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1.
Eur J Obstet Gynecol Reprod Biol ; 252: 300-302, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32650189

RESUMO

OBJECTIVE: EMA decided that with ulipristal acetate (UPA) treatment for uterine fibroids, should be discontinued due to the associated risk of hepatic failure, We analyzed whether the risk of recurrent symptoms due to fibroids may lead to an increased risk of Covid -19 infection and death, that would exceed the former risk of hepatic failure and transplantation. STUDY DESIGN, SIZE, DURATION: We used a Markov model to generate probabilities. PARTICIPANTS/MATERIALS, SETTING, METHODS: There are currently about 36,250 treated patients in Europe. We estimated bleeding probabilities, while using or discontinuing UPA, which may induce a need of medical or surgical management in symptomatic patients, and increase the risk of acquiring a Covid-19 infection, and die from it. We also estimated the risk of suffering a hepatic failure and hepatic transplantation. MAIN RESULTS AND THE ROLE OF CHANCE: Based on our assumptions, ceasing UPA during a Covid 19 pandemic may be associated with a fatality ratio between 4 and 18, due to the Pandemic, whereas pursuing UPA would be associated with a fatality rate due to the pandemic between 1-2, and an added fatality rate due to hepatic impairment of 1. The added risk of stopping UPA may range between 2 and 15 additional deaths. Our calculations suggest that the decision to stop UPA in the middle of the Covid- 19 pandemic may be untimely, since it may result in an increased risk of Covid-19 infection, due to the recurrence of symptoms and the need for medical and surgical treatment. WIDER IMPLICATIONS OF THE FINDINGS: A decision, like the one EMA took need to be taken in a wider health context of a population, than simply analyzing its role as regulating agent for medications.


Assuntos
Infecções por Coronavirus/mortalidade , Leiomioma/mortalidade , Norpregnadienos/efeitos adversos , Pneumonia Viral/mortalidade , Síndrome de Abstinência a Substâncias/mortalidade , Neoplasias Uterinas/mortalidade , Adulto , Idoso , Betacoronavirus , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/virologia , Infecções por Coronavirus/induzido quimicamente , Feminino , Humanos , Leiomioma/tratamento farmacológico , Leiomioma/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/induzido quimicamente , Medição de Risco , Fatores de Risco , Retirada de Medicamento Baseada em Segurança/estatística & dados numéricos , Síndrome de Abstinência a Substâncias/virologia , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/virologia , Suspensão de Tratamento/estatística & dados numéricos
2.
Fertil Steril ; 113(1): 176-186, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32033718

RESUMO

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.


Assuntos
Anticoncepcionais Femininos/farmacologia , Hormônios Esteroides Gonadais/farmacologia , Antagonistas de Hormônios/farmacologia , Leiomioma/metabolismo , Moléculas de Adesão de Célula Nervosa/biossíntese , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Anticoncepcionais Femininos/uso terapêutico , Método Duplo-Cego , Estradiol/farmacologia , Estradiol/uso terapêutico , Feminino , Proteínas Ligadas por GPI/agonistas , Proteínas Ligadas por GPI/biossíntese , Hormônios Esteroides Gonadais/uso terapêutico , Antagonistas de Hormônios/uso terapêutico , Humanos , Leiomioma/tratamento farmacológico , Leiomioma/patologia , Moléculas de Adesão de Célula Nervosa/agonistas , Norpregnadienos/farmacologia , Norpregnadienos/uso terapêutico
3.
Gynecol Obstet Invest ; 85(2): 178-183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31940645

RESUMO

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.


Assuntos
Contraceptivos Hormonais/administração & dosagem , Histeroscopia/métodos , Leiomioma/terapia , Norpregnadienos/administração & dosagem , Cuidados Pré-Operatórios/métodos , Miomectomia Uterina/métodos , Neoplasias Uterinas/terapia , Adulto , Procedimentos Cirúrgicos Ambulatórios/métodos , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Duração da Cirurgia , Preferência do Paciente , Gravidez , Cuidados Pré-Operatórios/psicologia , Estudos Prospectivos , Resultado do Tratamento
4.
Best Pract Res Clin Obstet Gynaecol ; 63: 111-119, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31362908

RESUMO

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.


Assuntos
Aborto Induzido/métodos , Anticoncepção Pós-Coito , Anticoncepcionais Pós-Coito , Dispositivos Intrauterinos , Levanogestrel/administração & dosagem , Norpregnadienos/administração & dosagem , Aborto Induzido/estatística & dados numéricos , Feminino , Humanos , Gravidez , Gravidez não Planejada
5.
Acta Obstet Gynecol Scand ; 99(1): 89-98, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31468503

RESUMO

INTRODUCTION: Laparoscopic myomectomy can be difficult when fibroids are large and numerous. This may result in extensive intraoperative bleeding and the need for a conversion to a laparotomy. Medical pretreatment prior to surgery might reduce these risks by decreasing fibroid size and vascularization of the fibroid. We compared pretreatment with ulipristal acetate (UPA) vs gonadotropin-releasing hormone agonists (GnRHa) prior to laparoscopic myomectomy on several intra- and postoperative outcomes. MATERIAL AND METHODS: We performed a non-inferiority double-blind randomized controlled trial in nine hospitals in the Netherlands. Women were randomized between daily oral UPA for 12 weeks and single placebo injection or single intramuscular injection with leuprolide acetate and daily placebo tablets for 12 weeks. The primary outcome was intraoperative blood loss. Secondary outcomes were reduction of fibroid volume, suturing time, total surgery time and surgical ease. RESULTS: Thirty women received UPA and 25 women leuprolide acetate. Non-inferiority of UPA regarding intraoperative blood loss was not demonstrated. When pretreated with UPA, median intraoperative blood loss was statistically significantly higher (525 mL [348-1025] vs 280 mL[100-500]; P = 0.011) and suturing time of the first fibroid was statistically significantly longer (40 minutes [28-48] vs 22 minutes [14-33]; P = 0.003) compared with GnRHa. Pretreatment with UPA showed smaller reduction in fibroid volume preoperatively compared with GnRHa (-7.2% [-35.5 to 54.1] vs -38.4% [-71.5 to -19.3]; P = 0.001). Laparoscopic myomectomies in women pretreated with UPA were subjectively judged more difficult than in women pretreated with GnRHa. CONCLUSIONS: Non-inferiority of UPA in terms of intraoperative blood loss could not be established, possibly due to the preliminary termination of the study. Pretreatment with GnRHa was more favorable than UPA in terms of fibroid volume reduction, intraoperative blood loss, hemoglobin drop directly postoperatively, suturing time of the first fibroid and several subjective surgical ease parameters.


Assuntos
Contraceptivos Hormonais/uso terapêutico , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Laparoscopia , Leiomioma/terapia , Norpregnadienos/uso terapêutico , Miomectomia Uterina , Neoplasias Uterinas/terapia , Adulto , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Método Duplo-Cego , Feminino , Humanos , Países Baixos , Duração da Cirurgia , Suturas
7.
Fertil Steril ; 112(6): 1150-1159, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31843092

RESUMO

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.


Assuntos
Antineoplásicos Hormonais/farmacologia , Proteínas Relacionadas à Autofagia/metabolismo , Autofagia/efeitos dos fármacos , Leiomioma/tratamento farmacológico , Norpregnadienos/farmacologia , Neoplasias Uterinas/tratamento farmacológico , Adulto , Feminino , Humanos , Leiomioma/metabolismo , Leiomioma/patologia , Pessoa de Meia-Idade , Transdução de Sinais , Células Tumorais Cultivadas , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
8.
Pak J Pharm Sci ; 32(3 Special): 1419-1422, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31551224

RESUMO

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.


Assuntos
Norpregnadienos/farmacologia , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Reação Acrossômica/efeitos dos fármacos , Adulto , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Contraceptivos Hormonais/farmacologia , Dano ao DNA/efeitos dos fármacos , Humanos , Masculino , Progesterona/farmacologia , Motilidade Espermática/efeitos dos fármacos
9.
Int J Gynaecol Obstet ; 147(3): 339-343, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31502668

RESUMO

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.


Assuntos
Leiomioma/tratamento farmacológico , Norpregnadienos/administração & dosagem , Miomectomia Uterina/estatística & dados numéricos , Neoplasias Uterinas/tratamento farmacológico , Adulto , Bélgica , Feminino , Humanos , Período Pré-Operatório , Estudos Prospectivos , Resultado do Tratamento
10.
Int J Clin Pharm ; 41(6): 1499-1506, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31564041

RESUMO

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.


Assuntos
Serviços Comunitários de Farmácia/estatística & dados numéricos , Anticoncepcionais Orais/provisão & distribução , Anticoncepcionais Pós-Coito/provisão & distribução , Farmacêuticos/estatística & dados numéricos , Serviços Comunitários de Farmácia/organização & administração , Feminino , Alemanha , Pesquisas sobre Serviços de Saúde , Humanos , Levanogestrel/administração & dosagem , Norpregnadienos/administração & dosagem , Farmacêuticos/organização & administração , Papel Profissional , Encaminhamento e Consulta/estatística & dados numéricos
11.
Int J Mol Sci ; 20(13)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284427

RESUMO

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.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Megestrol/farmacologia , Metformina/farmacologia , Norpregnadienos/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Fator de Iniciação 4G em Eucariotos/metabolismo , Feminino , Humanos , Megestrol/química , Metformina/química , Camundongos Nus , Norpregnadienos/química , Fosforilação/efeitos dos fármacos , Receptores de Progesterona/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Gynaecol Obstet ; 146(2): 141-148, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31127621

RESUMO

BACKGROUND: Uterine fibroids cause menorrhagia and adversely affect quality of life. Ulipristal acetate (UPA) can improve fibroid symptoms. OBJECTIVES: To assess the effectiveness of UPA in women with symptomatic uterine fibroids. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, Embase, and CINHAL on December 31, 2018, using relevant search terms. Clinical trials registries were searched for ongoing trials and there were no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing UPA with placebo/no treatment/any pharmacological intervention for symptomatic uterine fibroids. DATA COLLECTION AND ANALYSIS: Two authors independently screened trials, extracted data, and assessed the risk of bias in included studies. We used risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, plus their 95% confidence intervals (CIs). MAIN RESULTS: We identified six RCTs (1121 participants). Five studies (882 participants) compared UPA with placebo. UPA significantly achieved amenorrhea (RR 24.54; 95% CI, 10.82-55.64), reduced blood loss, and improved quality of life with insufficient evidence from RCTs for adverse events. There was insufficient evidence for improved outcomes when UPA was compared with leuprolide acetate. CONCLUSION: Compared with placebo, oral UPA significantly induces amenorrhea, reduces heavy menses, and improves quality-of-life in women with uterine fibroids.


Assuntos
Leiomioma/tratamento farmacológico , Menorragia/tratamento farmacológico , Norpregnadienos/uso terapêutico , Qualidade de Vida , Neoplasias Uterinas/tratamento farmacológico , Adulto , Amenorreia/induzido quimicamente , Feminino , Humanos , Leiomioma/complicações , Menorragia/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Obstet Gynecol ; 133(5): 869-878, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30969201

RESUMO

OBJECTIVE: To investigate effects of ulipristal acetate on health-related quality of life (QOL) and symptom severity in women with symptomatic uterine leiomyomas and abnormal uterine bleeding. METHODS: Women were randomized to ulipristal (5 mg, 10 mg) or placebo in two phase 3, multicenter, double-blind, placebo-controlled trials (VENUS I and II). Health-related QOL and symptom severity were assessed at baseline, and over one (VENUS I and II) and two (VENUS II) 12-week treatment courses using the Uterine Fibroid Symptom Health-Related Quality of Life questionnaire. In pooled VENUS I and II data, change from baseline to the end of the first course for each Uterine Fibroid Symptom Health-Related Quality of Life scale was analyzed, including a Revised Activities subscale that measured physical and social activities. The proportion of women achieving meaningful change in the Symptom Severity (20 or more points), Health-Related QOL Total (20 or more points), and Revised Activities (30 or more points) scales was calculated. In VENUS II data, change from baseline to the end of each course in each scale was analyzed for each treatment arm. RESULTS: In pooled analyses, the intent-to-treat population included 589 patients (placebo, n=169; ulipristal 5 mg, n=215; ulipristal 10 mg, n=205). Significantly greater improvements from baseline in all Uterine Fibroid Symptom Health-Related Quality of Life scales were observed with both ulipristal doses compared with placebo (P<.001). A meaningful change in Revised Activities was achieved by 51 patients receiving placebo (34.9%), compared with 144 (73.5%; OR 5.0 [97.5% CI 2.9-8.6]) and 141 (80.6%; OR 7.9 [97.5% CI 4.3-14.6]) patients receiving ulipristal 5 mg, and 10 mg, respectively. In VENUS II, at end of courses 1 and 2, both ulipristal doses demonstrated significant improvements from baseline compared with placebo for all Uterine Fibroid Symptom Health-Related Quality of Life scales (P<.01). Mean Revised Activities scores showed that beneficial ulipristal effects were maintained in course 2, and improvements occurred on switching to ulipristal; results for other scales were similar. CONCLUSION: Ulipristal was associated with significant improvements in health-related QOL and symptom severity compared with placebo for women with symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02147197 and NCT02147158. FUNDING SOURCE: Allergan plc, Dublin, Ireland.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Leiomioma/tratamento farmacológico , Norpregnadienos/uso terapêutico , Qualidade de Vida , Neoplasias Uterinas/tratamento farmacológico , Administração Oral , Adulto , Antineoplásicos Hormonais/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Leiomioma/psicologia , Norpregnadienos/administração & dosagem , Inquéritos e Questionários , Resultado do Tratamento , Neoplasias Uterinas/psicologia
16.
Gynecol Endocrinol ; 35(9): 756-761, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30822182

RESUMO

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.


Assuntos
Leiomioma/tratamento farmacológico , Menorragia/tratamento farmacológico , Norpregnadienos/administração & dosagem , Qualidade de Vida , Neoplasias Uterinas/tratamento farmacológico , Adulto , Densidade Óssea/efeitos dos fármacos , Esquema de Medicação , Feminino , Humanos , Itália , Leiomioma/complicações , Menorragia/etiologia , Pessoa de Meia-Idade , Resultado do Tratamento , Neoplasias Uterinas/complicações
17.
Recenti Prog Med ; 110(2): 98-99, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30843536

RESUMO

The 19 of February 2018 the Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco) temporary stopped the new administration of Ulipristal Acetate (UPA) for treating uterine leiomyomas symptoms, because liver injury and hepatic failure had been reported in relationship with UPA use. After the European Medicines Agency review of risks of UPA, the 3 of August 2018 the AIFA produced another note, disclosing that a cause-effect relationship between the UPA use and liver injury is not proved and that some patients can be discontinuously treated if surgery is not recommended. However, a close monitoring of hepatic function must be done in Ulipristal users. As Ulipristal has not been prescribed since February 2018 in our center, the rate of surgical operations for uterine leiomyomas significantly doubled. Therefore it will be useful know exactly which restricted indications allow to use UPA for more than 3 months. In this way it could be minimized the risks of liver injury and it could be prevented the rise of surgeries for uterine leiomyomas.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Leiomioma/tratamento farmacológico , Norpregnadienos/administração & dosagem , Neoplasias Uterinas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Feminino , Humanos , Itália , Leiomioma/cirurgia , Testes de Função Hepática , Norpregnadienos/efeitos adversos , Fatores de Tempo , Neoplasias Uterinas/cirurgia
18.
Reprod Biomed Online ; 38(5): 825-834, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30898512

RESUMO

RESEARCH QUESTION: What are the effects of ulipristal acetate (UPA) on the expression of endometrial proliferation and maturation markers? DESIGN: A total of 45 endometrium-containing blocks of hysterectomy samples from non-menopausal women with a diagnosis of moderate to severe symptoms of uterine fibroids: 14 women operated on at the end of a 3-month course of UPA; four women who had discontinued UPA treatment 1-12 months before surgery; 27 control unexposed samples (14 in the proliferative and 13 in the secretory phase). Immunohistochemical staining of Ki67, vascular endothelial growth factor-receptor 2 (VEGFR2), oestradiol receptor, progesterone receptor, interleukin-15 (IL-15), indoleamin-2,3-dioxygenase (IDO) and C-C motif chemokine ligand-2 (CCL2) markers were analysed in both endometrial compartments and layers. RESULTS: Under UPA, oestradiol receptor and progesterone receptor expression is similar to the proliferative phase in both layers, although with a decrease in cell proliferation. IL-15, IDO and CCL2 expressions are similar to the proliferative phase, suggesting a progesterone-antagonist effect of UPA. VEGFR2 staining suggests a trend to a mixed agonist-antagonist effect. No significant difference is observed in the post-UPA proliferative phase group compared with the control group in both layers of the endometrium. CONCLUSION: The effect of 3-month UPA treatment is mostly progesterone receptor antagonist-like. After treatment is discontinued, there are no signs of any long-term effects of this molecule on endometrial proliferation and maturation. Therefore, UPA may be administered to women willing to conceive in the short term without consequences for further implantation.


Assuntos
Contraceptivos Hormonais/farmacologia , Endométrio/efeitos dos fármacos , Leiomioma/tratamento farmacológico , Norpregnadienos/farmacologia , Neoplasias Uterinas/tratamento farmacológico , Adulto , Proliferação de Células/efeitos dos fármacos , Contraceptivos Hormonais/uso terapêutico , Endométrio/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Norpregnadienos/uso terapêutico , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
J Gynecol Obstet Hum Reprod ; 48(9): 781-783, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30898625

RESUMO

Uterine fibroids are the most common form of benign gynaecological tumors in women of childbearing age Piecak et al. (2017) [1]. These uterine fibroids can be responsible for abnormal uterine bleeding, pelvic pain, pelvic pressure and infertility Pritts et al. (2009), Ali and Al-Hendy (2017) [2,3]. Their treatment can be carried out according to several methods: medical treatment, uterine artery embolization or surgery (myomectomy or hysterectomy). Although surgery is the main option, there are medical treatments to reduce their size and decrease and control their symptoms. Ulipristal acetate (UPA) has been the first selective progesterone-receptor modulator approved for the preoperative and long-term treatment for uterine fibroids Ferrero et al. (2018) [4]. Here we present the case of a 38-years-old patient whose large fibroma (initially treated with UPA) totally disappeared after pregnancy.


Assuntos
Leiomioma/terapia , Neoplasias Uterinas/terapia , Adulto , Contraceptivos Hormonais/uso terapêutico , Feminino , Humanos , Leiomioma/diagnóstico por imagem , Imagem por Ressonância Magnética , Norpregnadienos/uso terapêutico , Gravidez , Remissão Espontânea , Neoplasias Uterinas/diagnóstico por imagem
20.
Fertil Steril ; 111(4): 806-815.e1, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30871768

RESUMO

OBJECTIVE: To characterize the effect of ulipristal acetate (UPA) treatment on transforming growth factor (TGF) canonical and noncanonical signaling pathways in uterine leiomyoma tissue and cells. UPA decreased extracellular matrix in surgical specimens; we characterize the mechanism in this study. DESIGN: Laboratory study. SETTING: University. INTERVENTION(S): Exposure of leiomyoma cell lines to UPA. MAIN OUTCOME MEASURE(S): RNAseq was performed on matched myometrium and leiomyoma surgical specimens of placebo- and UPA-treated patients. Changes in gene expression and protein were measured using quantitative polymerase chain reaction and western immunoblot analysis, respectively. RESULT(S): In surgical specimen, mRNA for TGF-ß3 was elevated 3.75-fold and TGFR2 was decreased 0.50-fold in placebo leiomyomas compared with myometrium. Analysis of leiomyomas from UPA-treated women by western blot revealed significant reductions of active TGF-ß3 (0.64 ± 0.12-fold), p-TGFR2 (0.56 ± 0.23-fold), pSmad 2 (0.54 ± 0.04-fold), and pSmad 3 (0.65 ± 0.09-fold) compared with untreated leiomyomas. UPA treatment demonstrated statistically significant reduction in collagen 1, fibronectin, and versican proteins. Notably, there was a statistically significant increase of the extracellular matrix protein fibrillin in leiomyoma treated with UPA (1.48 ± 0.41-fold). Data from in vitro assays with physiologic concentrations of UPA supported the in vivo findings. CONCLUSION(S): TGF-ß pathway is highly up-regulated in leiomyoma and is directly responsible for development of the fibrotic phenotype. UPA attenuates this pathway by reducing TGF-ß3 message and protein expression, resulting in a reduction in TGF-ß canonical signaling. In addition, UPA significantly increased fibrillin protein expression, which can serve to bind inactive TGF-ß complexes. Therefore, UPA inhibits leiomyoma fibrosis by decreasing active TGF-ß3 and diminishing signaling through the canonical pathway. CLINICAL TRIAL REGISTRATION NUMBER: NCT00290251.


Assuntos
Leiomioma/genética , Norpregnadienos/farmacologia , Fator de Crescimento Transformador beta3/genética , Neoplasias Uterinas/genética , Adulto , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leiomioma/metabolismo , Leiomioma/patologia , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Crescimento Transformador beta3/metabolismo , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
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