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.

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.

Selective progesterone receptor blockade prevents BRCA1-associated mouse mammary tumors through modulation of epithelial and stromal genes.

Pharmacological approaches to breast cancer risk-reduction for BRCA1 mutation carriers would provide an alternative to mastectomy. BRCA1-deficiency dysregulates progesterone signaling, promoting tumorigenesis. Selective progesterone receptor (PR) modulators (SPRMs) are therefore candidate prevention agents. However, their efficacy varies in different BRCA1-deficient mouse models. We examined chemopreventive efficacy of telapristone acetate (TPA), ulipristal acetate (UPA) and mifepristone (MFP) in mice with a conditional knockout of the Brca1 C-terminal domain. The SPRMs displayed a spectrum of efficacy: UPA was most effective, TPA less, and MFP ineffective. Compared to no-treatment controls, UPA reduced tumorigenesis (p = 0.04), and increased tumor latency (p = 0.03). In benign mammary glands, UPA decreased Ki67 (p < 0.001) and increased PR expression (p < 0.0001). RNA sequencing analysis revealed distinct gene expression in response to UPA and MFP. UPA downregulated glycolysis and extracellular matrix-inflammation genes (Fn1, Ptgs2, Tgfb2, Tgfb3) whereas MFP downregulated claudin genes and upregulated amino acid metabolism and inflammation genes. The anti-glucocorticoid effects of MFP appeared not to be tumor-protective, while altering estrogen receptor signaling and NF-kB activation. Our study points to an important role of epithelial PR and its paracrine action on the microenvironment in BRCA1-deficient mammary tumorigenesis, and prevention.

Efficacy of ulipristal acetate in women with fibroid induced menorrhagia: A systematic review and meta-analysis.

AIM: To evaluate the efficacy of UPA in women with fibroid induced menorrhagia. METHODS: Embase, MEDLINE, CAB Abstracts, Cochrane Central Register of Controlled Trials, PsychInfo were searched up to 18th May 2020 and updated on 7th February 2021. Randomised controlled trials evaluating the efficacy of UPA in women with fibroid induced menorrhagia were included in the study. RESULTS: Two authors independently reviewed and extracted the study data. Statistical heterogeneity was quantified using I2 statistics. Publication bias and data asymmetry was assessed by funnel plots. A meta-analysis was conducted where appropriate. Six studies were eligible for inclusion. UPA (5 mg and 10 mg) achieved statistically significant amenorrhoeic outcome when compared to placebo (p<0.00001). Increased adverse events (AE) profile was observed in the higher UPA dose, however, did not reach statistical significance. CONCLUSIONS: This review demonstrates the efficacy of UPA in achieving amenorrhoea in women with fibroid induced menorrhagia. However, the favourable dose of UPA remains inconclusive when AE profile is taken into account. Evidence remains obscure regarding liver damage and further research is warranted to attain a conclusive outcome.

Dual agonist-antagonist effect of ulipristal acetate in human endometrium and myometrium.

The aim of this study was to assess the molecular effect of ulipristal acetate (UPA) on gene expression in myometrium and endometrium of patients with symptomatic fibroids. Tissues isolated from four women treated preoperatively with UPA (5 mg) were compared to those from untreated controls using NanoString platform to assess the expression of 75 candidate genes modulated by UPA and ovarian steroids. Deregulated genes were then validated by real-time PCR. In myometrium, UPA exerted an antagonistic effect similar to that observed in fibroids. In UPA-treated endometrium, six genes were identified as highly and significantly upregulated, including matricellular genes CCN1 (54-fold, P = 0.0018) and CCN2 (11-fold, P = 0.00044), Krüppel-like factor 4 (>3-fold, P = 0.0036), and mast cell markers including tryptases TPSAB1/TPSB2 (31-fold, P = 0.023) and carboxypeptidase A (CPA3, 17-fold, P = 0.05). In endometrium, UPA induced the expression of genes involved in fibrogenesis and mast cell function-some of them being widely involved in hepatic injury, which could explain the marked fibrosis and inflammatory cell infiltration observed in explanted livers from patients under UPA treatment.

Glucose and fatty acid metabolism involved in the protective effect of metformin against ulipristal-induced endometrial changes in rats.

Ulipristal acetate (UPA) is effective in the treatment of uterine fibroids. However, its clinical use is hampered by the development of pathologic progesterone receptor modulator-associated endometrial changes (PAECs). The current study was designed to test the hypothesis that UPA-induced PAECs are associated with deranged expression of some metabolic genes. In addition, metformin can mitigate UPA-induced PAECs through modulating the expression of these genes. In the present study, twenty-eight female non-pregnant, nulligravid Wistar rats were treated with UPA (0.1 mg/kg/day, intragastric) and/or metformin (50 mg/kg/day, intragastric) for 8 weeks. Our results demonstrated that co-treatment with metformin significantly reduced UPA-induced PAECs. In addition, co-treatment with metformin and UPA was associated with significant increase in the Bax and significant reduction in Bcl-2, PCNA, Cyclin-D1and ER-α as compared to treatment with UPA alone. Furthermore, treatment with UPA alone was associated with deranged expression of 3-phosphoglycerate dehydrogenase (3-PHGDH), glucose-6-phosphate dehydrogenase (G6PD), transketolase (TKT), fatty acid synthase (FAS) and CD36. Most importantly, co-treatment with metformin markedly reduced UPA-induced altered expression of these metabolic genes in endometrial tissues. In conclusion, UPA-induced PAECs are associated with altered expression of genes involved in cell proliferation, apoptosis, estrogen receptor, glucose metabolism and lipid metabolism. Co-treatment with metformin abrogated UPA-induced PAECs most likely through the modulation of the expression of these genes.

Myostatin inhibitor YK11 as a preventative health supplement for bacterial sepsis.

Muscle wasting caused by catabolic reactions in skeletal muscle is commonly observed in patients with sepsis. Myostatin, a negative regulator of muscle mass, has been reported to be upregulated in diseases associated with muscle atrophy. However, the behavior of myostatin during sepsis is not well understood. Herein, we sought to investigate the expression and regulation of myostatin in skeletal muscle in mice inoculated with gram-negative bacteria. Interestingly, the protein level of myostatin was found to increase in the muscle of septic mice simultaneously with an increase in the levels of follistatin, NF-κΒ, myogenin, MyoD, p- FOXO3a, and p-Smad2. Furthermore, the inhibition of myostatin by YK11 repressed the levels of pro-inflammatory cytokines and organ damage markers in the bloodstream and in the major organs of mice, which originally increased in sepsis; thus, myostatin inhibition by YK11 decreased the mortality rate due to sepsis. The results of this study suggest that YK11 may help revert muscle wasting during sepsis and subdue the inflammatory environment, thereby highlighting its potential as a preventive agent for sepsis-related muscle wasting.

What happens after randomised controlled trials? Uterine fibroids and ulipristal acetate: systematic review and meta-analysis of "real-world" data.

PURPOSE: "Real-world" data incorporates studies performed outside of controlled environments, allowing for a better understanding of the effects of treatment in routine clinical practice. We, therefore, performed a systematic review to summarise available "real-world studies" reporting on the use of ulipristal acetate (UPA) for management of uterine fibroids. METHODS: We designed a prospective protocol according to PRISMA guidelines and registered it with PROSPERO (ID: CRD42019151393). We searched all major databases for relevant citations until 20th September 2019. Our screen included studies for risk of bias using an adapted structured quality assessment tool. Random-effects meta-analysis was used to calculate proportion estimates for each outcome including 95% confidence interval. Reported heterogeneity was assessed using I2. RESULTS: Initial search yielded 755 studies and 13 were included in the final synthesis. Administration of UPA resulted in reduction in the size of fibroids in 56.5% of women, improved menorrhagia in 83% of women, improved perception of pain in 80.1% of women and lead to an improvement in global symptom scores in 85.2% of women. Mean reduction in surgical blood loss and surgical time with use of UPA was 59.85 ml and 12.47 min, respectively. Qualitative analysis suggested that there was no difference in overall surgical experience for patients treated with UPA compared to those without pre-treatment. CONCLUSIONS: Our findings are consistent with previously reported data that UPA is an acceptable management option for women with fibroids. However, it provides limited benefits when used as a pre-operative adjunct, in terms of blood loss and surgical time.

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.

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.

Steroid hormones and hormone antagonists regulate the neural marker neurotrimin in uterine leiomyoma.

OBJECTIVE: To characterize the role of steroid hormone and antihormone exposure on neurotrimin (NTM) expression in human leiomyoma and myometrial tissue and cells. DESIGN: Laboratory study of placebo and ulipristal acetate (UPA)-treated patient tissue. In vitro assessment of immortalized myometrial and leiomyoma cell lines after hormone and antihormone exposure. SETTING: Academic research center. PATIENT(S): Not applicable. INTERVENTIONS(S): Exposure of leiomyoma cell lines to 17ß-E2, medroxyprogesterone acetate (MPA), UPA, and fulvestrant. MAIN OUTCOME MEASURE(S): Messenger RNA expression quantified with the use of RNASeq analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Protein levels quantified by means of Western blot analysis. Immunohistochemistry (IHC) on placebo- and UPA-treated patient uterine tissue specimens. RESULT(S): Expression of NTM in human uterine leiomyoma specimens according to RNASeq was increased compared with myometrium (5.22 ± 0.57-fold), which was confirmed with the use of qRT-PCR (1.95 ± 0.05). Furthermore, NTM protein was elevated in leiomyoma tissue compared with matched myometrium (2.799 ± 0.575). IHC revealed increased staining intensity in leiomyoma surgical specimens compared with matched myometrium of placebo patients. Western blot analysis in immortalized leiomyoma cell lines demonstrated an up-regulation of NTM protein expression (2.4 ± 0.04). Treatment of leiomyoma cell lines with 17ß-E2 yielded a 1.98 ± 0.11-fold increase in NTM protein expression; however, treatment with fulvestrant showed no significant change compared with control. Leiomyoma cell lines demonstrated a 1.91 ± 0.97-fold increase in NTM protein expression after progesterone treatment. RNASeq analysis demonstrated a reduced expression in patient leiomyoma after UPA treatment (0.75 ± 0.14). Treatment of leiomyoma cells with UPA demonstrated a reduced total NTM protein amount (0.54 ± 0.31) in patients, which was confirmed with the use of IHC (UPA10 147.2 ± 9.40, UPA20 182.8 ± 8.98). In vitro studies with UPA treatment revealed a concentration-dependent effect that supported these findings. CONCLUSION(S): NTM, a neural cell adhesion molecule, is increased in leiomyoma compared with myometrium in patient tissue and in vitro models after estrogen and progesterone treatment. Down-regulation of expression occurs after UPA treatment, but not after fulvestrant exposure. CLINICAL TRIAL REGISTRATION NUMBER: NCT00290251.

The Biological Impact of Ulipristal Acetate on Cellular Networks Regulating Uterine Leiomyoma Growth.

Uterine Fibroids (UFs), or leiomyomas, represent the most frequent pelvic tumor in reproductive-aged women. Although of benign origin, UFs decrease fertility and cause significant reproductive dysfunctions. Compared to normal myometrium, UFs are characterized by a clinical and molecular heterogeneity as demonstrated by the presence of multiple genetic alterations and altered signaling pathways. Recently, selective progesteronereceptor modulators (SPRM), as ulipristal acetate (UPA), have demonstrated their clinical benefits by reducing tumor growth and extracellular matrix deposition. For these reasons, UPA is used in the clinical practice as an intermittent treatment for women symptomatic for UFs or, sometimes, before a myomectomy. However, drug effects on signaling pathways frequently upregulated in UFs remain largely unknown. In fact, the mechanisms of action of the UPA on UFs and on the surrounding areas are not yet understood. To learn more about UPA molecular mechanisms, UF samples were treated ex vivo with UPA and profiled for drug effects on selected markers. During this preliminary ex vivo UPA administration, significant changes were observed in the expression levels of proteins related to cell cycle regulation, cytoskeleton remodeling, and drug resistance. The UPA administration reduced cofilin, Erk and Src phosphorylation, p27 and ezrin protein levels, but not Akt phosphorylation and cyclin D1 and ß-catenin levels. This preliminary ex vivo biological analysis provided new insights into the mechanism of action of UPA in the treatment of UFs, which could better explain the biological functioning of the drug on UFs.

Mechanisms involved in the contraceptive effects of ulipristal acetate.

The use of emergency contraception (EC) methods is increasing worldwide as it constitutes an effective way to prevent unplanned pregnancy after unprotected sexual intercourse. During the last decade, ulipristal acetate (UPA), a selective progesterone receptor modulator, has emerged as the most effective EC pill, and it is now recommended as first-line hormonal treatment for EC in several countries. Its principal mechanism of action involves inhibition or delay of follicular rupture, but only when administered during the follicular phase before the luteinizing hormone (LH) peak. However, considering the high efficacy of UPA, it is possible that it also exerts contraceptive effects besides ovulation. In the present review, we summarize and discuss the existing evidence obtained on the effect of UPA on sperm function and post-ovulatory events as potential additional mechanisms to prevent pregnancy. The bulk of evidence collected so far indicates that UPA would not affect gamete function; however, it could impair embryo-uterine interaction. Thus, besides the described effects on ovarian function, UPA contraceptive effectiveness might also be attributed to post-ovulatory effects, depending on the moment of the female cycle in which the drug is administered.

Use of an estradiol-based combined oral contraceptives has no influence on attentional bias or depressive symptoms in healthy women.

Combined oral contraceptive (COC) use is associated with small, albeit significant, increases in mental symptom scores, predominantly irritability, depressed mood, and anxiety. Yet, randomized prospective trials are needed to better characterize the women at risk for COC-induced negative mood change. Thus, the primary aim of this sub-study to a placebo-controlled randomized trial was to determine whether COC use influences emotional interference by negative and positive stimuli. Secondly, we wanted to evaluate what factors would predict depressive symptoms at the end of the trial, taking personality factors, history of mental disorders and other demographic factors into account. Sixty-nine women were included, randomized to three cycles of treatment with a COC (1.5 mg estradiol and 2.5 mg nomegestrolacetate) or placebo. An emotional verbal Stroop task was used to measure interference of emotional stimuli, in which participants were asked to only name the color of a presented word, while ignoring the meaning of the word. Four different word categories were used; neutral, positive, depression, and anxiety. For the second aim of the study, rating on the Montgomery-Åsberg Depression Rating Scale during the final days of the trial was used as outcome. We found no interaction between emotional verbal Stroop word category and treatment, indicating that COC treatment did not evoke any differences in emotional interference to the three word categories. Significant predictors for depressive symptoms at the end of the trial were trait anxiety at baseline and prior adverse mood effects by hormonal contraceptive use. Treatment (i.e. whether women had been treated with the COC or placebo) did not play a role in predicting depression scores at the end of the trial. In conclusion, we found no evidence that combined oral contraceptive use is associated with impaired cognitive-emotional processing. Instead, the main predictors of self-rated depression at the end of the trial were baseline trait anxiety and previous mental symptoms during hormonal contraceptive use.

Autophagy up-regulation by ulipristal acetate as a novel target mechanism in the treatment of uterine leiomyoma: an in vitro study.

OBJECTIVE: To assess the effect of ulipristal acetate (UPA) on the autophagic process of uterine leiomyoma cells. DESIGN: In vitro study in primary cultures of leiomyoma and myometrial cells isolated from biopsy specimen, and gene expression evaluation in biopsy material. SETTING: Cellular pathology laboratory. PATIENT(S): Premenopausal women (without hormonal treatment) undergoing myomectomy or hysterectomy for symptomatic leiomyomas. INTERVENTION(S): Surgical specimens collected from uterine leiomyomas and matched normal myometria. MAIN OUTCOME MEASURE(S): After treatment of myometrial and leiomyoma cells with UPA, autophagy was evaluated by Western blot analysis of the typical biochemical markers, LC3-II, LC3-II:LC3-I ratio, and p62/SQSTM1. The expression level of Atg7 and Atg4D proteins was also assessed by Western blot. RESULT(S): The increase of LC3-II protein, LC3-II:LC3-I ratio, and p62/SQSTM1 protein indicates that UPA treatment up-regulates the autophagic response in leiomyoma cells, whereas these markers were almost unchanged in myometrial cells. Consistently, an increased level of Atg7 and Atg4D proteins was observed only in UPA-treated leiomyoma cells. The autophagic machinery is put into motion selectively in these cells, despite that the basal messenger RNA levels of LC3, SQSTM1, and ATG7 in leiomyoma biopsy specimen were not significantly different from those found in normal myometrial biopsy material. CONCLUSION(S): In vitro UPA treatment stimulates the autophagic response selectively in leiomyoma cells, which adds a novel indication for the clinical use of this selective P receptor (PR) modulator. Autophagy up-regulation may potentially contribute to the leiomyoma shrinkage occurring in UPA-treated patients and warrants further study.

Predictors of uterine fibroid volume reduction under ulipristal acetate: a prospective MRI study.

RESEARCH QUESTION: Can patient and/or uterine fibroid characteristics predict the volume reduction of fibroids under ulipristal acetate (UPA) treatment? DESIGN: This was a monocentric observational prospective cohort study of women with symptomatic fibroids who were willing to undergo surgery after a 3-month treatment of daily 5 mg doses of UPA. Patients underwent magnetic resonance imaging before and after treatment, and the volumes of the three largest fibroids were assessed. The reduction in volume was assessed qualitatively: fibroids decreasing in volume were considered to be 'responsive' to treatment, and fibroids that were stable or increased in volume were considered to be 'non-responsive'. Comparisons were made of patient (age and body mass index) and fibroid (initial volume, number and location) characteristics between fibroids that were responsive and non-responsive to UPA treatment. RESULTS: Fifty-three women were included in the final analysis and 116 fibroids were measured. The initial number and initial volume of the fibroids were statistically associated with the response to UPA treatment (adjusted odds ratio [OR] 0.645, 95% confidence interval [CI] 0.461-0.903, P = 0.0115 for number of fibroids, and adjusted OR 1.447, 95% CI 1.063-1.970, P = 0.0195 for initial volume, with a log-linear relationship). Submucosal fibroids had a higher response rate to treatment (i.e. a decrease in volume) than intramural fibroids (21/25 [84.0%] versus 15/28 [53.6%]; P = 0.0490; adjusted OR 4.478, 95% CI 1.007-19.918). CONCLUSIONS: The location, initial volume and number of fibroids may allow prediction of the outcome of a single 3-month treatment course of daily 5 mg doses of UPA in terms of reduction in volume before surgery.

In vitro effect of ulipristal acetate on human sperm parameters and function.

To observe and investigate the in vitro effect of ulipristal acetate (UPA) on human sperm parameters and function. The 20 patients with normal semen parameters and average age of (32.5±8.5) years old, who were treated in our hospital from January 2018 to August 2018, were selected as research objects. They were subjected to density gradient centrifugation, and then four groups were incubated for about an hour in a culture medium containing different concentrates of ulipristal acetate and the other two groups were set as blank control group and dimethylsulphoxide (DMSO) control group. Indicators including sperm motility, sperm hyperactivation and sperm concentration of free calcium ions of each group were tested. Under the ulipristal acetate concentration of 0.0.4 mol/L, the proportion of sperm damage was increased, the length of tail was increased, and the proportion of sperm hyperactivation was decreased, p<0.05. In addition, the acrosome reaction was inhibited, which significantly reduced the calcium concentration in the sperm, p<0.05. Ulipristal acetate can significantly inhibit acrosome reaction and hyperactivation of sperm in vitro, and can reduce the concentration of calcium ions in sperm, thus causing sperm damage.

Metformin Enhances Nomegestrol Acetate Suppressing Growth of Endometrial Cancer Cells and May Correlate to Downregulating mTOR Activity In Vitro and In Vivo.

This study investigated the effect of a novel progestin and its combination with metformin on the growth of endometrial cancer (EC) cells. Inhibitory effects of four progestins, including nomegestrol acetate (NOMAC), medroxyprogesterone acetate, levonorgestrel, and cyproterone acetate, were evaluated in RL95-2, HEC-1A, and KLE cells using cell counting kit-8 assay. Flow cytometry was performed to detect cell cycle and apoptosis. The activity of Akt (protein kinase B), mTOR (mammalian target of rapamycin) and its downstream substrates 4EBP1 (4E-binding protein 1) and eIF4G (Eukaryotic translation initiation factor 4G) were assayed by Western blotting. Nude mice were used to assess antitumor effects in vivo. NOMAC inhibited the growth of RL95-2 and HEC-1A cells, accompanied by arresting the cell cycle at G0/G1 phase, inducing apoptosis, and markedly down-regulating the level of phosphorylated mTOR/4EBP1/eIF4G in both cell lines (p < 0.05). Metformin significantly increased the inhibitory effect of and apoptosis induced by NOMAC and strengthened the depressive effect of NOMAC on activity of mTOR and its downstream substrates, compared to their treatment alone (p < 0.05). In xenograft tumor tissues, metformin (100 mg/kg) enhanced the suppressive effect of NOMAC (100 mg/kg) on mTOR signaling and increased the average concentration of NOMAC by nearly 1.6 times compared to NOMAC treatment alone. Taken together, NOMAC suppressing the growth of EC cells likely correlates to down-regulating the activity of the mTOR pathway and metformin could strengthen this effect. Our findings open a new window for the selection of progestins in hormone therapy of EC.