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.
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/diagnóstico por imagem , Carcinoma Endometrioide/diagnóstico , Leiomioma/tratamento farmacológico , Leiomioma/diagnóstico por imagem , Norpregnadienos/uso terapêutico , Adenocarcinoma , Receptores de Progesterona , Diagnóstico DiferencialRESUMO
STUDY QUESTION: Does ulipristal acetate (UPA), a selective progesterone receptor modulator used for emergency contraception (EC), interfere with fertilization or early embryo development in vitro and in vivo? SUMMARY ANSWER: At doses similar to those used for EC, UPA does not affect mouse gamete transport, fertilization or embryo development. WHAT IS KNOWN ALREADY: UPA acts as an emergency contraceptive mainly by inhibiting or delaying ovulation. However, there is little information regarding its effects on post-ovulatory events preceding implantation. STUDY DESIGN, SIZE, DURATION: This was an in vitro and in vivo experimental study involving the use of mouse gametes and embryos from at least three animals in each set of experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS: For in vitro fertilization experiments, mouse epididymal spermatozoa capacitated in the presence of different concentrations of UPA (0-1000 ng/ml) were used to inseminate cumulus-intact or cumulus-free eggs in the presence or absence of UPA during gamete co-incubation, and the percentage of fertilized eggs was determined. For in vivo fertilization experiments, superovulated females caged with proven fertile males were injected with UPA (40 mg/kg) or vehicle just before or just after mating and the percentage of fertilized eggs recovered from the ampulla was determined. To investigate the effect of UPA on embryo development, zygotes were recovered from mated females, cultured in the presence of UPA (1000 ng/ml) for 4 days and the progression of embryo development was monitored daily. MAIN RESULTS AND THE ROLE OF CHANCE: In vitro studies revealed that the presence of UPA during capacitation and/or gamete co-incubation does not affect fertilization. Whereas the in vivo administration of UPA at the same time as hCG injection produced a decrease in the number of eggs ovulated compared with controls (vehicle injected animals, P < 0.05), no effects on fertilization were observed when UPA was administered shortly before or after mating. No differences were observed in either the percentage of cleaved embryos or the cleavage speed when UPA was present during in vitro embryo culture. LIMITATIONS, REASONS FOR CAUTION: Considering the ethical and technical limitations inherent to the use of human gametes for fertilization studies, the mouse model was used as an approach for exploring the potential effects of UPA on in vivo sperm transport and fertilization. Nevertheless, the extrapolation of these results to humans requires further investigation. WIDER IMPLICATIONS OF THE FINDINGS: This study presents new evidence on the lack of effect of UPA on gamete interaction and embryo development, providing new insights into the mechanism of action of UPA as an emergency contraceptive method with potential clinical implications. These new findings could contribute to increase the acceptability and proper use of UPA as an emergency contraceptive method. STUDY FUNDING/COMPETING INTERESTS: This study was partially supported by a National Agency of Scientific and Technological Promotion (ANPCyT), Argentina grants PICT 2011-061 to D.J.C. and PICT 2011-2023 to P.S.C. None of the authors has any competing interests to declare.
Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Fertilização in vitro/efeitos dos fármacos , Norpregnadienos/farmacologia , Receptores de Progesterona/efeitos dos fármacos , Interações Espermatozoide-Óvulo/efeitos dos fármacos , Animais , Anticoncepção Pós-Coito , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
La anticoncepción de emergencia se refiere al uso de medicación o a la inserción de un dispositivo intrauterino de cobre para prevenir el embarazo luego de una relación sexual no protegida o del fallo de un método anticonceptivo, en una mujer que no desea el embarazo. De entre las alternativas farmacológicas del método, se estima que el uso de levonorgestrel prevendría el 50% de los embarazos. A partir de una viñeta clínica, en la cual se describe el caso de una paciente obesa que resultó embarazada luego de utilizar anticoncepción hormonal de emergencia tras una relación sexual no protegida, se realizó una búsqueda bibliográfica para establecer la efectividad del método en pacientes con esta característica (obesidad). La búsqueda identificó un metaanálisis que relacionó al triple la probabilidad de embarazo en pacientes con índice de masa corporal superior a 30 kg/m2 que utilizaron anticoncepción de emergencia hormonal. (AU)
Emergency contraception refers to the use of medication or the insertion of a copper intrauterine device to prevent pregnancy after the occurance of unprotected sex intercourse or failure of a contraceptive method in a woman who does not desire pregnancy. Among the pharmacological alternatives of the method it is estimated that the use of levonorgestrel prevents 50% of pregnancies. From a clinical vignette, in which the case of an obese patient who became pregnant using hormonal emergency contraception after unprotected sex intercourse is described, a literature search was conducted to establish the effectiveness of the method in patients with this feature (obesity). The search identified a metaanalysis that shows an incresed probability (threetimes) of pregnancy in patients with body mass index greater than 30 kg/m2 that used hormonal emergency contraception. Emergency contraception is less effective in women with obesity. (AU)
Assuntos
Humanos , Feminino , Gravidez , Adulto , Anticoncepcionais Hormonais Pós-Coito , Anticoncepcionais Sintéticos Pós-Coito , Obesidade/complicações , Gravidez/estatística & dados numéricos , Índice de Massa Corporal , Metanálise como Assunto , Fatores de Risco , Levanogestrel/administração & dosagem , Anticoncepcionais Pós-Coito , Dispositivos Intrauterinos de Cobre/estatística & dados numéricos , NorpregnadienosRESUMO
STUDY QUESTION: Is there a pharmacodynamic interaction between ulipristal acetate (UPA) 30 mg for emergency contraception and a daily progestin-only contraceptive pill, desogestrel (DSG) 0.75 mg, when initiated the next day? SUMMARY ANSWER: In this study, DSG impaired the ability of UPA to delay ovulation, but UPA had little impact on the onset of contraceptive effects due to DSG. WHAT IS KNOWN ALREADY: UPA is a progesterone receptor modulator used for emergency contraceptive (EC) at the dose of 30 mg. UPA delays ovulation by at least 5 days when administered in the mid to late follicular phase. In theory, potent progestins could reactivate progesterone signaling that leads to follicle rupture, thereby impacting the effectiveness of UPA as EC. In addition, UPA could alter the onset of the contraceptive effect of progestin-containing contraceptives started immediately after UPA. STUDY DESIGN, SIZE, DURATION: A single-blind (for observer), placebo-controlled, partial crossover study was conducted in two sites [Dominican Republic (DR) and the Netherlands (NDL)] over 11 months from October 2012 to September 2013. Healthy female volunteers participated in two of the three treatment cycles separated by a washout cycle. Treatment combinations studied were as follows: (i) a single 30 mg dose of UPA followed by 75 µg per day DSG for 20 days, (ii) a single 30 mg dose of UPA followed by 20 days of placebo matching that of DSG (PLB2) or (iii) one tablet of placebo-matching UPA (PLB1) followed by 75 µg per day DSG for 20 days. Participants were randomized to one of the three treatment sequences (UPA + DSG/UPA + PLB2, PLB1 + DSG/UPA + DSG and UPA + PLB2/PLB1 + DSG) when a lead follicle was ≥ 14 to <16 mm diameter on transvaginal ultrasound imaging (TVU). PARTICIPANTS/MATERIAL, SETTING, METHODS: A total of 71 women were included, and 49 were randomized to a first treatment combination of the three period sequences (20 in the DR and 29 in the NDL); 41 of the 49 continued and completed two treatment combinations (20 in the DR and 21 in the NDL). MAIN RESULTS AND THE ROLE OF CHANCE: Initiating DSG treatment the day after UPA significantly reduced the ovulation delaying effect of UPA (P = 0.0054). While ovulation occurred in only one of the 29 UPA-only cycles (3%) in the first 5 days, it occurred in 13 of the 29 (45%) UPA + DSG cycles. LIMITATIONS, REASONS FOR CAUTION: This was a small, descriptive, pharmacodynamic study in which some findings differed by study site. Distinguishing between a cystic corpus luteum and a luteinized unruptured follicle (LUF) by TVU was difficult in some cases; however, the investigators reached consensus, when the study was still blinded, regarding ovulation based on hormone levels and careful review of daily TVU images. WIDER IMPLICATIONS OF THE FINDINGS: Initiating the use of a DSG progestin-only pill (POP) immediately after UPA reduces the ability of UPA to delay ovulation and thus may decrease its efficacy as EC. If starting a DSG POP after using UPA for EC, and possibly any progestin-only method, consideration should be given to delaying for at least 5 days after UPA intake in order to preserve the ovulation delaying effects of UPA.
Assuntos
Anticoncepção Pós-Coito/métodos , Anticoncepcionais Orais Sintéticos/administração & dosagem , Desogestrel/administração & dosagem , Norpregnadienos/uso terapêutico , Ovulação/efeitos dos fármacos , Adolescente , Adulto , Anticoncepcionais Orais Sintéticos/uso terapêutico , Estudos Cross-Over , Desogestrel/uso terapêutico , República Dominicana , Feminino , Humanos , Países Baixos , Estudos Prospectivos , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The days just prior to ovulation are the most crucial for emergency contraception (EC) efficacy. Ulipristal acetate (UPA) and levonorgestrel's (LNG) capacity to inhibit follicular rupture have never been compared directly at this time of the cycle. STUDY DESIGN: Raw data from three pharmacodynamics studies with similar methodology were pooled to allow direct comparison of UPA, LNG and LNG + meloxicam's ability to prevent ovulation when administered orally in the advanced follicular phase, with a leading follicle of ≥ 18 mm. RESULTS: Forty eight LNG-treated (1.5 mg) cycles, 31 LNG (1.5 mg) + meloxicam (15 mg), 34 UPA (30 mg) cycles and 50 placebo cycles were compared. Follicle rupture was delayed for at least 5 days in 14.6%, 38.7%, 58.8% and 4% of the LNG-, LNG + meloxicam-, UPA- and placebo-treated cycles, respectively. UPA was more effective than LNG and placebo in inhibiting follicular rupture (p = .0001), while LNG, when administered at this time of the cycle, was not different than placebo. The addition of meloxicam improved the efficacy of LNG in preventing follicular rupture (p = .0292 vs. LNG; p = .0001 vs. placebo; non-significant vs. UPA). UPA was effective in preventing rupture in the 5 days following treatment, even when administered at the time of the luteinizing hormone (LH) surge (UPA 79%, LNG 14% and placebo 10%). None of the treatments were effective when administered on the day of the LH peak. The median time from treatment to rupture was 6 days during the ulipristal cycles and 2 days in the placebo and LNG/LNG + meloxicam cycles (p = .0015). CONCLUSION: Although no EC treatment is 100% effective in inhibiting follicular rupture when administered in the late follicular phase, UPA is the most effective treatment, delaying ovulation for at least 5 days in 59% of the cycles. LNG is not different from placebo in inhibiting follicular rupture at this advanced phase of the cycle. No treatment was effective in postponing rupture when administered on the day of LH peak.
Assuntos
Anticoncepcionais Hormonais Pós-Coito/farmacologia , Anticoncepcionais Sintéticos Pós-Coito/farmacologia , Levanogestrel/farmacologia , Norpregnadienos/farmacologia , Folículo Ovariano/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Adolescente , Adulto , Chile , Estudos Cross-Over , Inibidores de Ciclo-Oxigenase/farmacologia , República Dominicana , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Luteinização/efeitos dos fármacos , Hormônio Luteinizante/sangue , Meloxicam , Tiazinas/farmacologia , Tiazóis/farmacologia , Adulto JovemRESUMO
OBJECTIVE: Ulipristal acetate (UPA) acts as an emergency contraceptive by inhibiting ovulation. This study explores possible additional effects on the fragmentation of sperm DNA during in vitro incubation. METHODS: Motile spermatozoa from healthy donors were selected by swim-up and incubated under capacitating conditions in control medium or with UPA (1, 10, 100, 1,000 or 10,000 ng/ml). In some experiments, 200 µM of H2O2 were added to induce oxidative stress. The sperm chromatin dispersion test was performed to analyse DNA integrity (400 cells; 1000×). Lipid peroxidation (thiobarbituric acid assay), induced-acrosome reaction (AR) and sperm vitality (Eosin Y) were also evaluated in spermatozoa exposed to UPA and/or H2O2. RESULTS: During sperm incubation, the percentage of fragmented DNA increased significantly, from 15.0 ± 1.3 to 41.0 ± 4.5% (p < 0.001). In the presence of UPA, DNA fragmentation decreased significantly (p < 0.05), in a dose-dependent manner. At 100 and 1000 ng/ml, UPA also counteracted the effect of H2O2 and prevented DNA fragmentation. No effect on sperm vitality, lipid peroxidation or induced-AR was found with any treatment. CONCLUSIONS: During in vitro sperm capacitation DNA fragmentation increased but the latter was counteracted in the presence of UPA, which possibly acted as a scavenger of reactive oxygen species produced by spermatozoa.
Assuntos
Anticoncepcionais Sintéticos Pós-Coito/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Norpregnadienos/farmacologia , Espermatozoides/efeitos dos fármacos , Reação Acrossômica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Peróxido de Hidrogênio/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Oxidantes/farmacologia , Estresse Oxidativo , Espermatozoides/fisiologiaRESUMO
OBJECTIVE: A pill containing ulipristal acetate (UPA) is used for emergency contraception (EC). Considering that, following its intake, spermatozoa may be exposed to UPA in the female genital tract we intended to evaluate sperm functions after incubation with this compound. METHODS: Motile spermatozoa were selected by swim-up and were incubated under capacitating conditions with UPA (at concentrations of 1, 10, 100, 1,000, and 10,000 ng/ml) or control medium. The main outcome measures were sperm vitality, sperm protein tyrosine phosphorylation (TyrP), spontaneous acrosomal reaction (AR), and human follicular fluid (hFF)-induced AR. RESULTS: Sperm vitality and TyrP pattern were similar between spermatozoa exposed to UPA or control. In addition, spontaneous AR ranged from 14.0 ±1.5% to 18.0 ±1.9% after exposure to UPA or control medium without significant differences, and UPA did not prevent hFF-induced AR. CONCLUSIONS: Incubation of sperm with UPA at concentrations around the expected plasma levels after ingestion of this EC pill (Ë100-200 ng/ml) did not modify the signal transduction of TyrP involved in sperm capacitation. Moreover, UPA showed no agonist effect on progesterone receptors because it did not induce AR. Considering that progesterone in hFF is essential for AR induction, and UPA did not prevent the hFF-induced AR, an antagonist action of UPA on the AR is unlikely.
Assuntos
Reação Acrossômica/efeitos dos fármacos , Anticoncepcionais Sintéticos Pós-Coito/farmacologia , Norpregnadienos/farmacologia , Espermatozoides/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Líquido Folicular/fisiologia , Humanos , Técnicas In Vitro , Masculino , Fosforilação/efeitos dos fármacos , Capacitação Espermática/efeitos dos fármacos , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologiaRESUMO
BACKGROUND: Progesterone receptor modulators (PRMs) delivered by contraceptive vaginal rings provide an opportunity for development of an estrogen-free contraceptive that does not require daily oral intake of steroids. The objective of this proof-of-concept study was to determine whether continuous delivery of 600-800 mcg of ulipristal acetate (UPA) from a contraceptive vaginal ring could achieve 80% to 90% inhibition of ovulation. STUDY DESIGN: This was a prospective, controlled, open-labeled, multicenter international trial to examine the effectiveness and safety of this prototype vaginal ring. Thirty-nine healthy women, 21-40 years old and not at risk of pregnancy, were enrolled at three clinic sites. Volunteers participated in a control cycle, a 12-week treatment period and a post-treatment cycle. Pharmacodynamic effects on follicular function and inhibition of ovulation, effects on endometrium, bleeding patterns and serum UPA levels were evaluated. RESULTS: Mean UPA levels during treatment were nearly constant, approximately 5.1 ng/mL throughout the study. Ovulation was documented in 32% of 111 "4-week treatment cycles." A correlation was observed between serum UPA and degree of inhibition of ovarian activity. There was no evidence of hyperplasia of endometrium, but PRM-associated endometrial changes were frequently observed (41%). CONCLUSION: In this study, the minimum effective contraceptive dose was not established. Further studies are required testing higher doses of UPA to attain ovulation suppression in a higher percentage of subjects.
Assuntos
Anticoncepcionais Femininos/farmacologia , Dispositivos Anticoncepcionais Femininos , Endométrio/efeitos dos fármacos , Menstruação/efeitos dos fármacos , Norpregnadienos/farmacologia , Inibição da Ovulação/efeitos dos fármacos , Receptores de Progesterona/antagonistas & inibidores , Adulto , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Anticoncepcionais Femininos/farmacocinética , Dispositivos Anticoncepcionais Femininos/efeitos adversos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Endométrio/citologia , Endométrio/metabolismo , Feminino , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/efeitos adversos , Antagonistas de Hormônios/farmacocinética , Antagonistas de Hormônios/farmacologia , Humanos , Imuno-Histoquímica , Menstruação/sangue , Menstruação/metabolismo , Norpregnadienos/administração & dosagem , Norpregnadienos/efeitos adversos , Norpregnadienos/farmacocinética , Folículo Ovariano/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: Current methods of hormonal emergency contraception (EC) are ineffective in preventing follicular rupture when administered in the advanced pre-ovulatory phase. This study was designed to determine the capacity of ulipristal acetate (UPA), a selective progesterone receptor modulator developed for EC, to block follicular rupture when administered with a follicle of >or=18 mm. METHODS: This was a double-blind, crossover, randomized, placebo-controlled study. Thirty-five women contributed with UPA (30 mg. oral) and a placebo cycle. Serial blood sampling for luteinizing hormone (LH), estradiol and progesterone measurements and follicular monitoring by ultrasound were performed before and for 5 days following treatment. Follicular rupture inhibition was assessed in the overall study population and in subgroups of women stratified by when treatment was administered in relation to LH levels (before the onset of the LH surge, after the onset of the surge but before the LH peak or after the LH peak). RESULTS: Follicular rupture failed to occur for at least 5 days following UPA administration in 20/34 cycles [59%; 95% confidence interval (CI) (40.7-75.4%)], whereas rupture took place in all cycles within 5 days of placebo intake. When UPA was administered before the onset of the LH surge, or after the onset but before the LH peak, follicle rupture had not occurred within 5 days in 8/8 (100%) and 11/14 [78.6%; 95% CI (49.2-95.3)] cycles, respectively. In contrast, when UPA was given after the LH peak, follicle rupture inhibition was only observed in 1/12 [8.3%; 95% CI (0.2-38.5)] cycles. CONCLUSIONS: This study demonstrates that UPA can significantly delay follicular rupture when given immediately before ovulation. This new generation EC compound could possibly prevent pregnancy when administered in the advanced follicular phase, even if LH levels have already begun to rise, a time when levonorgestrel EC is no longer effective in inhibiting ovulation.
Assuntos
Anticoncepção Pós-Coito/métodos , Anticoncepcionais Sintéticos Pós-Coito/uso terapêutico , Fase Folicular/efeitos dos fármacos , Norpregnadienos/administração & dosagem , Norpregnadienos/uso terapêutico , Folículo Ovariano/efeitos dos fármacos , Inibição da Ovulação/efeitos dos fármacos , Adulto , Anticoncepção Pós-Coito/efeitos adversos , Anticoncepcionais Sintéticos Pós-Coito/administração & dosagem , Anticoncepcionais Sintéticos Pós-Coito/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Estradiol/sangue , Feminino , Fase Folicular/sangue , Humanos , Hormônio Luteinizante/sangue , Norpregnadienos/efeitos adversos , Tamanho do Órgão , Folículo Ovariano/anatomia & histologia , Folículo Ovariano/diagnóstico por imagem , Progesterona/sangue , Receptores de Progesterona/antagonistas & inibidores , Estatística como Assunto , Fatores de Tempo , Ultrassonografia , Adulto JovemRESUMO
OBJECTIVE: To compare the effects of continuous 17-beta estradiol-only silastic implants with those of continuous 17-beta estradiol plus continuous nomegestrol acetate silastic implants on symptom control, lipid profile and tolerability in postmenopausal women. METHODS: This was an open-label, parallel-group study. Women with and without uterus and no contraindications to hormone therapy (HT) in this study, we consider as HT the replacement of Estrogens-only and Estrogens + Progestogens Therapy, were enrolled. Each subject was assigned to receive four 17-beta estradiol-only silastic implants (women without uterus), or four 17-beta estradiol plus one nomegestrol acetate silastic implant (women with intact uterus), for 1 year. RESULTS: A total of 40 subjects were enrolled and received, the silastic implants of which 40 (100.0%) subjects completed the study (n = 20, estradiol only; n = 20, estradiol plus nomegestrol acetate). The incidence of postmenopausal symptoms decreased significantly. No significant decreases in total cholesterol (1.3%), low-density lipoprotein cholesterol (1.1%), triglycerides (1.2%) and fasting glucose ((1.3%) serum levels were observed in both groups, whereas high-density lipoprotein (HDL) cholesterol increased significantly (2.8%), during the study in both groups. The incidences of adverse events were similar in both treatment groups. CONCLUSIONS: Women treated with 17-beta estradiol-only silastic implants or 17-beta estradiol plus nomegestrol acetate silastic implants showed significant improvement of postmenopausal symptoms, including urogenital and sexual health symptoms and a significant increase in HDL cholesterol and no significant differences in other lipid profiles and tolerability.
Assuntos
Implantes de Medicamento , Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios/métodos , Lipídeos/sangue , Megestrol/administração & dosagem , Norpregnadienos/administração & dosagem , Derme , Dimetilpolisiloxanos , Quimioterapia Combinada , Dispareunia/tratamento farmacológico , Estradiol/efeitos adversos , Feminino , Fogachos/tratamento farmacológico , Humanos , Megestrol/efeitos adversos , Menstruação/efeitos dos fármacos , Pessoa de Meia-Idade , Norpregnadienos/efeitos adversos , Doenças Vaginais/tratamento farmacológico , Aumento de Peso/efeitos dos fármacosRESUMO
HRA Pharma, under license from the Research Triangle Institute, is developing ulipristal, a progesterone receptor modulator, for the potential use as a contraceptive and an emergency contraceptive, and for the potential treatment of uterine fibroids. Phase II clinical trials for uterine fibroids and phase III trials for contraception are underway. The drug was expected to be launched in the US and Europe in 2009.