Ulipristal acetate simultaneously provokes antiproliferative and proinflammatory responses in endometrial cancer cells.
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ABSTRACT:
SUBMITTER: Kanda R
PROVIDER: S-EPMC8749191 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ulipristal acetate (UPA) is a selective progesterone receptor modulator (SPRM) used for emergency contraception and for the medical management of symptomatic uterine fibroids (UF). Treatment with UPA turns in amenorrhea and UF volume reduction. Treatment with UPA is associated with the frequent development of benign, transitory endometrial changes known as SPRM-associated endometrial changes (PAECs). Why PAECs develop and their biological or cellular basis is unknown. Sex steroids, including estrogen and progesterone, are established modulators of the actin cytoskeleton in various cells, including endometrial cells. This explains several morphological and functional changes in endometrial cells. We thus hypothesized that UPA may alter the appearance of the endometrium by interfering with the actions of 17β-estradiol (E2) or progesterone (P4) on actin dynamics. We isolated and cultured human endometrial stromal cells (ESC) from endometrial biopsies from healthy fertile women. Treatment with E2 or P4 stimulated visible actin rearrangements with actin remodeling toward the membrane. Activation through phosphorylation of the actin regulatory proteins, Moesin, and focal adhesion kinase (FAK), hacked actin remodeling induced by E2 and P4. Membrane re-localization of Paxillin and Vinculin were also induced by E2 and P4, showing the formation of focal adhesion complexes. All these E2 and P4 actions were inhibited by co-treatment with UPA, which was otherwise inactive if given alone. The cytoskeletal changes induced by E2 and P4 turned into increased motility of ESC, and UPA again blocked the actions E2 and P4. In conclusion, we find that UPA interferes with the cytoskeletal actions of E2 and P4 in ESC. This finding helps understanding the mode of actions of SPRMs in the endometrium and may be relevant for other potential clinical applications of UPA.
| S-EPMC6036300 | biostudies-literature
Project description:Aberrant progesterone signaling has been demonstrated in mechanistic studies to be a shared common pathway in fibroids and endometriosis. Progesterone receptor modulation with the selective progesterone receptor modulator (SPRM) ulipristal may decrease pain associated with endometriosis. A 25-year-old nulligravidae with endometriosis-related pelvic pain refractory to medical and surgical intervention was administered 15mg ulipristal every other day for 3 months. Daily pain scores and bleeding diary were recorded and serum chemistries and hormone levels were checked prior to, during, and after treatment. Pre-treatment and surveillance endometrial biopsy specimens were examined for histology and stained for estrogen and progesterone receptor status. During therapy, pain scores decreased to a median of 0 (P<0.05) and the patient became amenorrheic. Surveillance endometrial biopsy demonstrated SPRM-associated endometrial changes that appeared strikingly similar to simple hyperplasia and resolved with ulipristal discontinuation. Immunohistochemical evaluation demonstrated the presence of estrogen and progesterone receptors before and during ulipristal treatment. Progesterone receptor modulation with ulipristal substantially improved pain symptoms in a patient with treatment-refractory endometriosis. SPRM-associated changes in the endometrium closely mimicked hyperplasia, developed after less than three months of treatment, and resolved after discontinuation of ulipristal and induction of withdrawal bleed.
| S-EPMC6342495 | biostudies-literature
Project description:IntroductionThe European Medicines Agency has suspended the use of ulipristal acetate (UPA) in the treatment of uterine fibroids and is reassessing its association with a risk of liver injury.ObjectivesOur objectives were to characterize the post-marketing reporting of drug-induced liver injury (DILI) with UPA and investigate the underlying pharmacological basis.MethodsWe queried the worldwide FDA Adverse Event Reporting System and performed a disproportionality analysis, selecting only hepatic designated medical events (DMEs) where UPA was reported as suspect. The reporting odds ratios (RORs) were calculated, and we considered a lower limit of the 95% confidence interval (LL95% CI) > 1 as significant. Physiochemical/pharmacokinetic features were extracted to assess the risk of hepatotoxicity by applying predictive DILI risk models. Mifepristone and leuprolide were selected as comparators.ResultsA significantly higher proportion of liver disorders was reported for UPA than for mifepristone (2.9 vs. 0.8%; p < 0.00001) and leuprolide (2.9 vs. 1.6%; p = 0.015). As regards hepatic DMEs, statistically significant RORs were found for autoimmune hepatitis (N = 5; LL95% CI 16.8), DILI (n = 5; LL95% CI 5.9), and acute hepatic failure (N = 5; LL95% CI 9.3). No signals of DILI emerged for mifepristone and leuprolide acetate. UPA and mifepristone showed high lipophilicity and hepatic metabolism (predicted intermediate DILI risk). Leuprolide exhibited contrasting features, resulting in no DILI concern. Inhibition of different liver transporters and the presence of a reactive metabolite were also recognised for UPA.ConclusionDifferent drug properties previously linked to the occurrence of DILI may partially explain the reporting pattern observed with UPA. Our "bedside-to-bench" approach may support regulators in the risk-benefit assessment of UPA.
| S-EPMC7686198 | biostudies-literature
Project description:Unwanted pregnancy is a global reproductive health problem. Emergency contraception is defined as the use of drug or device after unprotected or underprotected intercourse to prevent an unwanted pregnancy. 1.5 mg of levonorgestrel as a single dose or in two doses with 12 h apart taken within 72 h of unprotected intercourse is the current gold standard emergency contraception regimen. This method is only effective if used as soon as possible after sexual intercourse and before ovulation. A single dose of 30 mg ulipristal acetate, a novel selective progesterone receptor modulator, has recently been proposed for the emergency contraception use up to 120 h of unprotected intercourse with similar side effect profiles as levonorgestrel. Ulipristal acetate could possibly prevent pregnancy when administered in the advanced follicular phase, even if luteinizing hormone levels have already begun to rise, a time when levonorgestrel is no longer effective in inhibiting ovulation.
| S-EPMC3356949 | biostudies-other
Project description:The progesterone receptor (PR) with its isoforms and ligands are involved in breast tumorigenesis and prognosis. We aimed at analyzing the respective contribution of PR isoforms, PRA and PRB, in breast cancer cell proliferation in a new estrogen-independent cell based-model, allowing independent PR isoforms analysis. We used the bi-inducible human breast cancer cell system MDA-iPRAB. We studied the effects and molecular mechanisms of action of progesterone (P4) and ulipristal acetate (UPA), a new selective progesterone receptor modulator, alone or in combination. P4 significantly stimulated MDA-iPRA expressing cells proliferation. This was associated with P4-stimulated expression of the anti-apoptotic factor BCL2-L1 and enhanced recruitment of PRA, SRC-1 and RNA Pol II onto the +58 kb PR binding motif of the BCL2-L1 gene. UPA decreased cell proliferation and repressed BCL2-L1 expression in the presence of PRA, correlating with PRA and SRC1 but not RNA Pol II recruitment. These results bring new information on the mechanism of action of PR ligands in controlling breast cancer cell proliferation through PRA in an estrogen independent model. Evaluation of PR isoforms ratio, as well as molecular signature studies based on PRA target genes could be proposed to facilitate personalized breast cancer therapy. In this context, UPA could be of interest in endocrine therapy. Further confirmation in the clinical setting is required.
| S-EPMC4608808 | biostudies-literature
Project description:ObjectiveTo assess long term safety of extended repeated 3-month courses of ulipristal acetate (UPA) 10 mg/day, for up to 8 courses, with focus on endometrial and laboratory safety parameters.MethodsThis long-term, multi-center, open-label cohort, follow up study consisted of up to 8 consecutive 3-month courses of daily UPA 10 mg, each separated by a drug free period of 2 spontaneous menstrual bleeds. Sixty-four pre-menopausal women, with moderate to severe symptomatic uterine myoma(s) and heavy bleeding were enrolled and were studied for approximately 4 years. The main outcome measures were endometrial histology, laboratory parameters and general safety.ResultsAll data was reported in a descriptive manner with no formal statistical comparisons. In the 64 women, non-physiological changes (mostly cyst formation, epithelial and vascular changes) in endometrial histology at screening and after treatment courses 4 and 8 were observed in 18.0%, 21.4% and 16.3% of biopsies, respectively. After treatment cessation, such changes were observed in 9.1% of biopsies. All endometrial biopsies were benign after course 8. The median endometrial thickness was 7.0 mm, 10-18 days after the start of menses following treatment courses 5-8, compared to 9.0 mm at screening (before UPA treatment). No changes in the number and type of laboratory results outside the normal ranges were observed with the increasing treatment courses. In total, adverse events were reported in 10 (16%), 12 (19%), 8 (14%) and 5 (9%) subjects, during treatment courses 5, 6, 7 and 8, respectively of which the most frequent adverse events were headache and hot flush.ConclusionThe results of this study further support the safety profile of extended repeated 3 months treatment of symptomatic fibroids with ulipristal acetate 10 mg/day. Repeated UPA treatment courses did not result in any changes of concern in endometrial histology, endometrial thickness, or laboratory safety measures.
| S-EPMC5340384 | biostudies-literature
Project description:PurposeThe proliferation of breast epithelial cells increases during the luteal phase of the menstrual cycle, when they are exposed to progesterone, suggesting that ulipristal acetate, a selective progestin-receptor modulator (SPRM), may reduce breast cell proliferation with potential use in breast cancer chemoprevention.MethodsWomen aged 18-39 were randomized 1:1 to ulipristal 10-mg daily or to a combination oral contraceptive (COC) for 84 days. Participants underwent a breast biopsy and breast MRI at baseline and at end of study treatment. Proliferation of breast TDLU cells was evaluated by Ki67 immunohistochemical stain. We evaluated the breast MRIs for background parenchymal enhancement (BPE). All slides and images were masked for outcome evaluation.ResultsTwenty-eight treatment-compliant participants completed the study; 25 of whom had evaluable Ki67 results at baseline and on-treatment. From baseline to end of treatment, Ki67 % positivity (Ki67%+) decreased a median of 84% in the ulipristal group (N = 13; 2-sided p (2p) = 0.040) versus a median increase of 8% in the COC group (N = 12; 2p = 0.85). Median BPE scores decreased from 3 to 1 in the ulipristal group (p = 0.008) and did not decrease in the COC group.ConclusionUlipristal was associated with a major decrease in Ki67%+ and BPE. Ulipristal would warrant further investigation for breast cancer chemoprevention were it not for concerns about its liver toxicity. Novel SPRMs without liver toxicity could provide a new approach to breast cancer chemoprevention.Trial registrationNCT02922127, 4 October 2016.
| S-EPMC10088437 | biostudies-literature
Project description:ObjectiveTo assess efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas.MethodsThis phase 3, double-blind, placebo-controlled study enrolled premenopausal women (aged 18-50 years) with abnormal uterine bleeding, one or more discrete leiomyomas, and uterine size 20 weeks of gestation or less. Patients were randomized 1:1:1 to 5 mg ulipristal, 10 mg ulipristal, or placebo once daily for 12 weeks followed by 12-week drug-free follow-up. Coprimary endpoints were rate of and time to amenorrhea, defined as no bleeding for the last 35 consecutive days of treatment. Secondary endpoints included rates of amenorrhea from day 11 and change from baseline to endpoint in the Revised Activities subscale of the Uterine Fibroid Symptom and Quality of Life questionnaire, which includes questions pertaining to physical and social activities. Safety assessments included adverse event monitoring and endometrial biopsies. A sample size of 150 was planned to compare separately each dose of ulipristal with placebo.ResultsFrom March 2014 to March 2016, 157 patients were randomized. Demographics were similar across treatment groups. Amenorrhea was achieved by 25 of 53 (47.2% [97.5% CI 31.6-63.2]) and 28 of 48 (58.3% [97.5% CI 41.2-74.1]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 1 of 56 (1.8% [97.5% CI 0.0-10.9]) placebo-treated patients (both P<.001). Time to amenorrhea was shorter for both ulipristal doses compared with placebo (P<.001), and both doses of ulipristal resulted in improved quality of life compared with placebo (P<.001). Common adverse events (5% or greater in either ulipristal group during treatment) were hypertension, elevated blood creatinine phosphokinase, and hot flushes. Serious adverse events occurred in four patients, but none was considered related to treatment. Endometrial biopsies were benign.ConclusionUlipristal at 5 mg and 10 mg were well tolerated and superior to placebo in rate of and time to amenorrhea in women with symptomatic uterine leiomyomas.Clinical trial registrationClinicaltrials.gov number, NCT02147197.
| S-EPMC7968372 | biostudies-literature
Project description:OBJECTIVE:To evaluate whether ulipristal acetate reduces the number of bleeding days in etonogestrel implant users in a 30-day period as compared with placebo. METHODS:We performed a single-center, randomized, double-blind, placebo-controlled trial. Eligible participants were women aged 18-45 years with an etonogestrel implant in place for greater than 90 days and less than 3 years who reported greater than one bleeding episode in a 24-day period. Enrolled participants were randomized to receive 15 mg ulipristal acetate compared with an identical-appearing placebo daily for 7 days. Participants completed daily bleeding diaries using automated text messaging to evaluate whether ulipristal acetate reduces the number of bleeding days as compared with placebo. Secondary outcomes included participant satisfaction with bleeding and the effect of ulipristal acetate on ovulation status. A sample size of 52 per group (n=104) was planned, calculated with an effect size of a 30% reduction in bleeding days, SD of 10 days, and dropout of 15%. Our study was terminated early (N=65) as a result of a U.S. Food and Drug Administration hold, but power was sufficient for analysis. The effect of ulipristal acetate on ovulatory potential was evaluated in a subset with weekly serum progesterone. RESULTS:From May 2017 to January 2018, 65 women were allocated to receive 15 mg ulipristal acetate (n=32) or placebo (n=33) daily for 7 days. Demographic characteristics were similar between groups. Women randomized to ulipristal acetate reported 5 fewer days of bleeding over a 30-day reference period after treatment (P=.002). At the conclusion of the 30-day follow-up period, women in the ulipristal acetate group were more satisfied with their bleeding profile than the placebo group (87.5% vs 60%, respectively; P<.001). Serum progesterone levels were nonovulatory in a subset of each group (placebo group range: less than 0.2-1.3 ng/mL; ulipristal acetate group range: less than 0.2-4.4 ng/mL). CONCLUSION:Ulipristal acetate is well-tolerated and reduced the number of bleeding days in etonogestrel implant users in our study. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT03118297.
| S-EPMC6153077 | biostudies-literature
Project description:ObjectiveTo assess the budget impact of using ulipristal acetate (UPA) 5 mg to treat women with uterine fibroids (UF) causing moderate to severe symptoms.DesignWe modelled trends in the number of surgical procedures for symptomatic UF, with and without the use of UPA for preoperative or intermittent treatment and assessed the budget impact of UPA use from the French national healthcare insurance system perspective.SettingA French national hospital database (PMSI) that records admissions and relative procedures to public and private hospitals.ParticipantsWomen eligible for surgical procedures for uterine fibroids.Main outcome measuresEconomic impact of UPA treatment.ResultsThis study based on observational retrospective data shows that the current use of UPA in its preoperative indication was associated with 5645 fewer surgeries from 2013 to 2015. Extrapolation suggests 17 885 fewer surgeries from 2016 to 2019. Overall, preoperative use of UPA results in substantial cost savings for the French national healthcare insurance system, with a cumulated budget impact estimated at €-5 million from 2013 to 2015 and €-13.5 million from 2016 to 2019. In addition, treating women nearing the menopause (≥48 years old) with intermittent treatment from 2017 to 2019 could produce an incremental cost saving of €19 million.ConclusionsThis study shows that the use of UPA in women eligible for surgical procedures for UF is associated with considerable savings for the French national healthcare insurance system in both preoperative and intermittent indications by decreasing the need to perform surgeries.
| S-EPMC5588963 | biostudies-literature