- Email: [email protected]
Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: Long-term follow-up
Maturitas 57 (2007) 210–213
Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: Long-term follow-up D. Wildemeersch a,∗ , D. Janssens b , K. Pylyser c , N. De Wever c , G. Verbeeck d , M. Dhont e , W. Tjalma f a
Gynecological Research Unit, Incubation and Innovation Center, Technology Park, Ghent, Belgium b Gynaecologische Dienst Broedersstraat, Turnhout, Belgium c Department of Anatomo-pathology, St. Augustinus Hospital, Veurne, Belgium d Department of Anatomo-pathology, St. Elisabeth Hospital, Turnhout, Belgium e Department of Obstetrics and Gynecology, University Hospital Ghent, Belgium f Department of Obstetrics and Gynecology, University of Antwerp, Belgium
Received 8 August 2006; received in revised form 17 November 2006; accepted 16 December 2006
Abstract Objectives: Levonorgestrel (LNG), delivered locally into the uterine cavity has a profound effect on the endometrium. The aim of the study was to use a LNG intrauterine system to treat non-atypical and atypical endometrial hyperplasia in women and to evaluate the long-term cure (remission) rate. Methods: Each of the 20 women in the study, of whom eight were diagnosed with atypical hyperplasia, received a LNG–IUS, releasing 20 g LNG/day. The study is a non-comparative study with long-term follow-up (range 14–90 months). Results: All women developed a normal endometrium, except one asymptomatic woman with atypical hyperplasia who still had focal residual non-atypical hyperplasia at 3 years follow-up in the presence of a thin (<4 mm) endometrium. Conclusion: Continuous intrauterine delivery of LNG appears to be a promising alternative to hysterectomy for the treatment of endometrial hyperplasia and could enhance the success rate when compared with other routes of progestagen administration as well as intrauterine progesterone delivery. The significant reduction of the PR expression observed during treatment with the LNG–IUS appears to be a marker for the strong antiproliferative effect of the hormone at a cellular level resulting in an inhibition of estrogen bioactivity and endometrial suppression. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Intrauterine system (IUS); Levonorgestrel (LNG); Endometrial hyperplasia; Long-term study
∗
Corresponding author at: Piers de Raveschootlaan, 8300 Knokke, Belgium. Tel.: +32 50 600 900; fax: +32 50 622 429. E-mail address: [email protected] (D. Wildemeersch).
0378-5122/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2006.12.004
D. Wildemeersch et al. / Maturitas 57 (2007) 210–213
211
1. Introduction
2. Materials and methods
Endometrial hyperplasia is considered a precursor of cancer of the endometrium but only women presenting with atypical hyperplasia have a risk of developing endometrial carcinoma. The risk is estimated to be between 27% and 30% [1]. Consequently, the classical treatment of atypical endometrial hyperplasia has been hysterectomy. Progestagens have been used since the 1960 mainly in young women with a wish for pregnancy. The most frequently used progestagen has been medroxyprogesterone acetate (MPA) but side effects were numerous (e.g. headache, nausea) and long-term use results in metabolic changes and exposes the woman to a higher risk of thromboembolic events [2]. More recently, GnRH analogues have been proposed for the treatment of endometrial cancer and endometrial hyperplasia but hormonal side effects preclude long-term treatment [3]. An alternative route to administer potent progestagens is an intrauterine drug delivery system. Locally acting progestagens act many times stronger on the endometrium than when given systemically. Dosage can, therefore, be reduced significantly, minimizing side effects and optimizing patient compliance. Clinical studies with a “frameless” levonorgestrel (LNG)–intrauterine system (IUS), releasing 14 g LNG/day, and a “framed” LNG–IUS, releasing 20 g LNG/day, suggest that both LNG delivery systems are effective to provide strong endometrial suppression which accounts for the endometrial suppressive effect observed during estrogen replacement therapy (ERT), the strong reduction in menstrual blood loss in women with excessive menstrual blood loss and menorrhagia as well as the high contraceptive action [4–8]. The interim results of the present study were published previously [9]. This study concluded that the LNG system, releasing 14 g LNG/day, is an effective method for suppressing the endometrium in women with non-atypical and atypical hyperplasia and constitutes an alternative to hysterectomy on condition that women can be properly followed-up. The purpose of the present paper is to report on the long-term results in the same women using the LNG–IUS to prevent recurrence.
The frameless, 14 g releasing LNG–IUS (FibroPlantTM , Contrel Research, Ghent, Belgium) has been described previously [9]. The IUS is implanted into the myometrium of the uterine fundus. Since the LNG–IUS has no frame, it is completely flexible, adapting to cavities of every size and shape. At expiry after 3 years of use of the FibroPlant LNG–IUS, the IUS was removed and replaced by a new T-shaped LNG–IUS (FemilisTM , Contrel Research, Ghent, Belgium), releasing 20 g LNG/day (Fig. 1) At the time of study analysis, 13 patients were using the framed, T-shaped LNG–IUS and seven the frameless LNG–IUS, releasing 20 g LNG/day (Fig. 2). Women with abnormal uterine bleeding and with endometrial hyperplasia, confirmed by pipelle biopsy or by curettage, received the LNG–IUS for local treatment of the condition. Written informed consent was obtained from each volunteer and the use of the LNG–IUS was approved by the Ethics Committee of the Ghent University Hospital. Prior to the insertion procedure, all women were screened for their clini-
Fig. 1. The FemilisTM LNG–IUS.
212
D. Wildemeersch et al. / Maturitas 57 (2007) 210–213
plasia’ in 12 women and ‘atypical hyperplasia’ in eight women (adenomatous hyperplasia with atypia in three of them). In one of the latter patients an invasive welldifferentiated adenocarcinoma was found on D&C but this was not confirmed in two subsequent endometrial pipelle samplings. To determine the endometrial progesterone receptor response during treatment (only performed in women with atypical endometrial hyperplasia), paraffin-embedded tissue sections were immunohistochemically stained with a mouse monoclonal antibody (NCL-PGR-312, Novo Castra Laboratories, Newcastle-upon-Tyne, UK. The percentage of immunoreactive nuclei was scored both in endometrial epithelium and stroma [12].
4. Results
Fig. 2. The FibroPlantTM LNG–IUS.
cal suitability for IUS insertion and compliance with the WHO eligibility criteria [10]. Following insertion, women were followed-up at 1, 3, 6, 12 months following insertion of the IUS and 6-monthly thereafter. Monitoring of the endometrium during treatment was conducted by transvaginal ultrasound (Ultramark® 4Plus, ATL Inc., Bothell, WA, USA) and by endometrial pipelle biopsy or D&C.
3. Patients Twenty women (16 parous and four nulliparous) were included in the study. Hypertension and diabetes was not present in any of them. Eight women developed postmenopausal bleeding as a result of unopposed estrogen stimulation (EST), after having taken the medication for at least 6 months up to approximately 2 years. One woman consulted because of abnormal bleeding during tamoxifen treatment for breast cancer. The other women had abnormal premenopausal bleeding. The histopathological diagnosis (Kurman classification [11]) was ‘non-atypical (simple) hyper-
The average age of the patients at study entry was 54 years (range 41–67) and the average duration of use of the LNG–IUS is 32 months (range 14–90). All women developed a thin endometrium (≤4 mm in thickness), as assessed by transvaginal ultrasound, except one patient. The latter patient presented with a polypoid structure of 20 mm in diameter prior to treatment which diminished gradually in size to 5 mm at the last follow-up examination, 53 months after insertion of the LNG–IUS. At study initiation all women presenting with atypical endometrial hyperplasia showed expression of PR in the epithelial cells. The percentage declined significantly over time during treatment. The endometrial histology specimen showed no progression of disease. Profound endometrial suppression with glandular atrophy and/or stromal decidualization was found in all women. Eight of the 20 women in the study resumed ERT. All women are continuing to use the method.
5. Comments In recent years, endometrial hyperplasia is caused most often by use of unopposed estrogen for ERT and tamoxifen for the treatment of breast cancer. Nonatypical (simple) hyperplasia is usually treated by oral administration of progestagens in sufficient dose and
D. Wildemeersch et al. / Maturitas 57 (2007) 210–213
duration. However, if the treatment is discontinued, recurrence may occur. Locally applied delivery of levonorgestrel is much more potent than oral treatment and it is, therefore, logical that this form of treatment should be preferred to oral and also to surgical treatment if it could be shown to be effective. An implantable method also provides better patient compliance. The preferred treatment for adenomatous hyperplasia with atypia or adenocarcinoma of the endometrium is hysterectomy. It is evident that this is a hard decision, especially in young women who want to preserve their fertility. The present study indicates that successful treatment is possible especially when a potent progestagen is administered locally. The study confirms preliminary studies with the Mirena® LNG–IUS (Schering AG, Berlin, Germany) in women with precancerous lesions of the endometrium [13]. Intrauterine progesterone delivery or oral administrations appears to be much less effective [14,15]. However, successful treatment of early endometrial carcinoma has been reported with a 65 g/day progesterone-releasing IUS, followed-up to 36 months, but, results of biopsies were negative only in 7 of 11 at 6 months and 6 of 8 at 12 months [16]. The significant reduction of the PR expression observed during treatment with the LNG–IUS in the present study appears to be a marker for the strong antiproliferative effect of the hormone at a cellular level resulting in an inhibition of estrogen bioactivity and endometrial suppression. Furthermore, as the treatment is continuous, compliance is not an issue.
6. Conclusion The results suggest that the LNG–IUS, releasing either 14 or 20 g LNG/day, is an effective method for suppressing the endometrium in women with non-atypical and atypical hyperplasia and constitutes an alternative to hysterectomy especially in younger women who still wish to become pregnant and in women who refuse operation or are in poor health. Treatment should be long-term and women should be closely followed-up by vaginal ultrasound and preferably by repeat endometrial biopsy.
213
References [1] Kurman RJ, Kaminski PF, Norris HJ. The behaviour of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 1985;56:403–12. [2] Randall TC, Kurman RJ. Progestagen treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under the age 40. Obstet Gynecol 1997;90:434–40. [3] Kullander S. Treatment of endometrial cancer with GnRH analogs. Recent Results Cancer Res 1992;124:69–73. [4] Wildemeersch D, Janssens D, Weyers S. Continuous combined parenteral estrogen substitution and intrauterine progestogen delivery: the ideal HST combination? Maturitas 2005;51:207–14. [5] Wildemeersch D, Janssens D, Vrijens M, Weyers S. Ease of insertion, contraceptive efficacy and safety of new T-shaped levonorgestrel-releasing intrauterine systems. Contraception 2005;71:465–9. [6] Wildemeersch D, Rowe P. Assessment of menstrual blood loss in Belgian users of a new T-shaped levonorgestrel-releasing intrauterine system. Contraception 2005;71:470–3. [7] Andrade ATL, Souza JP, Andrade GN, Rowe PJ, Wildemeersch D. Assessment of menstrual blood loss in Brasilian users of the frameless copper-releasing IUD with copper surface are of 330 mm2 and users of the levonorgestrel-releasing intrauterine system. Contraception 2004;70:173–7. [8] Wildemeersch D, Schacht E, Wildemeersch P, Calleweart K, Pylyser K, De Wever N. Endometrial safety with a low-dose intrauterine levonorgestrel-releasing system after three years of estrogen substitution therapy. Maturitas 2004;48:65–70. [9] Wildemeersch D, Dhont M. Treatment of non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system. Am J Obstet Gynecol 2003;138:1297–8. [10] World Health Organization (WHO). Medical eligibility criteria for contraceptive use. Geneva, Switzerland: WHO; 2000. [11] Kurman RJ, editor. Blaustein’s pathology of the female genital tract. 4th ed. New York: Springer Verlag; 1995., ISBN 3-54094166-5. [12] Tjalma W, Janssens D, Wildemeersch D, Colpaert C, Watty C. Conservative management of atypical endometrial hyperplasia and early invasive carcinoma with intrauterine levonorgestrel: a progesterone receptor study. Eur J Cancer 2004;2:93–4. [13] Scarselli G, Tantani C, Colafranceschi M. LevonorgestrelNova-T and precancerous lesions of the endometrium. Eur J Gynecol Oncol 1988;9:284–6. [14] Silverberg SG, Haukkamaa M, Arko H, Nilsson CG, Luukkainen T. Endometrial morphology during long-term use of levonorgestrel-releasing intrauterine devices. Int J Gynecol Pathol 1986;5:235–41. [15] Schindler AE. Progestogens, endometrial hyperplasia and endometrial cancer. Gynaecol Forum 2004;9:31–3. [16] Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002;186:651–7.
Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: Long-term follow-up D. Wildemeersch a,∗ , D. Janssens b , K. Pylyser c , N. De Wever c , G. Verbeeck d , M. Dhont e , W. Tjalma f a
Gynecological Research Unit, Incubation and Innovation Center, Technology Park, Ghent, Belgium b Gynaecologische Dienst Broedersstraat, Turnhout, Belgium c Department of Anatomo-pathology, St. Augustinus Hospital, Veurne, Belgium d Department of Anatomo-pathology, St. Elisabeth Hospital, Turnhout, Belgium e Department of Obstetrics and Gynecology, University Hospital Ghent, Belgium f Department of Obstetrics and Gynecology, University of Antwerp, Belgium
Received 8 August 2006; received in revised form 17 November 2006; accepted 16 December 2006
Abstract Objectives: Levonorgestrel (LNG), delivered locally into the uterine cavity has a profound effect on the endometrium. The aim of the study was to use a LNG intrauterine system to treat non-atypical and atypical endometrial hyperplasia in women and to evaluate the long-term cure (remission) rate. Methods: Each of the 20 women in the study, of whom eight were diagnosed with atypical hyperplasia, received a LNG–IUS, releasing 20 g LNG/day. The study is a non-comparative study with long-term follow-up (range 14–90 months). Results: All women developed a normal endometrium, except one asymptomatic woman with atypical hyperplasia who still had focal residual non-atypical hyperplasia at 3 years follow-up in the presence of a thin (<4 mm) endometrium. Conclusion: Continuous intrauterine delivery of LNG appears to be a promising alternative to hysterectomy for the treatment of endometrial hyperplasia and could enhance the success rate when compared with other routes of progestagen administration as well as intrauterine progesterone delivery. The significant reduction of the PR expression observed during treatment with the LNG–IUS appears to be a marker for the strong antiproliferative effect of the hormone at a cellular level resulting in an inhibition of estrogen bioactivity and endometrial suppression. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Intrauterine system (IUS); Levonorgestrel (LNG); Endometrial hyperplasia; Long-term study
∗
Corresponding author at: Piers de Raveschootlaan, 8300 Knokke, Belgium. Tel.: +32 50 600 900; fax: +32 50 622 429. E-mail address: [email protected] (D. Wildemeersch).
0378-5122/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2006.12.004
D. Wildemeersch et al. / Maturitas 57 (2007) 210–213
211
1. Introduction
2. Materials and methods
Endometrial hyperplasia is considered a precursor of cancer of the endometrium but only women presenting with atypical hyperplasia have a risk of developing endometrial carcinoma. The risk is estimated to be between 27% and 30% [1]. Consequently, the classical treatment of atypical endometrial hyperplasia has been hysterectomy. Progestagens have been used since the 1960 mainly in young women with a wish for pregnancy. The most frequently used progestagen has been medroxyprogesterone acetate (MPA) but side effects were numerous (e.g. headache, nausea) and long-term use results in metabolic changes and exposes the woman to a higher risk of thromboembolic events [2]. More recently, GnRH analogues have been proposed for the treatment of endometrial cancer and endometrial hyperplasia but hormonal side effects preclude long-term treatment [3]. An alternative route to administer potent progestagens is an intrauterine drug delivery system. Locally acting progestagens act many times stronger on the endometrium than when given systemically. Dosage can, therefore, be reduced significantly, minimizing side effects and optimizing patient compliance. Clinical studies with a “frameless” levonorgestrel (LNG)–intrauterine system (IUS), releasing 14 g LNG/day, and a “framed” LNG–IUS, releasing 20 g LNG/day, suggest that both LNG delivery systems are effective to provide strong endometrial suppression which accounts for the endometrial suppressive effect observed during estrogen replacement therapy (ERT), the strong reduction in menstrual blood loss in women with excessive menstrual blood loss and menorrhagia as well as the high contraceptive action [4–8]. The interim results of the present study were published previously [9]. This study concluded that the LNG system, releasing 14 g LNG/day, is an effective method for suppressing the endometrium in women with non-atypical and atypical hyperplasia and constitutes an alternative to hysterectomy on condition that women can be properly followed-up. The purpose of the present paper is to report on the long-term results in the same women using the LNG–IUS to prevent recurrence.
The frameless, 14 g releasing LNG–IUS (FibroPlantTM , Contrel Research, Ghent, Belgium) has been described previously [9]. The IUS is implanted into the myometrium of the uterine fundus. Since the LNG–IUS has no frame, it is completely flexible, adapting to cavities of every size and shape. At expiry after 3 years of use of the FibroPlant LNG–IUS, the IUS was removed and replaced by a new T-shaped LNG–IUS (FemilisTM , Contrel Research, Ghent, Belgium), releasing 20 g LNG/day (Fig. 1) At the time of study analysis, 13 patients were using the framed, T-shaped LNG–IUS and seven the frameless LNG–IUS, releasing 20 g LNG/day (Fig. 2). Women with abnormal uterine bleeding and with endometrial hyperplasia, confirmed by pipelle biopsy or by curettage, received the LNG–IUS for local treatment of the condition. Written informed consent was obtained from each volunteer and the use of the LNG–IUS was approved by the Ethics Committee of the Ghent University Hospital. Prior to the insertion procedure, all women were screened for their clini-
Fig. 1. The FemilisTM LNG–IUS.
212
D. Wildemeersch et al. / Maturitas 57 (2007) 210–213
plasia’ in 12 women and ‘atypical hyperplasia’ in eight women (adenomatous hyperplasia with atypia in three of them). In one of the latter patients an invasive welldifferentiated adenocarcinoma was found on D&C but this was not confirmed in two subsequent endometrial pipelle samplings. To determine the endometrial progesterone receptor response during treatment (only performed in women with atypical endometrial hyperplasia), paraffin-embedded tissue sections were immunohistochemically stained with a mouse monoclonal antibody (NCL-PGR-312, Novo Castra Laboratories, Newcastle-upon-Tyne, UK. The percentage of immunoreactive nuclei was scored both in endometrial epithelium and stroma [12].
4. Results
Fig. 2. The FibroPlantTM LNG–IUS.
cal suitability for IUS insertion and compliance with the WHO eligibility criteria [10]. Following insertion, women were followed-up at 1, 3, 6, 12 months following insertion of the IUS and 6-monthly thereafter. Monitoring of the endometrium during treatment was conducted by transvaginal ultrasound (Ultramark® 4Plus, ATL Inc., Bothell, WA, USA) and by endometrial pipelle biopsy or D&C.
3. Patients Twenty women (16 parous and four nulliparous) were included in the study. Hypertension and diabetes was not present in any of them. Eight women developed postmenopausal bleeding as a result of unopposed estrogen stimulation (EST), after having taken the medication for at least 6 months up to approximately 2 years. One woman consulted because of abnormal bleeding during tamoxifen treatment for breast cancer. The other women had abnormal premenopausal bleeding. The histopathological diagnosis (Kurman classification [11]) was ‘non-atypical (simple) hyper-
The average age of the patients at study entry was 54 years (range 41–67) and the average duration of use of the LNG–IUS is 32 months (range 14–90). All women developed a thin endometrium (≤4 mm in thickness), as assessed by transvaginal ultrasound, except one patient. The latter patient presented with a polypoid structure of 20 mm in diameter prior to treatment which diminished gradually in size to 5 mm at the last follow-up examination, 53 months after insertion of the LNG–IUS. At study initiation all women presenting with atypical endometrial hyperplasia showed expression of PR in the epithelial cells. The percentage declined significantly over time during treatment. The endometrial histology specimen showed no progression of disease. Profound endometrial suppression with glandular atrophy and/or stromal decidualization was found in all women. Eight of the 20 women in the study resumed ERT. All women are continuing to use the method.
5. Comments In recent years, endometrial hyperplasia is caused most often by use of unopposed estrogen for ERT and tamoxifen for the treatment of breast cancer. Nonatypical (simple) hyperplasia is usually treated by oral administration of progestagens in sufficient dose and
D. Wildemeersch et al. / Maturitas 57 (2007) 210–213
duration. However, if the treatment is discontinued, recurrence may occur. Locally applied delivery of levonorgestrel is much more potent than oral treatment and it is, therefore, logical that this form of treatment should be preferred to oral and also to surgical treatment if it could be shown to be effective. An implantable method also provides better patient compliance. The preferred treatment for adenomatous hyperplasia with atypia or adenocarcinoma of the endometrium is hysterectomy. It is evident that this is a hard decision, especially in young women who want to preserve their fertility. The present study indicates that successful treatment is possible especially when a potent progestagen is administered locally. The study confirms preliminary studies with the Mirena® LNG–IUS (Schering AG, Berlin, Germany) in women with precancerous lesions of the endometrium [13]. Intrauterine progesterone delivery or oral administrations appears to be much less effective [14,15]. However, successful treatment of early endometrial carcinoma has been reported with a 65 g/day progesterone-releasing IUS, followed-up to 36 months, but, results of biopsies were negative only in 7 of 11 at 6 months and 6 of 8 at 12 months [16]. The significant reduction of the PR expression observed during treatment with the LNG–IUS in the present study appears to be a marker for the strong antiproliferative effect of the hormone at a cellular level resulting in an inhibition of estrogen bioactivity and endometrial suppression. Furthermore, as the treatment is continuous, compliance is not an issue.
6. Conclusion The results suggest that the LNG–IUS, releasing either 14 or 20 g LNG/day, is an effective method for suppressing the endometrium in women with non-atypical and atypical hyperplasia and constitutes an alternative to hysterectomy especially in younger women who still wish to become pregnant and in women who refuse operation or are in poor health. Treatment should be long-term and women should be closely followed-up by vaginal ultrasound and preferably by repeat endometrial biopsy.
213
References [1] Kurman RJ, Kaminski PF, Norris HJ. The behaviour of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 1985;56:403–12. [2] Randall TC, Kurman RJ. Progestagen treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under the age 40. Obstet Gynecol 1997;90:434–40. [3] Kullander S. Treatment of endometrial cancer with GnRH analogs. Recent Results Cancer Res 1992;124:69–73. [4] Wildemeersch D, Janssens D, Weyers S. Continuous combined parenteral estrogen substitution and intrauterine progestogen delivery: the ideal HST combination? Maturitas 2005;51:207–14. [5] Wildemeersch D, Janssens D, Vrijens M, Weyers S. Ease of insertion, contraceptive efficacy and safety of new T-shaped levonorgestrel-releasing intrauterine systems. Contraception 2005;71:465–9. [6] Wildemeersch D, Rowe P. Assessment of menstrual blood loss in Belgian users of a new T-shaped levonorgestrel-releasing intrauterine system. Contraception 2005;71:470–3. [7] Andrade ATL, Souza JP, Andrade GN, Rowe PJ, Wildemeersch D. Assessment of menstrual blood loss in Brasilian users of the frameless copper-releasing IUD with copper surface are of 330 mm2 and users of the levonorgestrel-releasing intrauterine system. Contraception 2004;70:173–7. [8] Wildemeersch D, Schacht E, Wildemeersch P, Calleweart K, Pylyser K, De Wever N. Endometrial safety with a low-dose intrauterine levonorgestrel-releasing system after three years of estrogen substitution therapy. Maturitas 2004;48:65–70. [9] Wildemeersch D, Dhont M. Treatment of non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system. Am J Obstet Gynecol 2003;138:1297–8. [10] World Health Organization (WHO). Medical eligibility criteria for contraceptive use. Geneva, Switzerland: WHO; 2000. [11] Kurman RJ, editor. Blaustein’s pathology of the female genital tract. 4th ed. New York: Springer Verlag; 1995., ISBN 3-54094166-5. [12] Tjalma W, Janssens D, Wildemeersch D, Colpaert C, Watty C. Conservative management of atypical endometrial hyperplasia and early invasive carcinoma with intrauterine levonorgestrel: a progesterone receptor study. Eur J Cancer 2004;2:93–4. [13] Scarselli G, Tantani C, Colafranceschi M. LevonorgestrelNova-T and precancerous lesions of the endometrium. Eur J Gynecol Oncol 1988;9:284–6. [14] Silverberg SG, Haukkamaa M, Arko H, Nilsson CG, Luukkainen T. Endometrial morphology during long-term use of levonorgestrel-releasing intrauterine devices. Int J Gynecol Pathol 1986;5:235–41. [15] Schindler AE. Progestogens, endometrial hyperplasia and endometrial cancer. Gynaecol Forum 2004;9:31–3. [16] Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002;186:651–7.