Intraperitoneal levonorgestrel-releasing intrauterine device following uterine perforation: the role of progestins in adhesion formation

Ronit Haimov-Kochman1,3, Victoria Doviner2, Hagay Amsalem1, Diane Prus2, Amiram Adoni1 and Yuval Lavy1

1 Department of Obstetrics and Gynecology and 2 Department of Pathology, Hadassah University Hospital, 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{at}hotmail.com


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Intrauterine contraception is a widely used, highly effective means of birth control. Uterine perforation is a serious, albeit rare, complication of intrauterine device (IUD) use. Although uterine perforation by levonorgestrel-releasing (20 µg/day) intrauterine system (LNG-IUS) has already been reported, the peritoneal adhesion potential of this IUD is unknown. METHODS: The medical files of all patients diagnosed with an intra-peritoneal IUD between the years 1990–2002 at Hadassah Medical Center were reviewed. Histopathological study of peritoneal adhesion tissue adjacent to levonorgestrel medicated IUD was conducted in one case. RESULTS: Eight cases of dislocated IUDs were found. Four cases used LNG-IUS and four other cases used copper-IUD. Laparoscopy for IUD removal disclosed mild local peritoneal adhesions between omentum and pelvic organs in all cases. No difference was noted in the appearance of the peritoneum in the presence of either a copper-IUD or LNG-IUS. Histological examination of peritoneal tissue encasing the levonorgestrel-intrauterine system revealed loose connective tissue with aggregates of submesothelial cells with a pseudo-decidual change. Immunohistochemical staining for progesterone receptor was negative. CONCLUSIONS: The peritoneal adhesions potential of LNG-IUS is low, similar to that of the copper-bearing IUD.

Key words: adhesions/intrauterine device/levonorgestrel/perforation


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Intrauterine contraception is a widely used, highly effective means of birth control. Uterine perforation is a serious, albeit rare, potential complication of intrauterine device (IUD) use. Copper-bearing IUD is known to cause local peritoneal adhesions (Adoni and Ben Chetrit, 1991Go). Therefore its removal from the peritoneal cavity is recommended once perforation is diagnosed. Levonorgestrel-releasing (20 µg/day) intrauterine system (LNG-IUS) (Mirena®, Schering AG, Germany) was introduced to the market in Israel in 1998. Although uterine perforation by this form of IUD has already been reported (Andersson et al., 1998Go), the peritoneal adhesion potential of the levonorgestrel-releasing intrauterine device is unknown.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The medical files of all patients diagnosed with an IUD in the peritoneal cavity between the years 1990–2002 at Hadassah Medical Center were reviewed. In case number 4 (Table I) peritoneal adhesions encasing the IUD were separated, formalin fixed and paraffin embedded. Sections of 4 µm thickness were stained with haematoxylin and eosin. Immunohistochemistry was performed using antibodies to vimentin (clone Vim3B4; Dako, Glostrup, Denmark), smooth muscle actin (clone 1A4; Dako), CD-68 (clone KP1; Dako), caldesmon (clone h-CD; Dako), calretinin ([PAD:DC8]; Zymed, San Francisco, CA, USA), cytokeratin (clone LP34; Dako), desmin (clone NCL-DE-R-11; Ventana Medical Systems Inc., Harvard, MA, USA), estrogen receptor (clone 6F11; Ventana Medical Systems Inc.) and progesterone receptor (clone 1A6; Ventana Medical Systems Inc.).


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Table I. Data of eight patients with uterine perforation by an IUD
 

    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Eight cases of dislocated IUDs were treated at Hadassah Medical Center between the years 1990–2002 (Table I). Seven of them were inserted within 3 months post-partum. Six of the patients were breast-feeding at the time of IUD placement. In four cases LNG-IUS (Mirena) was used and in four other cases copper-IUD was inserted. The main reasons for investigation of the IUD localization were mild abdominal pain and irregular uterine bleeding. One patient was found to be 8 weeks pregnant. The means for investigation were a transvaginal ultrasonogram and an antero–posterior radiograph of the pelvis. Diagnosis of dislocated IUD was made 12 days to 7 months following insertion. Laparoscopy was performed uneventfully in all patients. On laparoscopy, the perforation site was noted in only four cases, when a relatively short time had elapsed from insertion to laparoscopic removal. The IUD was disclosed in five cases encased in the omentum. Mild peritoneal adhesions were reported between omentum and pelvic organs in all eight cases. Lysis of peritoneal adhesions was undertaken in only one case with a history of five previous Caesarean sections. No difference was noted in the appearance of the peritoneum in the presence of either a copper-IUD or a levonorgestrel-releasing intrauterine system.

Histological examination of peritoneal tissue adjacent to LNG-IUS (in case number 4), revealed richly vascularized loose connective tissue with calcifications and mild chronic inflammation admixed with a few foreign body-type giant cells. Aggregates of swollen cells with eosinophilic cytoplasm and vesicular nucleus were found embedded in the tissue. These cells stained with vimentin only and were identified as sub-mesothelial stromal cells of the peritoneal cavity that underwent pseudo-decidual changes (Figure 1). Immuno histochemical staining for estrogen receptor was positive, but staining for progesterone receptor was negative.



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Figure 1. Peritoneal adhesion tissue adjacent to levonorgestrel-releasing IUD. Aggregates of sub-mesothelial stromal cells showing pseudo-decidual changes (white arrows). Note calcifications (black arrows) between the cells (haematoxylin and eosin, original magnification x200).

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The most serious potential complication of IUD use is uterine perforation, which has been reported to happen in 0–1.3 events per 1000 insertions (Andersson et al., 1998Go; Markovitch et al., 2002Go). Uterine perforation by a copper-bearing IUD, although usually asymptomatic, could rarely entail severe morbidity such as bowel obstruction and infection. This type of IUD is known to cause local peritoneal adhesions. The process of adhesion formation in reaction to copper-bearing IUD is self-limited and stops after a short period of time (Adoni and Ben Chetrit, 1991Go). The recommended treatment of a misplaced copper-bearing IUD is its removal from the abdominal cavity by laparoscopy (Silva and Larson, 2000Go), although recently conservative management of mislocated IUDs has also been suggested (Markovitch et al., 2002Go). Laparotomy is considered to be by far too dangerous a procedure for the management of an ectopic asymptomatic copper-IUD (Adoni and Ben Chetrit, 1991Go).

Levonorgestrel-releasing (20 µg/day) intrauterine system (Mirena) is a relatively new form of contraception. Perforation of the uterus during its insertion has been reported among other IUD types in a Swedish survey (Andersson et al., 1998Go); however, the abdominal cavity in its presence was not described. The adhesion formation potential of LNG-IUD remained largely unknown. Mirena, similar to copper-bearing IUDs, consists of a plain plastic T-shaped frame. The development of peritoneal adhesions in response to a non-irritating plastic-made foreign body was described by Echenberg and Ledger (1968Go). This process involves encasement of the device in delicate peritoneal bands. The plastic skeleton of Mirena carries a cylindric progestogen reservoir that contains 52 mg levonorgestrel and is covered by a polydimethylsiloxane membrane which regulates the release of levonorgestrel. Local release of levonorgestrel by Mirena results in very high tissue concentrations, ranging from 470–1500 ng/g wet weight. The endometrial changes seen in the presence of LNG-IUD are: endometrial gland atrophy, stromal decidualization, thickened arterial walls and endometrial capillary thrombosis. An inflammatory reaction involving neutrophils, lymphocytes, plasma cells and macrophages is described (Zhu et al., 1989Go), and focal stromal necrosis may also occur (Silverberg et al., 1986Go). The local effect of high levonorgestrel concentrations on the peritoneum involves a pseudo-decidual change of swollen cells with rich eosinophilic cytoplasm identified as sub-mesothelial cells by immunohistochemical studies. So far, the pseudo-decidual change, also known as ectopic peritoneal decidua, was described as developing solely in relation to pregnancy, when it was found at sites such as the sub-mesothelial stroma of the uterus, the uterine ligaments, adnexae, appendix and omentum (Clement et al., 1999Go). No evidence of tissue necrosis was demonstrated in response to high local levonorgestrel concentrations. A high rate of progesterone receptivity was disclosed when pelvic adhesion tissue was evaluated for sex steroid receptors (Wiczyk et al., 1998Go). In our study negative staining for progesterone receptor in the connective tissue in proximity to levonogestrel-medicated IUD could indicate down-regulation of the receptor in reaction to local high levels of the progestogen.

The issue of the effect of progestogens on peritoneal adhesions is controversial. Progesterone has well-established anti-inflammatory and immunosuppressive properties that could play a role in the prevention of peritoneal adhesion formation. Intra-peritoneal instillation of progesterone was shown to prevent the development of adhesions in pelvic surgery (Maurer and Bonaventura, 1983Go). However, other studies using locally or parenterally administered progestogens failed to support this claim (Blauer and Collins, 1988Go; Confino et al., 1988Go). Recently, it was argued that pre-operative use of medroxyprogesterone acetate prevents post-operative adhesions development (Ustun et al., 1998Go; Sagol et al., 1999Go; Baysal, 2001Go). Our data demonstrated that high local concentrations of progestins neither affect nor dramatically prevent adhesion formation.

Our results show a lack of difference in the peritoneal cavity appearance in the presence of either a copper-IUD or a LNG-IUS. Although no treatment policy should be based on small case-series reports, in the infrequent event of uterine perforation by IUD, much is to be learnt from each report. Our presented cases, in accordance with what has been previously reported regarding perforating copper-bearing IUDs (Adoni and Ben Chetrit, 1991Go; Silva and Larson, 2000Go; Markovitch et al., 2002Go), disclosed only local and delicate peritoneal adhesions in the presence of both copper-bearing IUDs and LNG-IUS. Bands of adhesions that could cause bowel obstruction did not develop. Therefore, the same treatment mode of a suggested laparoscopy for IUD removal for symptomatic, medico-legal or psychological reasons, could fit both copper-bearing and levonorgestrel-medicated IUDs. From the point of view of peritoneal adhesion formation, given the risk associated with laparotomy, it may be safer to leave a perforated LNG-IUS in place than to remove it by laparotomy. However, our advice is based only on our limited experience and further data is needed, probably through a multi-centre study.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Andersson, K., Ryde-Blomqvist, E., Lindell, K., Odlind, V. and Milsom, I. (1998) Perforations with intrauterine devices. Report from a Swedish survey. Contraception, 57, 251–255.[CrossRef][ISI][Medline]

Baysal, B. (2001) Comparison of the resorbable barrier interceed (TC7) and preoperative use of medroxyprogesterone acetate in postoperative adhesion prevention. Clin. Exp. Obstet. Gynecol., 28, 126–127.

Blauer, K.L. and Collins, R.L. (1988) The effect of intraperitoneal progesterone on postoperative adhesion formation in rabbits. Fertil. Steril., 49, 144–149.[ISI][Medline]

Clement, P.B., Young, R.H. and Scully, R.E. (1999) The Peritoneum. In Sternberg, S.C. (ed) Diagnostic Surgical Pathology, Vol. 2, 3rd edn. Lippincott Williams and Wilkins, USA. p. 2437.

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Markovitch, O., Klein, Z., Gidoni, Y., Holzinger, M. and Beyth, Y. (2002) Extrauterine mislocated IUD: is surgical removal mandatory? Contraception, 66, 105–108.[CrossRef][ISI][Medline]

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Silverberg, S.G., Haukkamaa, M., Arko, H., Nilsson, C.G. and Luukkainen, T. (1986) Endometrial morphology during long-term use of levonorgestrel-releasing intrauterine devices. Int. J. Gynecol. Pathol., 5, 235–241.[ISI][Medline]

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Wiczyk, H.P., Grow, D.R., Adams, L.A., O’Shea, D.L. and Reece, M.T. (1998) Pelvic adhesions contain sex steroid receptors and produce angiogenesis growth factors. Fertil. Steril., 69, 511–516.[CrossRef][ISI][Medline]

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Submitted on September 13, 2002; resubmitted on December 12, 2002; accepted on January 14, 2003.





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