CASE REPORT
Use of Ulipristal Acetate for the Management of Fibroid-Related Acute Abnormal Uterine Bleeding Kristina Arendas, MD, FRCSC1, Nicholas A. Leyland, MD, MHCM, FRCSC2 1
Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, University of Ottawa, Ottawa, ON
2
Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON
Abstract Background: Episodes of acute abnormal uterine bleeding related to uterine fibroids can cause significant morbidity. Traditional management with high-dose hormonal regimens may not be as effective when used in women with fibroids. Case: A 32-year-old woman with a 12 cm uterine fibroid presented with an episode of acute abnormal uterine bleeding requiring blood transfusion. In lieu of using a hormonal maintenance regimen after the bleeding had stabilized, the patient was treated with ulipristal acetate 5 mg daily for three months. Amenorrhea was induced rapidly and the patient had no further episodes of acute excessive uterine bleeding. She subsequently underwent a laparoscopic myomectomy with a satisfactory outcome. Conclusion: Ulipristal acetate has been shown to induce amenorrhea rapidly in women with uterine fibroids, and it can be a useful treatment in the emergency management of fibroid-related acute abnormal uterine bleeding.
Résumé Contexte : Les épisodes de saignements utérins anormaux aigus associés aux fibromes utérins peuvent causer une morbidité considérable. La prise en charge traditionnelle au moyen de schémas posologiques à fortes doses d’hormones pourraient ne pas être aussi efficaces chez les femmes qui présentent des fibromes. Cas : Une femme de 32 ans présentant un fibrome utérin de 12 cm nous a consultés en raison d’un épisode de saignements utérins anormaux aigus nécessitant une transfusion sanguine. Plutôt que d’avoir recours à un schéma posologique hormonal d’entretien à la suite de la stabilisation des saignements, un traitement à l’acétate d’ulipristal (5 mg par jour pendant trois mois) a été administré à la patiente. Une aménorrhée s’est manifestée rapidement et la patiente n’a connu aucun autre épisode de saignements utérins excessifs aigus. La patiente a subséquemment subi une myomectomie laparoscopique ayant donné des résultats satisfaisants. Conclusion : Il a été démontré que l’acétate d’ulipristal provoque rapidement une aménorrhée chez les femmes qui présentent des fibromes utérins et qu’il peut constituer un traitement utile dans la
Key Words: Ulipristal acetate, fibroids, leiomyoma, acute uterine bleeding http://dx.doi.org/10.1016/j.jogc.2015.11.005
80
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prise en charge d’urgences liées aux saignements utérins anormaux aigus associés aux fibromes. Copyright ª 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.
J Obstet Gynaecol Can 2016;38(1):80e83
INTRODUCTION
terine leiomyomas, or fibroids, affect a significant proportion of reproductive age women, making them the most common benign gynaecologic tumour.1 Although in many women fibroids are asymptomatic and undiagnosed, significant numbers of women seek medical attention for symptoms related to fibroids.1 The most common presentation of women with fibroids is abnormal uterine bleeding,2 which can be chronic or acute. Other symptoms include dysmenorrhea, pressure symptoms affecting bladder and bowel function, and reproductive dysfunction.1
U
The management of uterine fibroids depends on the presenting symptoms, the size and location of the fibroids, and the desire for future fertility. Medical therapies, including combined oral contraceptives (COC), have been used in the management of fibroid-related heavy menstrual bleeding; however, their effectiveness in treating abnormal bleeding is limited, and reduction of fibroid volume has not been documented with these therapies.3 Until recently, leuprolide acetate, a GnRH agonist, was the only pharmacologic agent used for the medical management of uterine fibroids.3 The selective progesterone receptor modulator ulipristal acetate (UPA; Fibristal, Actavis Specialty Pharmaceuticals Co., Mississauga, ON) was recently also approved by Health Canada for treatment of signs and symptoms related to uterine fibroids in reproductive age women who are eligible for surgery.4
Use of Ulipristal Acetate for the Management of Fibroid-Related Acute Abnormal Uterine Bleeding
Figure 1. Pre-operative view of the uterus at laparoscopy
An acute episode of heavy uterine bleeding can be the first presentation of a previously asymptomatic woman with fibroids. Our usual approach to such episodes includes treatment with antifibrinolytic agents, intravenous estrogens, and Foley catheter balloon tamponade until bleeding stabilizes. This is followed by administration of an oral maintenance dose of hormonal therapy.5 We present here the case of a woman with acute heavy uterine bleeding associated with a uterine fibroid in which UPA was used in lieu of a hormonal maintenance regimen, with excellent results. THE CASE
An otherwise healthy 32-year-old woman presented to the emergency department on the fourth day of menstrual flow with acute, severe vaginal bleeding. Her gynaecologic history was unremarkable, with regular menstrual cycles of 30 days’ duration and menstrual flow lasting between four and six days. Menstrual blood loss was typically moderate to heavy, with moderate dysmenorrhea.
Figure 2. Post-operative view following laparoscopic myomectomy
vagina. Active bleeding from the external cervical os was identified. Initial investigations showed a hemoglobin concentration of 114 g/L, a normal coagulation profile, and negative serum beta hCG. The patient was resuscitated with intravenous fluid and was given tranexamic acid 1000 mg intravenously. Pelvic ultrasound showed the presence of a large anterior transmural fibroid, measuring 12.1 10.2 10.9 cm. She continued to have brisk vaginal bleeding, and was given conjugated equine estrogens 25 mg intravenously with intrauterine Foley catheter balloon tamponade. Her hemoglobin concentration fell to 72 g/L. The patient’s anemia was symptomatic, and she was transfused one unit of packed red blood cells. After approximately 12 hours of balloon tamponade, the intrauterine Foley catheter was removed. The bleeding had slowed significantly.
On the day of presentation, she had experienced brisk vaginal bleeding, with passage of large clots prompting her to seek medical attention. She had no associated symptoms, and had no history suggestive of a bleeding disorder. Her medical history was also unremarkable.
The patient was discharged approximately 24 hours after admission and began treatment with UPA 5 mg daily. She quickly developed amenorrhea after beginning UPA, and she remained amenorrheic throughout three months of treatment. The treatment was well tolerated. The fibroid decreased in size to 9.8 8.9 9.7 cm after the UPA treatment.
On examination, the patient was tachycardic but other vital signs were normal; cardiovascular examination was also normal. The abdomen was soft and non-tender, although the uterus was palpable above the symphysis pubis. Pelvic examination identified a smooth-contoured, non-tender uterus enlarged to the size of a 12- to 14-week pregnancy, with no adnexal masses. During speculum examination, a large amount of blood and clots was evacuated from the
After completion of three months of UPA treatment the patient underwent laparoscopically-assisted myomectomy with morcellation via a mini-laparotomy incision (Figures 1 and 2). The procedure was uneventful with no intraoperative complications. Estimated blood loss during the procedure was approximately 300 mL. Post-operatively, the patient was discharged on the day after surgery and had an unremarkable recovery. She resumed normal menstrual
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cycling, the heavy menstrual bleeding having resolved completely, and her dysmenorrhea was significantly improved. DISCUSSION
Acute abnormal uterine bleeding, excluding bleeding related to pregnancy, the postpartum period, trauma, or malignancy, and requiring emergency treatment, can occur in reproductive age women.6 Acute episodes of abnormal uterine bleeding can be associated with significant morbidity, such as severe anemia requiring blood transfusion.6 A wide variety of conditions can manifest as acute abnormal uterine bleeding, including coagulation disorders, endocrine dysfunction, and anatomic conditions such as uterine fibroids.5 The mainstay of management of acute abnormal uterine bleeding, whether fibroid-related or not, in patients without a bleeding disorder has been hormonal agents, in the form of intravenous estrogens, as well as antifibrinolytic agents and Foley catheter balloon tamponade.5 Once bleeding is stabilized, patients are transitioned to a tapering hormone regimen until an oral maintenance dose is reached.5 In the case presented, UPA was used in lieu of a hormonal maintenance regimen after initial stabilization of the patient’s condition during an episode of acute fibroid-related abnormal uterine bleeding. UPA is an orally dosed selective progesterone receptor modulator, and its mechanism of action is potentiated by high affinity binding of the progesterone receptor. It has both progesterone antagonist and partial progesterone agonist activity, depending on the target tissue, without having any effect on estrogen or androgen receptors.7 Therefore, without causing downregulation of estradiol receptors and by maintaining estradiol levels at follicular phase levels, UPA causes inhibition of ovulation and induction of amenorrhea in the majority of patients.7 Given the rapid onset of control of bleeding, however, there appear to be additional mechanisms invoking rapid-onset reduction in or cessation of bleeding.2,8,9 These mechanisms have not yet been fully elucidated, but direct effects on the endometrial vascular supply may contribute to the rates of amenorrhea.10 The reduction in size of fibroids associated with UPA therapy is believed to be achieved through the inhibition of cellular and extracellular matrix proliferation and the induction of apoptosis.9 The efficacy of UPA in the ambulatory setting, for management of fibroid-related heavy menstrual bleeding, has been established. Phase III randomized controlled trials showed that UPA controlled excessive uterine bleeding in at least 90% of women with fibroids.2,8 Moreover, control
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of bleeding was achieved rapidly, with 50% of women becoming amenorrheic within 10 days. In an RCT of women with fibroids causing heavy menstrual bleeding, women on UPA 5 mg daily became amenorrheic within a median time of seven days, compared with a median time of 21 days in women on leuprolide acetate (P < 0.001).8 There have been no studies comparing UPA to COC. However, in a small RCT comparing COC to medroxyprogesterone acetate in the management of women with heavy menstrual bleeding of any etiology, treatment with COC resulted in cessation of bleeding in 88% of women, with a median time to cessation of bleeding of three days.11 The use of COC in the management of abnormal uterine bleeding due to fibroids has been assessed in very few studies. In a recent meta-analysis of cohort and casecontrol studies on this subject, treatment with COC was associated with a 17% reduction in fibroid-related morbidity.12 An observational study comparing the use of COC with placebo found a significant reduction in bleeding without change in fibroid volume.13 In the present case, UPA was used as maintenance therapy during an episode of acute, transfusion-dependent, fibroid-related heavy menstrual bleeding, rather than in an ambulatory setting to improve fibroid-related abnormal uterine bleeding. UPA was used in lieu of COC to maintain control of the bleeding after the patient’s condition stabilized. In addition to its effect on heavy menstrual bleeding, UPA provides other advantages over estrogen-progestin hormone therapy. In well-designed phase III RCTs and trials comparing UPA with standard therapy, UPA was found to reduce fibroid volume significantly.2,8 UPA and leuprolide acetate both resulted in significant reductions in the volume of the three largest fibroids (36% with UPA 5 mg daily, 42% with UPA 10 mg daily, and 53% with leuprolide acetate).8 There has been concern that treatment with COC may increase fibroid volumes; however, in a large prospective population study, neither current nor past use of COC was associated with a risk of developing fibroids.14 There is no evidence that COC use can reduce fibroid volumes. Although COC may be effective in slowing or stopping acute abnormal uterine bleeding, use of these agents is often limited by contraindications and significant sideeffects, such as nausea, breast tenderness, and irregular bleeding.15 In RCTs to date, UPA has been well tolerated; the most frequently reported side-effects are headache and breast tenderness, but these did not occur more often than in the placebo group.2 Hot flashes are also a reported sideeffect, but they are significantly less likely to occur in women on UPA than in women on leuprolide acetate (P < 0.001).8 Moreover, unlike estrogen-containing oral
Use of Ulipristal Acetate for the Management of Fibroid-Related Acute Abnormal Uterine Bleeding
medications, which increase the risk of thromboembolism,15 UPA has not been associated with any effects on the clotting cascade after three months of treatment.2,8
5. James AH, Kouides PA, Abdul-Kadir R, Dietrich JE, Edlund M, Federici AB, et al. Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: Consensus from an international expert panel. Eur J Obstet Gynecol Reprod Biol 2011;158(2):124e34.
CONCLUSION
6. Singh S, Best C, Dunn S, Leyland N, Wolfman WL. Clinical Practice e Gynaecology Committee. Abnormal uterine bleeding in pre-menopausal women. J Obstet Gynaecol Can 2013;35(5):473e9.
Acute heavy menstrual bleeding, whether associated with fibroids or not, can be a life-threatening condition and is associated with significant morbidity.6 After women with this condition have been stabilized, usual maintenance treatment involves high-dose oral hormones.6 In the case presented, UPA was used in a woman with fibroid-related acute abnormal uterine bleeding as step-down therapy to maintain amenorrhea, help restore hemoglobin levels, and reduce the size of the fibroid in preparation for myomectomy. We believe that UPA is a good option for managing episodes of acute abnormal uterine bleeding in women with uterine fibroids, given its rapid induction of amenorrhea, positive side-effect profile, and beneficial effect on fibroid volume. REFERENCES 1. Singh SS, Belland L. Contemporary management of uterine fibroids: Focus on emerging medical treatments. Curr Med Res Opin 2015;31(1):1e12. 2. Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366(5):409e20. 3. De Leo V, Morgante G, La Marca A, Musacchio MC, Sorace M, Cavicchioli C, et al. A benefit-risk assessment of medical treatment for uterine leiomyomas. Drug Saf 2002;25(11):759e79. 4. Health Canada. Summary basis of decision (SBD): Fibristal; 2013. Available at http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_ smd_2013_fibristal_156861-eng.php. Updated 2013. Last accessed on April 6, 2015.
7. Chabbert-Buffet N, Pintiaux A, Bouchard P. The imminent dawn of SPRMs in obstetrics and gynecology. Molecular & Cellular Endocrinology 2012;358(2):232e43. 8. Donnez J, Tomaszewski J, Vazquez F, Bouchard P, Lemieszczuk B, Baró F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366(5):421e32. 9. Maruo T, Ohara N, Yoshida S, Nakabayashi K, Sasaki H, Xu Q, et al. Lessons learned from the preclinical drug discovery of asoprisnil and ulipristal for non-surgical treatment of uterine leiomyomas. Expert Opin Drug Discov 2011;6(9):897e911. 10. Ravet S, Munaut C, Blacher S, Brichant G, Labied S, Beliard A, et al. Persistence of an intact endometrial matrix and vessels structure in women exposed to VA-2914, a selective progesterone receptor modulator. J Clin Endocrinol Metab 2008;93(11):4525e31. 11. Munro MG, Mainor N, Basu R, Brisinger M, Barreda L. Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: A randomized controlled trial. Obstet Gynecol 2006;108(4):924e9. 12. Qin J, Yang T, Kong F, Zhou Q. Oral contraceptive use and uterine leiomyoma risk: A meta-analysis based on cohort and case-control studies. Arch Gynecol Obstet 2013;288(1):139e48. 13. Orsini G, Laricchia L, Fanelli M. Low-dose combination oral contraceptives use in women with uterine leiomyomas. Minerva Ginecol 2002;54(3):253e61. 14. Marshall LM, Spiegelman D, Goldman MB, Manson JE, Colditz GA, Barbieri RL, et al. A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril 1998;70(3):432e9. 15. Black A, Francoeur D, Rowe T, Collins J, Miller D. Society of Obstetricians and Gynaecologists of Canada Contraception Guidelines Committee. Canadian contraception consensus. SOGC clinical practice guidelines, No. 143 (Part 2 of 3), March 2004. J Obstet Gynaecol Can 2004;26:219e96.
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Use of Ulipristal Acetate for the Management of Fibroid-Related Acute Abnormal Uterine Bleeding Kristina Arendas, MD, FRCSC1, Nicholas A. Leyland, MD, MHCM, FRCSC2 1
Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, University of Ottawa, Ottawa, ON
2
Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON
Abstract Background: Episodes of acute abnormal uterine bleeding related to uterine fibroids can cause significant morbidity. Traditional management with high-dose hormonal regimens may not be as effective when used in women with fibroids. Case: A 32-year-old woman with a 12 cm uterine fibroid presented with an episode of acute abnormal uterine bleeding requiring blood transfusion. In lieu of using a hormonal maintenance regimen after the bleeding had stabilized, the patient was treated with ulipristal acetate 5 mg daily for three months. Amenorrhea was induced rapidly and the patient had no further episodes of acute excessive uterine bleeding. She subsequently underwent a laparoscopic myomectomy with a satisfactory outcome. Conclusion: Ulipristal acetate has been shown to induce amenorrhea rapidly in women with uterine fibroids, and it can be a useful treatment in the emergency management of fibroid-related acute abnormal uterine bleeding.
Résumé Contexte : Les épisodes de saignements utérins anormaux aigus associés aux fibromes utérins peuvent causer une morbidité considérable. La prise en charge traditionnelle au moyen de schémas posologiques à fortes doses d’hormones pourraient ne pas être aussi efficaces chez les femmes qui présentent des fibromes. Cas : Une femme de 32 ans présentant un fibrome utérin de 12 cm nous a consultés en raison d’un épisode de saignements utérins anormaux aigus nécessitant une transfusion sanguine. Plutôt que d’avoir recours à un schéma posologique hormonal d’entretien à la suite de la stabilisation des saignements, un traitement à l’acétate d’ulipristal (5 mg par jour pendant trois mois) a été administré à la patiente. Une aménorrhée s’est manifestée rapidement et la patiente n’a connu aucun autre épisode de saignements utérins excessifs aigus. La patiente a subséquemment subi une myomectomie laparoscopique ayant donné des résultats satisfaisants. Conclusion : Il a été démontré que l’acétate d’ulipristal provoque rapidement une aménorrhée chez les femmes qui présentent des fibromes utérins et qu’il peut constituer un traitement utile dans la
Key Words: Ulipristal acetate, fibroids, leiomyoma, acute uterine bleeding http://dx.doi.org/10.1016/j.jogc.2015.11.005
80
l
JANUARY JOGC JANVIER 2016
prise en charge d’urgences liées aux saignements utérins anormaux aigus associés aux fibromes. Copyright ª 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.
J Obstet Gynaecol Can 2016;38(1):80e83
INTRODUCTION
terine leiomyomas, or fibroids, affect a significant proportion of reproductive age women, making them the most common benign gynaecologic tumour.1 Although in many women fibroids are asymptomatic and undiagnosed, significant numbers of women seek medical attention for symptoms related to fibroids.1 The most common presentation of women with fibroids is abnormal uterine bleeding,2 which can be chronic or acute. Other symptoms include dysmenorrhea, pressure symptoms affecting bladder and bowel function, and reproductive dysfunction.1
U
The management of uterine fibroids depends on the presenting symptoms, the size and location of the fibroids, and the desire for future fertility. Medical therapies, including combined oral contraceptives (COC), have been used in the management of fibroid-related heavy menstrual bleeding; however, their effectiveness in treating abnormal bleeding is limited, and reduction of fibroid volume has not been documented with these therapies.3 Until recently, leuprolide acetate, a GnRH agonist, was the only pharmacologic agent used for the medical management of uterine fibroids.3 The selective progesterone receptor modulator ulipristal acetate (UPA; Fibristal, Actavis Specialty Pharmaceuticals Co., Mississauga, ON) was recently also approved by Health Canada for treatment of signs and symptoms related to uterine fibroids in reproductive age women who are eligible for surgery.4
Use of Ulipristal Acetate for the Management of Fibroid-Related Acute Abnormal Uterine Bleeding
Figure 1. Pre-operative view of the uterus at laparoscopy
An acute episode of heavy uterine bleeding can be the first presentation of a previously asymptomatic woman with fibroids. Our usual approach to such episodes includes treatment with antifibrinolytic agents, intravenous estrogens, and Foley catheter balloon tamponade until bleeding stabilizes. This is followed by administration of an oral maintenance dose of hormonal therapy.5 We present here the case of a woman with acute heavy uterine bleeding associated with a uterine fibroid in which UPA was used in lieu of a hormonal maintenance regimen, with excellent results. THE CASE
An otherwise healthy 32-year-old woman presented to the emergency department on the fourth day of menstrual flow with acute, severe vaginal bleeding. Her gynaecologic history was unremarkable, with regular menstrual cycles of 30 days’ duration and menstrual flow lasting between four and six days. Menstrual blood loss was typically moderate to heavy, with moderate dysmenorrhea.
Figure 2. Post-operative view following laparoscopic myomectomy
vagina. Active bleeding from the external cervical os was identified. Initial investigations showed a hemoglobin concentration of 114 g/L, a normal coagulation profile, and negative serum beta hCG. The patient was resuscitated with intravenous fluid and was given tranexamic acid 1000 mg intravenously. Pelvic ultrasound showed the presence of a large anterior transmural fibroid, measuring 12.1 10.2 10.9 cm. She continued to have brisk vaginal bleeding, and was given conjugated equine estrogens 25 mg intravenously with intrauterine Foley catheter balloon tamponade. Her hemoglobin concentration fell to 72 g/L. The patient’s anemia was symptomatic, and she was transfused one unit of packed red blood cells. After approximately 12 hours of balloon tamponade, the intrauterine Foley catheter was removed. The bleeding had slowed significantly.
On the day of presentation, she had experienced brisk vaginal bleeding, with passage of large clots prompting her to seek medical attention. She had no associated symptoms, and had no history suggestive of a bleeding disorder. Her medical history was also unremarkable.
The patient was discharged approximately 24 hours after admission and began treatment with UPA 5 mg daily. She quickly developed amenorrhea after beginning UPA, and she remained amenorrheic throughout three months of treatment. The treatment was well tolerated. The fibroid decreased in size to 9.8 8.9 9.7 cm after the UPA treatment.
On examination, the patient was tachycardic but other vital signs were normal; cardiovascular examination was also normal. The abdomen was soft and non-tender, although the uterus was palpable above the symphysis pubis. Pelvic examination identified a smooth-contoured, non-tender uterus enlarged to the size of a 12- to 14-week pregnancy, with no adnexal masses. During speculum examination, a large amount of blood and clots was evacuated from the
After completion of three months of UPA treatment the patient underwent laparoscopically-assisted myomectomy with morcellation via a mini-laparotomy incision (Figures 1 and 2). The procedure was uneventful with no intraoperative complications. Estimated blood loss during the procedure was approximately 300 mL. Post-operatively, the patient was discharged on the day after surgery and had an unremarkable recovery. She resumed normal menstrual
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CASE REPORT
cycling, the heavy menstrual bleeding having resolved completely, and her dysmenorrhea was significantly improved. DISCUSSION
Acute abnormal uterine bleeding, excluding bleeding related to pregnancy, the postpartum period, trauma, or malignancy, and requiring emergency treatment, can occur in reproductive age women.6 Acute episodes of abnormal uterine bleeding can be associated with significant morbidity, such as severe anemia requiring blood transfusion.6 A wide variety of conditions can manifest as acute abnormal uterine bleeding, including coagulation disorders, endocrine dysfunction, and anatomic conditions such as uterine fibroids.5 The mainstay of management of acute abnormal uterine bleeding, whether fibroid-related or not, in patients without a bleeding disorder has been hormonal agents, in the form of intravenous estrogens, as well as antifibrinolytic agents and Foley catheter balloon tamponade.5 Once bleeding is stabilized, patients are transitioned to a tapering hormone regimen until an oral maintenance dose is reached.5 In the case presented, UPA was used in lieu of a hormonal maintenance regimen after initial stabilization of the patient’s condition during an episode of acute fibroid-related abnormal uterine bleeding. UPA is an orally dosed selective progesterone receptor modulator, and its mechanism of action is potentiated by high affinity binding of the progesterone receptor. It has both progesterone antagonist and partial progesterone agonist activity, depending on the target tissue, without having any effect on estrogen or androgen receptors.7 Therefore, without causing downregulation of estradiol receptors and by maintaining estradiol levels at follicular phase levels, UPA causes inhibition of ovulation and induction of amenorrhea in the majority of patients.7 Given the rapid onset of control of bleeding, however, there appear to be additional mechanisms invoking rapid-onset reduction in or cessation of bleeding.2,8,9 These mechanisms have not yet been fully elucidated, but direct effects on the endometrial vascular supply may contribute to the rates of amenorrhea.10 The reduction in size of fibroids associated with UPA therapy is believed to be achieved through the inhibition of cellular and extracellular matrix proliferation and the induction of apoptosis.9 The efficacy of UPA in the ambulatory setting, for management of fibroid-related heavy menstrual bleeding, has been established. Phase III randomized controlled trials showed that UPA controlled excessive uterine bleeding in at least 90% of women with fibroids.2,8 Moreover, control
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of bleeding was achieved rapidly, with 50% of women becoming amenorrheic within 10 days. In an RCT of women with fibroids causing heavy menstrual bleeding, women on UPA 5 mg daily became amenorrheic within a median time of seven days, compared with a median time of 21 days in women on leuprolide acetate (P < 0.001).8 There have been no studies comparing UPA to COC. However, in a small RCT comparing COC to medroxyprogesterone acetate in the management of women with heavy menstrual bleeding of any etiology, treatment with COC resulted in cessation of bleeding in 88% of women, with a median time to cessation of bleeding of three days.11 The use of COC in the management of abnormal uterine bleeding due to fibroids has been assessed in very few studies. In a recent meta-analysis of cohort and casecontrol studies on this subject, treatment with COC was associated with a 17% reduction in fibroid-related morbidity.12 An observational study comparing the use of COC with placebo found a significant reduction in bleeding without change in fibroid volume.13 In the present case, UPA was used as maintenance therapy during an episode of acute, transfusion-dependent, fibroid-related heavy menstrual bleeding, rather than in an ambulatory setting to improve fibroid-related abnormal uterine bleeding. UPA was used in lieu of COC to maintain control of the bleeding after the patient’s condition stabilized. In addition to its effect on heavy menstrual bleeding, UPA provides other advantages over estrogen-progestin hormone therapy. In well-designed phase III RCTs and trials comparing UPA with standard therapy, UPA was found to reduce fibroid volume significantly.2,8 UPA and leuprolide acetate both resulted in significant reductions in the volume of the three largest fibroids (36% with UPA 5 mg daily, 42% with UPA 10 mg daily, and 53% with leuprolide acetate).8 There has been concern that treatment with COC may increase fibroid volumes; however, in a large prospective population study, neither current nor past use of COC was associated with a risk of developing fibroids.14 There is no evidence that COC use can reduce fibroid volumes. Although COC may be effective in slowing or stopping acute abnormal uterine bleeding, use of these agents is often limited by contraindications and significant sideeffects, such as nausea, breast tenderness, and irregular bleeding.15 In RCTs to date, UPA has been well tolerated; the most frequently reported side-effects are headache and breast tenderness, but these did not occur more often than in the placebo group.2 Hot flashes are also a reported sideeffect, but they are significantly less likely to occur in women on UPA than in women on leuprolide acetate (P < 0.001).8 Moreover, unlike estrogen-containing oral
Use of Ulipristal Acetate for the Management of Fibroid-Related Acute Abnormal Uterine Bleeding
medications, which increase the risk of thromboembolism,15 UPA has not been associated with any effects on the clotting cascade after three months of treatment.2,8
5. James AH, Kouides PA, Abdul-Kadir R, Dietrich JE, Edlund M, Federici AB, et al. Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: Consensus from an international expert panel. Eur J Obstet Gynecol Reprod Biol 2011;158(2):124e34.
CONCLUSION
6. Singh S, Best C, Dunn S, Leyland N, Wolfman WL. Clinical Practice e Gynaecology Committee. Abnormal uterine bleeding in pre-menopausal women. J Obstet Gynaecol Can 2013;35(5):473e9.
Acute heavy menstrual bleeding, whether associated with fibroids or not, can be a life-threatening condition and is associated with significant morbidity.6 After women with this condition have been stabilized, usual maintenance treatment involves high-dose oral hormones.6 In the case presented, UPA was used in a woman with fibroid-related acute abnormal uterine bleeding as step-down therapy to maintain amenorrhea, help restore hemoglobin levels, and reduce the size of the fibroid in preparation for myomectomy. We believe that UPA is a good option for managing episodes of acute abnormal uterine bleeding in women with uterine fibroids, given its rapid induction of amenorrhea, positive side-effect profile, and beneficial effect on fibroid volume. REFERENCES 1. Singh SS, Belland L. Contemporary management of uterine fibroids: Focus on emerging medical treatments. Curr Med Res Opin 2015;31(1):1e12. 2. Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366(5):409e20. 3. De Leo V, Morgante G, La Marca A, Musacchio MC, Sorace M, Cavicchioli C, et al. A benefit-risk assessment of medical treatment for uterine leiomyomas. Drug Saf 2002;25(11):759e79. 4. Health Canada. Summary basis of decision (SBD): Fibristal; 2013. Available at http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_ smd_2013_fibristal_156861-eng.php. Updated 2013. Last accessed on April 6, 2015.
7. Chabbert-Buffet N, Pintiaux A, Bouchard P. The imminent dawn of SPRMs in obstetrics and gynecology. Molecular & Cellular Endocrinology 2012;358(2):232e43. 8. Donnez J, Tomaszewski J, Vazquez F, Bouchard P, Lemieszczuk B, Baró F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366(5):421e32. 9. Maruo T, Ohara N, Yoshida S, Nakabayashi K, Sasaki H, Xu Q, et al. Lessons learned from the preclinical drug discovery of asoprisnil and ulipristal for non-surgical treatment of uterine leiomyomas. Expert Opin Drug Discov 2011;6(9):897e911. 10. Ravet S, Munaut C, Blacher S, Brichant G, Labied S, Beliard A, et al. Persistence of an intact endometrial matrix and vessels structure in women exposed to VA-2914, a selective progesterone receptor modulator. J Clin Endocrinol Metab 2008;93(11):4525e31. 11. Munro MG, Mainor N, Basu R, Brisinger M, Barreda L. Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: A randomized controlled trial. Obstet Gynecol 2006;108(4):924e9. 12. Qin J, Yang T, Kong F, Zhou Q. Oral contraceptive use and uterine leiomyoma risk: A meta-analysis based on cohort and case-control studies. Arch Gynecol Obstet 2013;288(1):139e48. 13. Orsini G, Laricchia L, Fanelli M. Low-dose combination oral contraceptives use in women with uterine leiomyomas. Minerva Ginecol 2002;54(3):253e61. 14. Marshall LM, Spiegelman D, Goldman MB, Manson JE, Colditz GA, Barbieri RL, et al. A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril 1998;70(3):432e9. 15. Black A, Francoeur D, Rowe T, Collins J, Miller D. Society of Obstetricians and Gynaecologists of Canada Contraception Guidelines Committee. Canadian contraception consensus. SOGC clinical practice guidelines, No. 143 (Part 2 of 3), March 2004. J Obstet Gynaecol Can 2004;26:219e96.
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