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PURPOSE: Since late 2017, the use of ulipristal acetate 5 mg (UPA; Proprietary name: Esmya) has been under review in the European Union, due to an emerging hepatic risk. In February 2018 and in July 2018, the Spanish Agency of Medicines and Medical Devices and the marketing authorization holder put two risk minimization measures (RMM) in place, in order to inform about new safety information and to mitigate this risk. This study aims to assess RMM effectiveness in Spain, by performing an interrupted time-series (ITS) analyses, between 2014 and 2019. METHOD: Two quasi-experimental ITS analyses to examine the use of UPA before and after the RMM release were performed: (a) an ecological study using aggregated data from a drug consumption database; and (b) a study using primary healthcare data gathered from electronic clinical records. RESULTS: Regulatory interventions were associated with an immediate and significant decrease level of DID (the number of DDD dispensed per 100 000 inhabitants and day) and incidence. The DID was 70% less than expected 12 months after the interventions. This value was 59% for the incidence. However, a change in the slope was not observed and the use started rising again in the last segment of the study period. CONCLUSION: Despite RMM had an immediate strong impact on UPA use, the last segment upward trend in the long-term might have been affected by the lack of comparable therapeutic alternatives. Further studies should be performed to confirm the increase trend observed and analyze subsequent measures and additional data.

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The World Health Organization includes oral emergency contraception (EC) in the list of essential medicines. Ulipristal acetate (UPA) and levonorgestrel (LNG) are the recommended oral methods. UPA has superior efficacy and a comparable side effect profile compared with LNG. Both work by inhibiting or delaying ovulation, so that sperm present in the reproductive tract will have lost their fertilising ability by the time the oocyte is eventually released. Neither LNG nor UPA at the EC doses have significant effects on the endometrium and are unable to prevent implantation. Mifepristone can also be used for EC but its availability is limited to few countries. LNG is less effective in women with a body mass index over 26 kg/m2 or weight over 70 kg. Hormonal contraception can be quickstarted immediately following LNG, or five days following UPA. LNG-releasing intrauterine devices and cyclo-oxygenase inhibitors are promising options for EC to be further studied.

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Selective progesterone receptor modulators (SPRMs) are synthetic steroid compounds that interact with the progesterone receptor, inducing various agonist, antagonist or mixed responses. First identified with mifepristone, they are now represented by ulipristal acetate (UPA), used for emergency contraception and uterine fibroids. Despite a few rare cases of severe hepatic insufficiency, SPRMs offer advantages in the treatment of uterine fibroids, reducing their volume without the hypoestrogenic side-effects of GnRH agonists, thus preserving patients' bone capital and quality of life. Despite temporary suspension of UPA administrated on a daily basis, research is exploring the potential of SPRMs in the management of endometriosis, adenomyosis and breast cancer. Despite certain concerns, SPRMs offer promising prospects in gynecological pathologies, opening up new therapeutic avenues to improve women's health and quality of life. This article describes the case of a patient with peritoneal leiomyomatosis for whom UPA significantly alleviated symptoms, reduced disease progression and improved quality of life, even allowing a pregnancy.

Les modulateurs sélectifs des récepteurs de la progestérone (SPRMs) sont des composés stéroïdiens synthétiques qui interagissent via le récepteur de la progestérone, induisant diverses réponses, agonistes, antagonistes ou mixtes. Les SPRMs ont d'abord été représentés par la mifépristone, utilisée pour ses propriétés antagonistes dans la gestion de l'interruption de la grossesse, puis par l'acétate d'ulipristal, qui est indiqué en contraception d'urgence, mais aussi pour la gestion de myomes utérins symptomatiques. Les SPRMs permettent de réduire le volume des myomes utérins, sans induire les effets secondaires d'hypo-œstrogénie des agonistes de la GnRH, préservant ainsi le capital osseux et la qualité de vie des patientes. Néanmoins, quelques cas graves d'insuffisance hépatique ont conduit à la suspension temporaire de l'acétate d'ulipristal en traitement chronique. En dépit de certaines réserves, les SPRMs offrent des perspectives dans les affections gynécologiques, ouvrant de nouvelles voies thérapeutiques pour améliorer la santé et la qualité de vie des femmes. Des recherches explorent leur potentiel dans l'endométriose, l'adénomyose et la chimioprévention du cancer du sein. Nous décrivons ici le cas d'une patiente avec léiomyomatose péritonéale pour laquelle l'acétate d'ulipristal a significativement réduit les symptômes et l'évolution de la maladie, tout en améliorant la qualité de vie de la patiente, avec même l'obtention d'une grossesse menée à terme.

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Introduction: Uterine fibroids (UFs) are benign tumors of the female reproductive system originating from the smooth muscle of the uterus. Currently, progesterone is known to play a key role in the differentiation of the myometrial tissue to form UFs and their abnormal growth. The mechanism of action of progesterone in UF tumorigenesis involves its effect on increasing the concentrations and dysregulation of selected growth factors. Material and methods: A retrospective cohort study was performed to evaluate and compare tumor necrosis factor α (TNF-α), insulin-like growth factor 1 (IGF-1), plasminogen activator inhibitor-1 (PAI-1) serum concentrations in patients with UFs without prior hormonal treatment, patients with UFs treated with a 3-month standard ulipristal acetate (UPA - a type of selective progesterone receptor modulator) scheme (5 mg/day) and in control patients without UFs. A total of 120 patients were divided into 3 groups (controls, UFs with UPA treatment, UFs without UPA treatment). Results: There were no significant differences in TNF-α serum concentrations between patients with UFs who underwent UPA treatment and patients who did not. Serum concentrations of IGF-1 and PAI-1 did not show significant intergroup differences. Conclusions: No significant differences were found between TNF-α concentrations in the serum of patients with UFs treated with UPA, and patients without UPA treatment. In addition, our data analysis did not show significant differences in the concentrations of IGF-1 and PAI-1 between patients with UFs and the control group. Further studies on the dependence of specific symptoms on selected growth factors are mandatory.

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BACKGROUND: Ulipristal acetate (UPA) and levonorgestrel are used as emergency hormonal contraceptives. Although both are highly effective in preventing pregnancy, UPA shows efficacy even when taken up to 120 h after unprotected sexual intercourse. AIMS: To investigate whether the mechanism of UPA's contraceptive action involves post-fertilization effects. METHODS: In vitro and in vivo studies using cultured human endometrial cells and a pre-clinical rat model. RESULTS: Endometrial cells treated with UPA showed changes in the expression of receptivity gene markers and a significant decrease in trophoblast spheroids attached to the cultured cells. In addition, administration of UPA to female unmated rats decreased the expression of implantation-related genes in the endometrium and inhibited the number of implantation sites in the mated group compared to the non-treated group. CONCLUSIONS: These results support that UPA as an emergency contraceptive might have post-fertilization effects that may affect embryo implantation.

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BACKGROUND: Emergency contraception includes several methods of contraception that can be used after unprotected sexual intercourse, after failure of any used method of contraception or in case of sexual abuse, to prevent pregnancy. PURPOSE OF THE STUDY: The aim of the study was to analyze the available methods of emergency contraception, their mechanisms of action, efficacy, forms of administration, clinical applications and possible adverse effects. MATERIAL AND METHOD: PubMed, Scopus and Cochrane datebases were searched for articles from 2010 to 2024 about emergency contraception. RESULTS: The analyzed types of emergency contraception included single oral dose of ulipristal acetate, single oral dose of levonorgestrel and intrauterine system releasing levonorgestrel or copper intrauterine device. Taking emergency contraception in the optimum time according to the drug characteristics allows for avoiding pregnancy in more than 90% of cases (depending on the type of emergency contraception and time from unprotected intercourse). The analyzed literature shows that intrauterine copper intrauterine device is the most effective method of emergency contraception, also together with intrauterine system releasing levonorgestrel leading to the lowest rate of adverse effects. CONCLUSIONS: Taking emergency contraception can result in various adverse effects, therefore it should be introduced after thorough analysis of woman's medical history, including gynecological and obstetric history and potential contraindications. Additionally, the patient should receive detailed information about the drug mechanism of efficacy and potential adverse effects.

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OBJECTIVES: To assess the availability of over-the-counter emergency contraceptive pills in the Australian community pharmacy setting. STUDY DESIGN: Representative national telephone survey. RESULTS: Only 70% of the 233 pharmacies surveyed stocked ulipristal acetate (UPA) emergency contraceptive pills, compared to levonorgestrel, which was stocked in 98%. When ulipristal acetate was stocked, it was on average $13 more expensive. CONCLUSIONS: Despite being recommended as the first-line oral emergency contraceptive, UPA is less likely to be available, and when available, it is likely to be more expensive. These findings support anecdotal reports UPA is challenging to access and less commonly used. IMPLICATIONS: Strategies are urgently required to improve equitable access to all methods of oral emergency contraception within the Australian community pharmacy setting and ensure pharmacists are aware of key differences between the available methods. This will ensure that they are prepared to facilitate shared decision making based on the individual needs of each woman.

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OBJECTIVES: To compare the efficacy of emergency contraception (EC) regimens used within 72 hours of unprotected intercourse in individuals weighing ≥80 kg. STUDY DESIGN: We enrolled reproductive-aged healthy women in a multicenter, single-blind, randomized study of levonorgestrel 1.5 mg (LNG1X) and 3.0 mg (LNG2X) and ulipristal acetate 30 mg (UPA) (enrollment goal 1200). Key eligibility requirements included regular cycles, weight >/= 80kg, unprotected intercourse within 72 hours, no recent use of hormonal contraception, a negative urine pregnancy test (UPT), and willingness to abstain from intercourse until next menses. To assess our primary outcome of incidence of pregnancy, participants completed home UPTs; if no menses by 2-weeks post-treatment, or a positive UPT, they returned for an in-person visit with quantitative serum human chorionic gonadotropin and ultrasound. RESULTS: We enrolled and randomized 532; 44 were not dosed or not evaluable for primary end point, leaving an analyzable sample of 488 (173 LNG1X, 158 LNG2X, 157 UPA) with similar demographics between groups (mean age 29.6 years [5.74], body mass index 37.09 kg/m2 [6.95]). Five pregnancies occurred (LNG1X n = 1, LNG2X n = 1, UPA n = 3); none occurred during the highest at-risk window (day of ovulation and the 3 days prior). We closed the study before achieving our enrollment goal because the low pregnancy rate in all groups established futility based on an interim blinded analysis. CONCLUSIONS: Although slow enrollment limited our study power, we found no differences in pregnancy rates between EC regimens among women weighing 80 kg or more. Our results are not able to refute or support differences between the treatment arms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clincialtrials.gov Clinical trials#: NCT03537768. IMPLICATIONS: Women weighing 80 kg or more experienced no differences in pregnancy rates between oral EC regimens but due to several significant study limitations including sample size and the lack of a study population at high risk of pregnancy, our results are not able to determine if differences in treatment effectiveness exist.

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OBJECTIVES: To evaluate ovulation risk among women enrolling in an emergency contraception (EC) study by measuring contraceptive steroids and ovarian hormones. STUDY DESIGN: We used standard chemiluminescent assays to evaluate endogenous hormones (estradiol, progesterone, follicle stimulating hormone, luteinizing hormone) and liquid chromatography-tandem triple quadrupole mass spectrometry to simultaneously analyze concentrations of ethinylestradiol, dienogest, norelgestromin (NGMN), norethindrone (NET), gestodene, levonorgestrel (LNG), etonogestrel (ENG), segesterone acetate, medroxyprogesterone acetate (MPA), and drospirenone in serum samples obtained at the time of enrollment in a recent study comparing oral ulipristal acetate and LNG EC in women with weight ≥80 kg reporting no recent use of hormonal contraception. RESULTS: We enrolled 532 and obtained a valid baseline blood sample from 520 women. Of these, 117 (22.5%) had detectable concentrations of progestin (MPA [n = 58, 11.2%], LNG [50, 9.6%], ENG [11, 2.1%], NET [5, 0.96%], NGMN [3, 0.06%], or drospirenone [1, 0.02%]). LNG was co-detected in all three participants with samples containing NGMN. Multiple progestins were detected in eight other women: ENG/MPA (1), ENG/LNG (2), and MPA/LNG (5). Samples from 55 (10.6%) had concentrations of one or more progestin considered above the minimum level for contraceptive (MPA ≥ 0.1 ng/mL, n = 19; NGMN/LNG ≥ 0.2 ng/mL, n = 31; ENG ≥ 0.09 ng/mL, n = 8; NET ≥ 0.35 ng/mL, n = 4). We detected concentrations of serum progesterone ≥ 3 ng/mL, indicative of luteal phase (postovulation) status, in an additional 194 (37.3%) samples. CONCLUSIONS: More than one-third of enrolled in our clinical trial of oral EC had evidence of prior ovulation at the time of enrollment. Additionally, about 23% had evidence of recent use of hormonal contraception. These results would have decreased the expected risk of pregnancy in the study. IMPLICATIONS: Many participants in a recent clinical trial of oral emergency contraception did not appear to be at risk for pregnancy or would not have benefited from intervention due to cycle timing. Investigators should consider the effects of these findings on expected pregnancy rates when determining sample size in future EC clinical trials, particularly when using noninferiority designs or historical controls.

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INTRODUCTION: Uterine fibroids, the most prevalent benign tumors among reproductive-age women, pose treatment challenges that range from surgical interventions to medical therapies for symptom control. Progestins and estroprogestins effectively manage uterine bleeding by suppressing dysfunctional endometrium over fibroids. While GnRH agonists represent a crucial milestone in symptom treatment, their prolonged use results in menopausal-like symptoms and irreversible bone mineral density loss. Advancements in understanding fibroid pathophysiology have prompted the exploration of new compounds to overcome current therapy limitations. AREAS COVERED: This manuscript offers an updated overview of investigational drugs for symptomatic uterine fibroids. EXPERT OPINION: Despite ulipristal acetate's well-established efficacy as a selective progesterone receptor modulator (SPRM) in fibroid treatment, its prescription has declined due to the rare but severe risk of liver damage. Oral GnRH antagonists, like elagolix, relugolix, and linzagolix, with their novel pharmacodynamic properties, are gaining traction in fibroid management, inducing a dose-dependent reduction in circulating sex hormone levels. Ongoing research on natural compounds, such as vitamin D and epigallocatechin gallate (EGCG), presents emerging options for treating uterine fibroids. This evolving landscape reflects the ongoing efforts to improve therapeutic outcomes for individuals with symptomatic uterine fibroids.

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Ulipristal (UPA), a selective progesterone receptor modulator, has both agonistic and antagonistic effects on progesterone receptors. UPA suppresses ovulation by inhibiting the luteinizing hormone (LH) surge from the pituitary gland; however, the direct effect of UPA on ovarian tissue remains poorly studied. In the present study, we examined the effects of UPA on the ovaries of rats. Rats were treated for 28 days with UPA, and the effects of UPA on ovarian tissue were examined histologically and the expression of antioxidant genes and cell death markers were also investigated. UPA treatment increased the number of primordial follicles at each treatment group, primordial follicles increased at all dose levels, but the size/magnitude of the effect decreased with the increasing dose. The number of primary and antral follicles tended to increase with increasing UPA levels. Furthermore, the decrease in primary follicle number could be attributed to the exhaustion of follicles, but the examination of proliferation markers, oxidative stress markers, and cell death markers revealed no remarkable toxic effects on ovarian tissues. These results suggest that UPA treatment promotes follicle development at each stage but inhibits ovulation by suppressing the LH surge, resulting in an increase in atretic follicles or unruptured luteinized cysts. These results suggest that UPA may not have both toxic effects on the ovary and a direct local effect on ovarian follicles, but we should be careful about the effects of prolonged UPA treatment in patients with uterine fibroids on their future fecundity.

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OBJECTIVE: To estimate the incidence of ovulation suppression within five days of etonogestrel 68 mg implant insertion in the presence of a dominant follicle with and without same-day ulipristal acetate. STUDY DESIGN: This single site non-masked, exploratory randomized trial recruited people age 18-35 years with regular menstrual cycles, no pregnancy risk, and confirmed ovulatory function. We initiated transvaginal ultrasound examinations on menstrual day 7-9 and randomized participants 1:1 to etonogestrel implant alone or with concomitant ulipristal acetate 30 mg oral when a dominant follicle reached ≥14 mm in diameter. We completed daily sonography and serum hormone levels for up to seven days or transitioned to labs alone if sonographic follicular rupture occurred. We defined ovulation as follicular rupture followed by progesterone >3 ng/mL. We calculated point estimates, risk ratios and 95% confidence intervals for ovulation for each group. Ovulation suppression of ≥44% in either group (the follicular rupture suppression rate with oral levonorgestrel emergency contraception), would prompt future method testing. RESULTS: From October 2020 to October 2022, we enrolled 40 people and 39 completed primary outcome assessments: 20 with etonogestrel implant alone (mean follicular size at randomization: 15.2 mm ± 0.9 mm) and 19 with etonogestrel implant + ulipristal acetate (mean follicular size at randomization: 15.4 mm ± 1.2 mm, p = 0.6). Ovulation suppression occurred in 13 (65%) of etonogestrel implant-alone participants (Risk ratio 0.6 (95% CI: 0.3, 1.1), p = 0.08) and seven (37%) of implant + ulipristal acetate participants. CONCLUSIONS: Ovulation suppression of the etonogestrel implant alone exceeds threshold testing for future research while the implant + ulipristal acetate does not. IMPLICATIONS: Data are lacking on midcycle ovulation suppression for the etonogestrel implant with and without oral ulipristal acetate. In this exploratory study, ovulation suppression occurred in 65% of implant participants and 37% of implant + ulipristal acetate participants. Ovulation suppression of the implant alone exceeds threshold testing for future emergency contraception research.

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Background: Access to emergency contraception is an important consideration in preventing unintended pregnancies. Inconsistent information about emergency contraceptive given to patients at retail pharmacies may limit access. Objective: In this study, we aimed to assess pharmacy students' knowledge of oral emergency contraception. Methods: Students in a Doctor of Pharmacy program completed a confidential survey about their knowledge of and training on oral emergency contraception. Respondents self-reported demographics included age, race, ethnicity, gender, and year in pharmacy school. The survey questions assessed student knowledge of indications, availability, side effects, and mechanisms of action of oral emergency contraception, as well as their training on emergency contraception. Chi-squared and Fisher's exact tests were used to determine if demographics influenced knowledge outcomes. A multivariate logistic regression, including age, gender, ethnicity, religion, year of training, hours of education, and source of knowledge acquisition, was used to adjust for confounding variables. Results: Among 296 pharmacy students, 31% (92/296) completed the survey. Among respondents, 34% (31/92) showed adequate knowledge of oral emergency contraception based on four critical knowledge questions. Third- and fourth-year students were more likely to have adequate knowledge than first- and second-year students (odds ratio [OR], 2.70; confidence interval [95% CI], 1.07-6.80). Students who reported learning about emergency contraception through reading assignments were more likely to have adequate knowledge than students who did not report learning from reading assignments (OR, 2.09; 95% CI, 1.30-3.35). Conclusions: Most pharmacy students at a single academic center did not have adequate knowledge of oral emergency contraception. These findings highlight the need for trainings to improve pharmacy student knowledge of oral emergency contraception.

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Endometriosis is a condition characterized by increased oxidative stress and chronic inflammation, which can be treated with progestins and other progesterone receptor ligands. However, some patients are refractory to this treatment and the reason is uncertain. Here we investigated the effects of the selective progesterone receptor modulator ulipristal acetate (UPA) on proliferation, reactive oxygen species (ROS), and proinflammatory cytokine production by endometriotic cells and endometrial cells from women with histologically proven endometriosis (n = 22) and endometriosis-free controls (n = 6). Epithelial and stromal cells were isolated and treated in triplicate for 24 h with 1 µM, 10 µM, or 100 µM UPA. Cells were tested for proliferation and ROS production, while cell supernatants were assayed for interleukin (IL)-6, C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor (TNF)-α concentrations. Proliferation, ROS production, and IL-6 and CCL2 secretion were increased in non-stimulated epithelial and stromal cells from endometriotic lesions compared to endometrial cells from endometriosis patients and controls. UPA induced a dose-dependent increase of cell proliferation only in endometriosis, while enhancing ROS production by all cell types evaluated. UPA reduced CCL2 production in controls but failed to do that in endometriosis, whereas TNF-α was undetectable. We conclude that treatment of endometriotic cells with UPA stimulated in vitro proliferation and ROS production and failed to revert the proinflammatory cytokine excess that characterized these cells, unravelling possible mechanisms of drug resistance in the treatment of endometriosis.

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BACKGROUND: Alabama's Human Life Protection Act (the Act) signed in 2019 became law in 2022, making provision of abortion a felony offense. OBJECTIVE: In 2020, we assessed the accessibility of emergency contraception (EC) pills in Birmingham, Alabama prior to the Act's enactment given the probable increased need for EC access due to abortion criminalization. STUDY DESIGN: Pharmacy staff were asked about availability, price, location, and identification requirements to obtain EC. RESULTS: Of 69 pharmacies, 59% had levonorgestrel EC and none had ulipristal acetate EC available. CONCLUSION: There are persistent barriers to EC accessibility that should be addressed as abortion is increasingly restricted.

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Ulipristal acetate (UPA) is a selective progesterone receptor modulator and is used for the treatment of uterine leiomyoma (a benign tumor). Uterine sarcoma which is highly malignant cancer with a poor prognosis is clinically resembled with uterine leiomyoma. There has been no experimental research on the effect of UPA on uterine sarcoma. In this study, we examined the efficacy of UPA in uterine sarcoma with in vitro and in vivo animal models. Cytotoxicity of UPA was determined in uterine sarcoma cell lines (MES-SA, SK-UT-1, and SK-LMS-1). Apoptotic genes and signaling pathways affected by UPA were analyzed by complementary DNA (cDNA) microarray of uterine sarcoma cell lines and western blot, respectively. An in vivo efficacy of UPA was examined with uterine sarcoma cell line- and patient-derived xenograft (PDX) mice models. UPA inhibited cell growth in uterine sarcoma cell lines and primary culture cells from a PDX mouse (PDX-C). cDNA microarray analysis revealed that CCL2 was highly down-regulated by UPA. Phosphorylation and the total expression of STAT3 were inhibited by UPA. UPA also inhibited CCL2 and STAT3 in PDX-C. The inhibitory effect of UPA had not changed in the overexpression of PR and treatment of progesterone. In vivo efficacy studies with cell line-derived xenografts and a PDX model with leiomyosarcoma, a typical uterine sarcoma, demonstrated that UPA significantly decreased tumor growth. UPA had significant anti-tumor effects in uterine sarcoma through the inhibition of STAT3/CCL2 signaling pathway and might be a potential therapeutic agent to treat this disease.

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Emergency contraception (EC), or postcoital contraception, is a therapy aimed at preventing unintended pregnancy after an act of unprotected or under-protected sexual intercourse. Options include both emergency contraceptive pills (most commonly containing levonorgestrel or ulipristal acetate) and insertion of an intrauterine device. The aim of this paper is to summarize current evidence surrounding the use of emergency contraceptives and to present an evidence-based approach to EC provision. Emergency contraception is a safe and effective option in preventing unwanted pregnancy, irrespective of age, weight, or breastfeeding status. Efforts should be made to increase their availability, as well as knowledge of these methods, both among patients and healthcare providers.

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Although more than ten years have passed since the marketing of Ulipristal acetate in Europe, emergency contraception remains a complex issue with many scientific, legal, ethical and social implications. The topic is an example of the differences that can exist between scientific evidence, the certainties on which law is based, and social implications. This paper shows the incompleteness of the scientific reconstruction on the effects of emergency hormonal contraceptives and the dangerousness of the decision to alienate the supply of over-the-counter drugs from the general rules of health care. This report shows the incompleteness of the scientific reconstruction on the effects of emergency hormonal contraceptives and the dangerousness of the decision to alienate the supply of over-the-counter drugs from the general rules of health care. Various ethical and medico-legal issues will be addressed, also focusing attention on underage women whose sexual and reproductive health requires not abandoning them, but actually taking charge of them without medicalizing their choices.

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Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

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