Abstract. – OBJECTIVE: Uterine myomas areone of the most common benign tumours, oc-curring in 20-40% of women of reproductive age.Ulipristal acetate (UPA) is a possible option formedical treatment of myomas. It induces amen-orrhea and can reduce myoma volume beforesurgical treatment. Since its introduction in ourdepartment, we uncovered an unknown effect:migration of myoma.

CLINICAL CASE REPORTS: We describe threeclinical case of myoma migration following threemonths UPA pre-operative treatment. The firstwoman presented with a FIGO 2 myoma, whichmigrated in FIGO 3. A previously planned hys-teroscopy converted into a laparoscopy. Thesecond woman also presented with a FIGO 2myoma, which migrated in FIGO 3. Initially, ahysteroscopy was planned, but ultimatelysurgery was no longer required. The thirdwoman presented with a FIGO 2-5 myoma,which migrated in FIGO 1. The previouslyplanned laparoscopy converted into a vaginalmyomectomy.

CONCLUSIONS: UPA induces a proapoptoticand anti proliferative effect of leiomyoma cells. Itreduces expression of VEGF and reduces colla-gen deposition in the extracellular matrix. Thesemechanisms could induce migration of myoma.UPA as pre-operative treatment can induce mi-gration of myoma and, therefore, can lead to pe-rioperative conversion of surgery.

Key Words:Ulipristal acetate, Myoma, Migration, Side effect,

Expulsion.

Introduction

Uterine myomas are one of the most commonbenign tumours, occurring in 20-40% of womenof reproductive age1. They represent one of themain causes of anaemia among young women.Myomas can alter fertility and cause abnormal

European Review for Medical and Pharmacological Sciences

Myoma migration: an unexpected “effect”with Ulipristal acetate treatment

A. WILLAME1, R. MARCI1,2, P. PETIGNAT1, J. DUBUISSON1

1Department of Gynecology and Obstetrics, University Hospital of Geneva, Switzerland2Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Italy

Alexia Willame and Roberto Marci contributed equally to this work

Corresponding Author: Jean Dubuisson, MD; e-mail: jean.dubuisson@hcuge.ch 1439

uterine bleeding, dysmenorrhoea and pelvicpain, as well as seriously reducing quality oflife (QoL)2-4. Surgery is currently the treatmentof choice5. Hysterectomy remains the only radi-cal therapy and is the most common treatmentstrategy6. It is, however, not suitable for womenwishing to preserve their fertility. Surgical my-omectomy represents an alternative treatmentstrategy, although it does not prevent recurrenceand it may not be appropriate in the case of apolymyomatous uterus. Perioperative haemor-rhagic risks must be taken into consideration, asthose women also suffer from anaemia. Uterineembolization has proven to be effective withrelatively minor long-term morbidity7,8. It repre-sents an alternative to surgery, but only forwomen who have no desire to conceive, as itsimpact on fertility is still a matter of debate9-11.Medical treatments have also been developed5,7.They are generally used preoperatively, but inspecific cases, they can also be an alternative tosurgery.

Ulipristal acetate (UPA) is a possible optionfor medical treatment of myomas. As myomagrowth is dependent on estrogen and in particu-lar on progesterone, a selective progesterone re-ceptor modulator (SPRM) UPA was certified in2012 by the European Medicines Agency forpreoperative treatment of a three-month dura-tion12-14. It induces amenorrhea in 80% of pa-tients after only 3.5 days of treatment15, and itreduces myoma volume by 45%15. It does notreduce the estrogen circulating rate13. Persistentamenorrhea and stabilization of the size of themyoma six months after discontinuation oftreatment make UPA an alternative to surgery15.At the moment, the drug has been studied for amaximum of 4 cycles of 12 weeks16. UPAseems to represent a good medical treatment al-ternative for women with symptomatic my-

2016; 20: 1439-1444

Figure 1.

Figure 2.

A. Willame, R. Marci, P. Petignat, J. Dubuisson

month later, per-operative ultrasound assessed aFIGO 3 myoma measuring 38×10×12 mm(equating to a volume of 7 cm3). Hysteroscopyconfirmed a FIGO 3 with an empty cavity (noimpact of the myoma on the mucosa). Because ofpatient’s infertility and its wish to get pregnantquickly, surgery was performed but a la-paroscopy approach was chosen to remove theentire myoma, without opening the endometrialcavity. The resulting loss of blood amounted to200 ml.

Case History No. 2This case involved a 28 years-old multiparous

woman who was originally from Serbia. She hadno immediate desire for pregnancies. She suf-fered from abnormal uterine bleeding that wasassociated with mild anaemia (i.e. a haemoglobinlevel of 104 g/l). A transvaginal ultrasound re-vealed a massive 54 mm-sized FIGO 2 myoma(Figure 3. Ultrasound June 2015: myoma FIGO 1of 54 mm 4 mm away from the serosa = volumeof 119 cm3). A diagnostic hysteroscopy con-firmed a FIGO 2 grade, with a posterior impacton the endometrial cavity. Treatment ofUlipristal Acetate was initiated to reduce the sizeof the myoma and to obtain amenorrhea prior toperform a hysteroscopic resection. Three monthslater, a vaginal ultrasound revealed a smaller-

oma17-22 and particularly for those sufferingfrom submucosal myoma scheduled for in vitro

fertilization23. Although endometrial thickeningcan be observed in some patients, several stud-ies indicate that this is benign and reversiblefollowing discontinuation of the treatment24–26.

Since the introduction of UPA as a certifiedtreatment in Switzerland, we have administeredUlipristal Acetate at over a three months periodto women suffering from myoma. Indications forUPA treatment followed the relevant SwissGuidelines27, which at that time only authorizedUPA as a preoperative treatment. We have un-covered an unexpected secondary effect, whichis myoma migration. We describe three clinicalcase reports of myoma migration.

Clinical Cases

Case History No. 1This first case involved a nulliparous woman

of 31 years of age who was originally from Rus-sia. She suffered from primary infertility and wasknown to have a myoma that was first detected 2years prior. She had no abnormal uterine bleed-ing. An MRI revealed a 37×32×25 mm-sized FI-GO 2 myoma (Figure 1. Cross-sectional MRI T2may 2015: myoma FIGO 2 of 37×32×25 mm 6mm away from the serosa= volume of 21 cm³). Apre-operative treatment with Ulipristal Acetatefollowed by a hysteroscopic myomectomy wasplanned because of patient’s infertility with a fastgrowth rate of the myoma. After three months, acontrol MRI revealed a smaller-sized FIGO 2myoma, with a maximal dimension of 28 mm(Figure 2. Sagittal MRI T2 august 2015: myomaFIGO 2 of 28 mm = volume of 7 cm3). One

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Figure 3.

Figure 5.

Figure 4. Figure 6.

sized myoma, with a maximal dimension of 44mm (Figure 4. Three-dimensional ultrasound Oc-tober 2015: myoma 44 mm = volume of 53 cM3).Amenorrhea was achieved. After one month, theperioperative ultrasound assessment revealed a25 mm-sized FIGO 3 myoma that was confirmedby hysteroscopy (there was no longer impact onthe mucosa). The patient’s haemoglobin level atthis time was 141 g/l. The surgery was cancelled(no desire to conceive).

Case History No. 3The final report provided here involved a 26

years old virgin female who was originally fromthe Philippines. She had no relevant prior med-ical history. She had suffered from abnormaluterine bleeding for 1 year. She presented withsevere anaemia that required iron injection. Her

lowest haemoglobin level was 60 g/l. An MRIrevealed a 48×38×31 mm-sized FIGO 2-5 my-oma (Figure 5. MRI T2 august 2015: myoma FI-GO 2-5 of 48×38×31 mm = volume of 30 cm3).Ulipristal Acetate was prescribed to treat thisanemia. Amenorrhea was not achieved. Afterthree months, a control MRI revealed an isthmicFIGO 1 myoma of 46×35×31 mm in size thathad migrated into the endometrial cavity (Figure6. MRI T2 November 2015: myoma FIGO 1isthmic of 46×35×31 mm which protrudes in thecavity = volume of 22 cm3). As this woman wasa virgin, and she wanted to preserve this status, acomplex laparoscopy was scheduled to achievemyomectomy, instead of relying on a hystero-scopic approach. One month later, during theper-operative vaginal examination, a myoma ex-pulsed through the cervix into the vagina wasdiscovered (Figure 7. Per-operative status my-oma expulsed in the vagina). The surgical proce-dure was switched from a laparoscopic to a vagi-nal approach, thus entailing a risk of breaking thehymen, of which the patient was informed pre-operatively. The surgery was entirely successful.

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Myoma migration: an unexpected “effect” with Ulipristal acetate treatment

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Blood loss was estimated to be 250 ml, but thepatient received a blood transfusion because ofher low pre-operative hemoglobin level.

Discussion

Among women treated with UPA prior tosurgery in our department, we observed threecases of myoma migration.

The first woman (i.e. case history No. 1) pre-sented with a FIGO 2 myoma, which migratedin FIGO 3 after a 70% reduction in size. Initial-ly, a hysteroscopy was planned, but the patientultimately underwent a laparoscopy. The sec-ond woman (i.e. case history No. 2) presentedwith a FIGO 2 myoma, which migrated in FI-GO 3 after a 55% reduction in size. Initially, ahysteroscopic myomectomy was planned, butsurgery was ultimately no longer required. Thethird woman (i.e. case history No. 3) presentedwith a FIGO 2-5 myoma, which migrated in FI-GO 1 after a 27% reduction in size. This pa-tient was initially scheduled to receive a la-paroscopy, but she finally benefited from avaginal myomectomy.

To our knowledge, there is only one publishedcase regarding myoma migration following pre-operative medical treatment with UPA28. Myomamigration has, however, been described follow-ing uterine artery embolization and GNRHatreatment29-31. Necrosis following artery em-bolization induces cytokine production, whichcauses myometrial contraction, and ultimatelymigration of the myoma. Regarding GNRHa, itsanti-proliferative effect results in the reduction ofthe myoma volume. This decrease in size causesseparation of myometrium from the adjacent en-

dometrium resulting in ischemic myoma. Thisleads to myometrial contraction and thus its mi-gration.

UPA acts as a progesterone antagonist, withpartial agonist activity depending on the tissuesite. By blocking progesterone, which acts as atranscriptional activator, UPA increases the lev-el of cleaved caspase-3, inducing a proapoptoticeffect32,33. Like GNRHa, it also inhibits prolifer-ation of leiomyoma cells. These mechanisms in-duce the reduction in the size of the myomaand, therefore, its migration34. UPA reduces ex-pression of VEGF, suppressing neovasculariza-tion and cell proliferation. This mechanismleads to ischemic myoma, followed by its mi-gration35,36. UPA also reduces collagen deposi-tion in the extracellular matrix. It can therebyimpair the stability and structural integrity ofmyomas, thus favouring myoma migration37. Inour series, only submucosal myomas migrated(hybrid myoma FIG0 2-5, FIGO 2). Submucos-al myoma has a smaller implantation area in themyometrium than intramural myoma. Matrix in-stability provoked by Ulipristal Acetate couldfavour myoma migration in case of submucosalmyoma.

Conclusions

Our results reflect those from the literaturesupporting UPA treatment as efficient and safe toreduce the size of myoma. However, our seriesrevealed an important effect that must be takeninto consideration before planning a surgery withpreoperative UPA treatment. We recommendprecise selection of women with a detailed car-tography of the myoma. Women should be in-formed about the possibility of perioperativeconversion of surgery and a pre-operative ultra-sound should be performed systematically toconfirm the surgical approach.

–––––––––––––––––-––––Conflict of InterestThe Authors declare that there are no conflicts of interest.

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