Ulipristal (UPA) effects on rat ovaries: Unraveling follicle dynamics, ovulation inhibition, and safety implications for prolonged use.

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

Pharmacodynamic evaluation of the etonogestrel contraceptive implant initiated midcycle with and without ulipristal acetate: An exploratory study.

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

Effects of Ulipristal Acetate on Reactive Oxygen Species and Proinflammatory Cytokine Release by Epithelial and Stromal Cells from Human Endometrium and Endometriosis.

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

Emergency contraception - A review.

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

Effects of long-term intermittent pharmacological therapy with ulipristal acetate on reducing the volume of uterine fibroids and relieving symptoms.

BACKGROUND: The aim of this study was to compare the effects of a 12-week course and four repeated 12-week courses of daily 5 mg ulipristal acetate (UPA) on reducing the volume and relieving symptoms of uterine fibroids. METHODS: From 2016 to 2019, 287 female patients with uterine fibroids diagnosed using ultrasonography were recruited. The patients received four 12-week course treatments of daily UPA administration in the first and fourth sessions, respectively. During the first and fourth courses of UPA, we measured the volume of the fibroids using ultrasonography to study the effect on volume reduction. The measured outcomes included symptomatic relief and adverse effects. RESULTS: After the first UPA treatment course, menorrhagia was improved in 82.2% of patients. A total of 59.5% of patients were responsive to treatment, and the volume of the three largest fibroids decreased from 160.9 cm3 to 104.6 cm3. After the fourth treatment course, 87.4% of patients reported decreased bleeding. A total of 67.2% of patients were responsive to treatment, and the volume of the three largest fibroids decreased from 171.7 cm3 to 106.5 cm3. In 64 (38.1%) patients in group A and 36 (30.3%) in group B, the fibroid volume increased. Among them, 72% of patients showed improved symptoms. CONCLUSIONS: Uterine bleeding, pain, and reduced fibroid volume were adequately regulated in patients with symptomatic fibroids with four repeated 12-week courses of daily UPA.

NOMAC-E2 compares to LNG combined oral contraceptives in women over forty: real-world PRO-E2 study.

OBJECTIVE: To investigate safety and effectiveness of NOMAC-E2 and levonorgestrel-containing COCs (COCLNG) in users over 40. METHODS: In this large, observational study, new users1 of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed-up via questionnaires. Incidence of venous thromboembolism (VTE) was expressed as incidence rate (IR; events/104 women-years [WY]). Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 WY). Mood and weight changes were defined as mean changes in mood score and percentage of body weight. RESULTS: Overall, 7,762 NOMAC-E2 and 6,059 COCLNG users over 40 were followed-up. NOMAC-E2 showed no increased VTE risk compared to COCLNG; confirmed events: 5 NOMAC-E2 (IR 5.9; 95% CI, 1.9-13.7) vs 4 COCLNG (IR 5.9; 95% CI, 1.6-15.1). Unintended pregnancy did not differ substantially between cohorts; confirmed events: 4 NOMAC-E2 (PI 0.05; 95% CI, 0.01-0.13) vs 5 COCLNG (PI 0.08; 95% CI, 0.03-0.18). No differential effect on mood and weight was observed between cohorts. CONCLUSIONS: NOMAC-E2 can be considered a valid alternative to COCLNG in perimenopausal women.

Society of Family Planning Clinical Recommendation: Emergency contraception.

Emergency contraception (EC) refers to several contraceptive options that can be used within a few days after unprotected or under protected intercourse or sexual assault to reduce the risk of pregnancy. Current EC options available in the United States include the copper intrauterine device (IUD), levonorgestrel (LNG) 52 mg IUD, oral LNG (such as Plan B One-Step, My Way, Take Action), and oral ulipristal acetate (UPA) (ella). These clinical recommendations review the indications, effectiveness, safety, and side effects of emergency contraceptive methods; considerations for the use of EC by specific patient populations and in specific clinical circumstances and current barriers to emergency contraceptive access. Further research is needed to evaluate the effectiveness of LNG IUDs for emergency contraceptive use; address the effects of repeated use of UPA at different times in the same menstrual cycle; assess the impact on ovulation of initiating or reinitiating different regimens of regular hormonal contraception following UPA use; and elucidate effective emergency contraceptive pill options by body mass indices or weight.

Ultrasonographic appearance of the endometrium after saline infusion in women presenting with PRM-associated endometrial changes, due to the use of ulipristal acetate.

Ulipristal acetate (UPA), used for the treatment in women with symptomatic fibroids, is associated with endometrial changes visualised on ultrasound as thickening up to more than 16 mm in approximately 10% of the patients. Is saline infusion sonography (SIS) a good alternative for more invasive techniques, to evaluate the presence of intrauterine pathology? Ten patients, presenting with UPA associated endometrial changes at their follow up ultra-sonographic evaluation, were included. Our study demonstrated that SIS is feasible and painless in patients presenting with UPA associated endometrial changes. The thickened endometrium appears to divide at the midline, making it possible to study both layers separately and exclude any suspected intrauterine pathology. Our findings suggest that SIS may be a first choice, non-invasive, painless technique to provide a proper visualisation to rule out intrauterine pathology when UPA associated endometrial changes are diagnosed after fibroid treatment. This is especially of clinical interest in front of assisted reproductive technology treatment. Invasive techniques can be withheld for patients in whom SIS examination is not contributive.Impact StatementWhat is already known on this subject? Reversible endometrial changes after ulipristal acetate (UPA) treatment in patients with symptomatic fibroids have been described. In patients who receive UPA, especially if planned to undergo ART, assessment of potential endometrial pathology is important as such interfere with proper implantation after ART. Consequently, clinicians may consider ruling out intrauterine pathology by invasive examinations such as biopsy or hysteroscopy after visualisation of the thickened endometrium.What do the results of this study add? Saline infusion sonography (SIS) was feasible and painless in patients presenting with UPA associated endometrial changes.What are the implications of these findings for clinical practice and/or further research? SIS may be a first choice, non-invasive, painless technique to provide a proper visualisation to rule out intrauterine pathology when UPA associated endometrial changes are diagnosed after fibroid treatment. This is especially of clinical interest in front of assisted reproductive technology treatment. Invasive techniques can be withheld for patients in whom SIS examination is not contributive in excluding intrauterine pathology.

Randomized study on the effectiveness of nomegestrol acetate plus 17ß-estradiol oral contraceptive versus dienogest oral pill in women with suspected endometriosis­associated chronic pelvic pain.

BACKGROUND: To evaluate the effects of a combined oral contraceptive containing 1.5 mg 17b-estradiol (E2) and 2.5 mg nomegestrol acetate (NOMAC) or 2 mg/daily dienogest (DNG) oral progestin on endometriosis-associated chronic pelvic pain (CPP) and on the quality of life (QoL) and sexual function, by a randomized study design. METHODS: The E2/NOMAC group and DNG group included 99 and 98 women, respectively. The levels of CPP were measured by the visual analogic scale (VAS). The QoL scores were investigated by the Short Form-36 questionnaire (SF-36). Finally, sexual function was studied using the Female Sexual Function Index (FSFI), while sexual distress was studied by the Female Sexual Distress Scale (FSDS). The study had 3, 6 and 12-month follow-ups. RESULTS: The intra-group analysis showed an improvement of the VAS score from baseline to the 12-month follow-up in the women of both groups (p < 0.001). The inter-group comparison showed a similar improvement of CPP (p = 0.06). Women on DNG had better SF-36 somatic (p < 0.01) and FSFI scores (p < 0.006) than women on E2/NOMAC at the 6- and 12-month follow-ups. CONCLUSIONS: The results support the efficacy of both hormonal treatments, even if DNG was more effective than E2/NOMAC in a limited intergroup comparison.

Potential candidate for oral pericoital contraception: evaluating ulipristal acetate plus cyclo-oxygenase-2 inhibitor for ovulation disruption.

BACKGROUND: There remains considerable global unmet contraceptive need, with almost 200 million women reporting desire to limit or space childbearing without contraceptive use. Researchers have documented worldwide interest in an oral, on-demand contraceptive option were it available. Candidates for use include ulipristal acetate (UA), levonorgestrel and cyclo-oxygenase-2 (COX-2) inhibitors alone or in combination. METHODS: We performed an exploratory, prospective study of matched menstrual cycles: one baseline cycle and one treatment cycle of UA 30 mg plus meloxicam 30 mg just prior to ovulation. The primary outcome was ovulation disruption, defined as unruptured dominant follicle for 5 days. Secondary outcomes included comparing cycle length, endometrial stripe thickness, and side effects. RESULTS: Nine participants completed all study procedures in both cycles. Ovulatory disruption occurred in 66.7% (n=6) of treatment cycles and all but one demonstrated features of ovulatory dysfunction. Cycle length (mean±SD) was longer in the treatment cycle (31.9±4.0 vs 28.6±3.5 days, p<0.01). Secondary outcomes did not differ between the two cycles. CONCLUSIONS: UA plus the COX-2 inhibitor meloxicam disrupts ovulation at peak luteal surge and is a promising candidate for evaluation as a pericoital oral contraceptive. TRIAL REGISTRATION NUMBER: NCT03354117.

Evaluation of ovulation and safety outcomes in a multi-center randomized trial of three 84 day ulipristal acetate regimens.

OBJECTIVES: To describe ovulation inhibition and safety of daily oral ulipristal acetate (UPA) over 84 days. STUDY DESIGN: This multi-center phase 1 and/or 2 trial randomized participants to use oral ulipristal 10 mg or 5 mg daily or a 3 cycle regimen of 5 mg for 24 days followed by four placebo days. We stratified randomization by body mass index (BMI) <32 or 32-40 kg/m2. To estimate ovulation inhibition, the primary outcome, participants underwent transvaginal ultrasound and blood sampling twice weekly; we analyzed compliant participants who completed the 84 day study. Safety endpoints included 3 endometrial biopsies and liver chemistry tests. RESULTS: We enrolled 180 participants and included 137 in the ovulation inhibition analyses. Progesterone values that remained below 3ng/mL throughout treatment suggested consistent ovulation inhibition in 52 of 137 (38%) participants; 25 of 47(53%), 20 of 44(45%), and 7 of 46(15%) among participants randomized to the 10 mg, 5 mg, and cyclic treatments, respectively (p < 0.01). Progesterone values consistently <3 ng/mL were more frequent in participants with a BMI > 32kg/m2 (25/50(50%) vs 27/87(31%), p = 0.01). Average ulipristal concentrations were higher among participants with low progesterone concentrations (p < 0.01). Endometrial biopsies during treatment showed progesterone-receptor-modulator-associated endometrial changes in 52 of 164 participants (32%); 22 of 49(40%), 16 of 48(29%), and 14 of 51(26%) in women randomized to the 10 mg, 5 mg, and the cyclic treatments, respectively (p = 0.07, test-for-trend); these changes resolved after treatment cessation. Liver transaminase changes were rare. CONCLUSIONS: Oral ulipristal acetate over 12 weeks did not reliably suppress ovulation, particularly in the 5 mg cyclic-dose group. Ovulation inhibition and endometrial changes were dose dependent. Reversible endometrial changes occurred during treatment. IMPLICATIONS: Progesterone-receptor modulators have been suggested for daily oral contraception. Since progesterone concentrations suggest that ovulation occurred during treatment, further studies would be necessary to assess whether these were functional ovulations and to evaluate other possible mechanisms of contraception.

Evaluation of marketing authorization and clinical implementation of ulipristal acetate for uterine fibroids.

Ulipristal acetate (UPA) is a medical treatment for uterine fibroids and was authorized for surgical pre-treatment in 2012 after the conduct of the PEARL I and II randomized controlled trials and for intermittent treatment after the observational PEARL III and IV trials. However, UPA came into disrepute due to its temporary suspension in 2017 and 2020 because of an apparent association with liver injury. This clinical opinion paper aims to review the process of marketing authorization and implementation of UPA, in order to provide all involved stakeholders with recommendations for the introduction of future drugs. Before marketing authorization, the European Medicines Agency (EMA) states that Phase III registration trials should evaluate relevant outcomes in a representative population, while comparing to gold-standard treatment. This review shows that the representativeness of the study populations in all PEARL trials was limited, surgical outcomes were not evaluated and intermittent treatment was assessed without comparative groups. Implementation into clinical practice was extensive, with 900 000 prescribed treatment cycles in 5 years in Europe and Canada combined. Extremely high costs are involved in developing and evaluating pre-marketing studies in new drugs, influencing trial design and relevance of chosen outcomes, thereby impeding clinical applicability. It is vitally important that the marketing implementation after authorization is regulated in such way that necessary evidence is generated before widespread prescription of a new drug. All stakeholders, from pharmaceutical companies to authorizing bodies, governmental funding bodies and medical professionals should be aware of their role and take responsibility for their part in this process.

The progesterone-receptor modulator, ulipristal acetate, drastically lowers breast cell proliferation.

PURPOSE: The 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. METHODS: Women 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. RESULTS: Twenty-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. CONCLUSION: Ulipristal 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 REGISTRATION: NCT02922127, 4 October 2016.

Antiproliferative, proapoptotic, and tumor-suppressing effects of the novel anticancer agent alsevirone in prostate cancer cells and xenografts.

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. IC50 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 IC50 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.

Hysteroscopic and ultrasonographic evaluation of ulipristal acetate treatment for symptomatic myomas in premenopausal women: a prospective study.

OBJECTIVE: This study aimed to analyze the effects of a six-month therapy with ulipristal acetate (UPA) on myoma size and endometrial thickness in premenopausal women. MATERIAL AND METHODS: Seventy-four women undergoing conservative therapy with UPA were enrolled for this study. All women underwent transvaginal ultrasound evaluation to assess the endometrial thickness, and the number and size of myomas at the beginning and after six months. Hysteroscopy and biopsy were performed after six months, if necessary. RESULTS: After six months of treatment, sonographic examination showed a statistically significant (p < .05) reduction of the size of the largest myoma (56.3 ± 5.1 vs. 31.7 ± 10.1 mm) and a statistically significant (p < .05) increase in endometrial thickness (5.9 ± 2.1 vs. 9.7 ± 3.4 mm). Twenty-two patients with endometrial thickness >10 mm or nonhomogeneous pattern and ten patients with metrorrhagia underwent hysteroscopy: the most frequent finding was the combination of endometrial hypotrophy, floating surface, and chicken-wire vascular pattern aspect (14 cases, 43.7%). Histologic findings showed no case of complex hyperplasia. CONCLUSION: UPA is a safe, effective and assured method to decrease symptoms, reduce the need for surgery in premenopausal women suitable for the treatment.

Nutraceuticals in fibroid management after ulipristal acetate administration: An observational study on patients' compliance.

OBJECTIVE: On May 13, 2020, the Italian government Pharmaceutical Agency (AIFA) stopped ulipristal acetate (UPA) treatments for uterine fibroids (UFs), so patients shifted to other natural treatments. The authors tested the patients' compliance with UF natural treatments. METHODS: Thirty patients of reproductive age (30-45 years) affected by UFs stopped UPA intake and started epigallocatechin gallate (EGCG) plus vitamin D3 treatment. Patients were asked to complete the Uterine Fibroid symptoms and Quality of Life (UFS-QOL) questionnaire, divided into symptoms severity (SS) and health-related quality of life (HRQL), after UPA suspension and to repeat it after 3 months of natural treatment. Collected data were analyzed using paired Student's t test, considering a P value less than 0.05 to be significant. RESULTS: The SS score was significantly lower (-12.19%) for natural treatment when compared with UPA administration. The HRQL score significantly improved (+11.79%) after shifting treatment from UPA to natural therapy. All the investigated parameters appeared improved by 10% after the natural treatment. No adverse effects were reported following the natural treatment. CONCLUSION: Natural treatments showed positive compliance in patients with UFs, based on HRQL score, representing an alternative therapeutic opportunity for patients forced to stop UPA therapy.

Effect of ulipristal acetate on gene expression profile in endometrial cells in culture and in vivo upon post-ovulatory administration in fertile women.

PURPOSE: To analyse the effect of ulipristal acetate (UPA) as emergency contraception (EC) on the gene expression of human endometrial cell line (HEC-1A) and endometrium from fertile women treated with UPA after ovulation. MATERIALS AND METHODS: HEC-1A cells were treated with UPA, and endometrial tissue from four healthy women was collected in cycles before, during and 2 months after post-ovulation pill intake. Ovulation and luteal phase were monitored, and endometrial biopsies were obtained at day LH + 7 in each cycle. In all cases, we analysed the expression profile of 192 genes associated to endometrial receptivity. RESULTS: We observed a significant change in total transcriptomic activity of UPA-treated HEC-1A cells compared to controls. In vivo, we also observed a trend to down-regulation of genes in the UPA-treated cycle that was partially restored in the post-treatment cycle. Altogether, our results supported a partially reversible effect of UPA in gene expression associated with uterine receptivity. CONCLUSIONS: When UPA was administered after ovulation, it seems to induce a down-regulation of the main genes involved in conditioning the endometrium for implantation. This effect is partially restored two months after pill intake. The action of UPA on the endometrium for users of EC should be further investigated.

Dispensing and practice use patterns, facilitators and barriers for uptake of ulipristal acetate emergency contraception in British Columbia: a mixed-methods study.

BACKGROUND: Ulipristal acetate 30 mg became available as prescription-only emergency contraception in British Columbia, Canada, in September 2015, as an addition to over-the-counter levonorgestrel emergency contraception. In this study, we determined dispensing and practice use patterns for ulipristal acetate, as well as facilitators of and barriers to emergency contraception for physicians, pharmacists and patients in BC. METHODS: In the quantitative component of this mixed-methods study, we examined ulipristal acetate use from September 2015 to December 2018 using a database that captures all outpatient prescription dispensations in BC (PharmaNet) and another capturing market sales numbers for all oral emergency contraception in BC (IQVIA). We analyzed the quantitative data descriptively. We conducted semistructured interviews from August to November 2019, exploring barriers and facilitators affecting the use of ulipristal acetate. We performed iterative qualitative data collection and thematic analysis guided by Michie's Theoretical Domains Framework. RESULTS: Over the 3-year study period, 318 patients filled 368 prescriptions for ulipristal acetate. Use of this agent increased between 2015 and 2018. However, levonorgestrel use by sales (range 118 897-129 478 units/yr) was substantially higher than use of ulipristal acetate (range 128-389 units/yr). In the 39 interviews we conducted, from the perspectives of 12 patients, 12 community pharmacists, and 15 prescribers, we identified the following themes and respective theoretical domains as barriers to access: low awareness of ulipristal acetate (knowledge), beliefs and experiences related to shame and stigma (beliefs about consequences), and multiple health system barriers (reinforcement). INTERPRETATION: Use of ulipristal acetate in BC was low compared with use of levonorgestrel emergency contraception; lack of knowledge, beliefs about consequences and health system barriers may be important impediments to expanding use of ulipristal acetate. These findings illuminate potential factors to explain low use of this agent and point to the need for additional strategies to support implementation.