- Email: [email protected]
Mirena® (Levonorgestrel intrauterine system): A successful novel drug delivery option in contraception
Advanced Drug Delivery Reviews 61 (2009) 808–812
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r
Mirena® (Levonorgestrel intrauterine system): A successful novel drug delivery option in contraception☆ Susan Rose ⁎, Angela Chaudhari, C. Matthew Peterson Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, 50 North Medical Drive, Suite 2B200, Salt Lake City, Utah 84132, USA
a r t i c l e
i n f o
Article history: Received 5 November 2008 Accepted 28 April 2009 Available online 13 May 2009 Keywords: Intrauterine device Progesterone Menorrhagia Endometrial hyperplasia Copper-T IUD Contraception
a b s t r a c t This manuscript serves as a review of Mirena®, the levonorgestrel intrauterine system (LNG IUS) as a very successful drug delivery system. The LNG IUS has a very high contraceptive efficacy rate, and low rates of patient discontinuation. In addition to its contraceptive benefits, most users experience a decrease in menstrual bleeding over the 5 years of use. LNG IUS has also been used for management of menorrhagia, dysmenorrhea, adenomyosis, and endometrial hyperplasia in some cases. The LNG IUS provides long term efficacy, high rates of compliance, rapid return to fertility, and minimal adverse effects during use. © 2009 Elsevier B.V. All rights reserved.
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . 1.1. The levonorgestrel intrauterine system-LNG 1.2. LNG IUS development . . . . . . . . . . 1.3. Mechanism of action . . . . . . . . . . . 2. LNG-IUS outcomes . . . . . . . . . . . . . . . 2.1. Candidates. . . . . . . . . . . . . . . . 2.2. Efficacy . . . . . . . . . . . . . . . . . 2.3. Discontinuation . . . . . . . . . . . . . 2.4. Bleeding patterns . . . . . . . . . . . . 2.5. Noncontraceptive benefits . . . . . . . . 2.6. Ovarian cysts . . . . . . . . . . . . . . 2.7. Insertion . . . . . . . . . . . . . . . . 2.8. Pregnancy . . . . . . . . . . . . . . . . 2.9. Comparison to similar methods . . . . . . 3. Conclusion . . . . . . . . . . . . . . . . . . . 3.1. The future . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . .
. . IUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
808 809 809 809 810 810 810 810 810 810 811 811 811 811 811 811 811
1. Introduction
☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “The Role of Gene- and Drug Delivery in Women's Health-Unmet Clinical Needs and Future Opportunities”. ⁎ Corresponding author. Tel.: +1 801 581 7640; fax: +1 801 585 5146. E-mail address: [email protected] (S. Rose). 0169-409X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2009.04.022
Each year there are 3 million unplanned pregnancies in the United States with half electively terminated [1]. Lack of use, not a lack of efficacy in available options, appears to be a root cause. In the United States, oral contraceptive pills (OCPs) are the most commonly prescribed reversible contraceptive agent [2], yet only 22% of
S. Rose et al. / Advanced Drug Delivery Reviews 61 (2009) 808–812
reproductive-aged women use OCPs, and 32–50% discontinue use in the first year [3,4]. Reasons for discontinuation include adverse effects and the requirement for daily administration [5]. The development of a long term contraceptive with an acceptable side effect profile has long been a goal of insightful practitioners and controlled drug delivery development teams. The development and release of the levonorgestrel intrauterine system (LNG IUS, Mirena®) represents one very successful example of novel drug delivery within the contraceptive arena. In addition to its primary indication, the non-contraceptive benefits of this system will propel its use beyond the contracepting population.
1.1. The levonorgestrel intrauterine system-LNG IUS The LNG IUS is a 32 mm T-shaped backbone (polydimethyl siloxane-PMDS) with a drug delivery cylinder wrapped around its stem. The cylinder is a polydimethyl siloxane/levonorgestrel (52 mg) mixture that allows a steady release of levonorgestrol through a regulating surface membrane. After insertion, 20 μg of levonorgestrel is released initially every 24 h and over a period of 5 years the release rate drops to 11 μg every 24 h [6]. The average release rate is 14 μg/day. The frame incorporates barium sulfate to render the system radioopaque. The LNG IUS is sold as LevonovaÆ (Schering AG, Germany), in Scandinavia and as Mirena (Berlex Laboratories, Inc, Montvale, NJ) in all other regions (Fig. 1).
809
1.2. LNG IUS development The levonorgestrel intrauterine system, Mirena®, invented by Tapani Luukkainen (Finland) and developed by the Population Council in the late 1980s and later with Schering Oy and Shering AG, now claims a place as one of the most efficacious contraceptive methods in the world. It is now approved for contraceptive use in over 100 countries. The historical record of the development of a progestin releasing intrauterine device (IUD) began in the 1960s. Dr. Antonio Scommegna first noted endometrial atrophy when intrauterine progesterone was administered with an IUD. The impetus for his trial of progesterone was to reduce IUD expulsion rates. While progesterone provided no benefit for reducing expulsion, the effects on the endometrial lining lead to the development of the Progestasert® IUD (Alza Corporation). The Progestasert® never gained widespread popularity because of a short duration of efficacy (1 year) and failure to protect against ectopic pregnancy [7]. The LNG IUS first emerged in 1976 and represented the combination of the Nova-T IUD (a copper-T intrauterine device with flexible arms) and levonorgestrel; the copper filament had been removed and the vertical arm had been replaced by a reservoir of levonorgesterol for local delivery [8]. Validation steps to justify clinical trials of the device first required evidence of low dose release of the progestogen, levonorgestrel, in utero [9,10]. This was then followed by the demonstration of consistent plasma concentrations from the intrauterine delivery method [10–13]. Low dose release of the progestogen revealed a uniform histologic pattern regardless of the duration of placement or ovulation [13,14]. The characteristic histologic findings included a 1– 3 mm mucosa with swollen stroma that contained pseudodecidually enlarged cells. The endometrial glands were sparse and atrophic showing an inactive epithelium. These findings confirmed a contraceptive effect not dependent on the inhibition of ovulation, but on the local effect of the progestin on the endometrium, myometrium and fallopian tubes. Tissue levels of levonorgestrel in the myometrium, fallopian tube and adipose tissue, individually, were consistently between 1–5 ng/gm wet weight [13], whereas the endometrial levels were 808 ± 511 ng/g wet weight. Plasma levels were 202 pg/ml in this study [13]. Also documented in preliminary studies were lower concentrations of levonorgestrel in the serum and fat using a LNG IUS compared to the oral administration of levonorgestrel [13]. Intermittently high plasma levels associated with oral administration resulted in higher fat tissue concentrations. Thus, one clear advantage of the LNG IUS and other non-oral delivery methods, such as subcutaneous capsules and vaginal rings, includes significantly reduced nonspecific delivery of steroid hormone [9,15–18]. The high endometrial levonorgestrel levels, low nonspecific tissue levels and relatively low plasma levels afforded by the 30 µg LNG IUS revealed a highly specific tissue uptake affording an increased safety margin. In fact, the endometrial concentration represented only 0.6–2.2% of the daily release [13]. When considering the concentration of endometrial cytosolic progesterone receptors, the mean endometrial concentration of levonorgestrel was sufficient to saturate these receptors. 1.3. Mechanism of action
Fig. 1. From the Mirena Product Information (reprinted with permission from Bayer HealthCare Pharmaceuticals, Inc.).
The mechanism of action of the LNG IUS as a contraceptive is unique and is, therefore, important to understand in its utilization. The major contraceptive action of LNG IUS appears to be local, and not systemic, consistent with tissue levels. The LNG IUS targets the endometrium by locally releasing levonorgestrel, a progestin derived from 19-nortestosterone, containing high progestational potency. Local delivery to the endometrium results in very effective suppression of endometrial proliferation: an inactive endometrial histology with a thin epithelium and decidualized stroma. These actions create an extremely inhospitable environment for sperm which is unsuitable
810
S. Rose et al. / Advanced Drug Delivery Reviews 61 (2009) 808–812
for survival and hence fertilization. Endometrial thinning seems to be the major component of the LNG IUS contraceptive action [19]. Despite producing endometrial gland atrophy and stromal decidualization, glycodelin A remains present in women using the LNG IUS [20,21]. Glycodelin A inhibits interaction between sperm and ova and, therefore, blocks fertilization, acting as an additional contraceptive barrier to prevent the fertilization of mature oocytes [21]. In addition to the actions on the endometrium, LNG IUS acts on the cervix by creating thick cervical mucous which prevents sperm transport and subsequent fertilization [17,22,23]. Finally, the polydimethyl siloxane T-frame induces a local inflammatory reaction that may also be spermatotoxic. In addition to the contraceptive actions, the intrauterine release of levonorgestrel may also provide protection against pelvic inflammatory disease because of its activity on cervical mucous and sperm transport [24] (Fig. 2). Ovulation is suppressed in only 25%–50% of users [25]. Because ovarian steroidogenesis is not consistently affected; circulating levels of estradiol remain well within the range of reproductive-aged women for both the cycling and the amenorrheic LNG IUS users.
Table 1 Efficacy of LNG [40,42].
marketing experience similar safety and efficacy characteristics to the initial clinical trials (Table 1). 2.3. Discontinuation
2. LNG-IUS outcomes 2.1. Candidates Appropriate candidates for LNG IUS use are very similar to copperbearing IUDs: women with no evidence of active cervicitis who are in stable, mutually monogamous relationships. The uterine cavity should be normal and measure 6–9 cm in length. Nulliparity is not a contraindication. The World Health Organization has concluded that women who have had PID in the past can use IUDs if they have subsequently demonstrated their fertility and are presently at low risk for acquiring sexually transmitted disease [26]. The intrauterine release of levonorgestrel offers some protection against pelvic inflammatory disease [25]. This system is an ideal alternative for those women who may have an allergic reaction or other difficulties with the copper IUD. Over 10 million US women appear to fit these criteria.
Post-marketing continuation rates for LNG IUS were 65% in 17,300 French women who continued to use the LNG IUS for the full 5 years [29]. In another study, 5-year discontinuation rates due to adverse effects were attributed to bleeding (10.7%), pain (4.9%), hormonerelated reasons (11.2%), and other medical conditions (9.2%) [27]. Other additional events in clinical practice that could contribute to discontinuation over a 5-year period include embedment, expulsion, infection and a risk of perforation (no cases in clinical trials). In addition to those adverse effects listed above, a comprehensive list of all complaints includes: abdominal pain, abnormal Papanicolaou smears, acne, back pain, decreased libido, depression, dysmenorrhea, headaches, hypertension, mastalgia, nausea, nervousness, sinusitis, skin disorders upper respiratory infection, vaginitis, and weight gain although, weight gain attributable to the LNG IUS has not yet been reported [30]. 2.4. Bleeding patterns
2.2. Efficacy The LNG IUS has been approved by the FDA for up to 5 years of use. The first-year failure rate measured by the Pearl Index was 0.14 pregnancies/100 women, with a 5 year cumulative pregnancy rate of 0.71/100 women [27]. This failure rate compares well with the effectiveness of female sterilization. A meta-analysis of comparative clinical trials concluded that the efficacy of the LNG IUS is comparable to copper IUDs with at least 250 mm2 copper [28]. Pre-approval clinical studies with 13,000 woman-years of experience and 58,000 woman-years of post-
The levonorgestrel intrauterine system results in changes in menstrual bleeding patterns. First, patients note irregular spotting and bleeding during the first 2–4 months followed by several months of regular, brief, 2–3 day menses. Over time, long-term users can anticipate a 70%–90% reduction in blood loss. [31]. By the end of the first year, 20% will have developed complete amenorrhea [11]. A significant reduction in bleeding is seen; thus, hemoglobin, hematocrit, and ferritin levels increase during the first through fifth years of use [32]. 2.5. Noncontraceptive benefits
Fig. 2. LNG IUS: Mechanism of Action. (Adapted from and reprinted with permission from Jonsson et al., Contraception 1991;43:447, and Videla-Rivero et al., Contraception 1987; 36:217).
Noncontraceptive benefits include: the control of primary and secondary menorrhagia and dysmenorrhea, reduction in adenomyosis, and prevention and/or treatment of endometrial hyperplasia in women with polycystic ovary syndrome and in estrogen users. The device has been particularly effective in controlling primary menorrhagia and menorrhagia associated with fibroids and/or adenomyosis [33]. Compared to medical interventions and hysteroscopic endometrial resection, the LNG IUS shows significant short term efficacy [34]. Nearly 70% of women treated with LNG IUS avoided surgical treatment for menorrhagia [35]. While long term outcomes remain to be seen and reported, preliminary experience with menorrhagia is encouraging. The LNG IUS also reduces dysmenorrhea by 80% in uncomplicated users [30], and in 70% of women with dysmenorrhea attributed to endometriosis [36]. Furthermore, the LNG IUS provides protection of the endometrium from stimulation by estrogen replacement
S. Rose et al. / Advanced Drug Delivery Reviews 61 (2009) 808–812
therapies in postmenopausal women and from stimulation by tamoxifen [37,38]. 2.6. Ovarian cysts Because progestin administration delays atresia of ovarian follicles, persistent functional cysts are noted in 12% of users which eventually resolve spontaneously [39]. Return to fertility is rapid after the LNG IUS is removed. Endometrial changes are reversed in 2– 6 months; 79% of women who desired pregnancy conceived within 1 year, and 87% achieved pregnancy within 2 years [40]. 2.7. Insertion Practitioners are advised to seek training before attempting LNG IUS insertion. It involves a one-handed technique that allows control of the device within the uterus and is quite simple once observed and practiced. Product information has full explanations. 2.8. Pregnancy If pregnancy occurs, immediate ultrasound is recommended to rule out an ectopic implantation and to confirm that the LNG IUS has not been expelled. The device incorporates barium sulfate to make it visible by both X-ray and ultrasound; however, ultrasound visualization of LNG IUS is more subtle than with the copper IUD. It should then be removed as soon as possible in the first trimester, after a consultation with the patient regarding the risks of unintended miscarriage with retention or removal. In pregnancies exposed to levonorgestrel, there have been no reported cases of masculinization of a female fetus. In the 32 reported live births, 30 infants were reported as healthy. Two anomalies were reported: one case of pulmonary artery hyperplasia and one case of cystic hypoplastic kidney in an infant whose sibling had renal agenesis [28]. 2.9. Comparison to similar methods The LNG IUS is more expensive than the currently available copperT 380A IUD. They are equally effective in protecting against pregnancy [41]. Only one study demonstrated a difference in adverse side effects, with more headaches and acne with the LNG IUS compared to the copper-T [42]. Expulsion rates were equal at 5 years [43]. Efficacy of the LNG IUS as emergency contraception has not yet been reported. 3. Conclusion 3.1. The future While the LNG IUS 20 µg/day is considered a low dose steroid delivery system with mainly local effects, some adverse lipid effects still may occur, thus, even lower doses are being evaluated [44,45]. Additionally the LNG IUS is too large for some nulliparous and post menopausal women. This has prompted the development of a new smaller LNG-IUS for smaller uteri [46]. Furthermore, a frameless LNG IUS is under development which contains a 14 µg/day coaxial fibrous delivery system within the conventional frameless GyneFIx IUD [47]. This lower dose unit appears to have minimal if any systemic effects. This device requires anchoring in the uterine cavity through an upgraded Mark 2 inserter [48]. Due to ease and familiarity with the Tshaped IUD, a T-LNG 14 µg/day delivery system is near release. The potential benefits of T-LNG 14 (small and regular) systems include simple insertion for a wide range of providers, a lower dose of progestin resulting in reduced adverse effects, and an extended efficacy of about 10 years [49].
811
It is clear that intrauterine delivery of steroids via an IUS has achieved widespread international acclaim for ease and efficacy. It provides long term efficacy, improved compliance, rapid reversibility and minimal adverse effects during use. It is anticipated that the indications for intrauterine drug/steroid delivery will grow and extend to other specialty and subspecialty needs. References [1] S.K. Henshaw, Unintended pregnancy in the United States, Fam. Plann. Perspect. 30 (1998) 24–29 46. [2] Ortho Pharmaceutical Corp. Annual Birth Control Study. Raritan, NJ: Ortho Pharmaceutical Corp, 1998. [3] R.A. Hatcher, F. Stewart, J. Trussell, et al., Contraceptive technology 1990–1992, Irvington Publishers, New York, 1994. [4] J. Trussell, B. Vaughan, Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth, Fam. Plann. Perspect. 31 (1999) 64–72. [5] P.J.A. Hillard, The patient's reaction to side effects of oral contraceptives, Am. J. Obstet. Gynecol. 161 (1989) 1412–1415. [6] K. Andersson, The levonorgestrel intrauterine system: more than a contraceptive, Eur. J. Contracept. Reprod. Health Care 6 (Suppl 1) (2001) 15–22. [7] R.M. Soderstrom, The Progestasert® intrauterine progesterone contraception system. A new look at IUDs—advancing contraceptive choices, in: C.W.B. Bardi, D.R. Mishell Jr. (Eds.), Fourth Conference on IUDs, Butterwords-Heinemann, Boston, 1992, pp. 319–327. [8] K. Andersson, L.A. Mattsson, G. Rybo, E. Stadberg, Intrauterine release of levonorgestrel—a new way of adding progestogen in hormone replacement therapy, Obstet. Gynecol. 79 (1992) 963–967. [9] C.G. Nilsson, T. Luukkainen, P. Lahteenmaki, Determination of plasma concentrations of d-norgestrel during a 1 year follow-up in women with a d-norgestrelreleasing IUD, Contraception 17 (1978) 569–573. [10] C.G. Nilsson, P. Lahteenmaki, D.N. Robertson, T. Luukkainen, Plasma concentrations of levonorgestrel as a function of the release rate of levonorgestrel from medicated intrauterine devices, Acta Endocrinol. (Copenhagen) 93 (1980) 38–40. [11] C.G. Nilsson, P. Lahteenmaki, T. Luukkainen, Patterns of ovulation and bleeding with a low levonorgestrel-releasing intrauterine device, Contraception 21 (1980) 155–164. [12] C.G. Nilsson, P. Lahteenmaki, T. Luukkainen, Levonorgestrel plasma concentrations and hormone profiles after insertion and after 1 year of treatment with a levonorgestrel-IUD, Contraception 21 (1980) 225–233. [13] C.G. Nilsson, M. Haukkamaa, T. Luukkainen, Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD, Clin. Endocrinol. 17 (1982) 529–536. [14] C.G. Nilsson, T. Luukkainen, H. Arko, Endometrial morphology in women using a dnorgestrel-releasing IUD, Fertil. Steril. 29 (1978) 397–401. [15] E. Weiner, E.B.D. Johansson, Plasma levels of d-norgestrel, estradiol and progesterone during treatment with silastic implants containing d-norgestrel, Contraception 14 (1976) 81–92. [16] J. Toivonen, P. Lahteenmaki, T. Luukkainen, Bleeding and ovulation control with use of a small contraceptive vaginal ring releasing levonorgestrel and estradiol, Contraception 20 (1979) 11–18. [17] R. French, J. Gullebaud, Mirena, the levonorgestrel intra-uterine system (20 ug/day), J. Drug Evaluation 1 (2) (2003) 43–69. [18] I. Sivin, Risks and benefits, advantages and disadvantages of levonorgestrelreleasing contraceptive implants, Drug Safety 26 (5) (2003) 303–335. [19] K. Andersson, V. Odlind, G. Rybo, Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during 5 years of use: a randomized comparative trial, Contraception 49 (1) (1994) 56–72. [20] H.O. Critchley, H. Wang, R.L. Jones, R.W. Kelly, T.A. Drudy, A.E. Gebbie, et al., Morphological and functional features of endometrial decidualization following long-term intrauterine levonorgestrel delivery, Hum. Reprod. 13 (1998) 1218–1224. [21] E. Mandelin, H. Koistinen, R. Koistinen, B. Affandi, M. Seppala, Levonorgestrelreleasing intrauterine device-wearing women express contraceptive glycodelin A in endometrium during midcycle: another contraceptive mechanism? Hum. Reprod. 12 (1997) 2671–2675. [22] T. Luukainen, P. Lahteenmaki, J. Toivonen, Levonorgestrel-releasing intrauterine device, Ann. Med. 22 (2) (1990) 85–90. [23] J. Gullebaud, The levonorgestrel intrauterine system: a clinical perspective from the U.K. Ann. N.Y. Acad. Sci. 997 (2003) 185–193. [24] I. Sivin, Protective effect of intrauterine release of levonorgestrel on pelvic infection: 3 years' comparative experience of levonorgestrel- and copper-releasing intrauterine devices, Obstet. Gynecol. 77 (1991) 960–961. [25] I. Barbosa, S.E. Olsson, V. Odlind, T. Goncalves, E. Coutinho, Ovarian function after 7 years' use of a levonorgestrel IUD, Adv. Contracept. 11 (1995) 85–95. [26] Increasing access to IUDs, in: D Grimes (Ed.), The Contraception Report, 1998, p. 9. [27] Mirena (LNG IUS) [package insert]. Montvale, Berlex Laboratories, Inc, NJ, 2000. [28] R.S. French, F.M. Cowan, D. Mansour, J.P. Higgins, A. Robinson, T. Procter, et al., Levonorgestrel-releasing (20 μg/day) intrauterine systems (Mirena) compared with other methods of reversible contraceptives, BJOG 107 (2000) 1218–1225. [29] T. Backman, S. Huhtala, T. Blom, R. Luoto, I. Rauramo, M. Koskenvuo, Length of use and symptoms associated with premature removal of the levonorgestrel
812
[30] [31] [32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
S. Rose et al. / Advanced Drug Delivery Reviews 61 (2009) 808–812 intrauterine system: a nation-wide study of 17,360 users, BJOG 107 (2000) 335–339. T. Luukkainen, P. Pakarinen, J. Toivonen, Progestin-releasing intrauterine systems, Semin. Reprod. Med. 19 (2001) 355–363. J.T. Jensen, Noncontraceptive applications of the levonorgestrel intrauterine system, Curr. Womens Health Rep. 2 (2002) 417–422. M. Ronnerdag, V. Odlind, Health effects of long-term use of the intrauterine levonorgestrel-releasing system: a follow-up study over 12 years of continuous use, Acta Obstet. Gynecol. Scand. 78 (1999) 716–721. A. Ikomi, E.F. Pepra, Efficacy of the levonorgestrel intrauterine system in treating menorrhagia: actualities and ambiguities, J. Fam. Plann. Reprod. Health Care 28 (2002) 99–100. P. Lahteenmaki, M. Haukkamaa, J. Puolakka, U. Riikonen, S. Sainio, J. Suvisaari, et al., Open randomized study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy, BMJ 316 (1998) 1122–1126. R. Nagrani, P. Bowen-Simpkins, J.W. Barrington, Can the levonorgestrel intrauterine system replace surgical treatment for the management of menorrhagia? BJOG 109 (2002) 345–347. P. Vercellini, G. Aimi, S. Panazza, O. De Giorgi, A. Pesole, P.G. Crosignani, A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study, Fertil. Steril. 72 (1999) 505–508. A. Ikomi, E.F. Pepra, Efficacy of the levonorgestrel intrauterine system in treating menorrhagia: actualities and ambiguities, J. Fam. Plann. Reprod. Health Care 28 (2002) 99–100. P. Lahteenmaki, M. Haukkamaa, J. Puolakka, U. Riikonen, S. Sainio, J. Suvisaari, et al., Open randomized study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy, BMJ 316 (1998) 1122–1126. I. Jarvela, A. Tekay, P. Jouppila, The effect of a levonorgestrel releasing intrauterine system on uterine artery blood flow, hormone concentrations and ovarian cyst formation in fertile women, Hum. Reprod. 13 (1998) 3379–3383. K. Andersson, I. Batar, G. Rybo, Return to fertility after removal of a levonorgestrelreleasing intrauterine device and Nova-T, Contraception 46 (1992) 575–584.
[41] R.S. French, F.M. Cowan, D. Mansour, J.P. Higgins, A. Robinson, T. Procter, et al., Levonorgestrel-releasing (20 μg/day)intrauterine systems (Mirena) compared with other methods of reversible contraceptives, BJOG 107 (2000) 1218–1225. [42] T. Luukkainen, H. Allonen, M. Haukkamaa, P. Lahteenmaki, C.G. Nilsson, J. Toivonen, Five years' experience with levonorgestrel-releasing IUDs, Contraception 5 (1986) 139–148. [43] C.G. Nilsson, T. Luukkainen, J. Diaz, H. Allonen, Intrauterine contraception with levonorgestrel: a comparative randomized clinical performance study, Lancet 1 (Pt 1) (1981) 577–580. [44] L.O. Wollter-Svensson, E. Stadberg, K. Andersson, et al., Intrauterine administration of levonorgestrel in two low doses in HRT administration, Maturitas 22 (1995) 199–205. [45] T. Raudaskoski, J. Tapanainen, E. Tomas, H. Luotola, F. Pekonen, H. Ronni-Sivula, H. Timonen, F. Riphagen, T. Laatikainen, Intrauterine 10 ug and 20 ug levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial, metabolic response, Br. J. Obstet. Gynecol. 109 (2002) 136–144. [46] M.H. Birkhauser, New routes of HRT administration, Int. J. Fertil. 43 (1998) 206–207. [47] D. Wildmeersch, E. Schacht, P. Wildemeersch, D. Janssens, M. Thiery, Development of a miniature, frameless intrauterine levonorgestrel-releasing system for contraception and treatment: a review of initial clinical experience, Reprod. BioMed. 4 (2001) 69–80 (www.rbmonline.com). [48] S. Wu, J. Hu, D. Wildemeersch, Performance of the frameless gyneFix and the TCu380A IUDs in a 3 year multicenter randomized comparative trial in parous women, Contraception 61 (2000) 91–99. [49] G.D. Andrews, K. French, C.L. Wilkinson, Appropriately trained nurses are competent at inserting intrauterine devices: an audit of clinical practice. Contraceptive Choices and Realities, in: RHW van Lunsen, V Unzeitig, G Creatas (Eds.), Proceedings of the 5th Congress of the European Society of Contraception, The Parthenon Publishing Group, London, 2000, pp. 160–163.
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r
Mirena® (Levonorgestrel intrauterine system): A successful novel drug delivery option in contraception☆ Susan Rose ⁎, Angela Chaudhari, C. Matthew Peterson Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, 50 North Medical Drive, Suite 2B200, Salt Lake City, Utah 84132, USA
a r t i c l e
i n f o
Article history: Received 5 November 2008 Accepted 28 April 2009 Available online 13 May 2009 Keywords: Intrauterine device Progesterone Menorrhagia Endometrial hyperplasia Copper-T IUD Contraception
a b s t r a c t This manuscript serves as a review of Mirena®, the levonorgestrel intrauterine system (LNG IUS) as a very successful drug delivery system. The LNG IUS has a very high contraceptive efficacy rate, and low rates of patient discontinuation. In addition to its contraceptive benefits, most users experience a decrease in menstrual bleeding over the 5 years of use. LNG IUS has also been used for management of menorrhagia, dysmenorrhea, adenomyosis, and endometrial hyperplasia in some cases. The LNG IUS provides long term efficacy, high rates of compliance, rapid return to fertility, and minimal adverse effects during use. © 2009 Elsevier B.V. All rights reserved.
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . 1.1. The levonorgestrel intrauterine system-LNG 1.2. LNG IUS development . . . . . . . . . . 1.3. Mechanism of action . . . . . . . . . . . 2. LNG-IUS outcomes . . . . . . . . . . . . . . . 2.1. Candidates. . . . . . . . . . . . . . . . 2.2. Efficacy . . . . . . . . . . . . . . . . . 2.3. Discontinuation . . . . . . . . . . . . . 2.4. Bleeding patterns . . . . . . . . . . . . 2.5. Noncontraceptive benefits . . . . . . . . 2.6. Ovarian cysts . . . . . . . . . . . . . . 2.7. Insertion . . . . . . . . . . . . . . . . 2.8. Pregnancy . . . . . . . . . . . . . . . . 2.9. Comparison to similar methods . . . . . . 3. Conclusion . . . . . . . . . . . . . . . . . . . 3.1. The future . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . .
. . IUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .
808 809 809 809 810 810 810 810 810 810 811 811 811 811 811 811 811
1. Introduction
☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “The Role of Gene- and Drug Delivery in Women's Health-Unmet Clinical Needs and Future Opportunities”. ⁎ Corresponding author. Tel.: +1 801 581 7640; fax: +1 801 585 5146. E-mail address: [email protected] (S. Rose). 0169-409X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2009.04.022
Each year there are 3 million unplanned pregnancies in the United States with half electively terminated [1]. Lack of use, not a lack of efficacy in available options, appears to be a root cause. In the United States, oral contraceptive pills (OCPs) are the most commonly prescribed reversible contraceptive agent [2], yet only 22% of
S. Rose et al. / Advanced Drug Delivery Reviews 61 (2009) 808–812
reproductive-aged women use OCPs, and 32–50% discontinue use in the first year [3,4]. Reasons for discontinuation include adverse effects and the requirement for daily administration [5]. The development of a long term contraceptive with an acceptable side effect profile has long been a goal of insightful practitioners and controlled drug delivery development teams. The development and release of the levonorgestrel intrauterine system (LNG IUS, Mirena®) represents one very successful example of novel drug delivery within the contraceptive arena. In addition to its primary indication, the non-contraceptive benefits of this system will propel its use beyond the contracepting population.
1.1. The levonorgestrel intrauterine system-LNG IUS The LNG IUS is a 32 mm T-shaped backbone (polydimethyl siloxane-PMDS) with a drug delivery cylinder wrapped around its stem. The cylinder is a polydimethyl siloxane/levonorgestrel (52 mg) mixture that allows a steady release of levonorgestrol through a regulating surface membrane. After insertion, 20 μg of levonorgestrel is released initially every 24 h and over a period of 5 years the release rate drops to 11 μg every 24 h [6]. The average release rate is 14 μg/day. The frame incorporates barium sulfate to render the system radioopaque. The LNG IUS is sold as LevonovaÆ (Schering AG, Germany), in Scandinavia and as Mirena (Berlex Laboratories, Inc, Montvale, NJ) in all other regions (Fig. 1).
809
1.2. LNG IUS development The levonorgestrel intrauterine system, Mirena®, invented by Tapani Luukkainen (Finland) and developed by the Population Council in the late 1980s and later with Schering Oy and Shering AG, now claims a place as one of the most efficacious contraceptive methods in the world. It is now approved for contraceptive use in over 100 countries. The historical record of the development of a progestin releasing intrauterine device (IUD) began in the 1960s. Dr. Antonio Scommegna first noted endometrial atrophy when intrauterine progesterone was administered with an IUD. The impetus for his trial of progesterone was to reduce IUD expulsion rates. While progesterone provided no benefit for reducing expulsion, the effects on the endometrial lining lead to the development of the Progestasert® IUD (Alza Corporation). The Progestasert® never gained widespread popularity because of a short duration of efficacy (1 year) and failure to protect against ectopic pregnancy [7]. The LNG IUS first emerged in 1976 and represented the combination of the Nova-T IUD (a copper-T intrauterine device with flexible arms) and levonorgestrel; the copper filament had been removed and the vertical arm had been replaced by a reservoir of levonorgesterol for local delivery [8]. Validation steps to justify clinical trials of the device first required evidence of low dose release of the progestogen, levonorgestrel, in utero [9,10]. This was then followed by the demonstration of consistent plasma concentrations from the intrauterine delivery method [10–13]. Low dose release of the progestogen revealed a uniform histologic pattern regardless of the duration of placement or ovulation [13,14]. The characteristic histologic findings included a 1– 3 mm mucosa with swollen stroma that contained pseudodecidually enlarged cells. The endometrial glands were sparse and atrophic showing an inactive epithelium. These findings confirmed a contraceptive effect not dependent on the inhibition of ovulation, but on the local effect of the progestin on the endometrium, myometrium and fallopian tubes. Tissue levels of levonorgestrel in the myometrium, fallopian tube and adipose tissue, individually, were consistently between 1–5 ng/gm wet weight [13], whereas the endometrial levels were 808 ± 511 ng/g wet weight. Plasma levels were 202 pg/ml in this study [13]. Also documented in preliminary studies were lower concentrations of levonorgestrel in the serum and fat using a LNG IUS compared to the oral administration of levonorgestrel [13]. Intermittently high plasma levels associated with oral administration resulted in higher fat tissue concentrations. Thus, one clear advantage of the LNG IUS and other non-oral delivery methods, such as subcutaneous capsules and vaginal rings, includes significantly reduced nonspecific delivery of steroid hormone [9,15–18]. The high endometrial levonorgestrel levels, low nonspecific tissue levels and relatively low plasma levels afforded by the 30 µg LNG IUS revealed a highly specific tissue uptake affording an increased safety margin. In fact, the endometrial concentration represented only 0.6–2.2% of the daily release [13]. When considering the concentration of endometrial cytosolic progesterone receptors, the mean endometrial concentration of levonorgestrel was sufficient to saturate these receptors. 1.3. Mechanism of action
Fig. 1. From the Mirena Product Information (reprinted with permission from Bayer HealthCare Pharmaceuticals, Inc.).
The mechanism of action of the LNG IUS as a contraceptive is unique and is, therefore, important to understand in its utilization. The major contraceptive action of LNG IUS appears to be local, and not systemic, consistent with tissue levels. The LNG IUS targets the endometrium by locally releasing levonorgestrel, a progestin derived from 19-nortestosterone, containing high progestational potency. Local delivery to the endometrium results in very effective suppression of endometrial proliferation: an inactive endometrial histology with a thin epithelium and decidualized stroma. These actions create an extremely inhospitable environment for sperm which is unsuitable
810
S. Rose et al. / Advanced Drug Delivery Reviews 61 (2009) 808–812
for survival and hence fertilization. Endometrial thinning seems to be the major component of the LNG IUS contraceptive action [19]. Despite producing endometrial gland atrophy and stromal decidualization, glycodelin A remains present in women using the LNG IUS [20,21]. Glycodelin A inhibits interaction between sperm and ova and, therefore, blocks fertilization, acting as an additional contraceptive barrier to prevent the fertilization of mature oocytes [21]. In addition to the actions on the endometrium, LNG IUS acts on the cervix by creating thick cervical mucous which prevents sperm transport and subsequent fertilization [17,22,23]. Finally, the polydimethyl siloxane T-frame induces a local inflammatory reaction that may also be spermatotoxic. In addition to the contraceptive actions, the intrauterine release of levonorgestrel may also provide protection against pelvic inflammatory disease because of its activity on cervical mucous and sperm transport [24] (Fig. 2). Ovulation is suppressed in only 25%–50% of users [25]. Because ovarian steroidogenesis is not consistently affected; circulating levels of estradiol remain well within the range of reproductive-aged women for both the cycling and the amenorrheic LNG IUS users.
Table 1 Efficacy of LNG [40,42].
marketing experience similar safety and efficacy characteristics to the initial clinical trials (Table 1). 2.3. Discontinuation
2. LNG-IUS outcomes 2.1. Candidates Appropriate candidates for LNG IUS use are very similar to copperbearing IUDs: women with no evidence of active cervicitis who are in stable, mutually monogamous relationships. The uterine cavity should be normal and measure 6–9 cm in length. Nulliparity is not a contraindication. The World Health Organization has concluded that women who have had PID in the past can use IUDs if they have subsequently demonstrated their fertility and are presently at low risk for acquiring sexually transmitted disease [26]. The intrauterine release of levonorgestrel offers some protection against pelvic inflammatory disease [25]. This system is an ideal alternative for those women who may have an allergic reaction or other difficulties with the copper IUD. Over 10 million US women appear to fit these criteria.
Post-marketing continuation rates for LNG IUS were 65% in 17,300 French women who continued to use the LNG IUS for the full 5 years [29]. In another study, 5-year discontinuation rates due to adverse effects were attributed to bleeding (10.7%), pain (4.9%), hormonerelated reasons (11.2%), and other medical conditions (9.2%) [27]. Other additional events in clinical practice that could contribute to discontinuation over a 5-year period include embedment, expulsion, infection and a risk of perforation (no cases in clinical trials). In addition to those adverse effects listed above, a comprehensive list of all complaints includes: abdominal pain, abnormal Papanicolaou smears, acne, back pain, decreased libido, depression, dysmenorrhea, headaches, hypertension, mastalgia, nausea, nervousness, sinusitis, skin disorders upper respiratory infection, vaginitis, and weight gain although, weight gain attributable to the LNG IUS has not yet been reported [30]. 2.4. Bleeding patterns
2.2. Efficacy The LNG IUS has been approved by the FDA for up to 5 years of use. The first-year failure rate measured by the Pearl Index was 0.14 pregnancies/100 women, with a 5 year cumulative pregnancy rate of 0.71/100 women [27]. This failure rate compares well with the effectiveness of female sterilization. A meta-analysis of comparative clinical trials concluded that the efficacy of the LNG IUS is comparable to copper IUDs with at least 250 mm2 copper [28]. Pre-approval clinical studies with 13,000 woman-years of experience and 58,000 woman-years of post-
The levonorgestrel intrauterine system results in changes in menstrual bleeding patterns. First, patients note irregular spotting and bleeding during the first 2–4 months followed by several months of regular, brief, 2–3 day menses. Over time, long-term users can anticipate a 70%–90% reduction in blood loss. [31]. By the end of the first year, 20% will have developed complete amenorrhea [11]. A significant reduction in bleeding is seen; thus, hemoglobin, hematocrit, and ferritin levels increase during the first through fifth years of use [32]. 2.5. Noncontraceptive benefits
Fig. 2. LNG IUS: Mechanism of Action. (Adapted from and reprinted with permission from Jonsson et al., Contraception 1991;43:447, and Videla-Rivero et al., Contraception 1987; 36:217).
Noncontraceptive benefits include: the control of primary and secondary menorrhagia and dysmenorrhea, reduction in adenomyosis, and prevention and/or treatment of endometrial hyperplasia in women with polycystic ovary syndrome and in estrogen users. The device has been particularly effective in controlling primary menorrhagia and menorrhagia associated with fibroids and/or adenomyosis [33]. Compared to medical interventions and hysteroscopic endometrial resection, the LNG IUS shows significant short term efficacy [34]. Nearly 70% of women treated with LNG IUS avoided surgical treatment for menorrhagia [35]. While long term outcomes remain to be seen and reported, preliminary experience with menorrhagia is encouraging. The LNG IUS also reduces dysmenorrhea by 80% in uncomplicated users [30], and in 70% of women with dysmenorrhea attributed to endometriosis [36]. Furthermore, the LNG IUS provides protection of the endometrium from stimulation by estrogen replacement
S. Rose et al. / Advanced Drug Delivery Reviews 61 (2009) 808–812
therapies in postmenopausal women and from stimulation by tamoxifen [37,38]. 2.6. Ovarian cysts Because progestin administration delays atresia of ovarian follicles, persistent functional cysts are noted in 12% of users which eventually resolve spontaneously [39]. Return to fertility is rapid after the LNG IUS is removed. Endometrial changes are reversed in 2– 6 months; 79% of women who desired pregnancy conceived within 1 year, and 87% achieved pregnancy within 2 years [40]. 2.7. Insertion Practitioners are advised to seek training before attempting LNG IUS insertion. It involves a one-handed technique that allows control of the device within the uterus and is quite simple once observed and practiced. Product information has full explanations. 2.8. Pregnancy If pregnancy occurs, immediate ultrasound is recommended to rule out an ectopic implantation and to confirm that the LNG IUS has not been expelled. The device incorporates barium sulfate to make it visible by both X-ray and ultrasound; however, ultrasound visualization of LNG IUS is more subtle than with the copper IUD. It should then be removed as soon as possible in the first trimester, after a consultation with the patient regarding the risks of unintended miscarriage with retention or removal. In pregnancies exposed to levonorgestrel, there have been no reported cases of masculinization of a female fetus. In the 32 reported live births, 30 infants were reported as healthy. Two anomalies were reported: one case of pulmonary artery hyperplasia and one case of cystic hypoplastic kidney in an infant whose sibling had renal agenesis [28]. 2.9. Comparison to similar methods The LNG IUS is more expensive than the currently available copperT 380A IUD. They are equally effective in protecting against pregnancy [41]. Only one study demonstrated a difference in adverse side effects, with more headaches and acne with the LNG IUS compared to the copper-T [42]. Expulsion rates were equal at 5 years [43]. Efficacy of the LNG IUS as emergency contraception has not yet been reported. 3. Conclusion 3.1. The future While the LNG IUS 20 µg/day is considered a low dose steroid delivery system with mainly local effects, some adverse lipid effects still may occur, thus, even lower doses are being evaluated [44,45]. Additionally the LNG IUS is too large for some nulliparous and post menopausal women. This has prompted the development of a new smaller LNG-IUS for smaller uteri [46]. Furthermore, a frameless LNG IUS is under development which contains a 14 µg/day coaxial fibrous delivery system within the conventional frameless GyneFIx IUD [47]. This lower dose unit appears to have minimal if any systemic effects. This device requires anchoring in the uterine cavity through an upgraded Mark 2 inserter [48]. Due to ease and familiarity with the Tshaped IUD, a T-LNG 14 µg/day delivery system is near release. The potential benefits of T-LNG 14 (small and regular) systems include simple insertion for a wide range of providers, a lower dose of progestin resulting in reduced adverse effects, and an extended efficacy of about 10 years [49].
811
It is clear that intrauterine delivery of steroids via an IUS has achieved widespread international acclaim for ease and efficacy. It provides long term efficacy, improved compliance, rapid reversibility and minimal adverse effects during use. It is anticipated that the indications for intrauterine drug/steroid delivery will grow and extend to other specialty and subspecialty needs. References [1] S.K. Henshaw, Unintended pregnancy in the United States, Fam. Plann. Perspect. 30 (1998) 24–29 46. [2] Ortho Pharmaceutical Corp. Annual Birth Control Study. Raritan, NJ: Ortho Pharmaceutical Corp, 1998. [3] R.A. Hatcher, F. Stewart, J. Trussell, et al., Contraceptive technology 1990–1992, Irvington Publishers, New York, 1994. [4] J. Trussell, B. Vaughan, Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth, Fam. Plann. Perspect. 31 (1999) 64–72. [5] P.J.A. Hillard, The patient's reaction to side effects of oral contraceptives, Am. J. Obstet. Gynecol. 161 (1989) 1412–1415. [6] K. Andersson, The levonorgestrel intrauterine system: more than a contraceptive, Eur. J. Contracept. Reprod. Health Care 6 (Suppl 1) (2001) 15–22. [7] R.M. Soderstrom, The Progestasert® intrauterine progesterone contraception system. A new look at IUDs—advancing contraceptive choices, in: C.W.B. Bardi, D.R. Mishell Jr. (Eds.), Fourth Conference on IUDs, Butterwords-Heinemann, Boston, 1992, pp. 319–327. [8] K. Andersson, L.A. Mattsson, G. Rybo, E. Stadberg, Intrauterine release of levonorgestrel—a new way of adding progestogen in hormone replacement therapy, Obstet. Gynecol. 79 (1992) 963–967. [9] C.G. Nilsson, T. Luukkainen, P. Lahteenmaki, Determination of plasma concentrations of d-norgestrel during a 1 year follow-up in women with a d-norgestrelreleasing IUD, Contraception 17 (1978) 569–573. [10] C.G. Nilsson, P. Lahteenmaki, D.N. Robertson, T. Luukkainen, Plasma concentrations of levonorgestrel as a function of the release rate of levonorgestrel from medicated intrauterine devices, Acta Endocrinol. (Copenhagen) 93 (1980) 38–40. [11] C.G. Nilsson, P. Lahteenmaki, T. Luukkainen, Patterns of ovulation and bleeding with a low levonorgestrel-releasing intrauterine device, Contraception 21 (1980) 155–164. [12] C.G. Nilsson, P. Lahteenmaki, T. Luukkainen, Levonorgestrel plasma concentrations and hormone profiles after insertion and after 1 year of treatment with a levonorgestrel-IUD, Contraception 21 (1980) 225–233. [13] C.G. Nilsson, M. Haukkamaa, T. Luukkainen, Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD, Clin. Endocrinol. 17 (1982) 529–536. [14] C.G. Nilsson, T. Luukkainen, H. Arko, Endometrial morphology in women using a dnorgestrel-releasing IUD, Fertil. Steril. 29 (1978) 397–401. [15] E. Weiner, E.B.D. Johansson, Plasma levels of d-norgestrel, estradiol and progesterone during treatment with silastic implants containing d-norgestrel, Contraception 14 (1976) 81–92. [16] J. Toivonen, P. Lahteenmaki, T. Luukkainen, Bleeding and ovulation control with use of a small contraceptive vaginal ring releasing levonorgestrel and estradiol, Contraception 20 (1979) 11–18. [17] R. French, J. Gullebaud, Mirena, the levonorgestrel intra-uterine system (20 ug/day), J. Drug Evaluation 1 (2) (2003) 43–69. [18] I. Sivin, Risks and benefits, advantages and disadvantages of levonorgestrelreleasing contraceptive implants, Drug Safety 26 (5) (2003) 303–335. [19] K. Andersson, V. Odlind, G. Rybo, Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during 5 years of use: a randomized comparative trial, Contraception 49 (1) (1994) 56–72. [20] H.O. Critchley, H. Wang, R.L. Jones, R.W. Kelly, T.A. Drudy, A.E. Gebbie, et al., Morphological and functional features of endometrial decidualization following long-term intrauterine levonorgestrel delivery, Hum. Reprod. 13 (1998) 1218–1224. [21] E. Mandelin, H. Koistinen, R. Koistinen, B. Affandi, M. Seppala, Levonorgestrelreleasing intrauterine device-wearing women express contraceptive glycodelin A in endometrium during midcycle: another contraceptive mechanism? Hum. Reprod. 12 (1997) 2671–2675. [22] T. Luukainen, P. Lahteenmaki, J. Toivonen, Levonorgestrel-releasing intrauterine device, Ann. Med. 22 (2) (1990) 85–90. [23] J. Gullebaud, The levonorgestrel intrauterine system: a clinical perspective from the U.K. Ann. N.Y. Acad. Sci. 997 (2003) 185–193. [24] I. Sivin, Protective effect of intrauterine release of levonorgestrel on pelvic infection: 3 years' comparative experience of levonorgestrel- and copper-releasing intrauterine devices, Obstet. Gynecol. 77 (1991) 960–961. [25] I. Barbosa, S.E. Olsson, V. Odlind, T. Goncalves, E. Coutinho, Ovarian function after 7 years' use of a levonorgestrel IUD, Adv. Contracept. 11 (1995) 85–95. [26] Increasing access to IUDs, in: D Grimes (Ed.), The Contraception Report, 1998, p. 9. [27] Mirena (LNG IUS) [package insert]. Montvale, Berlex Laboratories, Inc, NJ, 2000. [28] R.S. French, F.M. Cowan, D. Mansour, J.P. Higgins, A. Robinson, T. Procter, et al., Levonorgestrel-releasing (20 μg/day) intrauterine systems (Mirena) compared with other methods of reversible contraceptives, BJOG 107 (2000) 1218–1225. [29] T. Backman, S. Huhtala, T. Blom, R. Luoto, I. Rauramo, M. Koskenvuo, Length of use and symptoms associated with premature removal of the levonorgestrel
812
[30] [31] [32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
S. Rose et al. / Advanced Drug Delivery Reviews 61 (2009) 808–812 intrauterine system: a nation-wide study of 17,360 users, BJOG 107 (2000) 335–339. T. Luukkainen, P. Pakarinen, J. Toivonen, Progestin-releasing intrauterine systems, Semin. Reprod. Med. 19 (2001) 355–363. J.T. Jensen, Noncontraceptive applications of the levonorgestrel intrauterine system, Curr. Womens Health Rep. 2 (2002) 417–422. M. Ronnerdag, V. Odlind, Health effects of long-term use of the intrauterine levonorgestrel-releasing system: a follow-up study over 12 years of continuous use, Acta Obstet. Gynecol. Scand. 78 (1999) 716–721. A. Ikomi, E.F. Pepra, Efficacy of the levonorgestrel intrauterine system in treating menorrhagia: actualities and ambiguities, J. Fam. Plann. Reprod. Health Care 28 (2002) 99–100. P. Lahteenmaki, M. Haukkamaa, J. Puolakka, U. Riikonen, S. Sainio, J. Suvisaari, et al., Open randomized study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy, BMJ 316 (1998) 1122–1126. R. Nagrani, P. Bowen-Simpkins, J.W. Barrington, Can the levonorgestrel intrauterine system replace surgical treatment for the management of menorrhagia? BJOG 109 (2002) 345–347. P. Vercellini, G. Aimi, S. Panazza, O. De Giorgi, A. Pesole, P.G. Crosignani, A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study, Fertil. Steril. 72 (1999) 505–508. A. Ikomi, E.F. Pepra, Efficacy of the levonorgestrel intrauterine system in treating menorrhagia: actualities and ambiguities, J. Fam. Plann. Reprod. Health Care 28 (2002) 99–100. P. Lahteenmaki, M. Haukkamaa, J. Puolakka, U. Riikonen, S. Sainio, J. Suvisaari, et al., Open randomized study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy, BMJ 316 (1998) 1122–1126. I. Jarvela, A. Tekay, P. Jouppila, The effect of a levonorgestrel releasing intrauterine system on uterine artery blood flow, hormone concentrations and ovarian cyst formation in fertile women, Hum. Reprod. 13 (1998) 3379–3383. K. Andersson, I. Batar, G. Rybo, Return to fertility after removal of a levonorgestrelreleasing intrauterine device and Nova-T, Contraception 46 (1992) 575–584.
[41] R.S. French, F.M. Cowan, D. Mansour, J.P. Higgins, A. Robinson, T. Procter, et al., Levonorgestrel-releasing (20 μg/day)intrauterine systems (Mirena) compared with other methods of reversible contraceptives, BJOG 107 (2000) 1218–1225. [42] T. Luukkainen, H. Allonen, M. Haukkamaa, P. Lahteenmaki, C.G. Nilsson, J. Toivonen, Five years' experience with levonorgestrel-releasing IUDs, Contraception 5 (1986) 139–148. [43] C.G. Nilsson, T. Luukkainen, J. Diaz, H. Allonen, Intrauterine contraception with levonorgestrel: a comparative randomized clinical performance study, Lancet 1 (Pt 1) (1981) 577–580. [44] L.O. Wollter-Svensson, E. Stadberg, K. Andersson, et al., Intrauterine administration of levonorgestrel in two low doses in HRT administration, Maturitas 22 (1995) 199–205. [45] T. Raudaskoski, J. Tapanainen, E. Tomas, H. Luotola, F. Pekonen, H. Ronni-Sivula, H. Timonen, F. Riphagen, T. Laatikainen, Intrauterine 10 ug and 20 ug levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial, metabolic response, Br. J. Obstet. Gynecol. 109 (2002) 136–144. [46] M.H. Birkhauser, New routes of HRT administration, Int. J. Fertil. 43 (1998) 206–207. [47] D. Wildmeersch, E. Schacht, P. Wildemeersch, D. Janssens, M. Thiery, Development of a miniature, frameless intrauterine levonorgestrel-releasing system for contraception and treatment: a review of initial clinical experience, Reprod. BioMed. 4 (2001) 69–80 (www.rbmonline.com). [48] S. Wu, J. Hu, D. Wildemeersch, Performance of the frameless gyneFix and the TCu380A IUDs in a 3 year multicenter randomized comparative trial in parous women, Contraception 61 (2000) 91–99. [49] G.D. Andrews, K. French, C.L. Wilkinson, Appropriately trained nurses are competent at inserting intrauterine devices: an audit of clinical practice. Contraceptive Choices and Realities, in: RHW van Lunsen, V Unzeitig, G Creatas (Eds.), Proceedings of the 5th Congress of the European Society of Contraception, The Parthenon Publishing Group, London, 2000, pp. 160–163.