Analysis of the endometrial transcriptome at the time of implantation in women receiving a single post-ovulatory dose of levonorgestrel or mifepristone

Abstract Background: Levonorgestrel (LNG) is a progesterone receptor agonist used in both regular and emergency hormonal contraception; however, its effects on the endometrium as a contraceptive remain widely unknown and under public debate. Objective: To analyze the effects of LNG or mifepristone (MFP), a progesterone receptor antagonist and also known as RU-486, administered at the time of follicle rupture (FR) on endometrial transcriptome during the receptive period of the menstrual cycle. Methods: Ten volunteers ovulatory women were studied during two menstrual cycles, a control cycle and a consecutively treated cycle; in this last case, women were randomly allocated to two groups of 5 women each, receiving one dose of LNG (1.5 mg) or MFP (50 mg) the day of the FR by ultrasound. Endometrial biopsies were taken 6 days after drug administration and prepared for microarray analysis. Results: Genomic functional analysis in the LNG-treated group showed as activated the bio-functions embryo implantation and decidualization, while these bio-functions in the T-MFP group were predicted as inhibited. Conclusions: The administration of LNG as a hormonal emergency contraceptive resulted in an endometrial gene expression profile associated with receptivity. These results agree on the concept that LNG does not affect endometrial receptivity and/or embryo implantation when used as an emergency contraceptive.

Analysis of the Endometrial Transcriptome at the Time of Implantation in Women Receiving a Single Post-Ovulatory Dose of Levonorgestrel or Mifepristone.

BACKGROUND: Levonorgestrel (LNG) is a progesterone receptor agonist used in both regular and emergency hormonal contraception; however, its effects on the endometrium as a contraceptive remain widely unknown and under public debate. OBJECTIVE: To analyze the effects of LNG or mifepristone (MFP), a progesterone receptor antagonist and also known as RU-486, administered at the time of follicle rupture (FR) on endometrial transcriptome during the receptive period of the menstrual cycle. METHODS: Ten volunteers ovulatory women were studied during two menstrual cycles, a control cycle and a consecutively treated cycle; in this last case, women were randomly allocated to two groups of 5 women each, receiving one dose of LNG (1.5 mg) or MFP (50 mg) the day of the FR by ultrasound. Endometrial biopsies were taken 6 days after drug administration and prepared for microarray analysis. RESULTS: Genomic functional analysis in the LNG-treated group showed as activated the bio-functions embryo implantation and decidualization, while these bio-functions in the T-MFP group were predicted as inhibited. CONCLUSIONS: The administration of LNG as a hormonal emergency contraceptive resulted in an endometrial gene expression profile associated with receptivity. These results agree on the concept that LNG does not affect endometrial receptivity and/or embryo implantation when used as an emergency contraceptive.

[Hormonal (levonorgestrel) emergency contraception--effectiveness and mechanism of action]. / Antykoncepcja dorazna z uyciem lewonorgestrelu--skutecznosc i mechanizm dzialania.

Periodic abstinence and coitus interruptus are the most popular methods of contraception in Poland. Recent studies have provided us with evidence that the so-called "menstrual calendar" may be much less effective than it was believed. In these circumstances, promotion and use of safe and truly effective contraceptives is very important for Polish women. Emergency contraception (EC) is a method which could be used even in cases when other contraception methods have failed. Mechanism of action of levonorgestrel used for EC and possible disturbances in the process of implantation of the blastocyst in the endometrium, remain the source of heated discussion among medical professionals. The latest publications provide us with evidence that the use of levonorgestrel in EC neither alters endometrial receptivity nor impedes implantation. Hormonal EC effectiveness is another hot topic of gynecological endocrinology and statistics. There is, however, no better, safer, and more ethically accepted method of preventing unwanted pregnancy for patients in need of postcoital contraception.

A randomized clinical trial of two emergency contraceptive pill regimens in a Ugandan population.

BACKGROUND: Recent trials on emergency contraception (EC) have indicated that levonorgestrel (LNG) used alone has fewer side-effects and is more efficacious than the Yuzpe regimen (high dose combined oral contraceptive pills). However, the experienced side-effects and acceptability may vary between different groups or societies. OBJECTIVE: The primary objective of this study was to determine side-effects and acceptability of two emergency contraceptive pill (ECP) regimens among users in Kampala, Uganda. STUDY DESIGN: Randomized clinical trial. METHODS: A total of 337 women were enrolled in a double blind randomized clinical trial. Women requesting ECPs within 72 hours after unprotected sexual intercourse received either LNG or the Yuzpe regimen. The women returned for follow-up after three days and a follow-up interview was performed after one year. RESULTS: Levonorgestrel had significantly fewer side-effects than the Yuzpe regimen (p < 0.001). There was a significant association between having worries about the method and experiencing side-effects (p < 0.001). Most women (81%) were prime users of EC. The majority would recommend ECP to other clients. CONCLUSIONS: Levonorgestrel is a superior option to the Yuzpe regimen and should be promoted as the recommended ECP. Having worries about ECP may influence experience of the side-effects. Correct information is critical in promotion of ECP use.

Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis.

BACKGROUND: Emergency contraception can prevent unintended pregnancies, but current methods are only effective if used as soon as possible after sexual intercourse and before ovulation. We compared the efficacy and safety of ulipristal acetate with levonorgestrel for emergency contraception. METHODS: Women with regular menstrual cycles who presented to a participating family planning clinic requesting emergency contraception within 5 days of unprotected sexual intercourse were eligible for enrolment in this randomised, multicentre, non-inferiority trial. 2221 women were randomly assigned to receive a single, supervised dose of 30 mg ulipristal acetate (n=1104) or 1.5 mg levonorgestrel (n=1117) orally. Allocation was by block randomisation stratified by centre and time from unprotected sexual intercourse to treatment, with allocation concealment by identical opaque boxes labelled with a unique treatment number. Participants were masked to treatment assignment whereas investigators were not. Follow-up was done 5-7 days after expected onset of next menses. The primary endpoint was pregnancy rate in women who received emergency contraception within 72 h of unprotected sexual intercourse, with a non-inferiority margin of 1% point difference between groups (limit of 1.6 for odds ratio). Analysis was done on the efficacy-evaluable population, which excluded women lost to follow-up, those aged over 35 years, women with unknown follow-up pregnancy status, and those who had re-enrolled in the study. Additionally, we undertook a meta-analysis of our trial and an earlier study to assess the efficacy of ulipristal acetate compared with levonorgestrel. This trial is registered with ClinicalTrials.gov, number NCT00551616. FINDINGS: In the efficacy-evaluable population, 1696 women received emergency contraception within 72 h of sexual intercourse (ulipristal acetate, n=844; levonorgestrel, n=852). There were 15 pregnancies in the ulipristal acetate group (1.8%, 95% CI 1.0-3.0) and 22 in the levonorgestrel group (2.6%, 1.7-3.9; odds ratio [OR] 0.68, 95% CI 0.35-1.31). In 203 women who received emergency contraception between 72 h and 120 h after sexual intercourse, there were three pregnancies, all of which were in the levonorgestrel group. The most frequent adverse event was headache (ulipristal acetate, 213 events [19.3%] in 1104 women; levonorgestrel, 211 events [18.9%] in 1117 women). Two serious adverse events were judged possibly related to use of emergency contraception; a case of dizziness in the ulipristal acetate group and a molar pregnancy in the levonorgestrel group. In the meta-analysis (0-72 h), there were 22 (1.4%) pregnancies in 1617 women in the ulipristal acetate group and 35 (2.2%) in 1625 women in the levonorgestrel group (OR 0.58, 0.33-0.99; p=0.046). INTERPRETATION: Ulipristal acetate provides women and health-care providers with an effective alternative for emergency contraception that can be used up to 5 days after unprotected sexual intercourse. FUNDING: HRA Pharma.

Les contraceptifs oraux

Les contraceptifs (alias anticonceptionnels) sont des moyens qui empechent la fecondation; ou plus generalement la grossesse. Les raisons de recourir a une contraception sont variees; et les contraceptifs estroprogestatifs oraux font partie des moyens de contraception les plus efficaces pour les femmes (1 a 3). Quelles associations estroprogestatives retenir en priorite ?

Mecanismo de acción del levonorgestrel como anticoncepción de emergencia con principal énfasis en su acción sobre los espermatozoides / Mechanism of action of levonorgestrel as emergency contraception with principal emphasis in its spermatozoa action

A pesar de lo extendido del uso de la anticoncepción de emergencia (AE) con levonorgestrel (LNG) en el mundo, el mecanismo de acción continúa siendo discutido, lo que ha sido aprovechado para que grupos confesionales aaquen su uso, argumentando que la misma es abortiva. Actualmente, dos comprimido de LNG de 0,75 mg hasta 5 días posteriores al coito no protegido, ha sido recomendada y mostrada como eficaz para AE. El mecanismo de acción probablemente depende del momento de la toma en relación al día del ciclo menstrual. Cuando el LNG para AE es administrado antes del período ovulatorio, el mismo inhibe la ovulación en algunas mujeres y afecta el endometrio. Sin embargo la administración de LNG antes de la ruptura folicular no mostró tener influencia sobre la expresión de glicodelina-A en biopsias de endometrio tomadas 24 o 48 horas después de la toma de las píldoras de LNG. Los resultados de los estudios no apoyan la idea de que el LNG como AE causaría un efecto anti-implantatorio. Fue especulado que el LNG podría actuar sobre los espermatozoides. En estudios muy antiguos de la Argentina fue observado que la administración de 0,4 mg de LNG dado 3-10 horas post coito reducía el número de espermatozoides recuperados de la cavidad uterina, causaba alcalinización del fluido intrauterino, inmovilizaba los espermatozoides y aumentaba la viscosidad del moco cervical. Esto llevó a sugerir que la migración espermática a los lugares de fertilización podría esar comprometida después de la ingesta de LNG como AE. Sin embargo, nosotros hemos trabajado sobre esta hipótesis, pero no observamos efectos sobre reacción acrosomal después de la exposición in vitro al LNG de espermatozoides capacitados...

Mecanismo de acción del levonorgestrel como anticoncepción de emergencia con principal énfasis en su acción sobre los espermatozoides / Mechanism of action of levonorgestrel as emergency contraception with principal emphasis in its spermatozoa action

A pesar de lo extendido del uso de la anticoncepción de emergencia (AE) con levonorgestrel (LNG) en el mundo, el mecanismo de acción continúa siendo discutido, lo que ha sido aprovechado para que grupos confesionales aaquen su uso, argumentando que la misma es abortiva. Actualmente, dos comprimido de LNG de 0,75 mg hasta 5 días posteriores al coito no protegido, ha sido recomendada y mostrada como eficaz para AE. El mecanismo de acción probablemente depende del momento de la toma en relación al día del ciclo menstrual. Cuando el LNG para AE es administrado antes del período ovulatorio, el mismo inhibe la ovulación en algunas mujeres y afecta el endometrio. Sin embargo la administración de LNG antes de la ruptura folicular no mostró tener influencia sobre la expresión de glicodelina-A en biopsias de endometrio tomadas 24 o 48 horas después de la toma de las píldoras de LNG. Los resultados de los estudios no apoyan la idea de que el LNG como AE causaría un efecto anti-implantatorio. Fue especulado que el LNG podría actuar sobre los espermatozoides. En estudios muy antiguos de la Argentina fue observado que la administración de 0,4 mg de LNG dado 3-10 horas post coito reducía el número de espermatozoides recuperados de la cavidad uterina, causaba alcalinización del fluido intrauterino, inmovilizaba los espermatozoides y aumentaba la viscosidad del moco cervical. Esto llevó a sugerir que la migración espermática a los lugares de fertilización podría esar comprometida después de la ingesta de LNG como AE. Sin embargo, nosotros hemos trabajado sobre esta hipótesis, pero no observamos efectos sobre reacción acrosomal después de la exposición in vitro al LNG de espermatozoides capacitados...(AU)

Hormonal emergency contraception: a clinical primer.

Unintended and teenage pregnancies are major public health concerns in the United States. Emergency contraception is used to prevent pregnancy after failure of a contraceptive method or after unprotected intercourse. Expanded use of emergency contraception has the potential to reduce unintended pregnancy and induced abortions, while reducing state and federal healthcare expenditures. The recent approval of Plan B as an over-the-counter medication for individuals over 18 years of age should improve access to this medication. However, there are still widespread misconceptions about the mechanisms and implications of emergency contraception. Expanded access to emergency contraception is associated with increased use, but not associated with decreased efficacy, increased sexual risk-taking behavior, or less consistent use of traditional birth control methods. This review is designed to provide clinicians with information regarding the use of emergency contraception for reproductive age patients. It includes a brief description of methods of use, mechanisms of action, and side effect profiles of the most commonly used methods of emergency contraception, levonorgestrel and the Yuzpe method.

Pharmacokinetics and pharmacodynamics of sterylglucoside-modified liposomes for levonorgestrel delivery via nasal route.

For emergency contraceptive, the rapid delivery of levonorgestrel (LNG) to plasma is desirable, furthermore, a sustained delivery of LNG along with rapid absorption will be necessary. The pharmacokinetics and pharmacodynamics of LNG entrapped in different kinds of liposome formulations via nasal administration in rats were evaluated and compared with LNG suspension via the oral route. The relative bioavailabilities of these liposome formulations via nasal administration were 100% or higher than 100%. The Cmax and Tmax values of sterylglucoside (SG) and chitosan-contained formulations by nasal administration were 416.84 ng/mL and 1.02 hr, 227.97 ng/mL and 2.02 hr, respectively, compared with that of 334.94 ng/mL and 1.89 hr of oral suspension. Fully 100% contraception was observed for all the formulations. SG could promote the absorption of LNG via the nasal route and may provide a rapid onset of action of LNG for emergency contraception. Chitosan could retain LNG in the nasal cavity for long contact time to sustain delivery of LNG. The rapid onset and sustained delivery of LNG can be achieved via the nasal route using liposomes as the vehicle.

Contraception for women with epilepsy.

Antiepileptic drugs that induce hepatic enzyme activity may alter the metabolism of most hormonal methods of contraception, and this affects the contraceptive regime. This effect should be considered in the choice of both the treatment of the epilepsy and the choice of contraceptive method. This review considers these interactions and offers advice about their management.

Characteristics of women seeking emergency contraception in general practice.

The aim of this study was to profile the users of emergency contraception (EC) attending general practices and a general practice out-of-hours co-operative service using a pre-piloted questionnaire. Questionnaires were offered to 171 women and completed by 144 (84.2%). Mean age was 24.4 years (Standard Deviation = 6.7, range 14 to 51). Most were single, 116 (80.6%). Those who had no regular partner at the time of seeking EC were more likely to have > or =6 lifetime sexual partners than those in stable relationships (OR: 3.5; CI: 1.14-10.86, p < 0.03). At the time of seeking EC 121 (84.0%) were using some method of contraception. Ninety-three (64.6%) presented within 24 hours of sexual intercourse. Concerns about condoms were the commonest reason for seeking EC. For 55 (38.2%) this was their first time to use EC. Thirty-three (22.9%) were drunk at the time of intercourse.

Emergency contraception.

Teen birth rates in the United States have declined during the last decade but remain much higher than rates in other developed countries. Reduction of unintended pregnancy during adolescence and the associated negative consequences of early pregnancy and early childbearing remain public health concerns. Emergency contraception has the potential to significantly reduce teen-pregnancy rates. This policy statement provides pediatricians with a review of emergency contraception, including a definition of emergency contraception, formulations and potential adverse effects, efficacy and mechanisms of action, typical use, and safety issues, including contraindications. This review includes teens' and young adults' reported knowledge and attitudes about hormonal emergency contraception and issues of access and availability. The American Academy of Pediatrics, as well as other professional organizations, supports over-the-counter availability of emergency contraception. In previous publications, the American Academy of Pediatrics has addressed the issues of adolescent pregnancy and other methods of contraception.

Are women ready for more liberal delivery of emergency contraceptive pills?

OBJECTIVE: To investigate the knowledge, use and attitudes towards emergency contraception (EC) among women attending family planning clinics. DESIGN: Self-administered questionnaire survey. SETTINGS: Eight birth control clinics and three youth health care centers of The Family Planning Association of Hong Kong. SUBJECTS: A total of 2454 women aged 15 to 53 attending the clinics between 1 November 2003 and 13 December 2003 were recruited. RESULTS: A total of 1405 completed questionnaires were analyzed. 63.7% of women had heard of EC and 51.8% knew that they had to take it within 72 h. 15.7% had used EC before. More advertising on EC was considered desirable by 46.3% of subjects. 48.7% of subjects supported advanced provision of emergency contraceptive pills (ECPs) and 25.7% supported over-the-counter sales. CONCLUSION: The awareness and use of EC were low in our study population. They were not ready for more liberal delivery of ECPs as less than 50% of women supported these new delivery modes and their knowledge on ECPs use was inadequate.

A national study examining the effect of making emergency hormonal contraception available without prescription.

BACKGROUND: In January 2001, emergency hormonal contraception was made available for women over the age of 16 years directly from a pharmacist without prescription. It is of interest whether this change in the UK has led to any improvements or deterioration in the service provided for the women who need it. METHODS: Self- completed, anonymous questionnaires were distributed to women requesting emergency hormonal contraception through a single group of pharmacies located throughout England, Wales and Scotland. RESULTS: A total 419 women returned completed questionnaires. A greater proportion of women were able to take emergency contraception within 24 h when they obtained their tablets directly from a pharmacy without a prescription (64% versus 46%, P = 0.029). Women who obtained their drugs directly from the pharmacist were just as well informed, just as likely to arrange regular follow-up and generally preferred this system, although they disliked having to pay. CONCLUSION: Making emergency hormonal contraception available without prescription has improved services to women who need them, but these improvements are quantitatively minimal, preventing only five additional pregnancies per 10,000 users.