Levonorgestrel Intrauterine System: A First-Line Medical Treatment for Heavy Menstrual Bleeding

Abstract

Chronic heavy menstrual bleeding is a common gynecologic condition that causes significant health problems and negatively impacts a woman's quality of life. Surgical treatments should be reserved for women who have pelvic pathology and for those who fail medical therapy. The recent US FDA approval of the levonorgestrel-releasing intrauterine system as an indicated treatment for heavy menstrual bleeding in women who want to use intrauterine devices for birth control highlights the potential that this top tier contraceptive method offers as a first-line therapy for treatment of this problem in women of any reproductive age, without sacrificing their future fertility.

Keywords

heavy menstrual bleeding levonorgestrel-releasing intrauterine system menorrhagia

Heavy and prolonged menstrual bleeding exacts a toll on the health, productivity and quality of life of a significant proportion of women of reproductive age. It has been estimated that as many as 30% of women (objectively measured) experience excessive bleeding at some time in their reproductive lives [1]. Subjectively, a recent postal survey found that 30% of women reported having heavy blood loss and an additional 5% reported having very heavy blood loss [2]. Each year, 5% of women in the UK present to their General Practitioners with complaints of heavy menstrual bleeding (HMB) [3]. Women who suffer from excessive bleeding have been found to have substantially reduced income owing to lost days of work [4]. Excessive vaginal bleeding is responsible for nearly 500,000 endometrial ablations and up to 30% of hysterectomies in the USA each year [5].

There are very specific laboratory-based definitions of excessive menstrual blood loss. The menstrual effluent is collected onto standardized sanitary napkins and the hemoglobin is eluted from the dried pads. By measuring the patient's hemoglobin level, the quantity of the hemoglobin collected from the pads can be converted into an estimate of the volume of blood that the woman has lost. That estimate is an important predictor of the risk of anemia. Based on studies in the 1960s and early 1970s, only women who have a less than 80 ml blood loss per cycle are known to be able to maintain healthy serum hemoglobin levels. The impact that chronic heavy and prolonged menstrual blood loss can have on hematologic status is truly impressive and can even be life-threatening. In addition, it can significantly disturb a woman's functioning. Despite the introduction of a variety of very absorbent products for sanitary protection, women with excessive vaginal bleeding often find that their menstrual flow is uncontrollable and routinely stains their clothes, which causes social and professional embarrassment. Menstrual flow is comprised of blood, serous fluid and endometrial debris. Blood generally only comprises 30–50% of the total menstrual flow [6]. Some women lose up to 400 ml of blood per cycle; this translates into more than a liter of total fluid that must be contained and absorbed into products confined to a relatively small area – an almost impossible challenge.

It is notoriously difficult to determine if a patient has excessive blood loss from her history alone. Self-characterization of menstrual flow can be quite inaccurate. For example, 14% of women whose total blood loss was 20–40 ml described their menses as ‘heavy’. By contrast, 30% of women whose monthly blood loss exceeded 80 ml in one study described their losses as ‘light’ [7]. Asking women to report on the numbers of pads used introduces complications, such as variability in the absorption of different products as well as variability in the personal fastidiousness among different women. Attempts have been made to have women report on the surface area of each pad or tampon used that was stained with blood and to sketch in any areas involved with clots. These are the techniques commonly used in studies reporting a pictorial assessment of blood loss charting (PBAC) [8]. Unfortunately, it has been demonstrated that these techniques, although easier to implement, do not provide as accurate an estimate of blood loss as alkaline hematin elution techniques [9]. Classification of menstrual flow as normal, decreased or increased may be possible by weighing standardized pads, but that approach does not quantify actual blood loss [10]. Monitoring changes in serum hemoglobin can be suggestive of excessive blood loss, but it may be difficult to control for the impacts of diet and iron supplementation. In addition, by the time a significant change in hemoglobin level can be demonstrated, a woman will have already sustained a substantial loss of blood.

Fortunately, the problem can be simplified by assuming that if a woman complains of excessive blood loss, her loss is excessive for her. This is valid because it accounts for temporary heavy flows that can be quite distressing. The challenge at the other extreme of the bleeding continuum is to help women who have adapted to excessively heavy flows to recognize that they should not tolerate such extreme blood losses.

There are many different nonobstetrical causes of excessive blood loss. Local uterine causes include prostaglandin imbalances [11,12], elevated levels of fibrinolysis [13,14], adenomyosis, endometrial and endocervical polyps, endometrial infection, endometrial hyperplasia and uterine carcinoma. Anovulatory cycling can cause less frequent but prolonged and heavy bleeding owing to a thickened endometrium and dyssynchronous endometrial shedding. Bleeding disorders, such as von Willebrand's disease, other factor deficiencies, platelet deficiency (idiopathic thrombocytopenic purpura) and platelet aggregation disorders, can cause heavy and prolonged menstrual blood loss. The prevalence of HMB in women with von Willebrand's disease varies from 72 to 94% [15]. Systemic diseases, including thyroid disorders, renal insufficiency, hepatic disease, sepsis and certain hematologic cancers, can present with excessive blood loss, often in women with a limited ability to produce new red blood cells. Use of anticoagulants is an obvious cause of excessive menstrual blood loss, but chronic use of other drugs, such as the anticonvulsants phenytoin and phenobarbital, also increases menstrual blood loss by reducing hepatic production of vitamin K. Excessive use of NSAIDs may also lead to excessive bleeding.

Interestingly, 80% of women who are treated for HMB have no anatomic pathology [16]. Over a third of women undergoing hysterectomies for HMB have normal uteri [17]. In addition, many women with HMB desire to preserve their potential for fertility. Therefore, medical therapy should be the first-line treatment for the vast majority of women suffering from heavy and prolonged bleeding.

Overview of the market: medical therapies for heavy menstrual bleeding

Surprisingly, there are few officially approved medical treatments for heavy and prolonged menstrual bleeding. Until recently, the US FDA had only approved one drug – medroxyprogesterone acetate (MPA) – for the treatment of any type of abnormal uterine bleeding. MPA is approved for the treatment of “abnormal uterine bleeding owing to hormonal imbalance in the absence of organic causes, such as fibroids or uterine cancer” [101]. MPA is effective in the treatment of anovulatory cycling, but studies have shown that the cyclic use of progestins in women with ovulatory cycles may not be effective. For example, 5 mg of oral norethisterone taken two-times daily during the luteal phase (cycle days 15–25) resulted in no significant reduction in menstrual blood loss [18]. A Cochrane review, which was updated in 2008, concluded that luteal phase progestins offered no advantage over other medical therapies such as danazol, tranexamic acid, NSAIDs and the progestin-releasing intrauterine system (IUS) [19].

In the endometria of women with HMB, there are increased levels of plasminogen activators, the enzymes that cause fibrinolysis or dissolution of clots [20]. Tranexamic acid administered orally for the first 5 days of bleeding is associated with reduced levels of tissue plasminogen activator and plasmin activity in peripheral blood, in menstrual fluid and in the endometria [21]. Tranexamic acid has been used to treat HMB in many European countries for over 30 years and has been available over the counter in Sweden for more than a decade. A recent Cochrane review reported that baseline antifibrinolytic therapy resulted in a 40–50% reduction in mean blood loss [22]. The one study included in the Cochrane review, in which women were asked about their perceptions of improvement in bleeding, found that the objective improvement in bleeding observed with tranexamic action was not recognized subjectively by the users [23].

The concern that antifibrinolytic agents might be associated with an increased risk of venous thromboembolism (VTE; i.e., deep venous thrombosis and/or pulmonary embolism) initially tempered professional enthusiasm for this agent in the UK. The Royal College of Surgeons (RCS; London, UK) reported that tranexamic acid comprised less than 5% of the medical therapeutics given to women with heavy bleeding [24]. However, since then, a long-term study from Sweden demonstrated no increased risk of thrombosis among women using tranexamic acid compared with the general population [25]. Subsequent studies have shown that, in Britain, the rate of antifibrinolytic prescriptions rose to over 50% when education was provided regarding the safety of the products [26]. Interestingly, a case-controlled study in 2008 found a statistically nonsignificant increase in VTE with tranexamic acid and NSAIDs; the investigators suggested that the conditions of menorrhagia and anemia themselves may predispose to thrombosis [27].

In November 2009, the FDA approved a sustained-release formulation of tranexamic acid in which two tablets (each containing 650 mg tranexamic acid) are taken three-times daily for up to 5 days during monthly menstruation. In clinical trials, the 3900 mg/day dosing schedule reduced mean blood loss by 39% and significantly reduced the limitations imposed by bleeding on social, leisure and physical activities compared with placebo. Response to therapy was noted to be immediate and substantial. However, no statistically significant treatment difference was observed in reductions in the number of larger stains [102]. Reflecting older concerns regarding potential VTE risk, US product labeling also contained the following wording: “Concomitant therapy with hormonal contraceptives may further increase the risk of blood clots, stroke, or myocardial infarction”, and stated that the use of these agents together is only recommended in the case of “strong medical need and the benefit of treatment will outweigh the potential increased risk” [102]. It is hoped that clinicians will realize that this warning only applies to estrogen-containing hormonal contraception.

Many other agents are commonly used off-label to treat HMB, including NSAIDs, prolonged oral progestin therapy, depo MPA acetate and combined hormonal contraceptives. Interestingly, until recently there had only been one report of the efficacy of modern, low-dose oral contraceptive pills in the treatment of HMB. Use of a levonorgestrel (LNG) pill with 30 μg ethinyl estradiol reduced menstrual blood loss by 43% compared with the 35% reduction observed with mefenamic acid [28]. Extended cycle use of combined hormonal contraceptives is often recommended to reduce blood loss [29], but this is not an approved treatment indication.

Nonsteroidal anti-inflammatory agents are thought to be effective because prostaglandins have been implicated in the pathogenesis of HMB. The endometria of women with HMB contain high levels of prosta glandins E₂ and F_2α compared with those found in women with normal menses [30]. The ratio of vasodilating E₂: vasoconstricting F_2α is elevated [14], as is the ratio of prostaglandin I₂:thromboxane [31]. NSAIDs reduce prostaglandin levels by inhibiting cyclooxygenase. The most recent Cochrane review of NSAIDs in the treatment of HMB found that, compared with placebo, mean menstrual blood loss was significantly reduced with high-dose, but not low-dose, NSAIDs [16]. NSAIDs used included mefenamic acid, naproxen, ibuprofen, flurbiprofen, meclofenamic acid, diclofenac and indomethacin. No differences in clinical efficacy were observed among the different NSAIDs, but there may be differences in the individual responses to different formulations [16]. A persistent reduction in blood loss of 25–35% was observed in one 16-month trial of high-dose NSAIDs administered with each menses [32]. NSAIDs also offer relief from associated menstrual cramping pain and from nausea, vomiting and headache induced by prostaglandin release.

Levonorgestrel-releasing intrauterine system as treatment for heavy menstrual bleeding

The LNG-releasing IUS (LNG-IUS) has been approved in 120 countries worldwide for contraception and in 115 countries (including, most recently, the USA) for a second indication – the treatment of HMB.

The LNG-IUS is composed of a T-shaped plastic frame measuring 32 mm in either direction. The arms are flexible and fold for placement inside a tubing to allow placement of the LNG-IUS. A cylinder containing 52 mg of LNG mixed with polydimethylsiloxane is wrapped around the vertical stem of the device. The cylinder is covered by a polydimethylsiloxane membrane that controls the rate of release of LNG from the device. Initial release rates of LNG are 20 μg/day and by the end of the approved 5-year life, the LNG release rate is 11 μg/day [103]. The mean LNG release rate over the 5 years is 14 μg/day. Barium sulfate is infused into the frame to make the IUS visible on x-ray. Attached at the base of the vertical stem are two threads, which are trimmed after IUS placement and remain available at the top of the vagina to confirm the ongoing presence of the IUS during use and to facilitate its ultimate removal.

Levonorgestrel concentrations in the intrauterine cavity are very high. Tissue that was biopsied approximately 1 month after placement of a higher dose LNG-IUS (one with a release rate 50% higher than the model used in the USA) yielded endometrial concentrations of 470–1500 ng/g of the tissue weight; much lower levels were found in the myometrium and fallopian tubes (1.8–2.4 ng/g of tissue weight) [33]. LNG is rapidly absorbed into the capillary network in and below the basal endometrium. LNG has been detected in the serum within 15 min of LNG-IUS placement. Peak levels occur within a few hours, but initial serum steady-state levels of 150–200 pg/ml are achieved within weeks. These levels decline slowly over 5 years [34]. Interestingly, in a small cohort of women who continued with the same unit for 102 months, the serum levels were again halved to 119 ± 9 pg/ml by the end of the study period, although the authors did not recommend maintaining the same device for long after its approved lifespan [35]. For comparison, the serum levels of LNG of the LNG implants system average 400 pg/ml during the first several months of use. By the end of 5 years, the levels dropped to 250–270 pg/ml. The LNG-IUS system produces serum levels of progestin that are approaching 50% of those seen with the previously lowest dose hormone system [36,37].

The locally high concentration of LNG induces a profound thickening of the cervical mucus, which blocks sperm penetration [38] and results in a first year Pearl Index of 0.1–0.2% and a 5-year cumulative pregnancy rate of 0.5–1.5% [39,40]. This is very comparable to the failure rates of many techniques for female sterilization [41]. The effectiveness of the LNG-IUS, combined with its convenience and its reasonable continuation rates, places the LNG-IUS in the top tier of contraceptive options. Only intrauterine devices (IUDs) with more than 250 mm² of copper and contraceptive implants have demonstrated similar pregnancy protection in clinical trials and in typical use [42].

There are very few medical contraindications to use of the LNG-IUS [104]. The contraindications fall into the following main groups: uterine malformations, infections, existing carcinoma and contraindications to progestin. The uterine cavity must sound to a depth of 6–10 cm and the endometrial cavity cannot be so distorted by large fibroids or septa that placement of the LNG-IUS at the fundus would be impaired. Local infection in the woman's cervix or uterus is a temporary contraindication; placement should be delayed until treatment of the infection is successful. Carcinoma of the cervix or the uterus is a contraindication because definitive therapy would involve hysterectomy or radiation therapy, which will remove the woman's need for contraception. Current or recent breast cancer (within 5 years) is the only absolute contraindication related to the progestin therapy. Virtually every other woman, including nulliparous women, can be considered a candidate for LNG-IUS use [43,104].

The endometrial effects of the LNG-IUS are complex and have only been partially elucidated [44,45]. Just as with other IUDs, the LNG-IUS frame itself induces stromal inflammatory cell infiltrate and surface papillary formations [46]. What distinguishes the LNG-IUS from other IUDs is the impact of LNG. Estrogen and progesterone receptors in the endometrium are downregulated by high intracavity concentrations of LNG. The LNG induces atrophy of the endometrial glands and stoma, and decidualization of the stoma. This progestin also induces changes in the growth factors, cytokines, matrix remodeling enzymes (e.g., matrix metallo-proteinases) and morphology of the endometrial vasculature. Collectively, these endometrial effects account for the bleeding changes observed with the LNG-IUS.

In the Phase III trials of the LNG-IUS for contraceptive efficacy, it was noted that among the normally cycling subjects, there was initially a significant increase in the number of days of unscheduled spotting and bleeding. However, the number of days of such bleeding rapidly diminished, so that by 4 months of use, the median total number of days of spotting and bleeding approximately matched the number of days of bleeding that the women had at baseline. By 12 months, 20% of women had no spotting or bleeding [47]. Interestingly, nearly 50% of women perceived that they had amenorrhea by that time, since they often failed to notice light bleeding [48,49]. The percentage of women with objective amenorrhea grew to 40% by 24 months and 50% by 5 years [50].

This early experience prompted many investigators to study the LNG-IUS as a treatment for heavy and prolonged menstrual bleeding. In one of the early trials, Andersson and Rybo monitored monthly menstrual blood loss in 20 women who reported excessive bleeding [51]. At baseline, blood loss in these women ranged from 81 to nearly 400 ml with a median of 176 cc/cycle. After 3 months of LNG-IUS placement, only one woman still had excessive bleeding and her bleeding had normalized by 12 months. By 3 months, collective blood loss was reduced by 86% and by 12 months the reduction was 97% [51]. Five other studies, which investigated the effects of the LNG-IUS in treating women with HMB, reported reductions in blood loss ranging from 85 to 97% for up to 5 years of use [52]. There were significant increases in both hemoglobin [53 –55] and ferritin levels, which paralleled these improved bleeding patterns. In a comparative trial, Milsom et al. found that by 12 months, a nonsteroidal anti-inflammatory agent (flurbiprofen) reduced blood loss by 21%, tranexamic acid reduced blood loss by 44% and LNG-IUS users had a 96% reduction in blood loss [56]. In women with known coagulation disorders, the LNG-IUS has been found to be effective in reducing excessive menstrual bleeding. In one study of 16 women with inherited bleeding disorders, causing complaints of heavy bleeding that significantly affected their lives at least 1 day per cycle, the women were treated with the LNG-IUS. By 3 months, every woman reported improvement in her menses and by 9 months, nine of the 16 women had amenorrhea [57]. An international panel of experts evaluated the diagnosis and management of bleeding disorders in women, and endorsed the use of the LNG-IUS as first-line therapy in the management of bleeding in women who are not currently seeking pregnancies whether or not they desire to preserve future fertility [15]. The 2008 National Heart, Lung and Blood Institute (NHLBI) guidelines listed the LNG-IUS as a second choice for the treatment of HMB in women with von Willebrand disease, while combined hormone contraceptives were listed as the first choice [58]. Among women who suffer HMB associated with endometriosis, several studies have demonstrated that the LNG-IUS not only reduces their dysmenorrhea, but importantly, it also reduces their menstrual blood loss [59]. The LNG-IUS provided relief from menstrual problems for 85% of adolescents with a medical disorder or physical or learning disabilities [60].

The NICE in England and Wales recommends the LNG-IUS as first-line drug treatment for HMB, providing that the woman has no obvious problem with her uterus and that she plans to delay childbearing for at least 12 months [105]. Since that recommendation was made, even more evidence has been obtained that supports this conclusion.

In the Phase III clinical trials conducted to obtain FDA approval of the LNG-IUS for the treatment of idiopathic HMB, the impacts of the LNG-IUS were compared with those of cyclic MPA. MPA was selected as a comparator medication because, at the time, it was the only FDA-approved treatment for abnormal uterine bleeding. The study randomized 79 women to receive LNG-IUS and 81 women to receive cyclic MPA 10 mg administered orally on cycle days 16–25. In order to be randomized into the study, potential subjects first had to demonstrate HMB at baseline. This was defined as at least 80 ml of blood loss in each of two consecutive cycles. The bleeding had to be idiopathic; all known causes of bleeding had to be excluded (except small fibroids, with a total volume not greater than 5 ml) [61].

Standardized sanitary napkins were used by all study participants and the blood loss was analyzed using a modified alkaline hematin technique in a central laboratory. Median blood loss in each arm was approximately 150 ml per cycle. The response to the LNG-IUS was rapid and impressive. By the end of the 3 months, the LNG-IUS users experienced a reduction to 30 ml in blood loss, while those using cyclic MPA achieved a reduction to 136 ml. The effectiveness of each therapy continued to increase over time. By the close of the study at 6 months, the median menstrual blood loss in women using the LNG-IUS was only 7 ml, whereas in women using MPA it was 121 ml (p < 0.0001) [61,103].

For this trial, the FDA required that two conditions be met before a woman could be deemed as having been ‘successfully treated’. The first condition was that her blood loss had to be reduced by at least 50%; the second condition was that the woman's blood loss while on treatment had to be normalized (i.e., <80 ml/month). This combination of end points was fairly stringent. For example, if a woman whose baseline monthly blood loss was 210 ml experienced a 61% reduction in blood loss on treatment, she would not be counted as a success, because during treatment, her blood loss was 81.9 ml (>80 ml/month). Even in the face of this stringent definition, 85% of the LNG-IUS users were successfully treated compared with only 22% of the MPA subjects (p < 0.001). On the strength of these data, the LNG-IUS received FDA approval in late 2009 for the treatment of idiopathic HMB in women who desire to use an IUD for contraception [106].

In a smaller 12-month prospective, randomized, open-label study involving 39 Canadian women over 30 years of age who had idiopathic HMB (>80 ml/cycle), blood loss was estimated using a pictorial blood loss assessment (baseline PBAC score of 100, which is equivalent to 80 ml blood loss). Eligible women were randomized to the LNG-IUS or to an oral contraceptive pill, which contained 1 mg norethindrone acetate and 20 μg ethinyl estradiol. In both groups, the PBAC score had dropped dramatically by 12 months. However, the decrease in PBAC scores with the LNG-IUS was significantly greater (83%) than the decrease observed with oral contraceptive use (68%); (p > 0.002) [62].

Endometrial ablation is being used with increasing frequency to treat HMB, especially in the USA, where approximately 500,000 procedures were performed in 2008 alone. In a 2006 Cochrane review comparing LNG-IUS with surgical interventions, Marjoribanks et al. concluded:

“If bleeding is causing major problems, treatment options included surgery (either hysterectomy or surgery to reduce the lining of the uterus) or a device inserted into the uterus that releases hormones (LNG-IUS). The review of trials found that an LNG-IUS improves the quality of life of women with menorrhagia as effectively as surgical treatment, while a minority of women prefer long-term oral medication. Though all these treatments have potential side effects, hysterectomy is more likely to cause serious complications” [63].

More recently, Kaunitz et al. published a systematic review of randomized clinical trials comparing ablation with LNG-IUS in the treatment of women with HMB who were evaluated using PBAC scores [64]. Six studies met the inclusion criteria; three compared the first-generation ablation techniques with the LNG-IUS and three compared the second-generation ablation tools with the LNG-IUS. The results were impressive. By 6 months, the LNG-IUS reduced blood loss by as much as ablation. The similarity in blood loss reductions persisted at 12 and 24 months. There was no difference when the LNG-IUS was compared with each generation of ablation techniques separately. Overall, failure rates for bleeding control were similar in both groups; the LNG-IUS failure rate was 21.2% versus the 17.9% failure rate with ablation. Although there have been difficulties in developing meaningful instruments to measure quality of life in studies of menorrhagia [65], both methods were reported to have resulted in similar improvements in quality of life [64]. However, there were two important differences between the two treatments. LNG-IUS users had less need for an analgesic/anesthesia and they did not need a separate procedure or device to provide effective contraception. Because ablation destroys much of the endometrium, pregnancy postablation can result in serious placental problems, such as placenta percreta, higher spontaneous abortion rates and intrauterine growth retardation [66 –68]. Therefore, ablation should be restricted to women who desire no future pregnancy and to those who will use an effective method of birth control consistently and correctly until menopause. The LNG-IUS provides both contraception that is as effective as sterilization and effective treatment for HMB. It can be used by women who may want to preserve their fertility as well as by those who have completed their families.

Another important issue is that women whose HMB is caused by adenomyosis are more likely to fail treatment with endometrial ablation than women with other causes for their excessive blood loss [69]. When the LNG-IUS was used to treat women with adenomyosis, it caused a significant decrease in blood loss by 6 months that persisted for 2 years [70]. Small-scale studies have found that the LNG-IUS may be helpful with the treatment of heavy uterine bleeding owing to small- or medium-size uterine leiomyoma [71,72], although the size of the fibroids is not changed [73]. Other studies have not confirmed the reduction in blood loss with fibroids [74].

Hysterectomy has long been the definitive treatment for women with HMB. However, it is a surgical treatment that carries with it risks of anesthetic complications, infection and blood loss, as well as other risks. One early trial studied 56 women aged 33–49 years who were scheduled to have hysterectomies to treat their excessive bleeding, and randomized them to either the LNG-IUS or to continue their current medical therapies. At 6 months, 64.3% of the LNG-IUS users cancelled their surgeries compared with 14.3% of the women who received other medical therapies [54]. In a more definitive trial, 236 women aged 35–49 years who had HMB owing to benign causes were randomized to either hysterectomy or the LNG-IUS [75]. In 5 years of follow-up, the LNG-IUS users had similar scores on health-related quality-of-life tests. Importantly, 58% of the women in the LNG-IUS group avoided hysterectomy; only 42% of the LNG-IUS users underwent hysterectomies during the 5 years of follow-up. For those 42% of women, the cost of the LNG-IUS was not ultimately justified, but the success of the other 58% of the LNG-IUS users reduced the overall costs, so the discounted indirect and direct costs for the treatment of women in the LNG-IUS arm over 5 years was significantly lower (US$2817 [95% CI: US$2222–3530]) than the cost of taking all women to hysterectomy (US$4660 [95% CI: US$4014–5180]) [75]. In one study, sexual functioning and quality-of-life indicators were superior for women who underwent surgery compared with those with a LNG-IUS [76]. In a second study, sexual satisfaction increased and sexual problems decreased with hysterectomies, while among LNG-IUS users, satisfaction with partners declined [77].

Reassuring data regarding long-term efficacy of the LNG-IUS has recently been presented. In a group of women who had their first LNG-IUS removed at 5 years and replaced with a second LNG-IUS, there were no reports of repetition of the initial disrupted bleeding patterns. Virtually all women who had achieved amenorrhea with their first IUS experienced continued amenorrhea with the second device. Those who had spotting with the first LNG-IUS experienced reduced spotting with the second device [78].

While hysterectomy remains a definitive treatment, it is more often becoming the treatment of last resort for women without significant pelvic pathology. Since the introduction of conservative surgical alternatives (endometrial ablation and possibly uterine artery embolization) and the LNG-IUS, the numbers of hysterectomies carried out in the UK have decreased [79].

Conclusion

The LNG-IUS is one of the most effective methods of birth control and is the most effective medical therapy for idiopathic HMB. The LNG-IUS provides blood loss reduction and improvements in quality of life that rival the long-term successes of endometrial ablation. The LNG-IUS achieves this comparable efficiency without the need for an analgesic/anesthesia, and without the need to use a separate method of birth control, avoiding the potentially serious placentation problems seen with ablation. The LNG-IUS can be used by women of all ages and by women who desire future fertility as well as by those who have completed their families. The LNG-IUS is considerably more cost–effective than hysterectomy as a first-line therapy for HMB. Hysterectomy should be reserved for women with serious pelvic pathology and for those who fail medical treatment.

Future perspective

Heavy menstrual bleeding is a very frequent and serious medical problem for women of reproductive age; there is a need for a variety of both hormonal and nonhormonal medical therapies. Now that the FDA has approved the use of the LNG-IUS as a treatment for HMB in women who desire to use an IUD for contraception, utilization of this effective, convenient and cost-effective method should continue to increase. Although the LNG-IUS has been demonstrated to be quite acceptable for nulliparous women, a smaller version with lower doses of LNG and a shorter lifespan has been developed and is being tested. This targeted product should remove the last vestiges of concerns regarding the appropriateness of IUD use by women who have not yet proven their fertility. The FDA is now evaluating a new birth-control pill containing estradiol valerate and dienogest [80], which has also been found to be an effective treatment for HMB. Should these products all receive FDA approval, women in the USA would have a choice of several new medical treatments for HMB; a sustained-release tranexamic acid product, a daily birth-control pill and two different versions of the LNG-IUS tailored to the size of the woman's uterus. This variety of hormonal and nonhormonal therapies will help prevent many unnecessary surgical procedures.

The growing problem of obesity will make the use of estrogen-containing contraceptives less popular for other women of reproductive age owing to concerns regarding thromboembolism. At the same time, those women are more likely to have anovulatory cycling, increasing their risks for both HMB and endometrial hyperplasia. The role of the LNG-IUS as a preventative agent should increase and it also may have an important role in the treatment of endometrial hyperplasia.

Executive summary

The levonorgestrel-releasing intrauterine system (LNG-IUS) provides top tier contraceptive efficacy as one of the few ‘forgettable contraceptives’.

Medical contraindications to LNG-IUS use have decreased over time and in nonpregnant women are limited to acute infection, uterine distortion, gynecologic carcinoma or recent breast cancer. The contraindications and warning sections in product labeling were not changed by the addition of the treatment of heavy menstrual bleeding as a serious indication by the US FDA.

The LNG-IUS is more effective than every other medical treatment that has been approved by health authorities, including tranexamic acid and cyclic progestin, as well as those products that are used to treat the problem off-label, such as nonsteroidal anti-inflammatory agents, danazol, birth-control pills and daily progestin.

Compared with conservative surgical treatments, such as endometrial ablation, the LNG-IUS has a similar efficacy but is able to be used as a standalone treatment by women who desire future fertility as well as by those who have completed their families.

Long-term use of consecutive LNG-IUS has been shown to be well accepted. Introduction of the second intrauterine device continues or improves the bleeding pattern achieved by the woman by the end of her first LNG-IUS.

The LNG-IUS is more cost effective than hysterectomy as a first-line therapy for the treatment of heavy menstrual bleeding in women without significant pelvic pathology.

Footnotes

Anita L Nelson has received research grants from Bayer Health Care Pharmaceuticals and Teva Pharmaceutical Industries, Ltd. She is on the Speakers Bureau (receives honoraria) for Bayer and Teva. She serves on the advisory boards (receives honoraria) for Bayer, Teva and Xanodyne Pharmaceuticals, Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

of interest

Rees

: Role of menstrual blood loss measurements in management of complaints of excessive menstrual bleeding. Br. J. Obstet. Gynaecol. 98(3), 327–328 (1991).

Santer

Warner

Wyke

: A Scottish postal survey suggested that the prevailing clinical preoccupation with heavy periods does not reflect the epidemiology of reported symptoms and problems. J. Clin. Epidemiol. 58(11), 1206–1210 (2005).

Vessey

Villard-Mackintosh

McPherson

Coulter

Yeates

: The epidemiology of hysterectomy: findings in a large cohort study. Br. J. Obstet. Gynaecol. 99(5), 402–407 (1992).

Côté

Jacobs

Cumming

: Work loss associated with increased menstrual loss in the United States. Obstet. Gynecol. 100(4), 683–687 (2002).

Farquhar

Steiner

: Hysterectomy rates in the United States 1990–1997. Obstet. Gynecol. 99(2), 229–234 (2002).

Fraser

Warner

Marantos

: Estimating menstrual blood loss in women with normal and excessive menstrual fluid volume. Obstet. Gynecol. 98(5 Part 1), 806–814 (2001).

Chimbira

Anderson

Turnbull

: Relation between measured menstrual blood loss and patient's subjective assessment of loss, duration of bleeding, number of sanitary towels used, uterine weight and endometrial surface area. Br. J. Obstet. Gynaecol. 87(7), 603–609 (1980).

10.

Higham

O'Brien

Shaw

: Assessment of menstrual blood loss using a pictorial chart. Br. J. Obstet. Gynaecol. 97(8), 734–739 (1990).

11.

Reid

Virtanen-Kari

: 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 112(8), 1121–1125 (2005).

12.

Gudmundsdottir

Hjaltalin

Bragadottir

Hauksson

Geirsson

Onundarson

: Quantification of menstrual flow by weighing protective pads in women with normal, decreased or increased menstruation. Acta Obstet. Gynecol. Scand. 88(3), 275–279 (2009).

13.

Willman

Collins

Clayton

: Studies in the involvement of prostaglandins in uterine symptomatology and pathology. Br. J. Obstet. Gynaecol. 83(5), 337–341 (1976).

14.

Smith

Abel

Kelly

Baird

: Prostaglandin synthesis in the endometrium of women with ovular dysfunctional uterine bleeding. Br. J. Obstet. Gynaecol. 88(4), 434–442 (1981).

15.

Dockeray

Sheppard

Daly

Bonnar

: The fibrinolytic enzyme system in normal menstruation and excessive uterine bleeding and the effect of tranexamic acid. Eur. J. Obstet. Gynecol. Reprod. Biol. 24(4), 309–318 (1987).

16.

Edlund

Blombäck

: On the correlation between local fibrinolytic activity in menstrual fluid and total blood loss during menstruation and effects of desmopressin. Blood Coagul. Fibrinolysis 14(6), 593–598 (2003).

17.

James

Kouides

Abdul-Kadir

: Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel. Am. J. Obstet. Gynecol. 201(1), 12. E1–E8 (2009).

18.

Lethaby

Augood

Duckitt

Farquhar

: Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst. Rev. 17(4), CD000400 (2007).

19.

Important and comprehensive analysis of the efficacy and safety of nonsteroidal anti-inflammatory agents in the treatment of heavy menstrual bleeding.

20.

Clarke

Black

Rowe

Mott

Howle

: Indications for and outcome of total abdominal hysterectomy for benign disease: a prospective cohort study. Br. J. Obstet. Gynaecol. 102(8), 611–620 (1995).

21.

Cameron

Leask

Kelly

Baird

: The effects of danazol, mefenamic acid, norethisterone and a progesterone-impregnated coil on endometrial prostaglandin concentrations in women with menorrhagia. Prostaglandins 34(1), 99–110 (1987).

22.

Lethaby

Irvine

Cameron

: Cyclical progestogens for heavy menstrual bleeding. Cochrane Database Syst. Rev. 23(1), CD001016 (2008).

23.

Gleeson

: Cyclic changes in endometrial tissue plasminogen activator and plasminogen activator inhibitor type 1 in women with normal menstruation and essential menorrhagia. Am. J. Obstet. Gynecol. 171(1), 178–183 (1994).

24.

Fraser

Porte

Kouides

Lukes

: A benefit-risk review of systemic haemostatic agents: part 2: in excessive or heavy menstrual bleeding. Drug Saf. 31(4), 275–282 (2008).

25.

Lethaby

Farquhar

Cooke

: Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst. Rev. (4), CD000249 (2009).

26.

Edlund

Andersson

Rybo

Lindoff

Astedt

von Schoultz

: Reduction of menstrual blood loss in women suffering from idiopathic menorrhagia with a novel antifibrinolytic drug (Kabi 2161). Br. J. Obstet. Gynaecol. 102(11), 913–917 (1995).

27.

NHS Centre for Reviews and Dissemination: Management of menorrhagia. Eff. Health Care 1(9) (1995).

28.

Berntorp

Follrud

Lethagen

: No increased risk of venous thrombosis in women taking tranexamic acid. Thromb. Haemost. 86(2), 714–715 (2001).

29.

Fender

Prentice

Gorst

: Randomised controlled trial of educational package on management of menorrhagia in primary care: the Anglia menorrhagia education study. BMJ 318(7193), 1246–1250 (1999).

30.

Sundström

Seaman

Kieler

Alfredsson

: The risk of venous thromboembolism associated with the use of tranexamic acid and other drugs used to treat menorrhagia: a case-control study using the General Practice Research Database. BJOG 116(1), 91–97 (2009).

31.

Fraser

McCarron

: Randomized trial of 2 hormonal and 2 prostaglandin-inhibiting agents in women with a complaint of menorrhagia. Aust. NZ J. Obstet. Gynaecol. 31(1), 66–70 (1991).

32.

Archer

: Menstrual-cycle-related symptoms: a review of the rationale for continuous use of oral contraceptives. Contraception 74(5), 359–366 (2006).

33.

Willman

Collins

Clayton

: Studies in the involvement of prostaglandins in uterine symptomatology and pathology. Br. J. Obstet. Gynaecol. 83(5), 337–341 (1976).

34.

Mäkäräinen

Ylikorkala

: Primary and myoma-associated menorrhagia: role of prostaglandins and effects of ibuprofen. Br. J. Obstet. Gynaecol. 93(9), 974–978 (1986).

35.

Fraser

McCarron

Markham

Robinson

Smyth

: Long-term treatment of menorrhagia with mefenamic acid. Obstet. Gynecol. 61(1), 109–112 (1983).

36.

Nilsson

Haukkamaa

Vierola

Luukkainen

: Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD. Clin. Endocrinol. (Oxf.) 17(6), 529–536 (1982).

37.

Luukkainen

Lähteenmäki

Toivonen

: Levonorgestrel-releasing intrauterine device. Ann. Med. 22(2), 85–90 (1990).

38.

Hidalgo

Hidalgo-Regina

Bahamondes

Monteiro

Petta

Bahamondes

: Serum levonorgestrel levels and endometrial thickness during extended use of the levonorgestrel-releasing intrauterine system. Contraception 80(1), 84–89 (2009).

39.

Sivin

: Risks and benefits, advantages and disadvantages of levonorgestrel-releasing contraceptive implants. Drug Saf. 26(5), 303–335 (2003).

40.

Backman

: Benefit-risk assessment of the levonorgestrel intrauterine system in contraception. Drug Saf. 27(15), 1185–1204 (2004).

41.

Lewis

Taylor

Natavio

Melamed

Sokol

Mishell

: Effects of the levonorgestrel intrauterine system (LNG-IUS) on cervical mucus quality and sperm penetration. Fertil. Steril. 92(3 Suppl.), S27 (2009).

42.

Andersson

Odlind

Rybo

: Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 49(1), 56–72 (1994).

43.

Sivin

el Mahgoub

McCarthy

: Long-term contraception with the levonorgestrel 20 mcg/day (LNg 20) and the copper T 380Ag intrauterine devices: a five-year randomized study. Contraception 42(4), 361–378. (1990). Erratum in: Contraception 43(1), 100 (1991).

44.

Peterson

Xia

Hughes

Wilcox

Tylor

Trussell

: The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization. Am. J. Obstet. Gynecol. (4), 1161–1168; discussion 1168–1170 (1996).

45.

Trussell

Hatcher

Nelson

Cates

Jr Stewart

: Contraceptive Technology (19th Edition). Ardent Media, NY, USA 32 (2007).

46.

Suhonen

Haukkamaa

Jakobsson

Rauramo

: Clinical performance of a levonorgestrel-releasing intrauterine system and oral contraceptives in young nulliparous women: a comparative study. Contraception 69(5), 407–412 (2004).

47.

Sitruk-Ware

Inki

: The levonorgestrel intrauterine system: long-term contraception and therapeutic effects. Womens Health (Lond. Engl.) 1(2), 171–182 (2005).

48.

Comprehensive review of the contraceptive and noncontraceptive health benefits of the levonorgestrel-releasing intrauterine system (LNG-IUS).

49.

Prager

Darney

: The levonorgestrel intrauterine system in nulliparous women. Contraception 75(6 Suppl.), S12–S15 (2007).

50.

Phillips

Graham

Manek

McCluggage

: The effects of the levonorgestrel intrauterine system (Mirena coil) on endometrial morphology. J. Clin. Pathol. 56(4), 305–307 (2003).

51.

Suvisaari

Lähteenmäki

: Detailed analysis of menstrual bleeding patterns after postmenstrual and postabortal insertion of a copper IUD or a levonorgestrel-releasing intrauterine system. Contraception 54(4), 201–208 (1996).

52.

Hidalgo

Bahamondes

Perrotti

: Bleeding patterns and clinical performance of the levonorgestrel-releasing intrauterine system (Mirena) up to two years. Contraception 65(2), 129–132 (2002).

53.

Baldaszti

Wimmer-Puchinger

Löschke

: Acceptability of the long-term contraceptive levonorgestrel-releasing intrauterine system (Mirena): a 3-year follow-up study. Contraception 67(2), 87–91 (2003).

54.

Cameron

: The levonorgestrel intrauterine system: the benefits of reduced bleeding. Eur. J. Contracept. Reprod. Health Care 6(Suppl. 1), 27–32 (2001).

55.

Andersson

Rybo

: Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br. J. Obstet. Gynaecol. 97(8), 690–694 (1990).

56.

Xiao

Chong

Zeng

Han

Luukkainen

: Therapeutic effects of the levonorgestrel-releasing intrauterine system in the treatment of idiopathic menorrhagia. Fertil. Steril. 79(4), 963–969 (2003).

57.

Tang

: Levonorgestrel intrauterine device in the treatment of menorrhagia in Chinese women: efficacy versus acceptability. Contraception 51(4), 231–235 (1995).

58.

Lähteenmäki

Haukkamaa

Puolakka

: Open randomised study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy. BMJ 316(7138), 1122–1126 (1998).

59.

Monteiro

Bahamondes

Diaz

Perrotti

Petta

: Therapeutic use of levonorgestrel-releasing intrauterine system in women with menorrhagia: a pilot study(1). Contraception 65(5), 325–328 (2002).

60.

Milsom

Andersson

Andersch

Rybo

: A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am. J. Obstet. Gynecol. 164(3), 879–883 (1991).

61.

Classic study investigating the comparative efficacies of the three medical treatments of heavy menstrual bleeding.

62.

Kingman

Kadir

Lee

Economides

: The use of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders. BJOG 111(12), 1425–1428 (2004).

63.

James

Manco-Johnson

Yawn

Dietrich

Nichols

: Von Willebrand disease: key points from the 2008 National Heart, Lung, and Blood Institute guidelines. Obstet. Gynecol. 114(3), 674–678 (2009).

64.

Lockhat

Emembolu

Konje

: The efficacy, side-effects and continuation rates in women with symptomatic endometriosis undergoing treatment with an intrauterine administered progestogen (levonorgestrel): a 3 year follow-up. Hum. Reprod. 20(3), 789–793 (2005).

65.

Pillai

O'Brien

Hill

: The levonorgestrel intrauterine system (Mirena) for the treatment of menstrual problems in adolescents with medical disorders, or physical or learning disabilities. BJOG 117(2), 216–221 (2010).

66.

Nelson

: Mirena® in idiopathic menorrahgia: first-line treatment based on comprehensive clinical data. Presented at: XIX FIGO World Congress of Gynecology and Obstetrics. Cape Town, South Africa, 4–9 October 2009.

67.

Endrikat

Shapiro

Lukkari-Lax

: 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. 31(4), 340–347 (2009).

68.

Marjoribanks

Lethaby

Farquhar

: Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst. Rev. (2), CD003855 (2006).

69.

Comprehensive analysis comparing the efficacy of LNG-IUS with endometrial ablation in the treatment of heavy menstrual bleeding.

70.

Kaunitz

Meredith

Inki

Kubba

Sanchez-Ramos

: Levonorgestrel-releasing intrauterine system and endometrial ablation in heavy menstrual bleeding: a systematic review and meta-analysis. Obstet. Gynecol. 113(5), 1104–1116 (2009).

71.

Clark

Khan

Foon

Pattison

Bryan

Gupta

: Quality of life instruments in studies of menorrhagia: a systematic review. Eur. J. Obstet. Gynecol. Reprod. Biol. 104(2), 96–104 (2002).

72.

Cook

Seman

: Pregnancy following endometrial ablation: case history and literature review. Obstet. Gynecol. Surv. 58(8), 551–556 (2003).

73.

Hare

Olah

: Pregnancy following endometrial ablation: a review article. J. Obstet. Gynaecol. 25(2), 108–114 (2005).

74.

Pickersgill

: Pregnancy after endometrial ablation: English literature review and case report. J. Minim. Invasive Gynecol. 13(2), 88–91 (2006).

75.

Maia

Jr Maltez

Coelho

Athayde

Coutinho

: Insertion of mirena after endometrial resection in patients with adenomyosis. J. Am. Assoc. Gynecol. Laparosc. 10(4), 512–516 (2003).

76.

Cho

Nam

Kim

: Clinical effects of the levonorgestrel-releasing intrauterine device in patients with adenomyosis. Am. J. Obstet. Gynecol. 198(4), 373.E1–E7 (2008).

77.

Grigorieva

Chen-Mok

Tarasova

Mikhailov

: Use of a levonorgestrel-releasing intrauterine system to treat bleeding related to uterine leiomyomas. Fertil. Steril. 79(5), 1194–1198 (2003).

78.

Mansour

: Modern management of abnormal uterine bleeding: the levonorgestrel intrauterine system. Best Pract. Res. Clin. Obstet. Gynaecol. 21(6), 1007–1021 (2007).

79.

Magalhães

Aldrighi

de Lima

: Uterine volume and menstrual patterns in users of the levonorgestrel-releasing intrauterine system with idiopathic menorrhagia or menorrhagia due to leiomyomas. Contraception 75(3), 193–198 (2007).

80.

Mercorio

De Simone

Di Spiezio Sardo

: The effect of a levonorgestrel-releasing intrauterine device in the treatment of myoma-related menorrhagia. Contraception 67(4), 277–280 (2003).

81.

Hurskainen

Teperi

Rissanen

: Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 291(12), 1456–1463 (2004).

82.

Excellent long-term study investigating the effectiveness of LNG-IUS in reducing the need for unnecessary hysterectomy for heavy menstrual bleeding.

83.

Kuppermann

Varner

Summitt

Jr : Ms Research Group: Effect of hysterectomy vs medical treatment on health-related quality of life and sexual functioning: the medicine or surgery (Ms) randomized trial. JAMA 291(12), 1447–1455 (2004).

84.

Halmesmäki

Hurskainen

Teperi

: The effect of hysterectomy or levonorgestrel-releasing intrauterine system on sexual functioning among women with menorrhagia: a 5-year randomised controlled trial. BJOG 114(5), 563–568 (2007).

85.

Gemzell-Danielsson

Inki

Boubli

O'Flynn

Kunz

Heikinheimo

: Bleeding pattern and safety of consecutive use of the levonorgestrel-releasing intrauterine system (LNG-IUS) – a multicentre prospective study. Hum. Reprod. 25(2), 354–359 (2010).

86.

Reid

Mukri

: Trends in number of hysterectomies performed in England for menorrhagia: examination of health episode statistics, 1989 to 2002–2003. BMJ 330(7497), 938–939 (2005).

87.

Endrikat

Parke

Trummer

Schmidt

Duijkers

Klipping

: Ovulation inhibition with four variations of a four-phasic estradiol valerate/dienogest combined oral contraceptive: results of two prospective, randomized, open-label studies. Contraception 78(3), 218–225 (2008).

88.

Patient information for Provera (medroxyprogesterone acetate tablets) www.media.pfizer.com/files/products/ppi_provera.pdf (Accessed 2 February 2010)

89.

Highlights of prescribing information for Lysteda (tranexamic acid) www.accessdata.fda.gov/drugsatfda_docs/label/2009/022430lbl.pdf (Accessed 20 January 2010)

90.

Mirena (levonorgestrel-releasing intrauterine system) July 2008; detailed view: safety labeling changes approved by the US FDA Center for Drug Evaluation and Research (CDER) www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm121936.htm (Accessed 21 January 2010)

91.

WHO medical eligibility criteria for contraceptive use, 2008 update http://apps.who.int/rhl/fertility/contraception/mec_update_2008.pdf (Accessed 21 January 2010)

92.

NICE: Heavy menstrual bleeding (2007) www.nice.org.uk/guidance/CG44 (Accessed 24 February 2010)

93.

US FDA news release: FDA approves additional use for IUD Mirena to treat heavy menstrual bleeding in IUD users www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm184747.htm (Accessed 22 February 2010)

94.

Varma

Sinha

Gupta

: Non-contraceptive uses of levonorgestrel-releasing hormone system (LNG-IUS) – a systematic enquiry and overview. Eur. J. Obstet. Gynecol. Reprod. Biol. 125(1), 9–28 (2006).

95.

Provides a comprehensive review of the many noncontraceptive therapeutic applications for the LNG-IUS, of which treatment of heavy menstrual bleeding is only one such application.