Advanced Drug Delivery Reviews 61 (2009) 808812

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 efcacy rate, and low rates of
patient discontinuation. In addition to its contraceptive benets, 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
efcacy, 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.
Efcacy . . . . . . . . . . . . . . . . .
2.3.
Discontinuation . . . . . . . . . . . . .
2.4.
Bleeding patterns . . . . . . . . . . . .
2.5.
Noncontraceptive benets . . . . . . . .
2.6.
Ovarian cysts . . . . . . . . . . . . . .
2.7.
Insertion . . . . . . . . . . . . . . . .
2.8.
Pregnancy . . . . . . . . . . . . . . . .
2.9.
Comparison to similar methods . . . . . .
3.
Conclusion . . . . . . . . . . . . . . . . . . .
3.1.
The future . . . . . . . . . . . . . . . .
References. . . . . . . . . . . . . . . . . . . . . .

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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: Susan.rose@hsc.utah.edu (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
efcacy 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) 808812

reproductive-aged women use OCPs, and 3250% discontinue use in

the rst 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 prole 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 benets 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 g of levonorgestrel
is released initially every 24 h and over a period of 5 years the release
rate drops to 11 g every 24 h [6]. The average release rate is 14 g/day.
The frame incorporates barium sulfate to render the system radioopaque. The LNG IUS is sold as Levonova (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 efcacious 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 rst 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 benet 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 efcacy (1 year) and
failure to protect against ectopic pregnancy [7]. The LNG IUS rst
emerged in 1976 and represented the combination of the Nova-T IUD
(a copper-T intrauterine device with exible arms) and levonorgestrel; the copper lament 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 rst 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 [1013]. Low dose release of the progestogen revealed a
uniform histologic pattern regardless of the duration of placement or
ovulation [13,14]. The characteristic histologic ndings 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 ndings conrmed 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 15 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 signicantly reduced nonspecic delivery of
steroid hormone [9,1518]. The high endometrial levonorgestrel
levels, low nonspecic tissue levels and relatively low plasma levels
afforded by the 30 g LNG IUS revealed a highly specic tissue uptake
affording an increased safety margin. In fact, the endometrial
concentration represented only 0.62.2% of the daily release [13].
When considering the concentration of endometrial cytosolic progesterone receptors, the mean endometrial concentration of levonorgestrel was sufcient 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) 808812

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 inammatory reaction that may also be
spermatotoxic. In addition to the contraceptive actions, the intrauterine release of levonorgestrel may also provide protection against
pelvic inammatory 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
Efcacy of LNG [40,42].

marketing experience similar safety and efcacy 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 69 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
inammatory disease [25]. This system is an ideal alternative for
those women who may have an allergic reaction or other difculties
with the copper IUD. Over 10 million US women appear to t 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. Efcacy
The LNG IUS has been approved by the FDA for up to 5 years of use.
The rst-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
efcacy 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 rst 24 months followed by several months
of regular, brief, 23 day menses. Over time, long-term users can
anticipate a 70%90% reduction in blood loss. [31]. By the end of the
rst year, 20% will have developed complete amenorrhea [11]. A
signicant reduction in bleeding is seen; thus, hemoglobin, hematocrit, and ferritin levels increase during the rst through fth years of
use [32].
2.5. Noncontraceptive benets

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 benets 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 broids and/or adenomyosis
[33]. Compared to medical interventions and hysteroscopic endometrial resection, the LNG IUS shows signicant short term efcacy [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) 808812

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 conrm 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 rst 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]. Efcacy of
the LNG IUS as emergency contraception has not yet been reported.
3. Conclusion
3.1. The future
While the LNG IUS 20 g/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 g/day coaxial brous
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 g/day delivery system is near release. The
potential benets 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
efcacy 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 efcacy. It
provides long term efcacy, 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.
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