Endometrial changes during ulipristal acetate use a systematic review Accepted Manuscript Title Endometrial changes during ulipristal acetate use a systematic review Author Inge De Milliano Dominique.
Accepted Manuscript Title: Endometrial changes during ulipristal acetate use: a systematic review Author: Inge De Milliano Dominique Van Hattum Johannes C.F Ket Judith A.F Huirne Wouter J.K Hehenkamp PII: DOI: Reference: S0301-2115(17)30215-4 http://dx.doi.org/doi:10.1016/j.ejogrb.2017.04.042 EURO 9885 To appear in: EURO Received date: Revised date: Accepted date: 14-3-2017 20-4-2017 23-4-2017 Please cite this article as: De Milliano I, Van Hattum D, Ket JCF, Huirne JAF, Hehenkamp WJK, Endometrial changes during ulipristal acetate use: a systematic review, European Journal of Obstetrics and Gynecology and Reproductive Biology (2017), http://dx.doi.org/10.1016/j.ejogrb.2017.04.042 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain Endometrial changes and ulipristal use Endometrial changes during ulipristal acetate use: a systematic review Inge DE MILLIANOa, Dominique VAN HATTUMa, Johannes C.F KETb, Judith A.F HUIRNEa, Wouter J.K HEHENKAMPa cr us a an ip t Department of Obstetrics and Gynecology, VU Medical Center, P.O Box 7057, 1007 MB Amsterdam, b M The Netherlands Medical Library, VU University, P.O Box 7057, 1007 MB, Amsterdam, The Netherlands te Ac ce p 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 d Correspondence to: Inge De Milliano, MD Department of Obstetrics and Gynaecology VU Medical Center P.O Box 7057 1007 MB Amsterdam The Netherlands Phone: +31-20-4441851 Fax: +31-20-4443333 E-mail: i.demilliano@vumc.nl Page of 36 d te Ac ce p us an M cr ip t 30 31 Page of 36 31 34 Abstract 35 Ulipristal acetate is increasingly used for several clinical indications, like emergency contraception 36 and pre-treatment of uterine fibroids It has mixed progesterone agonist and antagonist effects in 37 the myometrium and endometrium Due to its progesterone antagonistic effect, an unopposed 38 estrogen effect could occur which could cause (pre-) malignant lesions in the endometrium Several 39 studies have been performed to evaluate this possible increased risk for endometrial malignancies 40 when using ulipristal acetate The specific spectrum of morphological changes due to ulipristal 41 acetate, named progesterone receptor modulator associated endometrial changes (PAEC), occurs to 42 be reversible after discontinuing ulipristal acetate In this systematic review we provide a detailed 43 overview of the literature on histopathological endometrial changes and imaging characteristics of 44 the endometrium in ulipristal acetate users We performed an extensive search in Embase.com, 45 Wiley/Cochrane Library and PubMed in accordance with the prisma guidelines All studies published 46 as full papers in peer reviewed journals using ulipristal acetate reporting on endometrial changes 47 were included, independent of clinical indication, dosage taken and duration of therapy No language 48 restrictions were applied 49 Ten studies with a total of 1450 participants were included Seven were randomized clinical trials 50 and three prospective cohort studies A quality assessment of all included studies was performed In 51 only five of ten studies an endometrial biopsy was performed during treatment All of these studies 52 described specific histological non-physiological endometrial changes (PAEC) due to ulipristal acetate, 53 varying from 41 to 78.8% of all patients Three of these studies also performed follow-up biopsies 54 after discontinuing ulipristal acetate The percentage of PAEC decreased from 62% to 0%, 78.8% to 55 0% and from 59% to 6-7% after the treatment period In six of 1450 women (0.4%) endometrial Ac ce p te d M an us cr ip t 33 Endometrial changes during ulipristal acetate use: a systematic review I De Milliano, D van Hattum, J.C.F Ket, J.A.F Huirne, W.J.K Hehenkamp 32 Page of 36 hyperplasia was reported during or after ulipristal acetate use Five were simple hyperplasia, one 57 biopsy showed simple atypical endometrial hyperplasia that resolved into benign secretory 58 endometrium by the end of the treatment One case of endometrial adenocarcinoma was reported, 59 however this does not seem to be related to ulipristal acetate use, since it was already present at the 60 baseline biopsy In eight of ten studies a transvaginal ultrasound or MRI was performed at any 61 moment to assess the endometrial thickness before, during and after treatment Most studies 62 showed a transient increase of endometrial thickness during treatment, which returned to normal 63 within a few weeks after discontinuing ulipristal acetate 64 Based on the literature found in this systematic review, follow-up after a maximum of four courses of 65 ulipristal acetate did not report any non-reversible (pre-)malignant lesions of the endometrium Most 66 studies focused on short term use of ulipristal acetate and their follow-up period was limited 67 Therefore, we believe more information concerning long term (intermittent) use is needed before it 68 can be concluded that its use is completely safe 71 72 cr us an M d te 70 Keywords: ulipristal acetate, PAEC, endometrial hyperplasia Ac ce p 69 ip t 56 Page of 36 Introduction 73 Ulipristal acetate, also known as CDB/VA-2914, is a selective progesterone receptor modulator (PRM) 74 that exerts tissue selective mixed progesterone agonist and antagonist effects in myometrial and 75 endometrial tissue (1, 2) This progesterone antagonistic action can result in an unopposed estrogen 76 effect and could therefore cause hyperplasia and malignant lesions in the endometrium In Europe 77 and the USA, ulipristal acetate has been registered for two clinical indications Ulipristal acetate 78 30mg is used as a single dose emergency contraceptive within 120 hours after unprotected 79 intercourse by inhibition or delaying ovulation, opposing proliferation of the endometrium and 80 inducing amenorrhea (3, 4) Secondly, in women with symptomatic fibroids it reduces fibroid size due 81 to its antiproliferative, antifibrotic and proapoptotive effects on the fibroid (5, 6) Patients taking 82 oral doses of or 10mg/day report an amenorrhea in 81% and 90% respectively and in 80% of 83 patients it suppresses ovulation (7) Both pre-operative use and intermittent three months courses 84 are registered for the treatment of fibroids The use of ulipristal acetate as a continuous 85 contraception (e.g vaginal ring) is still under evaluation 86 Besides the effect on fibroid growth and ovulation blocking, ulipristal acetate also might induce 87 specific endometrial effects inducing amenorrhea These effects are histologically characterized by 88 cystically dilatated glands, epithelial distortion, apoptosis and low mitotic activity in glands and 89 stroma (8) This specific spectrum of morphological changes has not been reported with any other 90 agent and is therefore named PRM associated endometrial changes (PAEC) (5, 8) In 2012, Williams 91 et al (9) provided a detailed assessment of these morphological changes A total of 1638 92 endometrial biopsies of patients using ulipristal acetate or placebo were assessed by gynecologic 93 pathologists blinded to treatment and timing of visit A detailed overview was provided to 94 differentiate between PAEC, unopposed estrogen effects and endometrial hyperplasia Besides, they 95 concluded that the morphological changes due to ulipristal acetate are non-physiological and Ac ce p te d M an us cr ip t 72 Page of 36 reversible The changes seem to spontaneously reverse in a few weeks to months after 97 discontinuation 98 In this systematic review, we provide a detailed overview of the literature on the endometrial effects 99 in patients using ulipristal acetate in various dosages and durations of administration We specifically 100 ip t 96 assess histological changes and imaging characteristics Ac ce p te d M an us cr 101 Page of 36 101 Material and methods 102 We conducted a systematic review in accordance to the prisma guidelines (10) No protocol was 103 registered in advance Eligibility criteria 106 Studies fulfilling the following inclusion criteria were included: cr 105 ip t 104 107 Types of studies 109 We included prospective studies, retrospective studies and case control studies on ulipristal acetate 110 reporting on endometrial changes published in peer reviewed journals No language restrictions 111 were applied an us 108 M 112 Types of participants 114 Participants were pre-menopausal women of 18 years and older 115 te d 113 Types of interventions 117 Admission of ulipristal acetate, independent of duration of therapy and dosage taken 118 Ac ce p 116 119 Types of outcome measures 120 Histopathological endometrial changes due to the use of ulipristal acetate As a secondary outcome 121 measurement findings at transvaginal ultrasound (TVUS) or MRI on the endometrium were reported 122 123 Search methods for identification of studies 124 Electronic searches Page of 36 A review protocol was developed based on the Preferred Reporting Items for Systematic Reviews and 126 Meta-Analysis (PRISMA)-statement (www.prisma-statement.org) Embase.com, Wiley/Cochrane 127 Library and PubMed were searched from inception (by IM and JCFK) up to 25 July 2016 The following 128 terms were used (including synonyms and closely related words) as index terms or free-text words: 129 ‘endometrium’ and ‘ulipristal’ The full search strategies for all the databases can be found in the 130 Supplementary Information Duplicate articles were excluded All languages were accepted cr ip t 125 us 131 Data collection and analysis 133 Study selection 134 Two authors (IM and DH) independently assessed all potential studies for inclusion If the title or 135 abstract suggested presentation of a case eligible for inclusion, the full article was retrieved and 136 reviewed against the inclusion and exclusion criteria Any disagreements were resolved by 137 discussion If no consensus was reached, a third author (WH) was asked to evaluate the full text of 138 the study te 139 d M an 132 Data collection process 141 One reviewer (IM) extracted the data using a data extraction form which was developed by the 142 authors A second reviewer (DH) checked the extracted data Disagreements were discussed Authors 143 were contacted in the case of missing data 144 Ac ce p 140 145 Quality assessment of individual studies 146 The quality assessments were performed independently by two reviewers (IM and DH) For the 147 included randomized controlled trials, the Cochrane Collaboration’s ‘Risk of Bias’ tool was used as 148 described in the Cochrane Handbook (11) Studies were classified as low risk of bias, unclear risk of 149 bias or high risk of bias For all included non-randomized studies, the Quality in Prognostic Studies Page of 36 150 (QUIPS) tool was used to assess the risk of bias (12) Studies were classified as low, moderate or high 151 risk of bias Ac ce p te d M an us cr ip t 152 Page of 36 419 Legends for figures 420 Figure PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 421 flowdiagram of study selection ip t 422 Figure Overall risk of bias for included RCT’s (Randomized Clinical Trials) The Cochrane 424 Collaboration’s ‘Risk of Bias’ tool was used as described in the Cochrane Handbook Studies were 425 classified as low risk of bias, unclear risk of bias or high risk of bias Quality items: random sequence 426 generation (selection bias), allocation concealment (selection bias), blinding of participants and 427 personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome 428 data (attrition bias) and selective reporting (reporting bias) an us cr 423 M 429 Figure Overall risk of bias for included cohort studies The Quality in Prognostic Studies (QUIPS) 431 tool was used to assess the risk of bias Studies were classified as low, moderate or high risk of bias 432 Quality items: study participation, study attrition, prognostic factor measurement, outcome 433 measurement, study confounding, statistical analysis and reporting te Ac ce p 434 d 430 435 Figure Risk of bias summary for RCT’s (Randomized Clinical Trials) The Cochrane Collaboration’s 436 ‘Risk of Bias’ tool was used as described in the Cochrane Handbook Studies were classified as low 437 risk of bias (green circle with ‘plus’ sign), unclear risk of bias (yellow circle with ‘question mark’ sign) 438 or high risk of bias (red circle with ‘minus’ sign) 439 440 Figure Risk of bias summary for cohort studies The Quality in Prognostic Studies (QUIPS) tool was 441 used to assess the risk of bias Studies were classified as low (green circle with ‘plus’ sign), moderate 442 (yellow circle with ‘question mark’ sign) or high risk of bias (red circle with ‘minus’ sign) 22 Page 22 of 36 Ac ce p te d M an us cr ip t 443 23 Page 23 of 36 i cr us Tables Design No of participants Mean age (±SD) Ulipristal acetate as a contraceptive Stratton, 2010 35.3±4.4 RCT 55 Low dose 33.5±3.6 Prospective RCT 56 Placebo Period of UPA treatment Imaging technique Number of endometrial biopsies Baseline During After Vaginal ring No 12 weeks N.A 1 1500µg/day (N=28) or 2500µg/day (N=27) Vaginal ring No Two 12 week courses TVUS UPA 30mg once weekly (N=12) or UPA 30mg every days (N=11) Per os No weeks TVUS 1 Placebo (N=15), 10mg (N=13), 50mg (N=14), 100mg (N=14) Per os Yes Once at LH+1 or LH+2 TVUS 0 35.3±3.2 5mg daily Per os No 30-50 days TVUS Placebo 41.6±5.6 5mg or 10mg daily Per os Yes 13 weeks MRI 1 5mg or 10mg daily Per os No 13 weeks TVUS 1 High dose 33.4±4.8 Weekly UPA 28.6±4.4 23 Route of administration 600-800µg/day ed 37 pt Jesam, 2016 Prospective ce Brache, 2012 Huang, 2014 Dosage of UPA M Author, year an Table Study characteristics daily UPA 32.2±1.6 30.8±9.8 Ulipristal acetate as pre-treatment of symptomatic fibroids before surgery Bettocchi, 2016 Donnez, 2012 PEARL I Prospective 74 Ac 444 Double blind RCT 242 Placebo (N=48) UPA 5mg (N=96) Donnez, 2012 PEARL II Double blind RCT UPA 10 mg (N=98) 307 UPA 5mg (N=98) UPA 5mg 41.2±5.9 UPA 10mg 42.0±5.6 UPA 5mg 40.1±6.2 UPA 10mg 40.7±6.3 24 Page 24 of 36 i cr Leuprolide acetate (N=101) 18 RCT Placebo 45.1±5.1 UPA 10mg 42.6±4.8 209 Extension study ≥ courses: N=132 Double blind RCT course 40.1±6.0 10 mg daily ≥ courses 40.5±5.8 NB: Followed by 10mg progestestin norethisterone acetate or placebo pt Donnez, 2015 PEARL IV Open label Extension study courses: N=107 451 ce Donnez, 2015 PEARL III UPA = ulipristal acetate 446 ET= endometrial thickness 447 NR = not reported 448 RCT = randomized clinical trial 449 LH = luteinizing hormone 450 AUB = abnormal uterine bleeding 451 TVUS = transvaginal ultrasound courses: 40.8±5.5 UPA 5mg 41.6±5.4 Per os Yes cycles or 90-102 days TVUS 0 Per os No 12 weeks TVUS PEARL III: PEARL III: PEARL III: PEARL III Extension: PEARL III Extension: PEARL III Extension: 5mg or 10mg daily 1 NB: post UPA medication 10 days Per os UPA 10mg 41.1±5.1 No Two 12 week courses Separated by a drug-free interval TVUS Ac 445 Placebo (N=8), UPA 10mg (N=8) or UPA 20mg (N=6) daily ed UPA 20mg 44.3±4.2 Ulipristal acetate as long term treatment in symptomatic fibroids an Leuprolide acetate 40.3±6.2 M Levens, 2008 us UPA 10mg (N=104) 25 Page 25 of 36 i cr us 452 454 †Simple atypical endometrial hyperplasia (resolved into benign secretory endometrium at follow-up) Ac ce pt ed M an 453 Table Reported histological changes at any moment during and after ulipristal acetate use PAEC Simple hyperplasia During treatment Follow-up During treatment Follow-up Ulipristal acetate as a contraceptive Brache, 2012 41% N.R 0% N.R N=37 Huang, 2014 Week 12: 64.2% 0% 0% 0% N=55 Week 24: 78.8% Jesam, 2016 N.R 20% N.R 0% N=23 Stratton, 2010 N.R N.R N.R 1.8% N= 56 Ulipristal acetate as pre-treatment of symptomatic fibroids before surgery Bettocchi, 2016 N.R.* N.R 0% N.R N=74 Donnez, 2012 UPA 5mg: 62% 0% 0% 0% PEARL I UPA 10mg: 57% N=242 Donnez, 2012 UPA 5mg: 58% UPA 5mg: 6-7% PAEC UPA 5mg: 1% 0% PEARL II UPA 10mg: 59% UPA 10mg: 6-7% PAEC UPA 10mg: 0% N=281 Levens, 2008 N.R N.R N.R 4.5% N=22 Ulipristal acetate as long term treatment in symptomatic fibroids Donnez 2015 N.R 25.6% N.R 0% PEARL III N=209 Donnez 2015 N.R After course 1: 28.7% N.R 0% PEARL III extension After course 4: 25.3% N=209 Donnez 2015 N.R UPA 5mg: 16.3% N.R UPA 5mg: 0.6% PEARL IV UPA 10mg: 19.2% UPA 10mg: 1.1%† N=451 *Not reported as PAEC, see table Adenocarcinoma During treatment Follow-up 0% N.R 0% 0% N.R 0% N.R 0% 0% N.R 0% 0% 0% 0% N.R 0% N.R 0% N.R 0% N.R UPA 5mg: 0.6% UPA 10mg: 0% 26 Page 26 of 36 i cr 456 NR = not reported 457 UPA = ulipristal acetate us PAEC = PRM associated endometrial changes an 455 Ac ce pt ed M 458 27 Page 27 of 36 i cr us 458 Ulipristal acetate as a contraceptive N.R 8.7 ± 3.0 13.6 ± 6.7* N.R N.R 10.3 ± 2.3 N.R M N.R N.R N.R N.R 9.7 ± 1.8 ed Brache, 2012 N=37 Huang, 2014 N=55 Jesam, 2016 N=23 Stratton, 2010 N= 56 an Table Reported mean endometrial thickness by TVUS or MRI before, during and after ulipristal acetate use (in mm) Before treatment (mean±SD) During treatment (mean±SD) After treatment (mean±SD) Ulipristal acetate as pre-treatment of symptomatic fibroids before surgery N.R 7.5 ± 4.1 Donnez, 2012 PEARL I N=242 UPA 5mg: 6.77 ± 3.05 UPA 10mg: 7.89 ± 3.33 Donnez, 2012 PEARL II N=281 UPA 5mg: 8.9 ± 4.2 UPA 10mg: 8.9 ± 4.3 ce Ac Levens, 2008 N=22 N.R pt Bettocchi, 2016 N=74 N.R UPA 5mg: 8.22 ± 3.46 UPA 10mg: 8.67 ± 6.12 UPA 5mg: 7.4 ± 4.2 UPA 10mg: 7.9 ± 5.4 UPA 5mg: 9.4 ± 5.7* UPA 10mg: 10.7 ± 5.9* UPA 5mg: 8.8 ± 4.1 UPA 10mg: 8.5 ± 3.4 N.R N.R Ulipristal acetate as long term treatment in symptomatic fibroids Donnez 2015 9.7 ± 3.7 9.2 ± 4.6 PEARL III N=209 Donnez 2015 PEARL III extension N=209 9.3 ± 4.0 Course 1: 9.4 ± 4.5 Course 4: 7.5 ± 3.4 Donnez 2015 PEARL IV N=451 UPA 5mg: 8.4 ± 3.9 UPA 10mg: 8.4 ± 3.9 Course 1: UPA 5mg: 8.8 ± 4.3 UPA 10mg: 9.5 ± 4.8 7.6 ± 3.4 8.9 ± 3.2 Course 2: UPA 5mg: 8.7 ± 4.9 UPA 10mg: 7.9 ± 4.4 UPA 5mg: 8.5 ± 3.8 UPA 10mg: 8.1 ± 4.3 28 Page 28 of 36 i cr 460 TVUS = Transvaginal ultrasound 461 UPA = ulipristal acetate 462 ET= double endometrial thickness 463 NR = not reported us *Statistically significant compared to ‘before treatment’ (p