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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., (© 2024 John Wiley & Sons Ltd.)

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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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/m 2 [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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the use of oral nomegestrol acetate/estradiol in random start rapid preparation of endometrium before office hysteroscopic polypectomy., Study Design: Multicenter, prospective, randomized controlled trial., Setting: University hospitals., Participants: 80 adult women undergoing office hysteroscopic polypectomy between January 2023 and March 2024 were randomized to intervention (n = 40) or control (n = 40). Exclusion criteria included the presence of endouterine pathology other than endometrial polyps solely., Methods: Subjects in the intervention group were treated with oral nomegestrol acetate/estradiol 1.5 mg/2.5 mg/day started taking the drug from an indefinite time in the menstrual cycle (random start) for 14 days. Subjects in the control group did not receive any pharmaceutical treatment and underwent polypectomy between days 8 and 11 of the menstrual cycle., Results: On the day of the procedure, the difference in pre- and post-office hysteroscopic polypectomy endometrial ultrasound thickness was statistically significant between the two groups, with endometrial thickness in both measurements being thinner for the intervention group (p < 0.001). In the nomegestrol acetate/estradiol-treated group, compared with the control, there was also a statistically significant difference in the physician's assessment of the quality of endometrial preparation (p < 0.001), the quality of visualization of the uterine cavity (p < 0.001), and satisfaction with the performance of the procedure (p < 0.001). Finally, all surgical outcomes analyzed were better in the treatment group., Conclusion: Treatment with nomegestrol acetate/estradiol could provide rapid, satisfactory and low-cost preparation of the endometrium before office polypectomy, thus improving surgical performance and woman's compliance., Trial Registration: ClinicalTrials.gov NCT06316219., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

What Is This Summary About?: This is a summary of findings from two research studies (known as clinical trials). The studies looked at how well a medicine called relugolix combination therapy worked in women with heavy menstrual bleeding (heavy bleeding during a period) with uterine fibroids (noncancerous or benign growths in the uterus). In this analysis of the studies, researchers looked at how patients self-reported their uterine fibroid symptoms before and after taking relugolix combination therapy. Researchers also looked at how patients self-reported the impact of uterine fibroids on their health-related quality of life before and after taking relugolix combination therapy., What Were the Results?: Women took either relugolix combination therapy or placebo (a pill that contains no medicine) by mouth once daily for 24 weeks. Women completed the Uterine Fibroid Symptom and Quality of Life questionnaire (where "quality of life" refers to the women's health-related quality of life related to uterine fibroids) before, during, and after treatment. The questionnaire let researchers see if the women felt that relugolix combination therapy decreased the burden of uterine fibroid symptoms and improved the women's health-related quality of life related to uterine fibroids. More women said that they felt less distress due to their uterine fibroid symptoms and that their health-related quality of life related to uterine fibroids was better after taking relugolix combination therapy compared with women who took placebo., What Do the Results Mean?: Relugolix combination therapy may lessen distress associated with uterine fibroid symptoms and improve health-related quality of life related to uterine fibroids.

The aim of this study was to explore the mechanisms of action of alsevirone in prostate cancer (PC) in vitro and in vivo: CYP17A1 inhibition, cytotoxic, apoptotic, and antitumor effects in comparison with abiraterone. The CYP17A1-inhibitory activity was investigated in rat testicular microsomes using high-performance liquid chromatography. Testosterone levels were evaluated using enzyme-linked immunoassay. IC 50 values were calculated for PC3, DU-145, LNCaP, and 22Rv1 cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test. The antitumor effect in vivo was studied in DU-145 and 22Rv1 subcutaneous xenografts in Balb/c nude mice. Alsevirone reduced the CYP17A1-inhibitory activity by 98% ± 0.2%. A statistically significant reduction in the testosterone concentration in murine blood was recorded after the 7th administration of 300 mg/kg alsevirone at 0.31 ± 0.03 ng/ml (p < .001) versus 0.98 ± 0.22 ng/ml (p = .392) after abiraterone administration and 1.52 ± 0.49 ng/ml in control animals. Alsevirone was more cytotoxic than abiraterone in DU-145, LNCaP, and 22Rv1 cells, with IC 50 values of 23.80 ± 1.18 versus 151.43 ± 23.70 μM, 22.87 ± 0.54 versus 28.80 ± 1.61 μM, and 35.86 ± 5.63 versus 109.87 ± 35.15 μM, respectively. Alsevirone and abiraterone significantly increased annexin V-positive, caspase 3/7-positive, and activated Bcl-2-positive cells. In 22Rv1 xenografts, alsevirone 300 mg/kg × 10/24 h per os inhibited tumor growth: on Day 9 of treatment, tumor growth inhibition = 59% (p = .022). Thus, alsevirone demonstrated significant antitumor activity associated with CYP17A1 inhibition, apoptosis in PC cells, and testosterone reduction., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

Background: Up to 80% of reproductive-aged women experience premenstrual symptoms. Premenstrual Dysphoric Disorder (PMDD) is a severe form, affecting 2-5% of women. Combined oral contraceptive pills (COCPs) are used in the treatment of PMDD. Clinical practice suggests that a newer COCP containing nomegestrol acetate (2.5mg) and 17-beta estradiol (1.5mg), may be a suitable treatment for mood symptoms in PMDD., Materials and Methods: This was a clinical follow-up feasibility study of women who had attended the Monash Alfred Psychiatry research centre, Women's Mental Health Clinic, with a diagnosis of PMDD. 67% of the sample also had concurrent cPTSD, 29% co-morbid anxiety, and 20% depression. They were recommended treatment with nomegestrol acetate/17-beta estradiol. Eligible women were contacted by telephone to answer a questionnaire to assess women's subjective response to nomegestrol acetate/17-beta estradiol, acceptability and the Depression, Anxiety and Stress Scale-21 (DASS-21) after being recommended nomegestrol acetate/17-beta estradiol. The paired-sample t-test was used to determine if there were any statistically significant differences in the DASS-21 scores over the study observation period (before and after taking nomegestrol acetate/17-beta estradiol)., Results: 35 (74.5%) women reported a subjective positive mood response to nomegestrol acetate/17-beta estradiol, 31 (63.3%) adhered to the medication, and only 10 (20.4%) women reported side effects as the main reason for discontinuing nomegestrol acetate/17-beta estradiol. There were statistically significant reductions ( p< 0.05) in the overall DASS-21 scores from before women commenced nomegestrol acetate/17-beta estradiol and after commencement of treatment., Conclusions: This preliminary study supports the acceptability and effectiveness of nomegestrol acetate/17-beta estradiol as a treatment for mood symptoms in PMDD. Further research, particularly a randomized controlled trial, is required to elucidate the effect of nomegestrol acetate/17-beta estradiol treatment on mood in PMDD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Robertson, Thew, Thomas, Karimi and Kulkarni.)

Objective: The use of ulipristal acetate (UPA) was indicated for the treatment of uterine fibroids. Following UPA suspension in March 2020, some patients presented worsening and required surgery. We aimed to identify patients at high-risk for undergoing surgery after UPA suspension., Methods: We evaluated 85 women receiving intermittent UPA treatment until March 2020. Following UPA suspension, patients received other medical treatments or surgery. The clinico-pathological features were recoded and a quality of life health survey was completed by patients at the time of UPA suspension and at 6-months thereafter., Results: After the suspension of UPA, 17 of the 85 patients receiving intermittent UPA (20%) required surgery, and 68 (80%) required other medical treatments. Patients who underwent surgery were younger and had greater fibroid volume., Conclusions: In our series, 20% of clinically stable patients receiving intermittent UPA required surgery following UPA suspension. These women should be considered for future medical strategies.

Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high-risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double-blind, placebo-controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3-336) in the oral vs. 2.82 (IQR: 1.4-5.5) in the transdermal group. Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R 2  = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P < 0.0001). Other skin-penetrant drugs should be tested for breast cancer prevention., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Uterine leiomyoma presents the highest incidence among benign tumors of the female reproductive tract. The present study compared the proteome of leiomyoma treated with ulipristal acetate with that of untreated leiomyoma to investigate protein expression patterns in relation to oxidative stress. Paired tissue samples from seven treated and untreated leiomyomas were collected and the proteome was analyzed by two‑dimensional gel electrophoresis (2‑DE). Western blotting was used to validate the results of 2‑DE, and mass spectrometry was used to identify proteins. The tissue expression of 30 proteins was markedly affected by treatment with ulipristal acetate. Bioinformatics analysis revealed that several of the differentially expressed proteins were involved in the degradation of hydrogen peroxide and the synthesis of reactive oxygen species. The present study suggested the involvement of oxidative stress as a novel mechanism of action of ulipristal acetate. These findings require further investigations to understand the role of ulipristal acetate in the treatment of the leiomyoma.

In this study, a simplified, sensitive and reliable LC-tandem mass spectrometry method was established and validated for the quantification of ulipristal acetate (UPA) in human plasma and for the investigation of pharmacokinetic profile of UPA following a single oral administration of ella (UPA 30-mg tablet) in healthy Chinese volunteers. Plasma samples were analyzed after being processed by protein precipitation with methanol. Chromatographic separation was performed on a Kinetex EVO C 18 column (2.1 × 50 mm, 2.6 μm) using gradient elution with a mobile phase composed of methanol and water containing 2 mm ammonium acetate and 0.3% formic acid at a flow rate of 0.3 mL/min. The chromatographic running time was 4.0 min per sample. The MS detection was performed via an LC system with the positive ion electrospray ionization interface in multiple reaction monitoring mode using the transition of m/z 476.2 → 134.1 for UPA and m/z 479.3 → 416.2 for UPA-d3 [internal standard (IS)], respectively. UPA and IS were monitored without severe interference from the biological matrices. The method was linear over the wide concentration range of 0.300-300 ng/mL. The intra- and inter-day precision and accuracy were well within the limits required for bioanalytical assays. The method was first used to describe the pharmacokinetic characteristic of UPA after a single oral administration of ella in healthy Chinese volunteers. Based on a between-study comparison, there were statistically significant differences (p < .05) between Chinese and Caucasian volunteers for the systemic exposure of UPA, suggesting that race seems to significantly impact the systemic exposure of UPA., (© 2020 John Wiley & Sons, Ltd.)

Background: To evaluate the effects of a 24/4 regimen combined oral contraceptive (COC) containing 1.5 mg 17β-estradiol (E2) and 2.5 mg nomegestrol acetate (NOMAC) compared to on-demand nonsteroidal anti-inflammatory drugs (NSAIDs) on women affected by endometriosis-associated chronic pelvic pain (the primary end point) and their quality of life (QoL) and sexual function (the secondary end points). Materials and Methods: Ninety-nine women on E2/NOMAC constituted the study group; and 63 women on NSAIDs constituted the control group. The visual analogic scale was used to measure the levels of pelvic pain, dysmenorrhea, and dyspareunia. To assess their QoL, sexual function, and sexual distress, the Short Form-36 (SF-36), the Female Sexual Function Index (FSFI), and the Female Sexual Distress Scale (FSDS) were used, respectively. The study included two follow-ups at 3 and 6 months. Results: Improvement in chronic pelvic pain was observed in the study group at both the 3- and 6-month follow-ups ( p  < 0.001). SF-36, FSFI, and FSDS had a similar trend at the 3- and 6-month follow-ups ( p  < 0.001). Women on NSAIDs did not report any reduction in pain symptoms or improvement in QoL ( p  ≤ 0.4). However, they had a limited improvement of their FSFI and FSDS ( p  < 0.001). The improvement of the pain symptoms, QoL, FSFI, and FSDS, was more evident in women on E2/NOMAC than in those on NSAIDs, when the study group and control group values were compared at the 3- and 6-month follow-ups ( p  < 0.001). Conclusions: Women on E2/NOMAC COC showed a better reduction of endometriosis-associated chronic pelvic pain and an improvement of their QoL and sexual activity than those of the women on NSAIDs.

To determine the effectiveness of quick starting combined oral contraception (COC) contain 2.5 mg nomegestrol acetate and 1.5 mg estradiol (NOMAC/E2) comparing with 0.075 mg gestodene and 0.02 mg ethinyl estradiol (GS/EE) on ovarian ovulation inhibition rate, we conducted a non-inferiority randomized controlled trial involving 69 healthy female volunteers aged 18-40 years who had normal menstrual history and were randomized at a 2:1 ratio to take one pack of COC containing either NOMAC/E2 (study group) or GS/EE (control group) starting on menstrual cycle Day7-9. The ovarian activity was assessed by using Hoogland and Skouby grading. Forty-six and 23 participants were randomized to NOMAC/E2 and GS/EE groups, respectively. Baseline characteristics were similar between groups. No significant difference was observed between the study and control groups for ovulation inhibition rate (93.4% vs. 95.6%, risk difference: -2.2%, 95% CI: -13.1, 8.8), ovarian quiescence rate (91.2% vs. 91.2%, P = 1.000), persistent cyst rate (2.2% vs. 4.4%, P = 1.000), and ovulation rate (6.6% vs. 4.4%, P = 1.000). Quick starting COC during day7-9 of menstrual cycle can inhibit ovulation for more than 90%. The quick starting NOMAC/E2 is non-inferior to GS/EE for preventing ovulation and suppressing follicular growth.

Objective: To assess the efficacy of ulipristal acetate (UPA) for reducing abnormal bleeding among women using the 52-mg levonorgestrel intrauterine system (LNG-IUS)., Methods: A randomized, double-blind, placebo-controlled pilot study conducted from September 1, 2016 to September 30, 2018, at the University of Campinas, Brazil. LNG-IUS users reporting prolonged or frequent uterine bleeding for at least 1 year were randomized to receive 5 mg UPA per day for 5 days or placebo at an identical regimen. Bleeding was recorded for 90 days after treatment began and was compared between the groups., Results: Of 94 eligible women, 64 with abnormal bleeding associated with LNG-IUS use declined treatment or device removal after counselling regarding anticipated bleeding patterns. For the 25 study participants, differences were nonsignificant between the UPA and placebo groups for number of days before bleeding stopped and days free of bleeding; however, UPA users displayed a trend for shorter duration before bleeding stopped and longer time free of bleeding. A similar trend for mean number of bleeding days at 30-, 60-, and 90-day follow-up was observed., Conclusion: A nonsignificant trend in reduction of abnormal bleeding was observed among LNG-IUS users taking 5 mg UPA per day for 5 days compared with placebo; however, further research is needed. CLINICALTRIALS.GOV: NCT03186586., (© 2019 International Federation of Gynecology and Obstetrics.)

Context: The selective progesterone modulator ulipristal acetate (ulipristal) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although ulipristal initially passed safety evaluations in Europe, postmarketing analysis identified cases of hepatic injury and failure, leading to restrictions on the long-term use of ulipristal. One of the factors potentially contributing to significant side effects with the selective progesterone modulators is cross-reactivity with other steroid receptors., Objective: To determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types., Design: Immortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or ulipristal. Primary uterine fibroid tissue was isolated from patients undergoing elective gynecological surgery and treated ex vivo with dexamethasone and/or ulipristal. In vivo ulipristal exposure was performed in C57Bl/6 mice to measure the effect on basal gene expression in target tissues throughout the body., Results: Dexamethasone induced the expression of established glucocorticoid-target genes period 1 (PER1), FK506 binding protein 51 (FKBP5), and glucocorticoid-induced leucine zipper (GILZ) in UtLM and HepG2 cells, whereas cotreatment with ulipristal blocked the transcriptional response to glucocorticoids in a dose-dependent manner. Ulipristal inhibited glucocorticoid-mediated phosphorylation, nuclear translocation, and DNA interactions of GR. Glucocorticoid stimulation of PER1, FKBP5, and GILZ was abolished by cotreatment with ulipristal in primary uterine fibroid tissue. The expression of glucocorticoid-responsive genes was decreased in the lung, liver, and uterus of mice exposed to 2 mg/kg ulipristal. Interestingly, transcript levels of Fkbp5 and Gilz were increased in the hippocampus and pituitary., Conclusions: These studies demonstrate that ulipristal inhibits endogenous glucocorticoid signaling in human fibroid and liver cells, which is an important consideration for its use as a long-term therapeutic agent., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Objective: To compare enucleation time, total operative time, and perioperative complications during laparoscopic myomectomy in patients pretreated with ulipristal acetate (UPA) compared with untreated patients., Design: Prospective, observational pilot study., Setting: Tertiary referral center of minimally invasive gynecologic surgery, Sant'Orsola Academic Hospital, Bologna, Italy., Patients: Seventy-four of 108 patients scheduled for laparoscopic myomectomy from January to November 2017 were enrolled., Interventions: Laparoscopic myomectomy following pretreatment with UPA or no hormonal pretreatment therapy., Measurements and Main Results: Of the 74 patients who were enrolled, 29 were pretreated with UPA (UPA group), and 45 did not receive any hormonal therapy before surgery (control group). Surgeons, blinded to patient pre-operative treatment, completed a 3-item questionnaire after each procedure to evaluate surgical difficulty. Based on surgeon response, myomas in the UPA group appeared softer and more difficult to enucleate because of less clear cleavage planes than the control group. The overall difficulty of myoma detachment from the myometrium was judged considerably higher in the UPA group. Despite this, enucleation time, total operative time, and perioperative complications were not statistically different in the 2 groups., Conclusion: Myomas in patients pretreated with UPA are subjectively less easy to enucleate; however, surgical times and perioperative outcomes are not affected by pretreatment with UPA., (Copyright © 2019 AAGL. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate differences in volume and fibroid vascularity expressed in vascular index after three months of (pre-)treatment with leuprolide acetate (LPA) or ulipristal acetate (UPA)., Study Design: Prospective pilot study of 23 premenopausal women with uterine fibroids. Patients who started with LPA or UPA and had at least one fibroid with a size between 3 and 12 cm, were included consecutively. Per patient one fibroid was evaluated. The ultrasound was performed at baseline and after three months using LPA or UPA using a standardized protocol. 3D scans were evaluated using VOCAL software to calculate outcomes of volume, vascular index (VI) without shell ("shell off") and of the inner shell., Results: Four patients in the LPA group were additionally excluded from analyses due to insufficient quality of 3D scans. In the ten remaining patients (pre-)treated with LPA both volume and vascular indices of the fibroid reduced significantly after three months from a median of 224.3 cm 3 (IQR 338.0) to 124.8 cm 3 (IQR 186.1) (p = 0,05); median VI fibroid (shell off) reduced from 4.30 (IQR 4.72) to 0.93 (IQR 1.54) (p = 0,05); and VI inner capsule from 6.34 (IQR 7.51) to 1.28 (IQR 2.13) (p = 0,05). After UPA (n = 9) changes in fibroid volume and vascular indices did not reach statistical significance. Volume reduced from 248.5 cm 3 (IQR 271.9) to 140.7 cm 3 (IQR 209.4) (p > 0,05); median VI fibroid (shell off) from 2.97 (IQR 3.81) to 2.90 (IQR 4.82) (p > 0,05); and VI inner capsule from 2.56 (IQR 7.48) to 2.89 (IQR 4.83) (p > 0,05). A strong positive correlation was found between the VI of the fibroid (shell off) at baseline with the volume change after three months of LPA use (LPA r = 0.636, p = 0.048, 95% CI = -0.03 - 1.00)., Conclusion: In this pilot study we observed a consistent and statistically significant decrease in VI and fibroid volume after three months of LPA treatment in patients with uterine fibroids. The decrease in fibroid volume and VI was less consistent after UPA use. The strong correlation between the VI at baseline and volume reduction, may in theory be used to predict the volume reduction after LPA., (Copyright © 2019. Published by Elsevier B.V.)

Importance: Uterine leiomyomas, also referred to as myomas or fibroids, are the most common benign tumors of the reproductive tract. Ulipristal acetate (UPA) is an active selective progesterone receptor modulator used as preoperative treatment for uterine myomas., Purpose: The aim of this review is to provide an overview of the literature about the effects of UPA administration before hysteroscopic myomectomy. The clinical question in "PICO" format was in patients affected by uterine myomas undergoing operative hysteroscopic management, "Does UPA impact the surgical outcomes?", Evidence Acquisition: We performed a systematic literature search in PubMed/MEDLINE and Embase for original studies written in English (registered in PROSPERO CRD42018092201), using the terms "hysteroscopy" AND "ulipristal acetate" published up to March 2019. Original articles about UPA treatment before hysteroscopic myomectomy (randomized, observational, retrospective studies) were considered eligible., Results: Our literature search produced 32 records. After exclusions, 4 studies were considered eligible for analysis. Results show that UPA does not worsen the overall technical difficulty of hysteroscopic myomectomy. Moreover, it may increase the chance of complete primary myomectomy in complex hysteroscopic procedures., Conclusions and Relevance: Despite the positive results presented in this systematic review, low-quality evidence exists yet on the impact of UPA treatment before hysteroscopic myomectomy. High-quality prospective randomized controlled trials are required to establish the impact of UPA on surgical outcomes of patients treated for uterine myomas by hysteroscopy. Moreover, long-term outcomes of myomectomies after UPA treatment (such as frequency of myoma recurrence, recovery time, and quality of life) should be determined.

Emergency contraception (EC) is a drug or a device that is taken after sexual intercourse to prevent unintended pregnancy. The most effective EC is the copper-bearing intrauterine device (Cu-IUD), but oral EC methods are more commonly used and include a single dose of either levonorgestrel (1.5 mg) or ulipristal acetate (30 mg). Although all EC methods are extremely safe, access to EC is often limited due to prevailing misconceptions over how EC works. Although EC can prevent unintended pregnancy for an individual woman, it has failed to make an impact on abortion rates at a population level. This may be because it is not used after every episode of unprotected sex and because existing oral EC methods are only effective if used before ovulation. Future strategies around EC should focus on maximising uptake of Cu-IUD, facilitating initiation of effective regular contraception after EC and developing a more effective oral EC., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Introduction: Nowadays, the resection of submucosal myomas is usually performed by hysteroscopy. No previous study has investigated the use of preoperative hormonal therapy before outpatient hysteroscopic myomectomy., Objective: To compare the usefulness of 3-month preoperative treatment with ulipristal acetate (UPA) before outpatient hysteroscopic myomectomy in patients with FIGO (International Federation of Gynecology and Obstetrics) type 0-1 myomas., Study Design: This prospective patient preference study included women requiring hysteroscopic resection of single FIGO type 0-1 myoma with the largest diameter <2 cm. Patients underwent either preoperative treatment with UPA (5 mg/day) for 3 months or direct surgery. Outpatient myomectomy was performed using the bipolar electrosurgical Versapoint system (Ethicon Gynecare, USA). The primary objective of the study was to compare the rate of complete resections in the 2 study groups. The secondary objective of the study was to compare the operative time and the volume of fluid infused/absorbed. The tertiary objective of the study was to assess the surgical appearance of the myomas in patients treated with UPA., Results: The study included 38 women treated with UPA and 45 women who underwent direct surgery. UPA treatment significantly decreased the volume of uterine myomas (p < 0.001). The percentage of complete resection was higher in patients treated with UPA (89.5%) than in those who underwent direct surgery (68.9%; p = 0.046). Preoperative UPA treatment decreased the operative time (p < 0.001) and the volume of fluid infused (p = 0.016), but it did not significantly affect the volume of fluid absorbed (p = 0.874). The texture of the myoma was not significantly affected by UPA treatment (p = 0.142)., Conclusions: Three-month UPA treatment improves the chance of single-step complete outpatient hysteroscopic resection of single FIGO type 0-1 myoma. Future randomized studies with a larger sample size should confirm these preliminary findings., (© 2020 S. Karger AG, Basel.)

Objective: To observe alterations in surgical planning that were due to the use of ulipristal acetate (UPA) 5 mg daily for symptomatic uterine fibroids., Methods: A prospective cohort trial involving women with symptomatic fibroids was undertaken in 23 clinical practice sites within Belgium between October 1, 2014, and March 31, 2016, to compare initial surgical planning to performed surgical procedures following the use of UPA 5 mg daily for 3 months. Secondary outcomes were surgical complications, reduction in fibroids, bleeding control, and adverse effects., Results: Two hundred and twenty-two women were recruited for the trial. The requirement for surgery decreased with the use of UPA, with 54% of women undergoing surgery after treatment. The reduction in surgery performed was lower for women willing to conceive (40%) compared to women who were not (49%). The volume of the fibroids decreased significantly, with the largest measured fibroid decreasing by 50%. Bleeding and pain were significantly decreased with the use of UPA. No major complications were recorded, and no liver function abnormalities were reported during the treatment and in follow-up., Conclusion: By administering UPA, the required rate of surgery was significantly decreased. Also, the resulting reduction in size of the fibroids could have the potential benefit of reducing surgery-related complications, and long-term use may be warranted to avoid surgery completely., (© 2019 International Federation of Gynecology and Obstetrics.)

Background Oral emergency contraceptives containing levonorgestrel or ulipristal acetate are available without prescription and only in pharmacies in Germany since March 2015. Due to this change community pharmacists are responsible for evaluating whether the product is appropriate and to educate women on proper use. Objective To measure the utilization of emergency contraceptives without a prescription and describe potential concerns and safety issues identified by community pharmacists in Germany. Setting The Drug Commission of German Pharmacists' nationwide network of reference pharmacies which includes 860 community pharmacies. Methods Reference community pharmacies were asked to participate in the eleven-questions online survey. Respondents were asked to recall their experiences with oral emergency contraceptives in the past 3 months. Data were collected between January 8 and February 19, 2018. Main outcome measure The survey focused on the utilization of emergency contraceptives without a prescription in Germany, and on the pharmacists' experiences with (potential) problems and concerns regarding safe use. Results In total, 555 community pharmacies (64.5%) participated. Overall 38.2% of community pharmacists stated they dispensed six to ten courses of emergency contraceptives within the past 3 months. In addition, 54.3% of the pharmacists estimated they dispensed emergency contraceptives exclusively without prescription and 35.9% dispensed more than 30% of emergency contraceptives during night-time and emergency services. Moreover, 82.8% of pharmacists stated that emergency contraceptives were requested not by the women concerned but a third person and 44.3% identified uncertainties in woman's self-diagnosis. Three out of four pharmacists had concerns about the effective and safe use of emergency contraceptives. In situations suggesting sexually transmitted diseases, or suspicion for use of force, 59.5% and 55.8% of the pharmacists, respectively, dispensed emergency contraceptives. In cases of acute health impairment or chronic disease, or (potentially) relevant drug/drug interaction, the vast majority (91.0% and 90.5%) did not. Here, most pharmacists referred to gynecologists. Conclusion Pharmacists had safety concerns when dispensing emergency contraceptives. Professional expertise in evaluating the need for oral emergency contraceptives and the proper use is needed.

Uterine fibroids (UFs) are associated with irregular or excessive uterine bleeding, pelvic pain or pressure, or infertility. Ovarian steroid hormones support the growth and maintenance of UFs. Ulipristal acetate (UPA) a selective progesterone receptor (PR) modulator (SPRM) reduce the size of UFs, inhibit ovulation and lead to amenorrhea. Recent liver toxicity concerns with UPA, diminished enthusiasm for its use and reinstate the critical need for a safe, efficacious SPRM to treat UFs. In the current study, we evaluated the efficacy of new SPRM, EC313, for the treatment for UFs using a NOD-SCID mouse model. EC313 treatment resulted in a dose-dependent reduction in the fibroid xenograft weight (p < 0.01). Estradiol (E2) induced proliferation was blocked significantly in EC313-treated xenograft fibroids (p < 0.0001). Uterine weight was reduced by EC313 treatment compared to UPA treatment. ER and PR were reduced in EC313-treated groups compared to controls (p < 0.001) and UPA treatments (p < 0.01). UF specific desmin and collagen were markedly reduced with EC313 treatment. The partial PR agonism and no signs of unopposed estrogenicity makes EC313 a candidate for the long-term treatment for UFs. Docking studies have provided a structure based explanation for the SPRM activity of EC313.

Objectives: To assess levonorgestrel (LNG) and ulipristal acetate (UPA) availability in pharmacies in a metropolitan area., Methods: A cross-sectional survey was conducted of all identified pharmacies within 25 miles of an urban medical center in Kansas City, KS. We categorized the pharmacies as dedicated commercial (national chains), store-associated (affiliated with a general merchandise or grocery store), or independent. We assessed LNG and UPA availability or time to availability if not currently stocked., Results: We contacted 165 pharmacies. Of the 165 pharmacies, few stocked UPA (12/165, 7%) whereas the majority stocked oral LNG (128/165, 78%). Dedicated commercial pharmacies were more likely to carry UPA than store-associated and independent pharmacies (11/84 [13%] vs. 1/61 [1%] vs. 0/20, respectively; P = 0.016). Most pharmacies that did not stock UPA reported that they could obtain it within 24 hours (94/153, 62%). Dedicated commercial pharmacies were most likely report the ability to obtain UPA in 24 hours (P = 0.016)., Conclusion: Few pharmacies stock UPA, the most effective form of oral emergency contraception. Enhanced communication between medical providers and pharmacists within current laws and regulations could enhance patient access to UPA., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Ulipristal acetate (UPA) 30 mg (ella®, HRA-Pharma, Paris, France) acts as an emergency contraceptive (EC) by delaying ovulation. Because it is a selective progesterone receptor modulator, an additional effect on interfering with implantation has been suggested., Objective: This review discusses the evidence for, and against, an anti-implantation effect of UPA-EC., Sources of Evidence: Primary research on the effect of UPA, at a relevant dose, on endometrium, implantation, efficacy and pregnancy outcome., Results: UPA-EC does not appear to have a direct effect on the embryo. Changes in endometrial histology are small and not consistent, varying among studies. While UPA-EC affects the profile of gene expression in human endometrium, the findings vary between studies, and it is not clear that these changes affect endometrial receptivity or prevent implantation. UPA at pharmacological concentrations does not appear to have any inhibitory effect on embryo attachment in in vitro systems of human endometrium. UPA-EC is not more effective at preventing pregnancy than chance alone if used after ovulation and does not increase miscarriage rates., Conclusions: An anti-implantation effect of UPA is highly unlikely at the dose used for EC. Maintaining the warning on the FDA-approved label that "it may also work by preventing implantation to the uterus" might deter some women from using EC, leaving them no option to prevent unwanted pregnancy after unprotected sexual intercourse., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This observational study was conducted in premenopausal women who presented themselves at the Obstetrics and Gynecology Department of the University Hospital of Cagliari (Italy), for heavy menstrual bleeding (HMB) dependent on uterine myomas. After a screening visit, 19 women without contraindications to ulipristal acetate (UPA) treatment, were included in the study that envisaged 12 months of observation in which each subject was asked to assume UPA (tablet of 5 mg, ESMYA ® , one tablet a day for 3 months: first cycle) two menstrual cycles of interruption and a second ESMYA ® cycle, followed by 3 months of observation (third follow-up month, visit 4). The significant decrease of myoma volume, diagnosed after the first ESMYA ® cycle, persisted until the visit 4. The HMB significantly decreased during the ESMYA ® treatment and persisted until visit 4. The quality of life (QoL), evaluated with the questionnaire SF-36, significantly improved during the study. The values of estradiol (E2), biochemical parameters of bone metabolism, as well as those of lumbar and hip bone mineral density, did not change during the study in comparison with basal levels. The efficacy of two repeated ESMYA ® cycles to treat uterine myomas and their related symptoms improves the QoL without interfering with bone health.

Objective: This study assesses emergency contraception (EC) dispensed before and after a 3-min video counseling intervention on EC., Methods: We used a quasi-experimental design and two data sources to assess the impact of offering the video counseling intervention. We used electronic health records from six Planned Parenthood Association of Utah health centers with onsite oral EC dispensing to determine pre- and postintervention EC distribution. Beginning July 2015, three participating locations offered the video counseling intervention to English-speaking EC clients. These clients completed a brief survey assessing EC knowledge and uptake, providing a patient-level data source. We used a difference-in-difference analysis of the clinic-level data to assess the effect of the video counseling intervention. This analysis compares the variation in oral EC distribution between clinics offering the video intervention and clinics not offering the video counseling before and after the video counseling was introduced. Multivariable logistic regression assessed client characteristics associated with receiving ulipristal., Results: The six health centers served 8269 English-language EC clients during 2015. At participating sites, provision of ulipristal increased from 12% (269/2315) preintervention to 28% (627/2266) postintervention (p<.001). Nonparticipating sites did not see a change. Clients seeking EC at sites offering video counseling were more likely to receive ulipristal even after controlling for age, insurance and ethnicity (adjusted OR 3.4, 95% CI 3.0-3.9). Using the difference-in-difference analysis, the video counseling intervention accounted for an 18% (95% CI 14%-21%) increase in ulipristal provision at the participating health centers. Among the 2266 women seeking EC who were offered video counseling, 19% (425/2266) watched the video, and 60% (254/425) reported the video affected their EC preferences. Knowledge of the IUD for EC increased, but reported uptake of this method remained low (6.8%)., Conclusions: Exposure to video counseling increased use of more effective oral EC and increased knowledge about all EC options., Implications: Use of a brief informational video about EC options at family planning clinics may increase the proportion of EC clients receiving more effective EC methods., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Both European and American trials showed superior effect of ulipristal acetate (UPA) to placebo. However, the latter, which included black patients with known higher vitaminD3 deficiency risk, showed lower rate of amenorrhea responders and insignificant uterine fibroid (UF) size reduction. Our objective is to investigate whether adding vitamin D 3 to UPA can enhance UPA potency on UF phenotype in vitro., Methods: We screened the antiproliferative effect of different (UPA/vitaminD3) combinations on UF cell proliferation using dimethylthiazolyl diphenyltetrazolium bromide assay. Cells then were treated with UPA 100 nM in the presence or absence of vitamin D 3 100 nM, and expression level of several markers related to proliferation, apoptosis, fibrosis, inflammation, and angiogenesis was measured on RNA or at protein level using quantitative real-time polymerase chain reaction, Western blot, immunofluorescence, or multiplex enzyme-linked immunosorbent assay techniques., Results: Significant dose- and time-dependent growth inhibitory effects of UPA/vitamin D 3 combinations were observed compared to untreated cells at 2 and 4 days ( P < .05). Importantly, vitamin D 3 /UPA combination significantly reduced cell proliferation as compared to UPA at 2, 4, 6, and 8 days ( P < .05). Combination treatment significantly decreased protein expression of proliferation markers Ki-67, PCNA, and CyclinD1 by more than 50% compared to UPA ( P < .05) along with a significant increase in apoptosis induction. Combination treatment resulted in a 2-fold decrease in protein levels of extracellular matrix markers collagen-1 and fibronectin besides pro-fibrogenic cytokine transforming growth factor β3 ( P < .05). Moreover, it significantly decreased the production of pro-inflammatory cytokines interleukins 6, 8, 1α, and 1β compared to UPA ( P < .05)., Conclusion: Combination of vitamin D 3 with UPA exhibits additional and orchestrated anti-UF effects, therefore might offer a more favorable clinical option.

Objective: To investigate effects of ulipristal acetate on health-related quality of life (QOL) and symptom severity in women with symptomatic uterine leiomyomas and abnormal uterine bleeding., Methods: Women were randomized to ulipristal (5 mg, 10 mg) or placebo in two phase 3, multicenter, double-blind, placebo-controlled trials (VENUS I and II). Health-related QOL and symptom severity were assessed at baseline, and over one (VENUS I and II) and two (VENUS II) 12-week treatment courses using the Uterine Fibroid Symptom Health-Related Quality of Life questionnaire. In pooled VENUS I and II data, change from baseline to the end of the first course for each Uterine Fibroid Symptom Health-Related Quality of Life scale was analyzed, including a Revised Activities subscale that measured physical and social activities. The proportion of women achieving meaningful change in the Symptom Severity (20 or more points), Health-Related QOL Total (20 or more points), and Revised Activities (30 or more points) scales was calculated. In VENUS II data, change from baseline to the end of each course in each scale was analyzed for each treatment arm., Results: In pooled analyses, the intent-to-treat population included 589 patients (placebo, n=169; ulipristal 5 mg, n=215; ulipristal 10 mg, n=205). Significantly greater improvements from baseline in all Uterine Fibroid Symptom Health-Related Quality of Life scales were observed with both ulipristal doses compared with placebo (P<.001). A meaningful change in Revised Activities was achieved by 51 patients receiving placebo (34.9%), compared with 144 (73.5%; OR 5.0 [97.5% CI 2.9-8.6]) and 141 (80.6%; OR 7.9 [97.5% CI 4.3-14.6]) patients receiving ulipristal 5 mg, and 10 mg, respectively. In VENUS II, at end of courses 1 and 2, both ulipristal doses demonstrated significant improvements from baseline compared with placebo for all Uterine Fibroid Symptom Health-Related Quality of Life scales (P<.01). Mean Revised Activities scores showed that beneficial ulipristal effects were maintained in course 2, and improvements occurred on switching to ulipristal; results for other scales were similar., Conclusion: Ulipristal was associated with significant improvements in health-related QOL and symptom severity compared with placebo for women with symptomatic uterine leiomyomas., Clinical Trial Registration: ClinicalTrials.gov, NCT02147197 and NCT02147158., Funding Source: Allergan plc, Dublin, Ireland.

Objective: To evaluate the effect of investigational vaginal rings containing nomegestrol acetate (NOMAC) plus 17β-estradiol (E2) or etonogestrel (ENG) plus E2 in women with moderate to severe primary dysmenorrhea., Study Design: This was a Phase 2b randomized, placebo-controlled, multicenter, double-blind study. We randomized participants to one of five treatment groups: four hormonal rings and one placebo ring. The investigational vaginal rings released 300 μg of E2 daily along with 700 μg or 900 μg of NOMAC or 100 μg or 125 μg of ENG. Each participant received 2 identical rings and was to insert each for 21 days followed by a 7-day ring-free period. The primary endpoint, as assessed by a daily electronic diary (e-Diary), was the change in menstrual pain score from baseline to the second in-treatment withdrawal bleeding episode (Cycle 2). The pain score was the mean of the three highest scores for menstrual cramping pain (0-4 point scale) recorded from the day before menses to the third day of bleeding. The primary hypothesis was that at least one investigational vaginal ring would demonstrate a statistically significant larger reduction from baseline in pain score compared to placebo. Secondary endpoints included total mean impact score (which assessed the negative impact on work/school, physical activities, leisure/social activities) and the amount and days of rescue medication (ibuprofen) used., Clinical Trial Registration Number: NCT01670656., Results: We randomized 439 participants. The mean pain score decreased from baseline to Cycle 2 in all groups; the decrease in all four treatment groups compared to placebo was statistically significant (p-values ≤0.002). All treatment groups had greater reductions than placebo in ibuprofen intake and greater improvement in impact scores; these differences were statistically significant for both endpoints for the ENG-E2 100/300 μg/day group, while the other groups were not statistically significant for one or both endpoints., Conclusion: All four investigational rings produced a statistically significantly larger reduction from baseline in mean menstrual pain score compared to placebo while pain medication use decreased., Implications: This placebo-controlled study provides evidence that vaginal contraceptive rings containing NOMAC-E2 or ENG-E2 improve moderate to severe dysmenorrhea, across all of doses studied. This adds to the evidence that hormonal contraceptives are effective treatments for dysmenorrhea., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The 19 of February 2018 the Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco) temporary stopped the new administration of Ulipristal Acetate (UPA) for treating uterine leiomyomas symptoms, because liver injury and hepatic failure had been reported in relationship with UPA use. After the European Medicines Agency review of risks of UPA, the 3 of August 2018 the AIFA produced another note, disclosing that a cause-effect relationship between the UPA use and liver injury is not proved and that some patients can be discontinuously treated if surgery is not recommended. However, a close monitoring of hepatic function must be done in Ulipristal users. As Ulipristal has not been prescribed since February 2018 in our center, the rate of surgical operations for uterine leiomyomas significantly doubled. Therefore it will be useful know exactly which restricted indications allow to use UPA for more than 3 months. In this way it could be minimized the risks of liver injury and it could be prevented the rise of surgeries for uterine leiomyomas.

Background: Emergency contraception (EC) is using a drug or copper intrauterine device (Cu-IUD) to prevent pregnancy shortly after unprotected intercourse. Several interventions are available for EC. Information on the comparative effectiveness, safety and convenience of these methods is crucial for reproductive healthcare providers and the women they serve. This is an update of a review previously published in 2009 and 2012., Objectives: To determine which EC method following unprotected intercourse is the most effective, safe and convenient to prevent pregnancy., Search Methods: In February 2017 we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Popline and PubMed, The Chinese biomedical databases and UNDP/UNFPA/WHO/World Bank Special Programme on Human Reproduction (HRP) emergency contraception database. We also searched ICTRP and ClinicalTrials.gov as well as contacting content experts and pharmaceutical companies, and searching reference lists of appropriate papers., Selection Criteria: Randomised controlled trials including women attending services for EC following a single act of unprotected intercourse were eligible., Data Collection and Analysis: We used standard methodological procedures recommended by Cochrane. The primary review outcome was observed number of pregnancies. Side effects and changes of menses were secondary outcomes., Main Results: We included 115 trials with 60,479 women in this review. The quality of the evidence for the primary outcome ranged from moderate to high, and for other outcomes ranged from very low to high. The main limitations were risk of bias (associated with poor reporting of methods), imprecision and inconsistency.Comparative effectiveness of different emergency contraceptive pills (ECP)Levonorgestrel was associated with fewer pregnancies than Yuzpe (estradiol-levonorgestrel combination) (RR 0.57, 95% CI 0.39 to 0.84, 6 RCTs, n = 4750, I 2 = 23%, high-quality evidence). This suggests that if the chance of pregnancy using Yuzpe is assumed to be 29 women per 1000, the chance of pregnancy using levonorgestrel would be between 11 and 24 women per 1000.Mifepristone (all doses) was associated with fewer pregnancies than Yuzpe (RR 0.14, 95% CI 0.05 to 0.41, 3 RCTs, n = 2144, I 2 = 0%, high-quality evidence). This suggests that if the chance of pregnancy following Yuzpe is assumed to be 25 women per 1000 women, the chance following mifepristone would be between 1 and 10 women per 1000.Both low-dose mifepristone (less than 25 mg) and mid-dose mifepristone (25 mg to 50 mg) were probably associated with fewer pregnancies than levonorgestrel (RR 0.72, 95% CI 0.52 to 0.99, 14 RCTs, n = 8752, I 2 = 0%, high-quality evidence; RR 0.61, 95% CI 0.45 to 0.83, 27 RCTs, n = 6052, I 2 = 0%, moderate-quality evidence; respectively). This suggests that if the chance of pregnancy following levonorgestrel is assumed to be 20 women per 1000, the chance of pregnancy following low-dose mifepristone would be between 10 and 20 women per 1000; and that if the chance of pregnancy following levonorgestrel is assumed to be 35 women per 1000, the chance of pregnancy following mid-dose mifepristone would be between 16 and 29 women per 1000.Ulipristal acetate (UPA) was associated with fewer pregnancies than levonorgestrel (RR 0.59; 95% CI 0.35 to 0.99, 2 RCTs, n = 3448, I 2 = 0%, high-quality evidence).Comparative effectiveness of different ECP dosesIt was unclear whether there was any difference in pregnancy rate between single-dose levonorgestrel (1.5 mg) and the standard two-dose regimen (0.75 mg 12 hours apart) (RR 0.84, 95% CI 0.53 to 1.33, 3 RCTs, n = 6653, I 2 = 0%, moderate-quality evidence).Mid-dose mifepristone was associated with fewer pregnancies than low-dose mifepristone (RR 0.73; 95% CI 0.55 to 0.97, 25 RCTs, n = 11,914, I 2 = 0%, high-quality evidence).Comparative effectiveness of Cu-IUD versus mifepristoneThere was no conclusive evidence of a difference in the risk of pregnancy between the Cu-IUD and mifepristone (RR 0.33, 95% CI 0.04 to 2.74, 2 RCTs, n = 395, low-quality evidence).Adverse effectsNausea and vomiting were the main adverse effects associated with emergency contraception. There is probably a lower risk of nausea (RR 0.63, 95% CI 0.53 to 0.76, 3 RCTs, n = 2186 , I 2 = 59%, moderate-quality evidence) or vomiting (RR 0.12, 95% CI 0.07 to 0.20, 3 RCTs, n = 2186, I 2 = 0%, high-quality evidence) associated with mifepristone than with Yuzpe. levonorgestrel is probably associated with a lower risk of nausea (RR 0.40, 95% CI 0.36 to 0.44, 6 RCTs, n = 4750, I 2 = 82%, moderate-quality evidence), or vomiting (RR 0.29, 95% CI 0.24 to 0.35, 5 RCTs, n = 3640, I 2 = 78%, moderate-quality evidence) than Yuzpe. Levonorgestrel users were less likely to have any side effects than Yuzpe users (RR 0.80, 95% CI 0.75 to 0.86; 1 RCT, n = 1955, high-quality evidence). UPA users were more likely than levonorgestrel users to have resumption of menstruation after the expected date (RR 1.65, 95% CI 1.42 to 1.92, 2 RCTs, n = 3593, I 2 = 0%, high-quality evidence). Menstrual delay was more common with mifepristone than with any other intervention and appeared to be dose-related. Cu-IUD may be associated with higher risks of abdominal pain than mifepristone (18 events in 95 women using Cu-IUD versus no events in 190 women using mifepristone, low-quality evidence)., Authors' Conclusions: Levonorgestrel and mid-dose mifepristone (25 mg to 50 mg) were more effective than Yuzpe regimen. Both mid-dose (25 mg to 50 mg) and low-dose mifepristone(less than 25 mg) were probably more effective than levonorgestrel (1.5 mg). Mifepristone low dose (less than 25 mg) was less effective than mid-dose mifepristone. UPA may be more effective than levonorgestrel.Levonorgestrel users had fewer side effects than Yuzpe users, and appeared to be more likely to have a menstrual return before the expected date. UPA users were probably more likely to have a menstrual return after the expected date. Menstrual delay was probably the main adverse effect of mifepristone and seemed to be dose-related. Cu-IUD may be associated with higher risks of abdominal pain than ECPs.

Background/aims: Ulipristal acetate ([UPA], Esmya®) is an orally active selective progesterone-receptor modulator that has been approved as preoperative treatment for uterine myomas. This systematic review aims to summarize the available data on surgical outcomes of patients undergoing myomectomy by hysteroscopy or by laparoscopy after preoperative treatment with UPA., Methods: this review was performed following PRISMA guidelines and was registered in PROSPERO (CRD42018092201). PubMed, EMBASE, and Medline databases were systematically searched electronically until March 2018 for keywords concerning this topic. There were included only peer-reviewed, English language journal articles., Results: two prospective studies and 4 retrospective studies were included. The effect of UPA on the endometrium does not increase the technical difficulty during hysteroscopic myomectomy, but it increases the chance of complete primary resection in complex hysteroscopic myomectomies. Moreover, UPA does not increase the overall technical difficulty of laparoscopic myomectomy. Contradictory results have been reported on the impact of UPA on the separation of the myoma from the myometrium and on the consistency of the myomas., Conclusion: current results support the use of UPA prior to both surgical procedures. Further studies should confirm these preliminary findings and to assess the long-term outcomes of myomectomies following UPA treatment., (© 2018 S. Karger AG, Basel.)

Objective: The aim of the study was to examine treatment continuation and satisfaction over 1 year among women receiving nomegestrol acetate (NOMAC)/oestradiol (E2) combined oral contraception (COC) in real-world clinical practice., Methods: The 17β-Estradiol and Nomegestrol Acetate (BOLERO) Study is an observational, non-interventional, prospective, multicentre cohort study of premenopausal women (aged 18-50 years) who received prescription NOMAC/E2 (2.5 mg/1.5 mg) for contraception during routine clinical practice. Assessments were carried out at enrolment and at 3, 6 and 12 months. Probability of treatment continuation through 12 months (primary outcome) was examined using Kaplan-Meier survival analysis. Secondary outcomes included treatment satisfaction, menstrual cycle-related symptoms, libido and adverse events (AEs)., Results: Of 298 enrolled women, 292 were evaluable. The probability of NOMAC/E2 continuation through 12 months was 73.7% (95% confidence interval [CI] 68.0%, 78.5%). Satisfaction with NOMAC/E2 increased from 56.9% (37/65) of women at initial evaluation to 89.2% (58/65) of women at 12 months. Physician ratings at 12 months showed satisfactory to very satisfactory in 84.0% (168/200) of women. Libido was not affected. Menstrual cycle-related symptoms significantly declined from enrolment (6.04 ± 4.32) to 3 months (3.25 ± 3.05) and 12 months (2.62 ± 2.74; p < .0001). Treatment-related AEs were reported by 38.7% (113/292) of women., Conclusion: The real-world experience of women receiving NOMAC/E2 indicated very good treatment continuation, high satisfaction and significantly improved menstrual cycle-related symptoms.

Objectives: Edit, by the French National College of Gynecologists and Obstetricians (CNGOF), recommendations based on the evidence available in the literature for the use in terms of effectiveness, safety and side effects of emergency contraception (EC)., Methods: A review of the literature was conducted by consulting Medline, Cochrane Library and international recommendations in French and English from January 1, 1979 to May 1, 2018., Results: It is recommended to inform patients that EC is not 100% effective. A pregnancy test is recommended if there is a delay after taking an EC. It is recommended to use EC as soon as possible after the unprotected intercourse. In the absence of long-term contraception, in the first 72hours after unprotected intercourse, ulipristal acetate (UPA) and levonorgestrel (LNG) may be offered with a superiority of UPA from 0 to 72h. Beyond 72hours, the data suggest a better efficiency of the UPA. However, taking into account practical elements (access to EC, cost, impact on the taking of hormonal contraception after UPA), it is difficult to recommend the UPA as a priority between 0 and 72h. Menstruation is more likely to happen early with LNG. The copper IUD is an effective method that can be used in EC until 120hours after unprotected intercourse or when there is a risk of contraceptive failure., Conclusions: EC is not 100% effective. The closer the intake of EC with the unprotected intercourse, the more effective is the EC in terms of pregnancy rate., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Introduction: Uterine fibroids are benign tumors within the uterine wall affecting women. Ulipristal acetate 5 mg was first authorized in the European Union on 23 February 2012, with a post-marketing exposure estimated to be more than 765,000 patients so far. During the post-marketing experience, sporadic cases of liver injury and hepatic failure were reported. A detailed review of the clinical trials carried out in the development of ulipristal acetate 5 mg was undertaken to further assess the liver safety data reported during the clinical trials., Areas Covered: A detailed review of clinical data from Phase I to Phase III of patients exposed to ulipristal acetate at any investigated dose levels and for any treatment duration was conducted and the liver function test values are presented. In addition, a literature review on drug-induced liver injury is provided., Expert Opinion: The experts present an evaluation of the liver safety findings observed during the clinical development and their views on the role of these findings in predicting the occurrence of drug-induced liver injury, the benefits of the treatment, the safety and the implications to the current clinical practice.

Female sex steroid hormones have a fundamental role in breast cancer. Meanwhile, current evidence supports the contribution of breast cancer stem cells in carcinogenesis, metastasis, and resistance to cytotoxic chemotherapy. Nevertheless, the interaction between breast cancer stem cells with sex hormones or key hormonal antagonists remains elusive., Objective: To investigate the effect of diverse sex hormonal stimulation and suppression regimens on the proliferation of a primary human breast cancer cells with stem cell activity., Methods: Cells were exposed to estradiol, progesterone, letrozole, ulipristal acetate, or a combination of ulipristal acetate-letrozole, continually for 6 months. Additionally, nanoparticle-linked letrozole and ulipristal acetate formulations were included in a subsequent short-term exposure study. Phenotypic, pathologic, and functional characteristics of unexposed cells were investigated., Results: The proliferation of breast cancer cells was comparable among all hormonal stimulation and suppression groups (P= 0.8). In addition, the nanoparticle encapsulated hormonal antagonists were not able to overcome the observed resistance of cells. Cell characterization showed a mesenchymal-like phenotype overexpressing three master pluripotency markers (Oct 4, SOX2, and Nanog), and 92% of cells were expressing ALDH1A1. Notably, the CD44 high /CD24 low cell population presented only 0.97%-5.4% over repeat analyses. Most cells lacked the expression of mesenchymal markers; however, they showed differentiation into osteogenic and adipogenic lineages. Upon transfer to serum-free culture, the long-term maintained mesenchymal-like cancer cells showed remarkable morphologic plasticity as they switched promptly into an epithelial-like phenotype with significant mammosphere formation capacity (P= 0.008)., Conclusion: Breast cancer cells can develop a pluripotent program with enhanced stemness activity that may together contribute to universal resistance to sex hormonal stimulation or deprivation. Isolation and characterization of patient-derived breast cancer stem cells in large clinical studies is therefore crucial to identify new targets for endocrine therapies, potentially directed towards stemness and pluripotency markers. Such direction may help overcoming endocrine resistance and draw attention to breast cancer stem cells' behaviour under endogenous and exogenous sex hormones throughout a woman's reproductive life., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In order to get further information on the effects of ulipristal acetate (UPA) upon the process of decidualization of endometrium, a functional analysis of the differentially expressed genes in endometrium (DEG) from UPA treated-versus control-cycles of normal ovulatory women was performed. A list of 1183 endometrial DEG, from a previously published study by our group, was submitted to gene ontology, gene enrichment and ingenuity pathway analyses (IPA). This functional analysis showed that decidualization was a biological process overrepresented. Gene set enrichment analysis identified LIF, PRL, IL15 and STAT3 among the most down-regulated genes within the JAK STAT canonical pathway. IPA showed that decidualization of uterus was a bio-function predicted as inhibited by UPA. The results demonstrated that this selective progesterone receptor modulator, when administered during the periovulatory phase of the menstrual cycle, may affect the molecular mechanisms leading to endometrial decidualization in response to progesterone during the period of maximum embryo receptivity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To assess the efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas., Methods: This phase 3, double-blind, double-dummy, placebo-controlled trial randomized premenopausal women (18-50 years) with uterine leiomyomas and abnormal uterine bleeding to once-daily 5 mg ulipristal, 10 mg ulipristal, or placebo in two 12-week treatment courses separated by a drug-free interval of two menses. Coprimary end points were rates of and time to amenorrhea during course 1. Change from baseline to end of course 1 in the Revised Activities subscale of the Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire was a secondary end point. A sample size of 400 was planned to compare separately each ulipristal dose with placebo., Results: From January 2014 through November 2016, 432 women were randomized. Demographic characteristics were similar across treatment groups. In course 1, 68 of 162 (42.0% [97.5% CI 33.3-51.1]) and 86 of 157 (54.8% [97.5% CI 45.5-63.8]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 0 of 113 (0.0% [97.5% CI 0.0-3.8]) patients treated with placebo achieved amenorrhea (P<.001 for each dose); most women who achieved amenorrhea did so within 10 days (time to amenorrhea, P<.001 for each dose). Significantly greater improvements in Uterine Fibroid Symptom and Health-Related Quality of Life Revised Activities subscale scores were reported with 5 mg and 10 mg ulipristal compared with placebo (least squares mean change from baseline: 48.3, 56.7, and 13.0, respectively; P<.001 for each dose). Both ulipristal doses were well tolerated; in course 1, hot flush occurred in 7.5%, 11.6%, and 1.7% of patients treated with 5 mg ulipristal, 10 mg ulipristal, and placebo, respectively., Conclusion: Treatment with 5 mg or 10 mg ulipristal was superior to placebo in achieving amenorrhea and generally well tolerated for the medical management of symptomatic uterine leiomyomas., Clinical Trial Registration: ClinicalTrials.gov, NCT02147158.

A steroidal compound was recently detected in a seized black market product and was identified as (17α,20E)-17,20-[(1-methoxyethylidene) bis (oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11). This compound is described to possess selective androgen receptor modulator- and myostatin inhibitor-like properties. As YK11 is an experimental drug candidate and a non-approved substance for humans, scientific data on its metabolism is scarce. Due to its steroidal backbone and the arguably labile orthoester-derived moiety positioned at the D-ring, substantial metabolic conversion in vivo was anticipated. To unambiguously detect urinary metabolites of YK11, an elimination study with six-fold deuterated YK11 was conducted. Post-administration specimens were analyzed using hydrogen isotope ratio mass spectrometry coupled to single quadrupole mass spectrometry to identify metabolites alongside basic mass spectrometric data. Further characterization of those metabolites relevant to sports drug testing was accomplished using gas chromatography-high resolution-high accuracy mass spectrometry. Fourteen deuterated urinary metabolites were detected comprising unconjugated, glucuronidated, and sulfoconjugated metabolites. As expected, no intact YK11 was observed in the elimination study urine samples. While the unconjugated metabolites disappeared within 24 hours post-administration, both glucuronidated and sulfated metabolites were traceable for more than 48 hours. The chemical structures of the two most promising glucuronidated metabolites (5β-19-nor-pregnane-3α,17β,20-triol and 5β-19-nor-pregnane-3α,17β-diol-20-one) were verified by in-house synthesis of both metabolites and confirmed by nuclear magnetic resonance analysis. In order to elucidate their potential in sports drug testing, both were successfully implemented into the currently applied analytical method for the detection of anabolic agents., (© 2018 John Wiley & Sons, Ltd.)

Objective: To determine pregnancy and fetal outcomes following treatment with ulipristal acetate (UPA) for symptomatic uterine fibroids., Methods: We conducted a systematic review and case series. We searched MEDLINE, EMBASE, PubMed, Web of Science, and Cochrane Register from inception to February 2017. From January 2014 to July 2017, we carried out a multi-centre retrospective chart review. All human studies that reported at least one pregnancy following UPA treatment were included. The case series included patients who conceived during/following UPA treatment. Titles and abstracts were screened for eligibility by two independent reviewers, and full texts were evaluated for inclusion and study quality. Data from the systematic review and case series were synthesized and reported separately., Results: Seven studies were included (six case reports, one retrospective series) and contributed 24 post-UPA pregnancies (19 live births, six spontaneous abortions [SA]). The case series contributed 47 post-UPA pregnancies (31 live births, 13 SA, 1 fetal death, 2 terminations, 1 ongoing). In total, 71 pregnancies were evaluated (44 underwent myomectomy post-UPA; 27 without interval surgery). Five pregnancies occurred during UPA use (10-36 days of exposure) and resulted in three live births, one SA, and one termination. Five women who did not undergo interval myomectomy experienced delivery complications related to their fibroid., Conclusions: This is the first systematic review and largest reported case series evaluating pregnancy outcomes following UPA treatment for uterine fibroids. UPA alone, or in conjunction with surgery, can permit conception and favorable pregnancy outcomes., (Copyright © 2018 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.)

Ulipristal acetate (UPA), is a selective progesterone-receptor modulator, it decreases fibroid size and reduces menstrual bleeding. We reviewed its use at the Heart of England Foundation Trust (HEFT), one of the largest prescribing trusts in the UK. The electronic records of patients treated with UPA from January 2013 to August 2015 were reviewed. One hundred and thirty four patients received UPA, 20 women (15%) received a second course. Eighty percent reported subjective global improvements in symptoms after the first course; 45.5% described amenorrhoea or light bleeding compared to 4.5% prior to treatment. Fewer patients were anaemic (Hb <11 g/dL) following treatment (8.2% versus 33.6%). The majority of fibroids (34%) reduced or remained the same size (25%). Two-thirds of women treated for symptom control avoided surgical intervention. UPA improves symptoms and modifies the use of surgery in treating fibroids. Correcting anaemia prior to major surgery reduces the risk of blood transfusion and optimises a patient's condition as part of an enhanced recovery pathway. Impact Statement What is already known on this subject: In women with heavy menstrual bleeding secondary to fibroids, UPA has been shown to reduce fibroid size and control uterine bleeding, inducing amenorrhoea in the majority. Initially, only licenced for pre-operative use, an expansion of the licence has included on-going intermittent use for symptomatic fibroids. What the results of this study add: Our review is the largest published cohort of women treated with UPA. It demonstrates symptomatic improvements and advantageous modifications in fibroid size in women of all ethnicities and ages. Our inclusion of women with a uterine size greater than 16 weeks and fibroid diameter larger than 10 cm demonstrates the benefits of UPA with increased fibroid dimensions. What the implications are of these findings for clinical practice and/or further research: These findings can allow clinicians to consider alternative surgical interventions or even avoid surgery completely in a proportion of patients with fibroids. Correcting anaemia and optimising a patient's pre-operative condition reduces post-operative complications and ongoing morbidity. However, 25% of fibroids failed to respond to UPA treatment, further research into the characteristics of women and fibroids that show favourable clinical outcomes will allow identification of those women who are likely to benefit from treatment and prevent futile use in others.

Background: To assess and compare the influence of three fibroid treatment options: supracervical hysterectomy, ulipristal acetate and uterine artery embolization on ovarian reserve., Methods: Prospective, observational, open-label study performed at the 3rd Chair and Department of Gynecology of the Medical University of Lublin, Poland. Premenopausal Caucasian women with symptomatic uterine fibroids were recruited into 3 groupspatients qualified for supracervical hysterectomies; patients qualified for preoperative ulipristal acetate (UPA) treatment scheduled for supracervical hysterectomies or myomectomies; patients qualified for uterine artery embolization (UAE). The following markers of ovarian reserve were investigated: antral follicle count (AFC), anti-Mullerian hormone (AMH), inhibin B (INHB), follicle stimulating hormone (FSH) and estradiol (E2). These markers were assessed before and 3 months after supracervical hysterectomies, before and 3 months after UAEs, and before and after 3 months of UPA treatment, before the scheduled surgeries. Baseline characteristics (age, parity, dominant fibroid volume, hemoglobin level, BMI, as well as AFC, AMH, INHB, FSH and E2) were compared between the study groups by Kruskall-Wallis ANOVA. Pre- and post-interventional values of AFC, AMH, INHB, FSH and E2 in the studied groups were compared with the Wilcoxon matched pairs test., Results: Twenty-six, 27 and 30 patients were included in the final analysis in the supracervical hysterectomy, UPA and UAE groups, respectively. Three months after supracervical hysterectomy INHB and E2 significantly decreased, while AFC, AMH and FSH remained unchanged. After 3 months of UPA treatment the values of all the assessed markers of ovarian reserve were not significantly different in comparison to baseline. Conversely, three months after UAE the values of AFC, AMH, INHB, and E2 were significantly decreased, while FSH was significantly increased., Conclusions: Of the compared fibroid treatment methods UAE seems to have the greatest impact on ovarian function and should not be offered to patients concerned about their ovarian function. Supracervical hysterectomy did not affect the most accurate markers of ovarian reserve, and therefore appears to be safe in terms of ovarian function. UPA did not change any of the studied markers of ovarian reserve and seems a reasonable option when ovarian function is concerned.

Objectives: Ulipristal acetate (UPA) is a selective progesterone receptor modulator, which has been used to treat uterine fibroids. Many published reports about the outcomes indicate effective control of bleeding and reduction in the fibroid volume following both short- and long-term therapy. However, the reported volume reduction varies across different reports. Therefore, the purpose of this study was to investigate the factors that can affect the volume reduction of uterine fibroids, after short-term UPA therapy in patients with symptomatic uterine fibroids., Study Design: Women treated with UPA for 3 months, between November 2013 and February 2017, for symptomatic uterine fibroids were evaluated retrospectively. The fibroid volume was measured using ultrasonography or magnetic resonance imaging. Response was defined as any reduction in volume after treatment and non-response was defined as no change or increase in volume., Results: Totally, 152 women were treated with UPA and the median volume reduction was 13.1% (interquartile range [IQR] -16.8 to 36.7). Response to treatment was seen in 92 of 152 (60.5%) patients, while 60 women (39.5%) showed no response. Median number of fibroids in the response group was less than that in the non-response group (P = 0.030; median 2, IQR 1-4 vs. median 4, IQR 1-6). On multivariate regression analysis, fewer number of uterine fibroids was an independent factor for predicting a good response to UPA (odds ratio 0.830, CI: 0.710-0.969, P = 0.019)., Conclusion: An independent factor that can affect the volume reduction after a 3-month UPA therapy in women with uterine fibroids was the number of fibroids. This indicates that UPA might be ineffective for volume reduction in cases with multiple leiomyomas. However, future prospective studies comparing solitary and multiple leiomyomas for response to UPA are necessary., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A highly sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry method is described for the simultaneous determination of nomegestrol acetate (NOMAC), a highly selective progestogen, and estradiol (E2), a natural estrogen in human plasma. NOMAC was obtained from plasma by solid-phase extraction, while E2 was first separated by liquid-liquid extraction with methyl tert-butyl ether followed by derivatization with dansyl chloride. Deuterated internal standards, NOMAC-d5 and E2-d4 were used for better control of extraction conditions and ionization efficiency. The assay recovery of the analytes was within 90-99%. The analytes were separated on UPLC BEH C 18 (50 × 2.1 mm, 1.7 μm) column using a mobile phase comprising of acetonitrile and 3.0 mm ammonium trifluoroacetate in water (80:20, v/v) with a resolution factor (R s ) of 3.21. The calibration curves were linear from 0.01 to 10.0 ng/mL for NOMAC and from 1.00 to 1000 pg/mL for E2, respectively. The intra- and inter-batch precision was ≤5.8% and the accuracy of quality control samples ranged from 96.7 to 103.4% for both analytes. The practical applicability of the method is demonstrated by analyzing samples from 18 healthy postmenopausal women after oral administration of 2.5 mg nomegestrol acetate and 1.5 mg estradiol film-coated tablets under fasting., (Copyright © 2017 John Wiley & Sons, Ltd.)

This case report describes a very rare coexistence of retroperitoneal lymphogenic and pulmonary metastases of a benign leiomyoma: benign metastasising leiomyoma (BML). Despite surgical treatment growth of multiple nodules in the lungs, omentum, mesenterium and retroperitoneum was observed by CT scan. We started off-label ulipristal acetate treatment with impressive results. The lesions on the CT scan disappeared, and the patient was asymptomatic after treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Selective progesterone receptor modulators (SPRMs), such as Mifepristone, Asoprisnil, Ulipristal acetate (UPA) and Vilaprisan, were tested for their antiproliferative effects on uterine fibroids. In Romania, despite the UPA availability, physicians remained reserved on the lack of experience and concerns about the safety of the drug on endometrium., Patients, Materials and Methods: We performed an observational study on premenopausal women with symptomatic uterine fibroids. The patients received UPA in doses of 5 mg for 12-13 weeks. The fibroids dimensions and endometrium thickness were recorded at before and after the treatment. The pathological samples were assessed by two pathologists, and they recorded progesterone receptor modulator associated endometrial changes (PAEC) as extensive PAEC (EPAEC), minimally PAEC (MPAEC), absent PAEC (APAEC) and Ki67 immunoexpression in endometrium., Results: A number of 57 women were introduced in our study and we had a dropout of one patient. The fibroid dimensions and endometrial thickness decreased after UPA. The pathological exam of the endometrium revealed: APAEC in 26.8% of cases, MPAEC in 60.7% of cases and EPAEC in 12.5% of cases. EPAEC were more frequent in patients with larger fibroids. PAEC had a strong correlation with Ki67 index (p≤0.01). PAEC were more frequent in older women (p≤0.01). Ki67 had a higher expression in EPAEC - mean: 69% (range: 63-75%), standard deviation (SD): 3.95., Conclusions: UPA treatment decreased fibroids dimension and improved patients' symptoms in our study. EPAEC was associated with abundant Ki67 antigen. UPA administration for three months is a safe method without endometrial atypia but longer protocols require extended studies about the proliferative potential of the endometrium.