Human Reproduction Vol.18, No.6 pp.

12311233, 2003

DOI: 10.1093/humrep/deg263

Management of a perforated levonorgestrel-medicated

intrauterine devicea pharmacokinetic study: Case report
Ronit Haimov-Kochman1,3, Hagay Amsalem1, Amiram Adoni1, Yuval Lavy1 and
Irving M.Spitz2
1

Department of Obstetrics and Gynecology, Hadassah University Hospital and 2Institute of Hormone Research, Shaare-Zedek
Medical Center, Jerusalem, Israel
3

To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Hadassah University Hospital, Mount
Scopus, P.O.B 24035 Il-91240, Jerusalem, Israel. E-mail: rkochman@hotmail.com

Key words: intrauterine device/levonorgestrel/perforation/pharmacokinetics/progestagen

Introduction
Intrauterine contraception is a widely used and a highly
effective means of birth control. Uterine perforation is a
potential complication with the use of an intrauterine device
(IUD). Although misplaced IUDs are usually managed by
laparoscopic removal, this approach has been questioned. It has
been claimed that since intestinal complications are negligible
after uterine perforation by copper-IUDs, their removal from
the pelvis is not mandatory (Adoni and Ben Chetrit, 1991;
Markovitch et al., 2002). Although uterine perforation by a
levonorgestrel-releasing (20 mg/d) intrauterine system (LNGIUS) has already been reported (Andersson et al., 1998;
Bobrow et al., 2000) the plasma LNG concentrations in this
setting have not been determined.

Case report
A 33-year-old woman, gravida 2, para 2, with history of regular
menstrual cycles and a Caesarean section for twin discordance
at the 32nd week of her rst pregnancy, opted for an LNG-IUD
(Mirena, Schering AG, Germany) for contraception. LNGIUD was inserted 8 weeks following a normal vaginal delivery
when she was experiencing her rst menstrual bleeding postpartum. The patient was not breast-feeding at the time of the
insertion. The procedure was reported to be uneventful.
European Society of Human Reproduction and Embryology

Routine trans-vaginal sonogram performed 2 months following

the procedure failed to demonstrate the device in utero. A
radiograph of the pelvis conrmed the diagnosis of a misplaced
intra-abdominal LNG-IUD. Laparoscopy for IUD removal was
scheduled. The patient reported cessation of regular menses
and intermittent spotting during the 5 months period until
laparoscopy was conducted.
On laparoscopy, the uterus and the adnexae appeared
normal. The perforation site was unidentied. An LNG-IUD
was observed encased in mild peritoneal adhesions in the
pouch of Douglas and was easily removed. The remainder of
the procedure was uneventful and the patient was discharged
the following day. Plasma concentrations of LNG and sex
hormone binding globulin (SHBG) were measured 1 day prior
to the procedure and serially for 24 h following the
laparoscopy. Assays for LNG determination were performed
at the Steroid Research Laboratory in Helsinki, Finland,
following the method described by Johansson et al. (2002)
Results
Intra-peritoneal dislocated LNG-IUS resulted in a plasma LNG
concentration of 4.7 nmol/l. Twenty ve hours following IUD
removal, the plasma LNG level dropped by 15% (4.7 to
4 nmol/l) and the SHBG level rose by 13% (79.5 to 91 nmol/l)
(SHBG normal range: 18114 nmol/l) (Table I).
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Intrauterine contraception is a widely used, highly effective method of birth control. Uterine perforation is a serious
albeit rare complication with the use of an intrauterine device (IUD). Although uterine perforation by the levonorgestrel-releasing intrauterine system (LNG-IUS) has already been described, no plasma LNG concentrations in this
setting were reported. Neither has the management of LNG-IUS been commented on to date. Two months after
insertion of an LNG-IUS into a 33-year-old woman, it was noted to be in the peritoneal cavity. Laparoscopy for IUD
removal was conducted 5 months after insertion. LNG and sex hormone-binding globulin plasma concentrations
were measured prior to and following the laparoscopic removal of the IUD. Intra-peritoneal dislocated LNG-IUS
resulted in plasma LNG levels 10 times higher (4.7 nmol/l) than the plasma level of LNG observed with LNG-IUS
placed in utero. This high plasma LNG level suppresses ovulation. Therefore a misplaced LNG-IUS should be
removed when pregnancy is desired.

R.Haimov-Kochman et al.
Table I. LNG and SHBG serum levels prior to and following LNG-IUD
removal

Table II. Comparison of levonorgestrel (LNG) plasma concentrations for

various methods of contraception

Sample no.

Date drawn

No of
hours

LNG
nmol/l

SHBG
nmol/l

Type of contraception

Plasma LNG levels (6 SD)

after steady state (nmol/l)

Reference
no.

1
2

Pre-laparoscopy
Day of IUD removalpost laparoscopy

2:00
+2:00

4.7
4.5

79.5

417 6 3.7

+4:00
+6:00
+9:00
+11:00
+19:00
+25:00

4.4
4.3
4.6
4.4
3.6
4.0

Microgynon EE2 0.03 mg +

LNG 0.15 mg
Microluton mini-pill LNG 30 mg
Norplant
Mirena in utero
Mirena in peritoneum

0.96 6 0.65
0.93 6 0.08
0.44 6 0.2
4.7

13
5
6,1113

3
4
5
6
7
8

1st day post laparoscopy

91

Discussion

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inter-individual variation of SHBG levels exists (Xiao et al.,

1990; Jia et al., 1992; Kuhnz et al., 1992).
Plasma SHBG levels increased in our patient by 15%, 25 h
following LNG-IUS removal. The concentrations of SHBG
have been shown to decrease slightly during the use of oral
LNG-containing contraceptive mini-pill, but not during the use
of LNG-IUS (Pakarinen et al., 1999). LNG released from either
subdermal or intrauterine devices is not subjected to a `rstpass' effect of the liver, unlike LNG administered orally or
released i.p. We presume that i.p. localization of LNG-IUS
may result in increased hepatic exposure to LNG via the portal
system, leading to decreased levels of SHBG.
Although no strong recommendations should be based on
case reports, in the infrequent event of uterine perforation by an
IUD, there is much to be learnt from each report. The very high
level of plasma LNG originating from the i.p. misplaced
LNG-IUD dictates a different therapeutic strategy towards its
presence and its removal. I.p. LNG-medicated IUD may
suppress ovulation, and could still be regarded as an effective
contraception. When pregnancy is desired, the therapeutic
approach differs from that of a copper IUD. The latter may be
left intraperitoneally, especially if asymptomatic. In contrast, a
misplaced LNG-IUD should be removed in order to permit
ovulation.
Acknowledgement
We thank Dr Sirpa Ranta from the Steroid Research Laboratory,
Institute of Biomedicine/Biochemistry, University of Helsinki,
Finland for the measurements of plasma LNG concentrations of the
patient.

References
Adoni, A. and Ben Chetrit, A. (1991) The management of intrauterine devices
following uterine perforation. Contraception, 43, 7781.
Andersson, K., Ryde-Blomqvist, E., Lindell, K., Odlind, V. and Milsom, I.
(1998) Perforations with intrauterine devices. Report from a Swedish
survey. Contraception, 57, 251255.
Bobrow, C., Cooling, H. and Bisson, D. (2000) Amenorrhoea despite
displaced levonorgestrel intra-uterine system. Br. J. Fam. Plann., 26,
105106.
Croxatto, H.B., Diaz, S., Pavez, M., Cardenas, H., Larsson, M. and Johansson,
E.D. (1988) Clearance of levonorgestrel from the circulation following
removal of NORPLANT subdermal implants. Contraception, 38, 509523.
Diaz, S., Pavez, M., Miranda, P., Johansson, E.D. and Croxatto, H.B. (1987)
Long-term follow-up of women treated with Norplant implants.
Contraception, 35, 551567.
Haukkamaa, M. and Holma, P. (1996) Five-year clinical performance of the

Downloaded from http://humrep.oxfordjournals.org/ by guest on November 14, 2015

To our knowledge, evaluation of LNG blood levels after

perforation into the peritoneal cavity has never been undertaken. The peritoneum is known to have a great absorptive
capacity, consequently, LNG blood levels are expected to be
higher when the IUD is in the peritoneum than when in utero.
Mirena releases LNG into the uterine cavity, where it is
quickly absorbed via the capillary network in the basal layer of
the endometrium into the systemic circulation. Within a few
weeks plasma LNG concentrations reach a plateau ranging
from 0.40.6 nmol/l (Nilsson et al., 1986; Haukkamaa and
Holma, 1996). LNG plasma concentrations achieved by
Mirena are lower than those seen with the subdermal LNGcontaining implant (Norplant), the combined oral contraception and the mini-pill (Nilsson et al., 1986; Diaz et al., 1987;
Kuhnz et al., 1992; Pakarinen et al., 1999) (Table II). Usually
this plasma level of LNG does not inhibit ovarian function
(Xiao et al., 1990). The level of LNG after intra-peritoneal
dislocation of Mirena is similar to levels reported following
combined oral contraceptive containing 0.15 mg LNG and
0.03 mg ethinyl estradiol (Microgynon) administration
(Kuhnz et al., 1992) (Table II). These higher LNG levels do
not have an untoward effect, however they may suppress
ovulation. The absence of cycle regularity and the vaginal
bleeding pattern, reported by our patient, support this speculation. The amenorrhoea, reported in another case of a
displaced LNG-IUS, could be attributed to inhibition of
ovulation (Bobrow et al., 2000).
The plasma concentration of LNG decreased moderately 25 h
following its removal from the peritoneum. The half-life of
elimination of plasma LNG after oral administration is
estimated to be 2025 h (Kuhnz et al., 1992; Nassr et al.,
1997), however, following the removal of a LNG-containing
subdermal implant, the decay rate of plasma LNG had a half
life of 42 6 16 h (range 1362). It was shown that the major
part of the steroid is cleared from the plasma within 96 h
(Croxatto et al., 1988).
Plasma LNG is mainly bound to SHBG (64%) and to
albumin (35%). The free fraction of LNG is only 1.3% (Kuhnz
et al., 1992). SHBG is a plasma binding protein with high
afnity to sex hormones such as testosterone, dihydrotestosterone, estradiol and LNG. A signicant correlation was found
between concentrations of LNG and SHBG, although a marked

EE2 = ethinyl estradiol

Misplaced levonorgestrel-medicated intrauterine device

new formulation of the levonorgestrel intrauterine system and serum
levonorgestrel concentration with the new formulation compared to that
with the original one. Leiras Study Report, 1, No.028953207.
Jia, M.C., Zhou, L.Y., Ren, S., Dong, L. and Xiao, B. (1992) Serum SHBG
levels during normal menstrual cycle and after insertion of levonorgestrelreleasing IUD. Adv. Contracept., 8, 3340.
Johansson, E., Brache, V., Alvarez, F., Faundes, A., Cochon, L., Ranta, S.,
Lovern, M. and Kumar, N. (2002) Pharmacokinetic study of different
dosing regimens of levonorgestrel for emergency contraception in healthy
women. Hum. Reprod., 17, 14721476.
Kuhnz, W., Al-Yacoub, G. and Fuhrmeister, A. (1992) Pharmacokinetics of
levonorgestrel and ethinylestradiol in 9 women who received a low-dose
oral contraceptive over a treatment period of 3 months and, after a wash-out
phase, a single oral administration of the same contraceptive formulation.
Contraception, 46, 455469.
Markovitch, O., Klein, Z., Gidoni, Y., Holzinger, M. and Beyth, Y. (2002)
Extrauterine mislocated IUD: is surgical removal mandatory?
Contraception, 66, 105108.

Nassr, N., Farker, K., Lautenschlager, M., Nagel, U., Zimmermann, H.,
Mellinger, U. and Hoffmann, A. (1997) Bioavailability study of 2 different
levonorgestrel-containing drugs in women. Int. J. Clin. Pharmacol. Ther.,
35, 123127.
Nilsson, C.G., Lahteenmaki, P.L., Luukkainen, T. and Robertson, D.N. (1986)
Sustained intrauterine release of levonorgestrel over ve years. Fertil.
Steril., 45, 805807.
Pakarinen, P., Lahteenmaki, P. and Rutanen, E.M. (1999) The effect of
intrauterine and oral levonorgestrel administration on serum
concentrations of sex hormone-binding globulin, insulin and insulinlike growth factor binding protein-1. Acta Obstet. Gynecol. Scand., 78,
423428.
Xiao, B.L., Zhou, L.Y., Zhang, X.L., Jia, M.C., Luukkainen, T. and Allonen,
H. (1990) Pharmacokinetic and pharmacodynamic studies of levonorgestrelreleasing intrauterine device. Contraception, 41, 353362.
Submitted on January 23, 2003; accepted on March 6, 2003

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