RESUMO
OBJECTIVES: To assess pharmacodynamic and pharmacokinetic outcomes of a novel copper (Cu) intrauterine system (IUS) releasing ulipristal acetate (UPA) in healthy women. STUDY DESIGN: In this single-blinded, randomized proof-of-concept study, ovulatory women received one of three Cu-IUSs releasing low-dose UPA (5, 20 or 40 µg/d) for 12 weeks. The study included a baseline cycle, three 4-week treatment-cycles and 2 recovery cycles. Primary outcomes included effects of the IUS on bleeding profile, ovarian function, and the occurrence of progesterone receptor modulator associated endometrial changes (PAEC). Pharmacokinetics and safety profile were secondary outcomes. We compared outcomes in treatment-cycle 3 with baseline, using generalized linear mixed models with orthogonal contrasts. RESULTS: We randomized 29 women (5 µg/d = 10, 20 µg/d = 10, 40 µg/d = 9). All had a successful IUS insertion; 27 completed the 12-week treatment period. Compared to baseline, the mean number of bleeding-only days at treatment-cycle 3 declined by 16.7% in the 5 µg/d group (3.6 vs 3.0, p = 0.66), 40.5% in the 20 µg/d group (4.2 vs 2.5, p = 0.14), and 77% in the 40 µg/d group (3.9 vs 0.9, p = 0.002). Most women reported reduction in the amount of bleeding: 4/8, 8/10, and 7/9 for the 5 µg/d, 20 µg/d, and 40 µg/d groups, respectively. During IUS use, ovulation occurred in most cycles [5 µg/d: 23/24 (96%), 20 µg/d: 26/30 (87%), 40 µg/d: 22/27 (81%)]. The frequency of PAEC at IUS removal was 1/10 (10%), 1/10 (10%) and 4/9 (44%) in the 5 µg/d, 20 µg/d, and 4 0 µg/d groups, respectively. No serious adverse events occurred. CONCLUSIONS: Reduction in bleeding, low incidence of PAEC, and no serious adverse events are reassuring findings of the novel Cu-UPA-IUS. The 20 µg/d seems the lowest dose promoting a favorable bleeding profile and limiting PAEC. IMPLICATIONS: The preliminary results of this short-term study of a novel copper intrauterine system (IUS) delivering ulipristal acetate showed reduction of bleeding, low incidence of progesterone receptor modulator associated endometrial changes, and absence of serious adverse events. By preventing copper-induced increase in bleeding, this IUS could provide a noncontraceptive benefit, especially for women with low hemoglobin.
Assuntos
Anticoncepcionais Femininos , Dispositivos Intrauterinos Medicados , Norpregnadienos , Feminino , Humanos , LevanogestrelRESUMO
INTRODUCTION: Uterine fibroids are frequently encountered in gynecology and are a therapeutic challenge. New therapies, such as ulipristal acetate, could help with symptomatic relief, improve quality of life, and decrease uterine fibroid size. Notwithstanding, there is controversy about adverse effects, especially for hepatotoxicity. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis, and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified nine systematic reviews and included ten studies overall, of which five were randomized trials. We conclude that ulipristal increases the likelihood of amenorrhea, improves the quality of life, and decreases menstrual bleeding. However, there is also a likely increase in the risk of adverse effects. Furthermore, ulipristal could decrease the size of fibroids.
INTRODUCCIÓN: Los miomas uterinos son una patología frecuente en ginecología, que tiene como desafío el enfrentamiento terapéutico. Existen nuevas terapias como el uso de acetato de ulipristal que podrían ayudar con el alivio sintomático y mejoría de la calidad de vida, además de la disminución del tamaño de los miomas uterinos. No obstante, existe controversia respecto a los efectos adversos, especialmente frente a la hepatotoxicidad. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el tamizaje de múltiples fuentes de información, incluyendo MEDLINE/PubMed, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos nueve revisiones sistemáticas que incluyeron diez estudios primarios, de los cuales cinco son ensayos aleatorizados. Concluimos que el uso de ulipristal aumenta la probabilidad de amenorrea, mejora la calidad de vida y disminuye el sangrado menstrual. Además, el uso de ulipristal podría disminuir el tamaño de los miomas. Sin embargo, podría aumentar el riesgo de efectos adversos.
Assuntos
Leiomioma , Norpregnadienos , Neoplasias Uterinas , Feminino , Humanos , Leiomioma/tratamento farmacológico , Norpregnadienos/uso terapêutico , Qualidade de Vida , Revisões Sistemáticas como Assunto , Resultado do Tratamento , Neoplasias Uterinas/tratamento farmacológicoRESUMO
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.
Assuntos
Anticoncepção Pós-Coito , Contraceptivos Hormonais/farmacologia , Norpregnadienos/farmacologia , Oviductos/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Implantação do Embrião/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Humanos , Masculino , Ovulação/efeitos dos fármacos , Espermatozoides/efeitos dos fármacosRESUMO
OBJECTIVE: To assess the efficacy of ulipristal acetate (UPA) for reducing abnormal bleeding among women using the 52-mg levonorgestrel intrauterine system (LNG-IUS). METHODS: A randomized, double-blind, placebo-controlled pilot study conducted from September 1, 2016 to September 30, 2018, at the University of Campinas, Brazil. LNG-IUS users reporting prolonged or frequent uterine bleeding for at least 1 year were randomized to receive 5 mg UPA per day for 5 days or placebo at an identical regimen. Bleeding was recorded for 90 days after treatment began and was compared between the groups. RESULTS: Of 94 eligible women, 64 with abnormal bleeding associated with LNG-IUS use declined treatment or device removal after counselling regarding anticipated bleeding patterns. For the 25 study participants, differences were nonsignificant between the UPA and placebo groups for number of days before bleeding stopped and days free of bleeding; however, UPA users displayed a trend for shorter duration before bleeding stopped and longer time free of bleeding. A similar trend for mean number of bleeding days at 30-, 60-, and 90-day follow-up was observed. CONCLUSION: A nonsignificant trend in reduction of abnormal bleeding was observed among LNG-IUS users taking 5 mg UPA per day for 5 days compared with placebo; however, further research is needed. CLINICALTRIALS.GOV: NCT03186586.
Assuntos
Anticoncepcionais Femininos/efeitos adversos , Dispositivos Intrauterinos Medicados/efeitos adversos , Levanogestrel/efeitos adversos , Norpregnadienos/administração & dosagem , Hemorragia Uterina/tratamento farmacológico , Adulto , Brasil , Anticoncepcionais Femininos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Levanogestrel/administração & dosagem , Projetos Piloto , Hemorragia Uterina/induzido quimicamente , Adulto JovemRESUMO
Ulipristal acetate (UPA) is a selective progesterone receptor modulator used for emergency contraception that has proven to be highly effective in preventing pregnancy when taken up to 120 h after unprotected sexual intercourse. Even though it may act mainly by delaying or inhibiting ovulation, additional effects of UPA on post-fertilization events cannot be excluded. Therefore, the aim of this study was to determine whether a single post-ovulatory dose of UPA could prevent pregnancy using the mouse as a pre-clinical model. Mated females received a single dose of UPA (40 mg/kg) on Day E1.5 or E2.5 (E0.5: copulatory plug detection) and post-fertilization events were evaluated. Our studies revealed that UPA administration produced a significant decrease in the number of conceptuses compared to control. Moreover, UPA-treated females exhibited a lower number of early implantation sites on Day E5.5, despite normal in vivo embryo development and transport to the uterus at E3.5. Administration of UPA produced histological and functional alterations in the uterine horns, i.e., a dyssynchronous growth between endometrial glands and stroma, with non-physiological combination of both fractions compared to controls, and a completely impaired ability to respond to an artificial decidualization stimulus. Altogether, our results show that the administration of a single post-ovulatory dose of UPA impairs mouse pregnancy probably due to an effect on embryo-uterine interaction, supporting additional effects of the drug on post-fertilization events. Although these studies cannot be performed with human samples, our results with the mouse model provide new insights into the mechanism of action of UPA as an emergency contraception method.
Assuntos
Contraceptivos Hormonais/farmacologia , Implantação do Embrião/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Fertilização/fisiologia , Norpregnadienos/farmacologia , Ovário/efeitos dos fármacos , Animais , Anticoncepção Pós-Coito/métodos , Copulação/fisiologia , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Implantação do Embrião/fisiologia , Desenvolvimento Embrionário/fisiologia , Feminino , Humanos , Masculino , Camundongos , Ovário/fisiologia , Ovulação/fisiologia , GravidezRESUMO
In order to get further information on the effects of ulipristal acetate (UPA) upon the process of decidualization of endometrium, a functional analysis of the differentially expressed genes in endometrium (DEG) from UPA treated-versus control-cycles of normal ovulatory women was performed. A list of 1183 endometrial DEG, from a previously published study by our group, was submitted to gene ontology, gene enrichment and ingenuity pathway analyses (IPA). This functional analysis showed that decidualization was a biological process overrepresented. Gene set enrichment analysis identified LIF, PRL, IL15 and STAT3 among the most down-regulated genes within the JAK STAT canonical pathway. IPA showed that decidualization of uterus was a bio-function predicted as inhibited by UPA. The results demonstrated that this selective progesterone receptor modulator, when administered during the periovulatory phase of the menstrual cycle, may affect the molecular mechanisms leading to endometrial decidualization in response to progesterone during the period of maximum embryo receptivity.
Assuntos
Decídua/fisiologia , Endométrio/fisiologia , Ciclo Menstrual/efeitos dos fármacos , Norpregnadienos/administração & dosagem , Norpregnadienos/farmacologia , Ovulação/efeitos dos fármacos , Adulto , Biomarcadores/metabolismo , Biópsia , Decídua/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Acetato de Medroxiprogesterona/farmacologia , Mifepristona/farmacologia , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacosRESUMO
Introducción: Los "Criterios Médicos de Elegibilidad para el Uso de Anticonceptivos" de la Organización Mundial de la Salud (OMS) son una guía para la correcta elección y uso de los métodos anticonceptivos en variadas condiciones de salud. En este documento revisaremos las principales modificaciones en su quinta y última edición publicada en inglés el año 2015. Desarrollo: Las modificaciones de la quinta edición son fundamentalmente la adición de nuevos métodos y la modificación de la categoría de recomendación para algunas condiciones de salud. Se agregan el acetato de medroxiprogesterona de depósito vía subcutánea, el anillo vaginal de progesterona, el implante anticonceptivo subcutáneo sinoimplant(II)® y el método anticonceptivo de emergencia acetato de ulipristal. Se modifican las recomendaciones para las mujeres en lactancia, permitiendo el uso de algunos métodos de progestágeno solo desde el posparto inmediato, salvo el acetato de medroxiprogesterona de depósito por entregar una dosis elevada del esteroide y el dispositivo intrauterino (DIU) con levonorgestrel, el cual sigue las normas de los DIU con cobre. También hay modificación en las recomendaciones en cuanto al uso de anticonceptivos combinados en el puerperio, con más restricciones para mujeres sin lactancia. Por último, sobre el uso de terapia antiretroviral, cambian algunas categorías y se amplía el listado de fármacos detallados. Conclusión: Es necesario que los profesionales de salud conozcan estas modificaciones para poder entregar una atención de calidad a las usuarias de anticoncepción.
Introduction: The "Medical Eligibility Criteria for Contraceptive Use" published by the World Health Organization (WHO) is a guide for the correct choice and use of the contraceptive methods in many different health conditions. In this document we will review the main changes made in the fifth and last edition of this guide published in English in 2015. Development: The modifications of this last edition are the addition of new contraceptive methods and the modification of the category of the recommendation for some health conditions. It adds the medroxiprogesterone acetate subcutaneous injection, the progesterone vaginal ring, the subcutaneous contraceptive implant sinoimplant(II)® and ulipristal acetate as emergency contraception. There are modifications of the recommendations for breastfeeding women, allowing the use of some progestin only methods since the immediate postpartum, with the exception of medroxiprogesterone acetate because it delivers a high dose of the steroid and the levonorgestrel intrauterine device that follows the same recommendations as the copper intrauterine device. There are also modifications in the recommendations for the use of combined contraceptives in the first 42 days postpartum, with more restrictions for non-breastfeeding women. Finally, on the use of antiretroviral therapy drugs, there were changes of some categories and a detailed categorization for each drug. Conclusion: It is necessary for health care providers to know these changes in order to deliver a quality care to contraception users.
Assuntos
Humanos , Feminino , Gravidez , Anticoncepção/métodos , Anticoncepcionais/uso terapêutico , Organização Mundial da Saúde , Aleitamento Materno , Levanogestrel/uso terapêutico , Guias de Prática Clínica como Assunto , Definição da Elegibilidade , Medroxiprogesterona/uso terapêutico , Norpregnadienos/uso terapêuticoRESUMO
OBJECTIVE: Ulispristal acetate (UPA) is a selective progesterone receptor modulator widely used for emergency contraception (EC). The described main mechanism of action is by inhibiting or delaying ovulation; however, the postovulatory effects of the drug are still on debate. Therefore, the aim of this study was to determine whether UPA could interfere with human sperm fertilizing ability. STUDY DESIGN: Human motile spermatozoa were incubated under capacitating conditions with or without UPA, and then used to inseminate human tubal explants, mouse cumulus-oocyte complexes and zona-free hamster eggs. The ability of UPA to interact with human sperm progesterone (P)-binding sites was investigated by incubating the cells with fluorescent-labeled P and analyzing them by fluorescence microscopy. RESULTS: UPA did not affect the ability of human sperm to bind to human tubal tissue explants surface or to penetrate the mouse cumulus mass and the zona-free hamster eggs. In addition, concentrations of UPA much higher than those present in the plasma of EC pill users were required to bind to human sperm P-binding sites. CONCLUSIONS: Our study supports a lack of an agonist or antagonist action of UPA on different functional parameters associated with the fertilizing ability of human sperm. IMPLICATIONS: This study provides new functional evidence supporting that the contraceptive action of UPA is not related to effects on human sperm cells, contributing to a better understanding of the mechanism of action of UPA as EC.
Assuntos
Anticoncepcionais Femininos/farmacologia , Tubas Uterinas/metabolismo , Norpregnadienos/farmacologia , Interações Espermatozoide-Óvulo/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Animais , Sítios de Ligação/efeitos dos fármacos , Anticoncepção Pós-Coito , Cricetinae , Células do Cúmulo/fisiologia , Feminino , Humanos , Masculino , Camundongos , Norpregnadienos/metabolismo , Progesterona/metabolismo , Receptores de Progesterona/efeitos dos fármacosRESUMO
The Medical Eligibility Criteria for Contraceptive Use of the World Health Organization have been updated recently. These criteria constitute a guideline for the selection of family planning methods appropriated for women and men with known medical conditions or personal characteristics of medical relevance. The guidelines last updating incorporates recommendations for the use of a new emergency contraceptive pill and three long-acting hormonal methods, and revises some previously established recommendations. This article provides information on the last edition of such document and aims to contribute to its dissemination.
Assuntos
Anticoncepção/métodos , Guias de Prática Clínica como Assunto , Organização Mundial da Saúde , Anticoncepção/normas , Comportamento Contraceptivo , Anticoncepção Pós-Coito/normas , Anticoncepcionais Femininos , Política de Planejamento Familiar , Feminino , Humanos , Dispositivos Intrauterinos , Contracepção Reversível de Longo Prazo , Masculino , NorpregnadienosRESUMO
Los miomas uterinos son las tumoraciones genitales más frecuentes cuyo tratamiento más habitual es el quirúrgico. Actualmente existe un tratamiento médico eficaz para reducir su volumen y la clínica asociada que es el acetato de ulipristal (AU), que es un modulador selectivo de los receptores de la progesterona. A nivel endometrial puede ocasionar cambios histológicos que cuando son muy marcados plantean dudas diagnósticas. Se presenta el caso de una paciente con útero miomatoso sintomático bajo tratamiento con AU, la histología en las muestras de biopsia planteó el diagnóstico diferencial con adenocarcinoma de endometrio.
Uterine fibroids are the most common genital tumors and the most common treatment is surgery. Actually there is an effective medical treatment to reduce its volume and the symptoms. It is ulipristal acetate (UA), a selective progesterone receptor modulator. In the endometrium it can cause some peculiar histological changes. We present a patient with symptomatic uterine fibroid with UA, and it was difficult to make differential diagnosis with endometrial cancer.