Impact of Regulatory Interventions on Ulipristal Acetate 5 mg (Esmya) Use in Spain: An Interrupted Time-Series Analysis.

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.

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.

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.

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.

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.

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.

Interventions for emergency contraception.

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, I2 = 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, I2 = 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, I2 = 0%, high-quality evidence; RR 0.61, 95% CI 0.45 to 0.83, 27 RCTs, n = 6052, I2 = 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, I2 = 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, I2 = 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, I2 = 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 , I2 = 59%, moderate-quality evidence) or vomiting (RR 0.12, 95% CI 0.07 to 0.20, 3 RCTs, n = 2186, I2 = 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, I2 = 82%, moderate-quality evidence), or vomiting (RR 0.29, 95% CI 0.24 to 0.35, 5 RCTs, n = 3640, I2 = 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, I2 = 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.

Repeated two cycles of ulipristal acetate treatment improve the quality of life in premenopausal women with heavy menstrual bleeding dependent on uterine myomas, without impairment of bone health.

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.

Ulipristal Acetate before Hysteroscopic and Laparoscopic Surgery for Uterine Myomas: Help or Hindrance?

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.

Availability of ulipristal acetate: A secret shopper survey of pharmacies in a metropolitan area on emergency contraception.

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.

Pregnancy Outcomes Following Ulipristal Acetate for Uterine Fibroids: A Systematic Review.

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.

Ultra-performance liquid chromatography-tandem mass spectrometry assay for determination of plasma nomegestrol acetate and estradiol in healthy postmenopausal women.

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 C18 (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 (Rs ) 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.

Treatment continuation and satisfaction in women using combined oral contraception with nomegestrol acetate and oestradiol: a multicentre, prospective cohort study (BOLERO).

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 17ß-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.

Ulipristal acetate for uterine fibroids: 2 years of real world experience in a UK hospital.

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.

Effect of ulipristal acetate and mifepristone at emergency contraception dose on the embryo-endometrial attachment using an in vitro human trophoblastic spheroid and endometrial cell co-culture model.

STUDY QUESTION: Do both ulipristal acetate (UPA) and mifepristone inhibit embryo-endometrial attachment at concentrations corresponding to the emergency contraception (EC) dose? SUMMARY ANSWER: Both UPA and mifepristone at concentrations corresponding to the EC dose do not have an inhibitory effect on embryo implantation, although mifepristone at a higher concentration appeared to have such an effect. WHAT IS KNOWN ALREADY: Levonorgestrel is commonly used for EC, but it only acts through inhibition of ovulation. UPA and mifepristone have higher efficacy as EC compared to levonorgestrel; while there is some suggestion that mifepristone may interfere with implantation, whether UPA has post-ovulatory action in inhibiting implantation is yet to be confirmed. STUDY DESIGN, SIZE, DURATION: An in vitro experimental study using trophoblastic spheroids made from JAr cell line as the embryo surrogate, and the Ishikawa cell line and primary human endometrial cells cultured to monolayer as the endometrial surrogate. The primary endometrial cells were collected from nine volunteer women in the mid-luteal phase with consent. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university gynaecology unit. The JAr and Ishikawa cell lines (or primary endometrial cells) were treated with graded concentrations of UPA (0, 0.04, 0.4 and 4 µM) or mifepristone (0, 0.1, 1 and 10 µM) for 24 h. Embryo-endometrial attachment was studied using an in vitro JAr spheroid-endometrial co-culture model. Expressions of progesterone receptor, ß-catenin and glycogen synthase kinase 3 ß (GSK-3ß) were studied with real-time RT-PCR and Western blotting, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: In the Ishikawa experiments, there was no significant difference in the JAr spheroid attachment rate after treatment with UPA at 0 (93.0%), 0.04 (93.6%), 0.4 (93.4%) and 4 (91.4%) µM concentrations (P > 0.05); the attachment rate was reduced after treatment with mifepristone only at 10 µM (79.8%, P < 0.0001) but not at 0.1 (92.1%) or 1.0 (95.2%) µM concentrations. In the primary endometrial cell experiments, again no significant difference was observed in the JAr spheroid attachment rate after treatment with UPA 4 µM (42.6%) compared to control (46.5%, P > 0.05). Both UPA and mifepristone could significantly up-regulate progesterone receptor expression. There was no significant alteration in expression of ß-catenin and GSK-3ß after treatment with UPA 4 µM or mifepristone 10 µM (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: The co-culture model is only a surrogate which may not fully represent the complicated process of embryo implantation in vivo, although there is no existing perfect model for studying implantation in vitro which fully resembles the latter. WIDER IMPLICATIONS OF THE FINDINGS: The lack of inhibitory effect on embryo implantation by UPA and possibly mifepristone at concentrations corresponding to the EC dose is an important information for contraceptive counseling. STUDY FUNDING/COMPETING INTEREST(S): We had free supply of the UPA compound used in this study from Laboratoire HRA Pharma. This work was supported by a Seed Fund from the Centre of Reproduction, Development and Growth, Faculty of Medicine, The University of Hong Kong, Hong Kong.

Interventions for emergency contraception.

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, I2 = 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, I2 = 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, I2 = 0%, high-quality evidence; RR 0.61, 95% CI 0.45 to 0.83, 27 RCTs, n = 6052, I2 = 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, I2 = 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, I2 = 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, I2 = 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 , I2 = 59%, moderate-quality evidence) or vomiting (RR 0.12, 95% CI 0.07 to 0.20, 3 RCTs, n = 2186, I2 = 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, I2 = 82%, moderate-quality evidence), or vomiting (RR 0.29, 95% CI 0.24 to 0.35, 5 RCTs, n = 3640, I2 = 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, I2 = 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 was 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.

The sexuological impact of hormonal contraceptives based on their route of administration.

Evidence on the effects of hormonal contraceptives on female sexuality is conflicting. We enrolled 556 women, divided into six groups: two composed of subjects using a combined hormonal contraceptive (COC) containing 0.020 ("COC20") and 0.030 ("COC30") mg of ethynyl estradiol (EE), "natural", using COC containing 1.5 mg of estradiol (E2), "ring", using a vaginal ring releasing each day 0.015 mg of EE + 0.120 of etonogestrel, "subcutaneous", using a progestin only subcutaneous contraceptive implant releasing etonogestrel and "controls", using no hormonal contraceptive methods. The subjects were required to answer to the McCoy female sexuality questionnaire and were subjected to a blood test for hormonal evaluation. An ultrasound evaluation of the dorsal clitoral artery was also performed. The higher McCoy sexological value were recorded in the subdermal group; significant differences were recorded among the groups in terms of hormone distribution, with the higher levels of androstenedione in subdermal and control groups. The ultrasound evaluation of dorsal clitoral artery shows a significative correlation between pulsatility and resistance indices and orgasm parameters of McCoy questionnaire. The recorded difference in the sexual and hormonal parameters among the studied hormonal contraceptives may guide toward the personalization of contraceptive choice.

[The molecular mechanisms and morphological manifestations of leiomyoma reduction induced by selective progesterone receptor modulators]. / Molekuliarnye mekhanizmy i morfologicheskie proiavleniia reduktsii leiomiomy pod vozdeistviem selektivnykh moduliatorov retseptorov progesterona.

AIM: to investigate the molecular mechanisms and morphological substrate of reduced uterine leiomyoma in patients receiving the selective progesterone receptor modulator (SPRM) ulipristal acetate for 3 months, by estimating the immunohistochemical expression of the markers steroid receptor coactivator 1 (SRC-1), nuclear receptor corepressor 1 (NCoR-1), ER, PgR, Ki-67, p16, TGF-ß, and VEGF in tumor tissue. SUBJECTS AND METHODS: The investigation enrolled 75 women with uterine leiomyoma, menorrhagias, and anemia. Group 1 included 40 patients who were treated with ulipristal for 3 months, followed by laparoscopic myomectomy. Group 2 consisted of 35 patients who underwent surgery without previous preparation. The intra- and postoperative parameters and molecular and morphological changes in the myomatous nodules were comparatively analyzed in both groups. RESULTS: After 3 months of therapy initiation, menorrhagia completely ceased, myomatous nodules decreased in size (p<0.05), hemoglobin levels were elevated (p<0.01), and total intraoperative blood loss and operative time decreased in all the patients in Group 1. The morphological substrate of partial leiomyoma reduction was leiomyocyte apoptosis and dystrophy, tumor stroma sclerosis and hyalinosis with diminished Ki-67 expression and elevated p16 in the smooth muscle cells, trophic nodular tissue disorders exhibited by vascular wall sclerosis and lower VEGF and TGF-ß expression, and leiomyocyte hormonal reception dysregulation that made itself evident through the reduced expression of SRC-1 with the unchanged expression of PR and ER and the maintained level of NCoR-1. CONCLUSION: The molecular mechanisms of tumor reduction involved the reduced Ki-67 expression and elevated p16, lower VEGF and TGF-ß, diminished SRC-1 expression with the maintained level of PR, ER, and NCoR-1. Overall, this is suggestive of enhanced apoptosis and reduced leiomyoma proliferation and angiogenesis induced by SPRM and indicative of the expediency of using ulipristal acetate as a preoperative agent for organ-sparing surgery in reproductive-aged patients with uterine myoma, menorrhagias, and anemia.

Efficacy of ulipristal acetate for emergency contraception and its effect on the subsequent bleeding pattern when administered before or after ovulation.

STUDY QUESTION: Does ulipristal acetate (UPA) have similar efficacy as emergency contraception (EC) when administered before and after ovulation? SUMMARY ANSWER: The efficacy of UPA-EC was significantly better when administered before than after ovulation. WHAT IS KNOWN ALREADY: Levonorgestrel (LNG) is effective as EC only when administered before, but not after ovulation. LNG EC taken in the pre-ovulatory and post-ovulatory phase results in shortening and lengthening of the index menstrual cycle, respectively. Whether the same applies to UPA is not known. STUDY DESIGN, SIZE, DURATION: Prospective, open-label clinical cohort study conducted on 700 women between May 2011 and March 2014. PARTICIPANTS, SETTING, METHODS: Seven hundred women requesting EC within 120 h after a single act of unprotected sexual intercourse in the index menstrual cycle were recruited at a community family planning clinic in Hong Kong. Each subject received a single oral dose of UPA 30 mg, and 693 of them completed follow-up. Ovulatory status at the time of UPA administration was determined by serum progesterone level supplemented by menstrual history and ultrasound tracking. The main outcome measure was the percentage of pregnancies prevented (PPP). MAIN RESULTS AND THE ROLE OF CHANCE: The PPP was significantly higher in subjects who were pre-ovulatory (77.6%) compared with those who were post-ovulatory (36.4%) at the time of UPA administration (P < 0.0001). The observed pregnancy rate following UPA administration was significantly lower than the expected pregnancy rate only in the pre-ovulatory group (P < 0.0001), but not the post-ovulatory group (P = 0.281). The overall failure rate was 1.7% (1.4 versus 2.1% in the pre- and post-ovulatory groups, respectively). Pre-ovulatory administration of UPA resulted in a small delay (median of 3 days), whereas post-ovulatory administration resulted in a minimal advancement (median of 1 day) of the next menstruation, compared with that predicted from previous menstrual pattern. More pre-ovulatory subjects (19.1%) than post-ovulatory subjects (7.8%) had deviation of the next menses of more than 7 days (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The ovulatory status of the subjects was determined based only on menstrual history and a spot sonographic finding together with serum hormonal profile at the time of recruitment. WIDER IMPLICATIONS OF THE FINDINGS: Our findings confirmed comparable efficacy of UPA in the Asian population as in western populations. The comparison between pre- and post-ovulatory use of UPA is a novel finding, which provides insights to its possible pharmacological action. STUDY FUNDING/COMPETING INTERESTS: The UPA tablets were provided free of charge by Laboratoire HRA Pharma, who were not involved in the design and execution of the study, or the drafting and final approval of the manuscript. The authors have no other conflicts of interest to declare. TRIAL REGISTRATION NUMBER: The University of Hong Kong Clinical Trials Registry (reference number: HKUCTR-1197).