Advances in the use and insertion of Mirena-IUS

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Introduction

More than six million women have used Mirena IUS as contraception since 1995 worldwide. Mirena IUS is an intrauterine hormonal system which is one of the most effective long-term reversible contraceptive methods. It is a small, long-acting, levonorgestrel-releasing intrauterine system (LNG-IUS) that provides high reliability in preventing pregnancy, with the added benefit of shorter, lighter and less painful periods. Mirena provides contraceptive protection for up to five years, after which it should be removed.¹

Figure 1. Intrauterine contraception tools (left), like the Mirena IUS, are effective and reversible. The intrauterine contraceptive sits in the uterus (right).

The Mirena system consists of a 32mm long, flexible plastic T-shaped frame impregnated with barium sulphate. This makes it radio-opaque and thus detectable on x-ray examination. A cylindrical reservoir, wrapped around the vertical stem, contains 52mg of levonorgestrel (LNG). After placement into the uterus, the LNG is released in small doses (20ug/day initially and declining to around 10mg/day after five years) through a polydimethylsiloxane membrane into the uterine cavity. The resulting low systemic hormone level is associated with a low incidence of hormone-related adverse effects. The local release of LNG into the uterine cavity is responsible for many of the benefits of Mirena.¹

It provides many non-contraceptive benefits including a decrease in menstrual bleeding, improvement in haemoglobin levels, less dysmenorrhea and less premenstrual tension. It appears to be an effective treatment for uterine fibroids, adenomyosis and endometriosis. When unopposed oestrogen is required to treat premenstrual tension or as an hormone replacement therapy, Mirena can provide endometrial protection by releasing progestogen locally, thus avoiding the systemic side-effects.

Mirena IUS and heavy menstrual bleeding

Heavy menstrual bleeding (HMB) affects quality of life of a woman. It is defined as blood loss of > 80ml or beyond a volume which the woman deems abnormal. Mirena IUS is an effective treatment for menorrhagia. This is because levonorgestrel is a very potent blocker of oestrogen activity on the endometrium.² The LNG gradually reduces the thickness and vascularity of the endometrium over an initial three to six months of use. As a result of this suppression of the endometrium, most women experience a reduction of blood loss but its therapeutic significance appears greatest in women with menorrhagia.³

A study comparing use of the Mirena IUS with medroxy progesterone acetate in women having heavy menstrual bleeding showed Mirena IUS to be more effective in increasing hemoglobin level and serum ferritin level.⁴

The reduction in the amount and duration of menstrual bleeding in women using the Mirena IUS to treat their idiopathic menorrhagia, has been shown to lead to a significant improvement in health-related quality of life, and compares well with the surgical alternative of hysterectomy.⁵

Mirena and pelvic pain

Mirena has been recognised for many years as one of the effective treatment option for pelvic pain. Recent studies have confirmed these findings. It is well tolerated and is especially suitable for long-term therapy after conservative surgery for moderate to severe pain related to endometriosis. It also improves patient’s quality of life including physical and mental health.⁶

Not only are the patients who had conservative surgery for endometriosis relieved of pain by using Mirena IUS, the women with recurrent pain in whom previous medical and surgical treatments have failed, Mirena IUS had been found to provide an effective option before radical surgery is performed.⁷

Mirena and fibroid

Fibroids are the most common benign tumour in reproductive age women. Symptoms of fibroids can be managed with medical treatment, but they remain the most common indication for hysterectomy. When symptomatic, fibroids can adversely affect the quality of life by causing menorrhagia, dysmenorrhoea, infertility, pelvic pain and obstructive symptoms such as urinary frequency and constipation. Mirena IUS has been studied in women with leiomyomas. They are effective in decreasing menorrhagia from fibroids, as measured by pictorial blood less assessment, haemoglobin levels and blood loss calendars.⁸

Mirena IUS has also been compared with endometrial ablation in patients with uterine fibroids. A group of women with uterus of < 380g were treated with Mirena IUS. They were evaluated at three, six and 12 months and compared to controls who were treated with thermal balloon ablation.

At three months, blood loss was significantly less in endometrial ablation, at six months there was no difference in haemoglobin levels and uterine volume in both groups. At 12 months these findings remained the same. The studies showed conflicting results on the effects of Mirena IUS on the uterine volume. Another study assessing sonographic measurements found a significantly decreased uterine volume in Mirena IUS users. The fibroid size decreased in about six to 12 months. In other studies, no significant decrease in uterine volume was noted.⁹ Further studies are needed to evaluate the role of intrauterine progestogens in women with fibroids, but for a patient with menorrhagia and fibroid less than four millimetres in size, a trial of Mirena IUS is recommended.

The response rate of Mirena IUS on fibroids however, depends on fibroids location as sub mucosal fibroids and a unicornate uterus are associated with increased risk of failed therapy.

Tamoxifen and Mirena

Tamoxifen is the adjuvant treatment for estrogen receptor positive breast cancer, and has a proliferative effect on post-menopausal endometrium resulting in endometrial polyps, endometrial hyperplasia and endometrial cancer. The risk of developing endometrial cancer is two to three times more in women using Tamoxifen.

A randomised controlled trial compared the impact of a ‘prophylactic’ Mirena IUS with observation in women undergoing Tamoxifen therapy after breast cancer surgery.

Comparison of endometrial biopsies at 12 months revealed that Mirena IUS had a lower relative risk for formation of endometriosis and polyps and a well accepted therapy with 95 percent retention at one year. However, Cochrane systemic reviews conclude that the Mirena IUS prevents the development of benign endometrial polyps in breast cancer patients taking Tamoxifen, over a one year period, but there is no clear evidence from available randomised controlled trials that Mirena IUS prevents endometrial hyperplasia or adenocarcinoma. Larger studies are needed.¹¹

Mirena and endometrial cancer

Endometrial cancer is the most common gynaecological cancer in developed countries with an incidence of 7/100,000 per population per year. Surgery is the main management option involving total abdominal hysterectomy and bilateral salpingo-oophorectomy. It affects nearly 20 percent of premenopausal women and in these women conserving fertility can be a concern.

Use of progestogens in recurrent diseases has been recommended for many years, but recent studies now show promising results in treatment of stage one endometrial cancer in selected group of patients. The use of progestogens in the form of Mirena IUS is an acceptable option for these patients and the results are not different from oral progestogens. The response rate of 66 percent is seen in one of the recent study in patients with endometrial hyperplasia and 48 percent in patients with stage one endometrial cancer. Disease persistence is more common in women with carcinoma (25 percent) compared to hyperplasia (14 percent). Reproductive outcomes do not seem to differ between the both groups. However, it is still not recommended as the primary treatment and further trials are underway.¹²

Low dose IUS

To identify a new dose for intrauterine systems, a phase two randomised trial has been conducted to assess efficacy, side effects and patient acceptability of different forms of intrauterine systems. LNG IUS releasing 12, 16 and already available 20 microgram were compared. LNG-IUS12 and LNG-IUS16 provided effective contraception, acceptable bleeding patterns, and were well tolerated compared with Mirena.¹³

Evoinserter

Mirena is now available with an evoinserter. It provides a simple and easy way to insert Mirena IUS. Threads are already inside the inserter handle and Mirena is already in a horizontal position, no handling of threads is now required, avoiding their entanglement. The heading is simple by only pushing the slider forwards to the furthest position. Its shape is more ergonomic and the ‘cm scale’ is present on both sides.

References

1. Mirena: An intrauterine system. Product Monograph. Bayer Schering Pharma. September 2011.
2. Zhu P, Liu X, Luo H, et al. The effect of a levonorgestrel – releasing intra-uterine device on human endometrial oestrogen and progesterone receptors after one year of use. Hum Reprod (1999)145; 970-975.
3. Andersson JK, Rybo G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol (1990) 97:690–94
4. Kaunitz AM, Bissonnette F, Monteiro I, Lukkari-Lax E, Desanctis Y, Jensen, J.Levonorgestrel-releasing intrauterine system for heavy menstrual bleeding improves hemoglobin and ferritin levels. Contraception.(2012) Nov;86(5):452-7. doi: 10.1016/j.
5. Hurskainen R, Teperi J, Rissanen P 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, 273-277.
6. Tanmahasamut P, Rattanachaiyanont M, Angsuwathana S, Techatraisak K, Indhavivadhana S, Leerasiri P. Postoperative levonorgestrel-releasing intrauterine system for pelvic endometriosis-related pain: a randomized controlled trial. Obstet Gynecol. (2012) 119(3):519-26
7. Matorras R, Ballesteros A, Prieto B, Ocerin I, Expósito A, Pijoan JI, Crisol L. Efficacy of the levonorgestrel-releasing intrauterine device in the treatment of recurrent pelvic pain in multitreated endometriosis. J Reprod Med. (2011) 56(11-12):497-503.)
8. Kriplani A, Awasthi D, Kulshrestha V, Agarwal N. Efficacy of the levonorgestrel-releasing intrauterine system in uterine leiomyoma. Int J Gynaecol Obstet (2012) 116(1):35-8.
9. Soysal S, Soysal ME. The efficacy of levonorgestrel-releasing intrauterine device in selected cases of myoma-related menorrhagia: a prospective controlled trial. Gynecol Obstet Invest (2005) 59(1):29-35.
10. Grigorieva V, Chen-Mok M, Tarasova M, Mikhailov A. Use of a levonorgestrel-releasing intrauterine system to treat bleeding related to uterine leiomyomas. Fertil Steril(2003) 79(5):1194-8.
11. Chin J, Konje JC, Hickey M . Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. Cochrane Database sys. Rev (2009) 7;940:CD007245.
12. Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1adenocarcinoma: a systematic review.Gynecol Oncol (2012) 125(2):477-82.
13. Gemzell-Danielsson K, Schellschmidt I, Apter D . A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena.Fertil Steril(2012) 97(3):616-22.e1-3.

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