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doi:10.1111/jog.12370
J. Obstet. Gynaecol. Res. Vol. 40, No. 6: 1807–1810, June 2014
Disappearance of a uterine arteriovenous malformation following long-term administration of oral norgestrel/ ethinyl estradiol Aki Oride, Haruhiko Kanasaki and Kohji Miyazaki Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane, Japan
Abstract Uterine arteriovenous malformation (AVM) can cause sudden massive hemorrhage. We report a case of uterine AVM following curettage in a patient treated conservatively with an intermediate-dose pill. An 18-year-old gravida 2 para 0 underwent curettage at 12 weeks of gestation and was examined for massive genital hemorrhage that occurred in postoperative month 4. Abundant blood flow in a mass within the uterine lumen was observed on color Doppler ultrasonography, and the patient was diagnosed with AVM. Six days after starting oral norgestrel/ethinyl estradiol, the hemorrhage ceased, and computed tomography on day 37 of administration showed disappearance of the abnormal vasculature. After 12 months, the patient’s course remains favorable without relapse. Transarterial embolization for AVM can cause ovarian failure and subsequent placental malpositioning. Administration of oral norgestrel/ethinyl estradiol may be an alternative conservative treatment option for patients who wish to maintain fertility. Key words: arteriovenous malformation, conservative therapy, drug treatment, fertility, norgestrel/ethinyl estradiol.
Introduction Uterine arteriovenous malformation (AVM) is a rare disorder, with only approximately 100 cases reported to date. It sometimes causes massive genital hemorrhage and is therefore an important cause of atypical genital hemorrhage. Diagnosis is confirmed by the presence of a vascular mass with abundant blood flow within the myometrium and is conventionally made by pelvic angiography. Although the confirmation of a flow void is the gold standard, less invasive modalities such as color Doppler ultrasonography, computed tomography (CT) and magnetic resonance imaging are currently being used.1 Total hysterectomy is a curative treatment, but uterine transarterial embolization (TAE) is more commonly
being performed for patients who wish to maintain fertility. After conducting TAE, however, there is the possibility of infertility2 due to decreased ovarian function and Asherman syndrome, and increased incidence of placenta accreta and intrauterine growth retardation3 is problematic. Here, we report a case of uterine AVM following artificial termination of pregnancy in a patient who was successfully treated conservatively with an intermediate-dose birth control pill.
Case Report The patient was an 18-year-old single woman with gravidity 2 parity 0 (two previous artificial terminations of pregnancy). On day 2 of the 12th week of pregnancy, she attended her local gynecology clinic for artificial
Received: October 1 2013. Accepted: December 5 2013. Reprint request to: Dr Aki Oride, Department of Obstetrics and Gynecology, Shimane University School of Medicine, 89-1 Enya Cho, Izumo City, Shimane 693-8501, Japan. Email: [email protected]
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1807
A. Oride et al.
Figure 1 Imaging results on the first visit. (a) Transvaginal grayscale sonography showing a multicystic hypoechoic area in the posterior wall of the uterus. (b) 3-D computed tomography showing a cluster of hypertrophic and coiled vascular channels in the uterus.
termination of pregnancy and uterine curettage was performed. A small amount of persistent genital hemorrhage occurred postoperatively and was followed by menstrual-like hemorrhage, but the volume of hemorrhage decreased 1 week later. The menstrual-like hemorrhage continued from postoperative day 37, and at bedtime on postoperative day 38 she noticed a large amount of blood. Color Doppler ultrasonography performed at a gynecology clinic early the next day revealed a uterine mass with abundant blood flow, and the patient was referred to our department for further detailed investigations. On examination, a large clot was observed in the vagina, but no persistent active hemorrhage was evident. Inflammation was observed in the vaginal region, and the cervix was roughly the size of a pigeon’s egg. On bimanual palpation, the uterine corpus was the size of a hen’s egg with no tenderness. Bilateral adnexal regions showed no resistance, and no tenderness was evident. On transvaginal ultrasound, a 3.5 cm × 2 cm cystic hyperechoic lesion was observed on the posterior uterine wall (Fig. 1). In addition, pulsatile flow in a mosaic pattern was observed in the myometrium on color Doppler ultrasonography. Urinary human chorionic gonadotrophin was negative. Contrast-enhanced CT revealed a dilated uterine artery and surrounding veins protruding into the uterine lumen (Fig. 1). Based on these results, the patient was diagnosed with uterine AVM. Hemoglobin was 11.0 g/dL and no anemia was observed. After the available treatment options were explained, the patient was started on oral norgestrel/ethinyl estradiol (Pranoval) as she wished to maintain fertility. Numerous episodes of genital hemorrhage were noted from
1808
Figure 2 Imaging results 37 days after starting norgestrel/ethinyl estradiol treatment. (a) Transvaginal sonography showing the uterine cavity filled with fluid. The uterine arteriovenous malformation disappeared completely after the steroid treatment. (b) 3-D computed tomography showing the disappearance of the enlarged hypertrophic veins.
day 6 after starting steroid treatment, but the volume of hemorrhage gradually decreased and eventually ceased. Transvaginal ultrasound was conducted on day 28 of steroid treatment and showed fluid accumulation in the uterine lumen (Fig. 2), but no pulsatile flow was evident on color Doppler ultrasonography. Contrastenhanced CT on the same day showed markedly reduced contrast enhancement of the myometrium during the arterial phase and the disappearance of abnormal vasculature (Fig. 2). Hemoglobin was 10.2 g/dL and mild anemia was evident. When norgestrel/ethinyl estradiol was discontinued on day 37 of administration, menstrual-like hemorrhage occurred from day 3 after medication withdrawal and hemorrhage ceased within 7 days. On transvaginal ultrasound, the endometrium appeared normal and no abnormal masses were observed. In the last 12 months, the patient’s menstrual cycle has been regular with no relapse of AVM.
Discussion Uterine AVM can cause continuous genital hemorrhage and massive genital hemorrhage, both of which can be life-threatening; therefore, rapid diagnosis and management are required. Total hysterectomy is a curative treatment, but TAE is considered the first choice for patients who wish to maintain fertility. Among the several reports which have described treating AVM with TAE since 1982,4 Badawy et al.5 reported a TAE success rate of 96% in 25 patients with AVM and a complication rate of 4% (transient sensory dysfunction and paralysis of the left arm). Sentilhes et al., who performed TAE for post-partum hemorrhage to determine
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Hormone treatment of AVM
the rate of menstrual abnormalities after TAE, showed that 15 of 68 cases had amenorrhea or oligomenorrhea. Although 19 patients delivered, relapse of post-partum hemorrhage occurred in six patients (31.6%), due to placenta previa in two patients, and placenta accreta and post-partum fever of more than 38.5°C was observed significantly more frequently.6 Peitsidis et al.7 reported pregnancy in 17 of 100 patients who underwent TAE for AVM. One patient exhibited uncontrollable hemorrhage at 7.4 weeks of pregnancy and subsequently developed massive hemorrhage, necessitating a hysterectomy. Another patient experienced spontaneous rupture of membranes at 28 weeks, while a third patient presented with AVM complicated by pre-eclampsia at 34 weeks. According to a report by Berkane and Moutafoff-Borie,8 who performed TAE for post-partum hemorrhage and fibroids, pregnancy was achieved in 116 of 420 patients (28%) in whom embolization was conducted, and when limited to those who wished to maintain fertility, 52 of 66 patients (79%) achieved pregnancy. Regarding the outcome of pregnancy, the following conditions were observed in 50 patients who achieved pregnancy after undergoing TAE for AVM or leiomyomas: malpresentation (17%), small for gestational age (7%), premature delivery (28%), cesarean delivery (58%) and post-partum hemorrhage (13%). There is currently no pharmaceutical treatment for AVM. Administration of methylergonovine maleate, danazol and gonadotropin-releasing hormone (GnRH) agonists have had limited success. Flynn and Levine have reported the disappearance of AVM after administrating methylergonovine maleate for 1 week,9 while Onoyama et al. have reported the full-term birth of a normal infant following treatment with methylergonovine maleate.10 In other reports, after unsuccessful TAE, AVM disappeared following administration of danazol for 2 weeks,11 suggesting the direct effect of danazol on both the uterine artery and the endometrium. In addition, the disappearance of AVM has been reported following 6 months of GnRH agonist administration and a healthy infant was born 5 months later via normal vaginal delivery.12 However, due to the small number of reported cases, there is no clear evidence that medical treatments for AVM can avert the risk of complications in subsequent pregnancy and delivery. Therefore, further studies are needed on the outcomes of pregnancy after medical treatment for AVM. Because estrogen regulates the process of angiogenesis, anti-estrogen drugs may influence the vascular proliferation of AVM. In our patient, we observed the
disappearance of a uterine AVM due to administration of norgestrel/ethinyl estradiol. In another report, effects were observed when estrogen therapy (either combination estrogen and progesterone or estrogen alone) was given for gastrointestinal bleeding due to long-standing AVM.13 The mechanism of these effects is unclear, but it has been suggested that estrogen repairs abnormal vasculature and may improve coagulatory function. The application of TAE for treating AVM is a useful method with a high success rate, and TAE is widely conducted in patients in whom fertility-preserving treatment is required. However, amenorrhea following TAE and the risk of complications during pregnancy are points that should not be ignored. In patients with stable hemodynamics, a trial of pharmaceutical treatment that includes norgestrel/ethinyl estradiol should be considered as a first option. Nonetheless, as there are very few reports on the use of pharmaceutical therapy, careful follow-up is required.
Disclosure No author has any potential conflict of interest.
References 1. Grivell RM, Reid KM, Mellor A. Uterine arteriovenous malformations: A review of the current literature. Obstet Gynecol Surv 2005; 60: 761–767. 2. Zanati J, Resch B, Roman H et al. [Buttock necrosis after subtotal hysterectomy, bilateral internal iliac arteries ligature and pelvic embolization for control of severe post-partum haemorrhage.] J Gynecol Obstet Biol Reprod (Paris) 2010; 39: 57–60. 3. Goldberg J, Pereira L, Berghella V. Pregnancy after uterine artery embolization. Obstet Gynecol 2002; 100: 869–872. 4. Forssman L, Lundberg J, Schersten T. Conservative treatment of uterine arteriovenous fistula. Acta Obstet Gynecol Scand 1982; 61: 85–87. 5. Badawy SZ, Etman A, Singh M, Murphy K, Mayelli T, Philadelphia M. Uterine artery embolization: The role in obstetrics and gynecology. Clin Imaging 2001; 25: 288–295. 6. Sentilhes L, Gromez A, Clavier E, Resch B, Verspyck E, Marpeau L. Fertility and pregnancy following pelvic arterial embolisation for postpartum haemorrhage. BJOG 2010; 117: 84–93. 7. Peitsidis P, Manolakos E, Tsekoura V, Kreienberg R, Schwentner L. Uterine arteriovenous malformations induced after diagnostic curettage: A systematic review. Arch Gynecol Obstet 2011; 284: 1137–1151. 8. Berkane N, Moutafoff-Borie C. Impact of previous uterine artery embolization on fertility. Curr Opin Obstet Gynecol 2010; 22: 242–247.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1809
A. Oride et al.
9. Flynn MK, Levine D. The noninvasive diagnosis and management of a uterine arteriovenous malformation. Obstet Gynecol 1996; 88: 650–652. 10. Onoyama I, Fukuhara M, Okuma A, Watanabe Y, Nakamura G. Successful pregnancy after the noninvasive management of uterine arteriovenous malformation. Acta Obstet Gynecol Scand 2001; 80: 1148–1149. 11. Takeuchi K, Yamada T, Iwasa M, Maruo T. Successful medical treatment with danazol after failed embolization of uterine arteriovenous malformation. Obstet Gynecol 2003; 102: 843– 844.
1810
12. Nonaka T, Yahata T, Kashima K, Tanaka K. Resolution of uterine arteriovenous malformation and successful pregnancy after treatment with a gonadotropin-releasing hormone agonist. Obstet Gynecol 2011; 117: 452–455. 13. Siple JF, Joseph CL, Pagel KJ, Leigh S. Use of estrogen therapy in a patient with gastrointestinal bleeding secondary to arteriovenous malformations. Ann Pharmacother 1997; 31: 1311– 1314.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
doi:10.1111/jog.12370
J. Obstet. Gynaecol. Res. Vol. 40, No. 6: 1807–1810, June 2014
Disappearance of a uterine arteriovenous malformation following long-term administration of oral norgestrel/ ethinyl estradiol Aki Oride, Haruhiko Kanasaki and Kohji Miyazaki Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Shimane, Japan
Abstract Uterine arteriovenous malformation (AVM) can cause sudden massive hemorrhage. We report a case of uterine AVM following curettage in a patient treated conservatively with an intermediate-dose pill. An 18-year-old gravida 2 para 0 underwent curettage at 12 weeks of gestation and was examined for massive genital hemorrhage that occurred in postoperative month 4. Abundant blood flow in a mass within the uterine lumen was observed on color Doppler ultrasonography, and the patient was diagnosed with AVM. Six days after starting oral norgestrel/ethinyl estradiol, the hemorrhage ceased, and computed tomography on day 37 of administration showed disappearance of the abnormal vasculature. After 12 months, the patient’s course remains favorable without relapse. Transarterial embolization for AVM can cause ovarian failure and subsequent placental malpositioning. Administration of oral norgestrel/ethinyl estradiol may be an alternative conservative treatment option for patients who wish to maintain fertility. Key words: arteriovenous malformation, conservative therapy, drug treatment, fertility, norgestrel/ethinyl estradiol.
Introduction Uterine arteriovenous malformation (AVM) is a rare disorder, with only approximately 100 cases reported to date. It sometimes causes massive genital hemorrhage and is therefore an important cause of atypical genital hemorrhage. Diagnosis is confirmed by the presence of a vascular mass with abundant blood flow within the myometrium and is conventionally made by pelvic angiography. Although the confirmation of a flow void is the gold standard, less invasive modalities such as color Doppler ultrasonography, computed tomography (CT) and magnetic resonance imaging are currently being used.1 Total hysterectomy is a curative treatment, but uterine transarterial embolization (TAE) is more commonly
being performed for patients who wish to maintain fertility. After conducting TAE, however, there is the possibility of infertility2 due to decreased ovarian function and Asherman syndrome, and increased incidence of placenta accreta and intrauterine growth retardation3 is problematic. Here, we report a case of uterine AVM following artificial termination of pregnancy in a patient who was successfully treated conservatively with an intermediate-dose birth control pill.
Case Report The patient was an 18-year-old single woman with gravidity 2 parity 0 (two previous artificial terminations of pregnancy). On day 2 of the 12th week of pregnancy, she attended her local gynecology clinic for artificial
Received: October 1 2013. Accepted: December 5 2013. Reprint request to: Dr Aki Oride, Department of Obstetrics and Gynecology, Shimane University School of Medicine, 89-1 Enya Cho, Izumo City, Shimane 693-8501, Japan. Email: [email protected]
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1807
A. Oride et al.
Figure 1 Imaging results on the first visit. (a) Transvaginal grayscale sonography showing a multicystic hypoechoic area in the posterior wall of the uterus. (b) 3-D computed tomography showing a cluster of hypertrophic and coiled vascular channels in the uterus.
termination of pregnancy and uterine curettage was performed. A small amount of persistent genital hemorrhage occurred postoperatively and was followed by menstrual-like hemorrhage, but the volume of hemorrhage decreased 1 week later. The menstrual-like hemorrhage continued from postoperative day 37, and at bedtime on postoperative day 38 she noticed a large amount of blood. Color Doppler ultrasonography performed at a gynecology clinic early the next day revealed a uterine mass with abundant blood flow, and the patient was referred to our department for further detailed investigations. On examination, a large clot was observed in the vagina, but no persistent active hemorrhage was evident. Inflammation was observed in the vaginal region, and the cervix was roughly the size of a pigeon’s egg. On bimanual palpation, the uterine corpus was the size of a hen’s egg with no tenderness. Bilateral adnexal regions showed no resistance, and no tenderness was evident. On transvaginal ultrasound, a 3.5 cm × 2 cm cystic hyperechoic lesion was observed on the posterior uterine wall (Fig. 1). In addition, pulsatile flow in a mosaic pattern was observed in the myometrium on color Doppler ultrasonography. Urinary human chorionic gonadotrophin was negative. Contrast-enhanced CT revealed a dilated uterine artery and surrounding veins protruding into the uterine lumen (Fig. 1). Based on these results, the patient was diagnosed with uterine AVM. Hemoglobin was 11.0 g/dL and no anemia was observed. After the available treatment options were explained, the patient was started on oral norgestrel/ethinyl estradiol (Pranoval) as she wished to maintain fertility. Numerous episodes of genital hemorrhage were noted from
1808
Figure 2 Imaging results 37 days after starting norgestrel/ethinyl estradiol treatment. (a) Transvaginal sonography showing the uterine cavity filled with fluid. The uterine arteriovenous malformation disappeared completely after the steroid treatment. (b) 3-D computed tomography showing the disappearance of the enlarged hypertrophic veins.
day 6 after starting steroid treatment, but the volume of hemorrhage gradually decreased and eventually ceased. Transvaginal ultrasound was conducted on day 28 of steroid treatment and showed fluid accumulation in the uterine lumen (Fig. 2), but no pulsatile flow was evident on color Doppler ultrasonography. Contrastenhanced CT on the same day showed markedly reduced contrast enhancement of the myometrium during the arterial phase and the disappearance of abnormal vasculature (Fig. 2). Hemoglobin was 10.2 g/dL and mild anemia was evident. When norgestrel/ethinyl estradiol was discontinued on day 37 of administration, menstrual-like hemorrhage occurred from day 3 after medication withdrawal and hemorrhage ceased within 7 days. On transvaginal ultrasound, the endometrium appeared normal and no abnormal masses were observed. In the last 12 months, the patient’s menstrual cycle has been regular with no relapse of AVM.
Discussion Uterine AVM can cause continuous genital hemorrhage and massive genital hemorrhage, both of which can be life-threatening; therefore, rapid diagnosis and management are required. Total hysterectomy is a curative treatment, but TAE is considered the first choice for patients who wish to maintain fertility. Among the several reports which have described treating AVM with TAE since 1982,4 Badawy et al.5 reported a TAE success rate of 96% in 25 patients with AVM and a complication rate of 4% (transient sensory dysfunction and paralysis of the left arm). Sentilhes et al., who performed TAE for post-partum hemorrhage to determine
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
Hormone treatment of AVM
the rate of menstrual abnormalities after TAE, showed that 15 of 68 cases had amenorrhea or oligomenorrhea. Although 19 patients delivered, relapse of post-partum hemorrhage occurred in six patients (31.6%), due to placenta previa in two patients, and placenta accreta and post-partum fever of more than 38.5°C was observed significantly more frequently.6 Peitsidis et al.7 reported pregnancy in 17 of 100 patients who underwent TAE for AVM. One patient exhibited uncontrollable hemorrhage at 7.4 weeks of pregnancy and subsequently developed massive hemorrhage, necessitating a hysterectomy. Another patient experienced spontaneous rupture of membranes at 28 weeks, while a third patient presented with AVM complicated by pre-eclampsia at 34 weeks. According to a report by Berkane and Moutafoff-Borie,8 who performed TAE for post-partum hemorrhage and fibroids, pregnancy was achieved in 116 of 420 patients (28%) in whom embolization was conducted, and when limited to those who wished to maintain fertility, 52 of 66 patients (79%) achieved pregnancy. Regarding the outcome of pregnancy, the following conditions were observed in 50 patients who achieved pregnancy after undergoing TAE for AVM or leiomyomas: malpresentation (17%), small for gestational age (7%), premature delivery (28%), cesarean delivery (58%) and post-partum hemorrhage (13%). There is currently no pharmaceutical treatment for AVM. Administration of methylergonovine maleate, danazol and gonadotropin-releasing hormone (GnRH) agonists have had limited success. Flynn and Levine have reported the disappearance of AVM after administrating methylergonovine maleate for 1 week,9 while Onoyama et al. have reported the full-term birth of a normal infant following treatment with methylergonovine maleate.10 In other reports, after unsuccessful TAE, AVM disappeared following administration of danazol for 2 weeks,11 suggesting the direct effect of danazol on both the uterine artery and the endometrium. In addition, the disappearance of AVM has been reported following 6 months of GnRH agonist administration and a healthy infant was born 5 months later via normal vaginal delivery.12 However, due to the small number of reported cases, there is no clear evidence that medical treatments for AVM can avert the risk of complications in subsequent pregnancy and delivery. Therefore, further studies are needed on the outcomes of pregnancy after medical treatment for AVM. Because estrogen regulates the process of angiogenesis, anti-estrogen drugs may influence the vascular proliferation of AVM. In our patient, we observed the
disappearance of a uterine AVM due to administration of norgestrel/ethinyl estradiol. In another report, effects were observed when estrogen therapy (either combination estrogen and progesterone or estrogen alone) was given for gastrointestinal bleeding due to long-standing AVM.13 The mechanism of these effects is unclear, but it has been suggested that estrogen repairs abnormal vasculature and may improve coagulatory function. The application of TAE for treating AVM is a useful method with a high success rate, and TAE is widely conducted in patients in whom fertility-preserving treatment is required. However, amenorrhea following TAE and the risk of complications during pregnancy are points that should not be ignored. In patients with stable hemodynamics, a trial of pharmaceutical treatment that includes norgestrel/ethinyl estradiol should be considered as a first option. Nonetheless, as there are very few reports on the use of pharmaceutical therapy, careful follow-up is required.
Disclosure No author has any potential conflict of interest.
References 1. Grivell RM, Reid KM, Mellor A. Uterine arteriovenous malformations: A review of the current literature. Obstet Gynecol Surv 2005; 60: 761–767. 2. Zanati J, Resch B, Roman H et al. [Buttock necrosis after subtotal hysterectomy, bilateral internal iliac arteries ligature and pelvic embolization for control of severe post-partum haemorrhage.] J Gynecol Obstet Biol Reprod (Paris) 2010; 39: 57–60. 3. Goldberg J, Pereira L, Berghella V. Pregnancy after uterine artery embolization. Obstet Gynecol 2002; 100: 869–872. 4. Forssman L, Lundberg J, Schersten T. Conservative treatment of uterine arteriovenous fistula. Acta Obstet Gynecol Scand 1982; 61: 85–87. 5. Badawy SZ, Etman A, Singh M, Murphy K, Mayelli T, Philadelphia M. Uterine artery embolization: The role in obstetrics and gynecology. Clin Imaging 2001; 25: 288–295. 6. Sentilhes L, Gromez A, Clavier E, Resch B, Verspyck E, Marpeau L. Fertility and pregnancy following pelvic arterial embolisation for postpartum haemorrhage. BJOG 2010; 117: 84–93. 7. Peitsidis P, Manolakos E, Tsekoura V, Kreienberg R, Schwentner L. Uterine arteriovenous malformations induced after diagnostic curettage: A systematic review. Arch Gynecol Obstet 2011; 284: 1137–1151. 8. Berkane N, Moutafoff-Borie C. Impact of previous uterine artery embolization on fertility. Curr Opin Obstet Gynecol 2010; 22: 242–247.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1809
A. Oride et al.
9. Flynn MK, Levine D. The noninvasive diagnosis and management of a uterine arteriovenous malformation. Obstet Gynecol 1996; 88: 650–652. 10. Onoyama I, Fukuhara M, Okuma A, Watanabe Y, Nakamura G. Successful pregnancy after the noninvasive management of uterine arteriovenous malformation. Acta Obstet Gynecol Scand 2001; 80: 1148–1149. 11. Takeuchi K, Yamada T, Iwasa M, Maruo T. Successful medical treatment with danazol after failed embolization of uterine arteriovenous malformation. Obstet Gynecol 2003; 102: 843– 844.
1810
12. Nonaka T, Yahata T, Kashima K, Tanaka K. Resolution of uterine arteriovenous malformation and successful pregnancy after treatment with a gonadotropin-releasing hormone agonist. Obstet Gynecol 2011; 117: 452–455. 13. Siple JF, Joseph CL, Pagel KJ, Leigh S. Use of estrogen therapy in a patient with gastrointestinal bleeding secondary to arteriovenous malformations. Ann Pharmacother 1997; 31: 1311– 1314.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
