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Mirena

Gynecological Endocrinology, 31 July 2009

Mirena® - the discontinuing story

Dr. Ayman A. A. Ewies, MBChB, MSc, MRCOG, MD
Consultant Gynaecologist
Sandwell and West Birmingham Hospitals NHS Teaching Tru

Abstract:
Mirena® is licensed for use as a contraceptive, for the treatment of heavy menstrual bleeding and during estrogen replacement therapy. It is publicized as a local source of progestogen with minimal systemic adverse effects. However, there is overwhelming evidence of elevated serum and tissue levels of levonorgestrel, and high discontinuation and dissatisfaction rates amongst users. The guidelines of The National Institute for Health and Clinical Excellence (NICE), United Kingdom recommended that healthcare professionals should be aware that up to 60% of women discontinue using Mirena within 5 years due to unscheduled bleeding, pain and/or systemic progestogenic adverse effects. This article highlights these issues to healthcare professionals to ensure that the rate of adverse effects are not underestimated, and full information are made available to women to them making an informed choice.

Introduction:
Mirena ® (The Levonorgestrel-releasing Intrauterine System; LNG-IUS; Bayer Schering Pharma, Berkshire, UK) was first licensed for use in Finland in 1990 and it became very popular within a few years. The estimated number of users worldwide in year 2004 was more than 4 million in approximately 100 countries. It delivers levonorgestrel (LNG) 20 µg to the endometrium every 24h in a sustained fashion lasting up to 5 years (1). In most countries, it is licensed for use as a contraceptive, for the treatment of heavy menstrual bleeding (HMB) and for the prevention of endometrial hyperplasia during estrogen replacement therapy (ERT) (1,2).
Mirena is publicized as a local source of progestogen with minimal systemic adverse effects. The National Institute for Health and Clinical Excellence (NICE) guidelines, on HMB, recommended that Mirena should be the first line pharmaceutical treatment(3), and it is a common practice to encourage women to use Mirena first before offering any surgical treatment (3-5). The British National Formulary documented that Mirena produces mainly local effects with little systemic progestogenic activity (2). However, there is overwhelming evidence of high discontinuation and dissatisfaction rates amongst Mirena users. The NICE guidelines, on long-acting reversible contraception, recommended that healthcare professionals should be aware that up to 60% of women discontinue using Mirena within 5 years due to unscheduled bleeding, pain and/or systemic progestogenic adverse effects (6). The high discontinuation rate suggests that women are not given full information before insertion and/or healthcare professionals underestimate the rate of adverse effects.

High discontinuation and dissatisfaction rates:
There is growing evidence to suggest limited women’s satisfaction with Mirena due to high incidence of adverse effects leading to removal of the device before the 5 years effective life-time recommended by the manufacturer. Recent studies documented continuation rates of ≤50% after 4-5 years of using Mirena to treat HMB (1,4,7). The rate of the adverse effects varied between studies, but the most commonly reported were unscheduled bleeding (15%-71%) (1,7,8), progestogenic adverse effects (24%-61%) (1,7-12), and pelvi-abdominal pain (12%-40%) (8,9). The recorded progestogenic adverse effects were depression, mood changes, breast tenderness and swelling, weight gain, bloating, headache, acne, excessive hair growth, greasy skin and sexual disinterest. Similarly, we recently reported, in a survey of 212 women, who had Mirena inserted for HMB, that the discontinuation rate was 15%, 30%, 41%, 44%, 50% and 50% at 6 months, 1, 2, 3, 4 and 5 years, respectively. The median duration of use was 270 days (range 4-1460), and 50% of women only were satisfied with the device. In agreement with previous reports, the common reasons for early removal were unscheduled bleeding, progestogenic adverse effects and pelvic pain in 28%, 22%, and 13% of women, respectively (13).

Further, high discontinuation rates were also observed when Mirena was used for indications other than HMB. Lockhat et a l(9) reported a discontinuation rate of 32%, 38% and 44% at 1, 2, and 3 years, respectively when Mirena was used to treat endometriosis, and another study (n=678) reported discontinuation rates of 30%, 43%, 51%, and 56% and 60% at 1, 2, 3, 4, and 5 years, respectively when Mirena was used for contraception (14). In a research evaluating the efficacy of Mirena in 47 women with adenomyosis, only 32 (68%) completed the 3-year study. The mean uterine volume, pain scores and menstrual blood loss were significantly reduced in the first 2 years of use. Thereafter, there was a significant increase in these three parameters at the 36th month when compared with the values at the 12th month. Likewise, the uterine artery blood flow increased significantly 12 month after insertion, but started to decrease after 2 years when the uterine volume increased (15).

The largest Finnish survey, that included 17914 respondents who used Mirena for contraception, reported a 71% continuation rate and a 74% satisfaction rate after 5 years. Although this was higher than other studies, but the data could be biased because more than 70% of women in this survey used Mirena because of dissatisfaction with previous methods of contraception (8). Moreover, many studies in the literature that reported high continuation rates with Mirena were either of poor quality, included a small number of women or only reported data of short-term follow up (11,16).

High rate of progestogenic adverse effects:
It was claimed that Mirena provides a local effect with low constant systemic level of LNG instead of the fluctuating levels obtained with the daily progestogen only pill (POP), and the progestogenic adverse effects were limited to the first few months after insertion (2,17); rarely leading to early removal (8). It was also suggested that the low serum concentration of LNG in Mirena users had a weak effect on ovarian function (18), and 45% (19) to 85% (18) of menstrual cycles were found to be ovulatory after the first year of use.
Nonetheless, these reports were challenged by finding similar, or higher, serum levels of LNG in the users of Mirena and POP, and recounting high rates of progestogenic adverse effects leading to discontinuation before the 5 years life span recommended by the manufacturer (9,10,12,13,20). A multicentre 7-year randomized controlled trial (RCT, n=2246) comparing Mirena with copper TCu 380 Ag intrauterine contraceptive device (IUCD) found that women were 4 times more likely to discontinue Mirena because of progestogenic adverse effects and the incidence of headaches and acne were significantly higher in the Mirena group (12). Another European multicentre RCT, with 2758 women, reported that removal rate at 5 years was significantly higher in Mirena users when compared with Nova-T 200 IUCD users because of depression, acne, headaches and weight gain (10). Ilse et al. reported 5 women with new-onset acne 1-3 months after insertion of Mirena, and recommended that dermatologists, family planning practitioners, and women should be aware of this side effect before considering the devise (21). Furthermore, The World Health Organisation Medical Eligibility Criteria for Contraceptive Use (WHOMEC) recommended that Mirena usage by women with current breast cancer presents an unacceptable risk and for those with a past history of breast cancer (no disease for 5 years) the risks outweigh the benefits (22). This indicates that Mirena is considered as a systemic source of LNG.

High serum and tissue levels of levonorgestrel:
LNG in serum is primarily bound to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. It forms a stable long-lived complex with SHBG from which it dissociates slowly, and there is a positive correlation between total serum LNG and SHBG concentrations, irrespective of the mode of administration. Metabolic clearance rates of LNG may differ among individuals by several-fold, and this may partially account for the wide variations in serum concentrations in individuals using LNG-containing contraceptive products (23).
There are large variations among different studies as regards the mean LNG concentrations after administration of the same dose of LNG, and there is insufficient data to show whether there is a correlation between dose and serum concentrations. In addition, there is a wide inter and intra-individual variations in serum concentrations and pharmacokinetic parameters of LNG, irrespective of the route of administration (23).
On taking a single oral dose of the mini pill Norgeston® (Bayer plc, Berkshire, UK), containing 30μg of LNG, a maximum serum level of 2560 pmol/L is reached 1h after ingestion. Thereafter, LNG serum levels decline biphasically with half-lives of 12-24 min. and 20h., respectively (24). Following daily repeated administration, a steady-state condition is reached after about 3-4 days, with less serum levels because of the inhibitory effect of LNG on SHBG. The reported steady-state level after oral administration of 30μg LNG was 800 pmol/L (25).
Following insertion of Mirena, LNG is released at a rate of approximately 20 μg/day, and a steady-state plasma level occurs after few weeks (17). The reported steady-state LNG serum levels in Mirena users are summarized in table 1. The elimination half-life for LNG at steady state is approximately 36±13h (26), and some studies reported values as short as 9h and others as long as 80h (17). Therefore, it is plausible to substantiate that using Mirena has the same effect as taking 1-2 Noregeston® tablets daily on a continuous basis (27). Moreover, women with slow metabolic clearance rates could have, at any one point, up to three times higher serum levels of LNG than the above mentioned averages.
Additionally, Nilsson et al (28) found that the concentrations of LNG in the myometrium, fallopian tubes and fat tissue were similar (ranged from 3.2 to 16 pmol/g of wet weight of tissue) in the users of an LNG-releasing IUS that releases 30µg daily and in those taking oral contraceptive pill containing 250µg LNG. The fat tissue concentrations correlated with the plasma levels. Nonetheless, the mean LNG endometrial tissue concentrations were 2586pmol/g and 11.2pmol/g of wet tissue weight in the IUS and tablets users, respectively. This means that LNG tissue concentrations, other than the endometrium, in Mirena users could be equivalent to that of 6 LNG-containing POP.
The serum levels of LNG could be further elevated in women using Mirena with ERT. A double blind cross-over placebo RCT found that giving 50µg of ethinyl estradiol (EE) in addition to 250µg of LNG produced up to 6-fold higher LNG serum levels than giving the same dose of LNG alone, which was statistically significant. The concomitant administration of EE also doubled the plasma half-life of LNG, which was attributed to the EE-induced elevation (2-6 folds) of the concentration of SHBG (29). Similarly, on studying the pharmacokinetics of an oral contraceptive tablet containing LNG (150µg) and EE (30µg), it was found that EE induced SHBG synthesis, and possibly reduced the hepatic metabolic capacity leading to decreased LNG clearance (30). Additionally, in women with constant serum levels of LNG, for example, those using implants, studies showed that oral administration of EE increased SHBG, which in turn increased LNG concentrations by delaying its clearance (23). The consequence of this interaction on postmenopausal women using Mirena and ERT needs to be elucidated in future research.

High rate of sexual dissatisfaction:
A recent RCT (7), compared the effect of hysterectomy (n=117) with Mirena (n=119) on sexual functioning in women with HMB, found that only 48.7% of women randomized to Mirena kept it in situ for 5 years. The sexual satisfaction increased and sexual problems decreased in those who underwent hysterectomy, whereas the Mirena did not have such an effect. This was attributed to the higher incidence of lower abdominal pain. Furthermore, there was a significant reduction in satisfaction of sexual partners of Mirena users which could be explained by the unscheduled bleeding or as a result of the decreased sex drive in women.
It is well reported that progesterone modulates estrogen action in animals by significantly suppressing estrogen receptor gene transcription (31), and estrogen receptor levels (32). In addition, immunohistochemical staining of human endometrial biopsies revealed that Mirena significantly suppressed the expression of estrogen receptors when compared with controls (33). Although Mirena does not inhibit ovulation in most of women but the possible suppression of estrogen receptors may render the estrogen to be of no use, particularly that LNG is known to have much stronger antiestrogenic activity than the other progestagens (23). Wahab and Al-Azzawi (27) reported that Mirena induces a clinical situation similar to premature menopause in at least 50% of treated women. The prolonged estrogen deprivation will have a profound negative effect on a woman’s sex drive, which may reflect on the sexual partner.
The recent studies that reported improvement in the sexual function in Mirena users have major flaws. A survey in Poland included 200 Mirena users, 48 IUCD users, and 50 women not using contraception revealed that the quality of life parameters for women using Mirena were higher than other groups, especially in the aspect of general health, energy, emotional well-being, and sexual functioning (desire and arousal). The rate of sexual dysfunction was 9.6%, 20.8%, and 34.7% in the users of Mirena, IUCD, and no contraception, respectively. There are many concerns that make the credibility of this study questionable. First, there was no randomization or blinding. Second, the drive behind using Mirena, IUCD or no contraception was not known. Third, the small number questions the generalizability of the results. Fourth, it is possible that women with good sexual function were the ones who sought for effective contraceptives, while those with lower level of sexual function and interest did not use any. Last, 100%, 62.5%, and 13% of users of Mirena, IUCD, and no contraception were married, and the authors commented that being in a stable relationship could have correlated positively with sexual functioning (34). Gorgen et al. (35) also reported improvement in libido scores in 32 (53.3%) out of 60 Turkish women after 6 month of using Mirena. The authors attributed this to the reduction in HMB and pelvic pain. Nevertheless, in addition to being a small study for a short-term, 6 (9%) of the initially recruited 66 women were excluded from the analysis after discontinuing Mirena because of side effects, which caused a major bias in the result. Further, in the absence of a control group, it is impossible to exclude the placebo effect.

Does Mirena replace hysterectomy?
The role of Mirena as a conservative alternative to hysterectomy is debatable. A Finnish randomized controlled trial, comparing Mirena (n=119) and hysterectomy (n=117) in treating HMB, found that 50 (42%) of women assigned to the Mirena group eventually underwent hysterectomy. Nevertheless, the discounted direct and indirect costs in the Mirena group (2817 dollars, 95% CI: 2222-3530 per participant) remained substantially lower than in the hysterectomy group (4660 dollars, 95% CI: 4014-5180 per participant) (36). Another open multi-centre Finnish study randomized women, who were scheduled to undergo hysterectomy for HMB, to either have medical treatment (n=28) or to have Mirena inserted (n=28). After 6 month, it was found that 18 (64.3%) and 4 (14.3%) women in the Mirena and control group, respectively changed their decision to undergo hysterectomy; however, in the long-term follow up to a mean of 3 years (range 23-49 months), the continuation rate with Mirena was decreased to 48% only (5).

A recent retrospective cohort study in Netherlands, estimating the influence of Mirena (n=246) and hysteroscopic surgery (n=337) for HMB on hysterectomy rates over a 10-year period, reported that the proportion of women receiving hysterectomy as a first line therapy decreased significantly overtime from 40.6% to 31.4%. However, the total number of hysterectomy remained similar as a consequence of failure of alternatives. Interestingly, the number of hyeroscopic polypectomy/myomectomy and Mirena insertion significantly increased overtime in younger women, and 75% of treated women did not need subsequent hysterectomy suggesting that the threshold for these interventions was lowered to include women who would not need hysterectomy any way. The authors pointed out that Mirena and hysteroscopic surgery seem to be more additive rather than substitutive, making them costly modalities (37).
Therefore, it may be plausible to assume that Mirena delays rather than replaces hysterectomy. The decreased efficacy and increased side effects after 2 years of insertion (13,15,38) suggest that it may best suit the subgroup of women who are approaching the age of menopause.

Conclusion
Healthcare professionals should be aware that up to 60% of women discontinue using Mirena within five years due to unscheduled bleeding, pain and/or progestogenic adverse effects. The notion that Mirena works as entirely a local source of LNG should be revised since the serum LNG in users may be equivalent to that of two LNG-containing progestogen only pill taken daily on a continuous basis, and the tissue concentrations of LNG, other than the endometrium, users may be equivalent to that of six LNG-containing progestogen only pill. Mirena seems to delay rather than replace hysterectomy, and it may best suit women who are approaching the age of menopause. The high discontinuation and adverse effects rates should be readily available to women to be able to make an informed choice as regards using Mirena.

References:
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Table 1: The reported steady state serum levels of levonorgestrel in users of Mirena and 30µg levonorgestrel only pill
Study Levonorgestrel Serum Level (pmol/L)
Levonorgestrel 30µg pillWeiner et al (25) 800
MirenaRatsula et al (39)Suhonen et al (40)Lockhat et al (9)Nilsson et al (41)Xiao et al (42)Raudaskoski et al (20) 455480-6401062640-1601960-16011504