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.

Pilot Data on the Feasibility And Clinical Outcomes of a Nomegestrol Acetate Oral Contraceptive Pill in Women With Premenstrual Dysphoric Disorder.

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.

Management of symptomatic uterine fibroids after ulipristal acetate suspension and identification of high risk patients for surgery at 6-months of follow-up.

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.

Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double-Blind, Placebo-Controlled Phase II Trial.

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 (R2  = 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.

Proteins involved in oxidative stress in leiomyoma tissues treated with ulipristal acetate.

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 two­dimensional gel electrophoresis (2­DE). Western blotting was used to validate the results of 2­DE, 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.

Does Nomegestrol Acetate Plus 17ß-Estradiol Oral Contraceptive Improve Endometriosis-Associated Chronic Pelvic Pain in Women?

Background: To evaluate the effects of a 24/4 regimen combined oral contraceptive (COC) containing 1.5 mg 17ß-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.

The effectiveness of quick starting oral contraception containing nomegestrol acetate and 17-ß estradiol on ovulation inhibition: A randomized controlled trial.

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.

A simplified and reliable LC-tandem mass spectrometry method for determination of ulipristal acetate in human plasma and its application to a pharmacokinetic study in healthy Chinese volunteers.

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 C18 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.

Ulipristal Acetate Before Hysteroscopic Myomectomy: A Systematic Review.

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.

Preoperative Treatment with Ulipristal Acetate before Outpatient Hysteroscopic Myomectomy.

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.

First Impressions Can Be Deceiving: Surgical Outcomes of Laparoscopic Myomectomy in Patients Pretreated with Ulipristal Acetate.

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.

Emergency contraception and impact on abortion rates.

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.

The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits the Activity of the Glucocorticoid Receptor.

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.

A randomized controlled pilot study of ulipristal acetate for abnormal bleeding among women using the 52-mg levonorgestrel intrauterine system.

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.

Differences in fibroid vascularity after three months of pre-treatment with leuprolide acetate or ulipristal acetate: A pilot study.

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 cm3 (IQR 338.0) to 124.8 cm3 (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 cm3 (IQR 271.9) to 140.7 cm3 (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.

EC313-a tissue selective SPRM reduces the growth and proliferation of uterine fibroids in a human uterine fibroid tissue xenograft model.

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.

Trends in dispensing oral emergency contraceptives and safety issues: a survey of German community pharmacists.

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.

Effect on surgical decisions: Ulipristal acetate as key player in Belgian phase IV registration trial.

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.

Does ulipristal acetate emergency contraception (ella®) interfere with implantation?

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.