CASE REPORT Expulsion of a uterine myoma in a patient treated with ulipristal acetate Frederic Chantraine1, Gaelle Poismans1, Julia Nwachuku2, Elke Bestel2 & Michelle Nisolle1 1Department of Obstetrics and Gynecology, CHR Citadelle, University of Liege, Liege, Belgium 2PregLem S.A., Geneva, Switzerland Correspondence Key Clinical Message Frederic Chantraine, Department of Obstetrics and Gynecology, University of Description of a spontaneous expulsion of a submucosal myoma in a patient Liege, CHR Citadelle, Blv 12eme de Ligne 1, treated with ulipristal acetate. 4000 Liege, Belgium. Tel: +32 4 223 89 02; Fax: +32 4 224 00 05; Keywords E-mail: [email protected] Expulsion, myoma, selective progesterone receptor modulator, ulipristal acetate. Funding Information No sources of funding were declared for this study. Received: 16 September 2014; Revised: 28 October 2014; Accepted: 4 December 2014 Clinical Case Reports 2015; 3(4): 240–242 doi: 10.1002/ccr3.211 Introduction Case History Ulipristal acetate is a selective progesterone receptor modu- This report concerns a gravida 2 para 2 patient aged 45 lator (SPRM). It has clinical applications in emergency con- with no relevant medical–surgical history who had been traception and presurgical treatment of uterine myomas [1]. suffering from menometrorrhagia for 6 months. She had Uterine myomas are the most common pelvic tumors been using estrogen–progestin contraception (ethinyl- â in women [2] and are frequently responsible for pre- estradiol 0.02 mg, desogestrel 0.15 mg; Deso20 ) for menopausal menometrorrhagia and pelvic pain. The most 6 months. Menorrhagia treatment with tranexamic acid â common treatment options include surgical interventions (Exacyl ) had proven ineffective. A transvaginal ultra- such as hysterectomy or myomectomy. A study on hyster- sound exam diagnosed a polyfibromatous uterus (>four ectomy patients found myomas in 77% of hysterectomy myomas with diameters of between 43 and 15 mm). specimens [3]. Several drugs have been shown to be bene- Participation in the PEARL III study (a phase III, random- ficial in preparation for myomectomy or vaginal hysterec- ized, double-blind clinical study) was suggested. This study tomy. The effects sought are a reduction in the size of involves the administration of UPA at a dose of 10 mg per myomas and an improvement in the patient’s general day for 3 months. The patient is then allocated, by randomi- health by stopping the menorrhagia. zation, either a progestin (norethisterone acetate [NETA] Clinical studies are currently underway which aim 10 mg) or a placebo for a period of 10 days. This cycle is to examine the benefits of ulipristal acetate (UPA) treat- administered once in total and then followed by an optional ment on myomas, assessing improvement of symptoms, extension study, which repeats the UPA/NETA or UPA/pla- bleeding profile, and quality of life. It is in the context of cebo course three more times. Each treatment cycle is sepa- the PEARL III study (PGL4001’s Efficacy Assessment in rated by an “off-drug interval” allowing for return of Reduction of Symptoms due to uterine Leiomyomata III) menstruation and a full menstrual cycle. The aim of this study [4] that we report a case of spontaneous expulsion of a was to demonstrate the efficacy and safety of using UPA as a uterine myoma in a patient treated with UPA. long-term intermittent treatment of uterine myomas. 240 ª 2015 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. F. Chantraine et al. Expulsion of a uterine myoma Outcome and Follow-up After study enrolment, the patient was given the study medication between September 2010 and September 2011. Amenorrhea was achieved after 3 days and persisted while UPA was being taken, apart from intervals when the med- ication was suspended. No adverse effects were noted and clinical monitoring, as well as routine laboratory tests, was normal. The sizes of the three largest myomas and the thickness of the endometrium were measured regu- larly via ultrasound (Fig. 1). A continuous decrease in size of the myomas was observed over the study period. The expulsed myoma was not one of those followed by ultrasound measurements; however, we can assume a sim- ilar size reduction. Figure 2. Transvaginal ultrasound, sagittal view of the cervix: 21 mm Endometrial biopsies, repeated several times within the myoma in the external orifice of the cervix. The vascular end-foot context of the study, showed no abnormalities when ascends to the cervical canal. The arrow shows the internal opening of the cervix. examined histologically. At the follow-up visit of September 2011, the endova- ginal ultrasound indicated that a myoma was in the pro- size) with no deleterious effect on the endometrium cess of being expelled at the cervix uteri (Fig. 2). A [6–8]. gynecological exam confirmed the presence of the myoma Three recent publications have demonstrated the effect in the endocervix. The diagnosis of spontaneous expul- of UPA, derived from 19-norprogesterone, on the control sion of submucosal myoma was postulated. Pedicle tor- of menorrhagia related to uterine myomatosis and on the sion enabled the myoma to be extracted in the outpatient reduction in size of myomas [4, 9, 10]. UPA is an SPRM, clinic, with no complications or excessive bleeding during which acts as a progesterone receptor antagonist and can the procedure. also act as an agonist [5, 11–13] in certain conditions. It Anatomopathological analysis confirmed the diagnosis acts specifically on the progesterone receptor with no of a submucosal myoma of 25 9 20 9 18 mm. The clinically relevant antiglucocorticoid activity (less than endometrium was at that time in a state of progesterone mifepristone, a 19-nortestosterone derivative [14]). impregnation and had a secretory appearance. Myoma expulsions reported in the published literature are mainly expulsions secondary to postembolization Discussion necrosis. In addition, some descriptions of myoma expul- sion following treatment with GnRH agonists have been There is a vast amount of literature published on the published [15–17]. This is the first incidence of myoma treatment of uterine myomas. The growth of myomas expulsion under SPRM treatment to our knowledge. The is not only estrogen dependent but is also influenced link between the administration of UPA and expulsion by progesterone [5]. Several SPRMs have shown an of the myoma in our case is not clear. In in vitro models antagonist effect on myomagrowth(reductionin of myoma cell cultures, UPA has antiproliferative, (A) (B) Figure 1. Transvaginal ultrasound, sagittal view of the uterus: two subserosal myomas in the posterior wall. (A) before UPA treatment, (B) after UPA-treatment. UPA, ulipristal acetate. ª 2015 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 241 Expulsion of a uterine myoma F. Chantraine et al. 1 proapoptotic and antifibrotic effects [18]. Therefore, we progesterone receptor modulator CP8947 inhibits 2 theorize that a reduction in the size of the myoma causes leiomyoma cell proliferation without adversely affecting 3 the submucosal myoma to separate from the myometrium endometrium or myometrium. J. Steroid Biochem. Mol. 4 and the adjacent endometrium. Then, the ischemic submu- Biol. 122:279–286. 5 cosal myoma is expelled by contractions of the myometri- 7. Ohara, N., A. Morikawa, W. Chen, J. Wang, D. A. 6 um, as in a pregnancy that terminates in the first trimester. DeManno, K. Chwalisz, et al. 2007. Comparative effects of 7 In order to understand the molecular mechanism SPRM asoprisnil (J867) on proliferation, apoptosis, and 8 responsible for the reported persistence, for several months the expression of growth factors in cultured uterine 9 after treatment, of the beneficial effect of UPA on myoma leiomyoma cells and normal myometrial cells. Reprod. Sci. 10 size [10], further studies are required. Optimal manage- 14:20–27. 11 ment of uterine myomatosis remains a real challenge in 8. Chwalisz, K., M. C. Perez, D. Demanno, C. Winkel, G. 12 gynecology. It is important to be alert to the frequency of Schubert, and W. Elger. 2005. Selective progesterone receptor 13 this disease and to the presentation of its classic clinical modulator development and use in the treatment of – 14 symptoms. Despite the abundance of published literature leiomyomata and endometriosis. Endocr. Rev. 26:423 438. 15 on this disease, there are still numerous pathways to be 9. Donnez, J., T. F. Tatarchuk, P. Bouchard, L. Puscasiu, N. 16 explored, particularly with regard to drug treatment. To F. Zakharenko, T. Ivanova, et al. 2012. Ulipristal acetate 17 date, no molecule has resulted in a permanent therapeutic versus placebo for fibroid treatment before surgery. N. – 18 solution. UPA may offer an interesting and reassuring alter- Engl. J. Med. 366:409 420. 10. Donnez, J., J. Tomaszewski, F. Vazquez, P. Bouchard, B. 19 native and longer term studies with UPA are ongoing. Lemieszczuk, F. Baro, et al. 2012. Ulipristal acetate versus 20 leuprolide acetate for uterine fibroids. N. Engl. J. Med. 21 Conclusion 366:421–432. 22 11. Pintiaux, A., N. Chabbert-Buffet, and J. M. Foidart. 2009. 23 This case describes the potential of UPA to result in size Gynaecological uses of a new class of steroids: the selective 24 reduction of a myoma, which can result in the expulsion progesterone receptor modulators. Gynecol. Endocrinol. 25 of a submucosal myoma. 25:67–73. 26 12. Spitz, I. M. 2003. Progesterone antagonists and 27 Conflict of Interest progesterone receptor modulators: an overview. Steroids 28 68:981–993. 29 None declared. 13. Chabbert-Buffet, N., G. Meduri, P. Bouchard, and I. M. 30 Spitz. 2005. Selective progesterone receptor modulators References 31 and progesterone antagonists: mechanisms of action and 32 1.