options.3,6 At the time this trial was performed, the only approved medical treatments for the indication “abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology” in the United States were oral medroxyprogesterone acetate (5 or 10 mg) and norethindrone acetate (2.5–10 mg) administered daily for 5 to 10 days during the luteal phase of the menstrual cycle.
A recent small, short-term, randomized trial assessed the efficacy of depot medroxyprogesterone acetate, oral medroxyprogesterone acetate (5 mg daily, every day starting on the first day of the cycle), and the levonorgestrel-releasing intrauterine system in reducing bleeding in a population of older reproductive-aged women with heavy menstrual bleeding.9 This report found that, although each of the treatments significantly reduced menstrual blood loss (assessed by pictorial blood loss assessment chart), the efficacy of the levonorgestrel-releasing intrauterine system was superior to both depot and oral progestin.9
We undertook this study to objectively compare the efficacy and safety of the levonorgestrel-releasing intrauterine system and oral medroxyprogesterone acetate for the treatment of heavy menstrual bleeding (using the objective alkaline hematin method)10 in women who choose to use intrauterine contraception.
MATERIALS AND METHODS
This was a multicenter, randomized, open-label, parallel-group, active-control study conducted in 55 centers in the United States, Canada, and Brazil between July 2006 and June 2008. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization–Good Clinical Practice guidelines. The study protocol was approved by local Ethics Committees or Institutional Review Boards of all participating centers. Written informed consent was obtained from all participants before entry into the study.
Parous women aged 18 years or older with idiopathic heavy menstrual bleeding (menstrual blood loss 80 mL or more per cycle) desiring intrauterine contraception and willing to use barrier contraception if required were considered for participation in this study. Exclusion criteria included changes in menstrual regularity, hot flushes, sleeping disorders, or changes in mood within the 3 months preceding the study; breastfeeding; congenital or acquired uterine abnormality, including fibroids if they distorted the uterine cavity or cervical canal (three or more subserous or intramural fibroids with a total volume of less than 5 cm3 were acceptable); history of organic causes of abnormal uterine bleeding (eg, endometriosis, adenomyosis, endometrial polyps); use of the levonorgestrel-releasing intrauterine system or a copper intrauterine device during the 30 days before the study; history of vascular or coagulation disorders; concomitant use of medication or presence of an underlying disease/condition known to affect the metabolism or pharmacokinetics of the study medication; and a body mass index greater than 35 kg/m2.
All eligible women underwent a screening phase lasting two to three menstrual cycles to assess baseline menstrual blood loss. During this phase, participants were instructed to use standardized tampons and pads as appropriate and to collect all sanitary protection used (excluding panty liners) in sealed plastic bags for objective analysis of total menstrual blood loss at a central laboratory using the alkaline hematin method.10 Menstrual blood loss of 80 mL or more per cycle was confirmed in at least two screening menstrual cycles before the participants were randomized in a 1:1 ratio to receive treatment with either the levonorgestrel-releasing intrauterine system or oral medroxyprogesterone acetate. Randomization was performed using a centralized interactive voice-response system (ClinPhone, East Windsor, NJ). Random permuted block lengths of four were used to attain balance within the strata and by country.
Women randomly assinged to the levonorgestrel-releasing intrauterine system had the system placed within 7 days of the onset of menstruation (in case of initial placement failure, only one attempt at replacement could be made). Those randomly assigned to oral medroxyprogesterone acetate received 10 mg of the drug once daily for 10 consecutive days in each cycle (the highest dose and regimen indicated in the current label for the treatment of abnormal uterine bleeding attributable to hormonal imbalance in the absence of organic pathology), starting on day 16 of their menstrual cycle. All women were given diary cards to record menstrual bleeding on a daily basis. Those women in the oral medroxyprogesterone acetate group also used the diary cards to record tablet intake (along with the return of unused treatment packs) so that treatment adherence could be monitored. All participants were provided dedicated containers and instructed to collect all used sanitary protection during cycles three and six to assess menstrual blood loss (as performed in the screening phase).
The day on which the levonorgestrel-releasing intrauterine system was placed was considered the first day of cycle 1, and each cycle was considered to last for 30 days. In the oral medroxyprogesterone acetate group, each menstrual cycle was considered to start on the first day of menstrual bleeding and last until the last nonbleeding day before the onset of the next bleeding episode.
Safety evaluation included clinical assessments (physical and gynecologic examinations), monitoring of adverse events, and changes in laboratory values for hematological, serum chemistry, and urinalysis variables. All adverse events (observed, volunteered, and solicited) were coded using MedDRA (the Medical Dictionary for Regulatory Activities [MedDRA] is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use), version 11.0, and classified by the study investigators according to their intensity (mild, moderate, or severe) and their likely relationship to study medication (ie, none, unlikely, possible, probable, or definite).
At the end of the study, women randomly assinged to medroxyprogesterone acetate were able to select using the levonorgestrel-releasing intrauterine system if they desired one. Likewise, those allocated to the levonorgestrel-releasing intrauterine system were allowed to continue its use.
The two primary efficacy variables were the absolute change in menstrual blood loss from baseline to the end of the study and the proportion of those in which the treatment was successful (defined as menstrual blood loss less than 80 mL at end of study and 50% or greater reduction in menstrual blood loss from baseline).
The sample size (calculated using nQuery Advisor Release 5.0; Statistical Solutions, Saugus, MA) was based on data from previous trials with the levonorgestrel-releasing intrauterine system or oral medroxyprogesterone acetate11,12; it assumed that the mean menstrual blood loss at baseline would be 150 mL, the mean absolute reduction in menstrual blood loss at the end of study would be −125 mL (corresponding to 83% reduction from baseline) with the levonorgestrel-releasing intrauterine system and −75 mL (corresponding to 50% reduction from baseline) with oral medroxyprogesterone acetate, and the corresponding standard deviations would be 80 mL. Based on these assumptions, a total of 110 participants (55 per treatment group) would yield 90% power at a two-sided alpha level of 0.05 to detect a significant difference in menstrual blood loss between groups, and a power of 99% to detect a 40% difference in the proportions of participants with successful treatment (90% and 50% in the levonorgestrel-releasing intrauterine system and oral medroxyprogesterone acetate groups, respectively). Considering a drop-out rate of 20%, a total of 138 women (69 per treatment group) were required to be enrolled.
All outcomes were assessed using the intention-to-treat principle except for safety parameters, which were analyzed according to the treatment received (at least one dose of oral medroxyprogesterone acetate or attempted or successful placement of the levonorgestrel-releasing intrauterine system). The absolute change (least-square means, 95% confidence interval, and median values) in menstrual blood loss from baseline to the end of the study (defined as cycle 6 or the last observation) was assessed using the Wilcoxon rank-sum test. This test was also used for changes in menstrual blood loss from baseline to other time points. The proportion of participants with successful treatment was analyzed using the Pearson χ2 test. The percent change in menstrual blood loss from baseline to cycle three and to end of the study were analyzed using the t test with two-sided 95% confidence intervals.
A total of 807 women were screened. One hundred sixty-five women were randomly assigned to treatment and comprised the intention-to-treat population (Fig. 1). Of these, 162 women received at least one dose of oral medroxyprogesterone acetate (n=82) or underwent levonorgestrel-releasing intrauterine system placement or attempted placement (n=80). The groups were similar with respect to participants' baseline characteristics (Table 1). Most participants (levonorgestrel-releasing intrauterine system, n=73 [89.0%]; oral medroxyprogesterone acetate, n=70 [84.3%]) completed the six-cycle treatment phase of the study and more than 90% of participants completed at least three cycles of treatment.
Table 2 summarizes the menstrual blood loss parameters for both treatment groups. Levonorgestrel-releasing intrauterine system users experienced significantly greater absolute reductions in median menstrual blood loss than participants using medroxyprogesterone acetate at midstudy (−115.1 mL compared with −3.2 mL; P<.001) and end of study (−128.8 mL compared with −17.8 mL; P<.001). The percentage decrease in mean menstrual blood loss at end of study with the levonorgestrel-releasing intrauterine system (−70.8%) was also significantly greater than with medroxyprogesterone acetate (−21.5%, P<.001). Although fewer than 30% of participants treated with medroxyprogesterone acetate experienced more than 50% reduction in blood loss, approximately 80% of women treated with the levonorgestrel-releasing intrauterine system experienced at least 70% decrease at study end (Fig. 2). By the end of the study, the levonorgestrel-releasing intrauterine system had successfully treated 67 of 79 (84.8%) women compared with 18 of 81 (22.2%) women in the oral medroxyprogesterone acetate group (P<.001).
No deaths or drug-related serious adverse event occurred during the study. Six participants (four in the levonorgestrel-releasing intrauterine system group and two in oral medroxyprogesterone acetate group) discontinued treatment because of adverse events (Fig. 1). Mean values for all chemistry and hematological parameters were within normal ranges at all times during the study. The levonorgestrel-releasing intrauterine system was partially expelled in two participants and completely expelled in another two. The two participants who experienced partial expulsions were discontinued from study treatment, without attempts to replace with a new levonorgestrel-releasing intrauterine system. The two participants who experienced complete expulsion of the levonorgestrel-releasing intrauterine system had a new system placed that was subsequently retained, resulting in the reduction of the bleeding that occurred after expulsion. One of the participants who had complete expulsion of the levonorgestrel-releasing intrauterine system experienced heavy bleeding after expulsion of the system (see outlier in Table 2); however, a gynecologic examination yielded normal results, and the bleeding diminished and then stopped after the placement of a new system. No uterine perforations or pregnancies were observed during the study. Drug-related adverse events were recorded for 69 (42.6%) women. The most common adverse events (occurring in more than 5% of women who received treatment with either the levonorgestrel-releasing intrauterine system or oral medroxyprogesterone acetate) are detailed in Table 3.
Compared with medroxyprogesterone acetate, treatment with the levonorgestrel-releasing intrauterine system resulted in greater absolute and percentage reductions in menstrual blood loss and a higher likelihood of treatment success. Our results are similar to those of previous studies using the alkaline hematin method to assess blood loss in women using the levonorgestrel-releasing intrauterine system.13,14 In contrast to the mean 22% reduction in menstrual blood loss observed at end of our study in women using 10 mg oral medroxyprogesterone acetate for 10 days, superior results with cyclical oral medroxyprogesterone acetate (assessed with the alkaline hematin method) have been reported using 10 mg three times daily from day 5 to 25 for ovulatory women (49% decrease) or day 12 to 25 for anovulatory women (36% decrease).11 An even greater mean reduction (57%) in menstrual blood loss after 3 months was achieved with oral medroxyprogesterone acetate (10 mg twice daily from day 5 to day 25 of the cycle) in another study that used pictorial blood loss assessment chart scores.15 The higher efficacy with oral medroxyprogesterone acetate observed in the other studies may be attributed, in part, to the higher progestin dose and longer treatment duration per cycle compared with our study.16 Nonetheless, we used the highest oral medroxyprogesterone acetate dose (10 mg) and the longest duration of treatment (10 days) approved for “abnormal uterine bleeding” in the United States. Although a higher dose and longer duration of treatment may have improved results with oral medroxyprogesterone acetate, it is not likely that the treatment would have been superior to the more than 70% reduction observed with the levonorgestrel-releasing intrauterine system.
The reduction in menstrual blood loss with the levonorgestrel-releasing intrauterine system has been shown to be greater than with oral nonsteroidal antiinflammatory agents, tranexamic acid, or a combination estrogen–progestin oral contraceptive.13,14,17 Although a randomized trial found that the median reduction in menstrual blood loss was not significantly different over three cycles between the levonorgestrel-releasing intrauterine system and norethindrone (5 mg three times daily from day 5 to 26), more women elected to continue treatment with the levonorgestrel-releasing intrauterine system after study completion (77% compared with 22%).18 Other advantages of using the levonorgestrel-releasing intrauterine system over oral progestin therapy include improved adherence (no action required by the user after placement) and the effective contraception that it provides.
A recent meta-analysis showed that the levonorgestrel-releasing intrauterine system had similar therapeutic effects to endometrial ablation at up to 2 years of follow-up.19 In a recently published Dutch report, investigators noted that as the levonorgestrel-releasing intrauterine system became more widely used, the proportion of women undergoing endometrial ablation decreased.20 In a Finnish trial, in women randomly assigned to receive either levonorgestrel-releasing intrauterine system or hysterectomy for treatment of heavy menstrual bleeding, no difference in health-related quality of life was noted in the two treatment groups; at 5 years, 48% of the levonorgestrel-releasing intrauterine system group continued to use the device and 42% had undergone hysterectomy. Costs were threefold higher in the hysterectomy group up to 5 years of follow-up.21,22 Although hysterectomy negates the need for contraception, it represents an irrevocable step that some women would prefer to avoid. Similarly, although endometrial ablation limits fertility, women undergoing this procedure require effective contraception and any subsequent pregnancy would be at high risk of major obstetric complications.23
Clinicians managing women with heavy menstrual bleeding should counsel their patients regarding medical management, including the levonorgestrel-releasing intrauterine system, before surgical treatments.3 The levonorgestrel-releasing intrauterine system is licensed for up to 5 years of use, and correct and consistent use is not patient dependent. Accordingly, continued use of the levonorgestrel-releasing intrauterine system beyond the 6-month study duration should result in continued endometrial suppression and reduced menstrual blood loss, with more women becoming amenorrheic.24,25 To the best of our knowledge, data for continued use of medroxyprogesterone acetate for more than 6 months with heavy menstrual bleeding are lacking. In addition, the levonorgestrel-releasing intrauterine system has been shown to reduce the preference for hysterectomy and to be a cost-effective option in the management of heavy menstrual bleeding.21,22,26
Although all women in this study received the levonorgestrel-releasing intrauterine system within labeling in effect at the time the study was conducted (intrauterine contraception for parous women), the system may represent an appropriate option for women with heavy menstrual bleeding who are nulliparous or who do not require contraception. The levonorgestrel-releasing intrauterine system is effective at reducing menstrual blood loss because the constant release of levonorgestrel directly into the uterine cavity suppresses the endometrium, resulting in reduced uterine bleeding. The levonorgestrel-releasing intrauterine system is currently approved for the treatment of heavy menstrual bleeding in the majority of the countries where it is approved for contraception. In October 2009, the Food and Drug Administration approved the new indication for the levonorgestrel-releasing intrauterine system in the treatment of heavy menstrual bleeding for women who choose to use intrauterine contraception as their method of contraception.27
Oral tranexamic acid, an inhibitor of fibrinolysis used in many countries outside of the United States, was also approved by the Food and Drug Administration in late 2009.28 Although tranexamic acid was not used as a comparator in our study, a randomized study conducted by Milsom et al13 showed that the reduction in menstrual blood loss achieved by the levonorgestrel-releasing intrauterine system (81.6% after 3 months) was significantly greater than that seen with tranexamic acid (44.4%). Moreover, the levonorgestrel-releasing intrauterine system was the only form of treatment to reduce mean menstrual blood loss to less than 80 mL.
Most of the adverse events reported during our study were mild to moderate in intensity in both groups. These results confirm that the levonorgestrel-releasing intrauterine system and oral medroxyprogesterone acetate have favorable safety profiles and are well-tolerated in women with heavy menstrual bleeding.
We used a rigorous research definition of heavy bleeding to demonstrate the effect of these treatments among a group of women with severe symptoms. The high proportion of women who underwent the screening phase of our study and had an assessment of baseline menstrual blood loss but did not have blood loss of 80 mL or more (approximately 50%) suggests that many women without organic pathology who perceive their bleeding to be heavy do not meet the threshold required to have heavy menstrual bleeding objectively diagnosed, which is consistent with other studies.14,29 The National Institute of Clinical Excellence in the United Kingdom defines heavy menstrual bleeding as “excessive menstrual blood loss that interferes with the woman's physical, emotional, social, and material quality of life, and that can occur alone or in combination with other symptoms.”3 This definition focuses on the impact that heavy menstrual bleeding has on daily life rather than on volume of menstrual blood loss. In this respect, the levonorgestrel-releasing intrauterine system has been shown to improve health-related quality of life to a similar extent as endometrial ablation or hysterectomy.19,21,22
In conclusion, among women with documented idiopathic heavy menstrual bleeding, the levonorgestrel-releasing intrauterine system results in a greater reduction in menstrual blood loss and a higher likelihood of treatment success than treatment with oral medroxyprogesterone acetate. This trial adds to a substantial body of evidence demonstrating the utility of the levonorgestrel-releasing intrauterine system in the treatment of heavy menstrual bleeding.
1. Wu JM, Wechter ME, Geller EJ, Nguyen TV, Visco AG. Hysterectomy rates in the United States, 2003. Obstet Gynecol 2007;110:1091–5.
2. Whiteman MK, Hillis SD, Jamieson DJ, Morrow B, Podgornik MN, Brett KM, et al. Inpatient hysterectomy surveillance in the United States, 2000–2004. Am J Obstet Gynecol 2008;198:34 e1–7.
4. Cote I, Jacobs P, Cumming D. Work loss associated with increased menstrual loss in the United States. Obstet Gynecol 2002;100:683–7.
5. Nieboer TE, Johnson N, Barlow D, Lethaby A, Tavender E, Curr E, et al. Surgical approach to hysterectomy for benign gynaecological disease. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD003677.
6. National Health Committee New Zealand Working Party. Guidelines for the management of heavy menstrual bleeding. Wellington: National Health Committee New Zealand; 1998. Available at: www.nzgg.org.nz/guidelines/0032/HMB_fulltext.pdf
. Retrieved April 28, 2009.
7. McCausland AM, McCausland VM. Long-term complications of endometrial ablation: cause, diagnosis, treatment, and prevention. J Minim Invasive Gynecol 2007;14:399–406.
8. Zarek S, Sharp HT. Global endometrial ablation devices. Clin Obstet Gynecol 2008;51:167–75.
9. Kucuk T, Ertan K. Continuous oral or intramuscular medroxyprogesterone acetate versus the levonorgestrel releasing intrauterine system in the treatment of perimenopausal menorrhagia: a randomized, prospective, controlled clinical trial in female smokers. Clin Exp Obstet Gynecol 2008;35:57–60.
10. Hallberg L, Nilsson L. Determination of menstrual blood loss. Scand J Clin Lab Invest 1964;16:244–8.
11. Fraser IS. Treatment of ovulatory and anovulatory dysfunctional uterine bleeding with oral progestogens. Aust N Z J Obstet Gynaecol 1990;30:353–6.
12. Dunphy BC, Goerzen J, Greene CA, de la Ronde S, Seidel J, Ingelson B. A double-blind randomised study comparing danazol and medroxyprogesterone acetate in the management of menorrhagia. J Obstet Gynaecol 1998;18:553–5.
13. Milsom I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am J Obstet Gynecol 1991;164:879–83.
14. Reid PC, Virtanen-Kari S. Randomised comparative trial of the levonorgestrel intrauterine system and mefenamic acid for the treatment of idiopathic menorrhagia: a multiple analysis using total menstrual fluid loss, menstrual blood loss and pictorial blood loss assessment charts. BJOG 2005;112:1121–5.
15. Kriplani A, Kulshrestha V, Agarwal N, Diwakar S. Role of tranexamic acid in management of dysfunctional uterine bleeding in comparison with medroxyprogesterone acetate. J Obstet Gynaecol 2006;26:673–8.
16. Lethaby A, Irvine G, Cameron I. Cyclical progestogens for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD001016.
17. Endrikat J, Shapiro H, Lukkari-Lax E, Kunz M, Schmidt W, Fortier M. A Canadian, multicentre study comparing the efficacy of a levonorgestrel-releasing intrauterine system to an oral contraceptive in women with idiopathic menorrhagia. J Obstet Gynaecol Can 2009;31:340–7.
18. Irvine GA, Campbell-Brown MB, Lumsden MA, Heikkila A, Walker JJ, Cameron IT. Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia. Br J Obstet Gynaecol 1998;105:592–8.
19. Kaunitz AM, Meredith S, Inki P, Kubba A, Sanchez-Ramos L. Levonorgestrel-releasing intrauterine system and endometrial ablation in heavy menstrual bleeding: a systematic review and meta-analysis. Obstet Gynecol 2009;113:1104–16.
20. van Dongen H, van de Merwe AG, de Kroon CD, Jansen FW. The impact of alternative treatment for abnormal uterine bleeding on hysterectomy rates in a tertiary referral center. J Minim Invasive Gynecol 2009;16:47–51.
21. Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivela A, et al. Quality of life and cost-effectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial. Lancet 2001;357:273–7.
22. Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivela A, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 2004;291:1456–63.
23. Lo JS, Pickersgill A. Pregnancy after endometrial ablation: English literature review and case report. J Minim Invasive Gynecol 2006;13:88–91.
24. Monteiro I, Bahamondes L, Diaz J, Perrotti M, Petta C. Therapeutic use of levonorgestrel-releasing intrauterine system in women with menorrhagia: a pilot study(1). Contraception 2002;65:325–8.
25. Xiao B, Wu SC, Chong J, Zeng T, Han LH, Luukkainen T. Therapeutic effects of the levonorgestrel-releasing intrauterine system in the treatment of idiopathic menorrhagia. Fertil Steril 2003;79:963–9.
26. Blumenthal PD, Trussell J, Singh RH, Guo A, Borenstein J, Dubois RW, et al. Cost-effectiveness of treatments for dysfunctional uterine bleeding in women who need contraception. Contraception 2006;74:249–58.
© 2010 by The American College of Obstetricians and Gynecologists.
29. Higham JM, Shaw RW. Clinical associations with objective menstrual blood volume. Eur J Obstet Gynecol Reprod Biol 1999;82:73–6.