Surrogate post-coital testing for contraceptive efficacy against human sperm activity in the ovine vaginal model†.

High unintended pregnancy rates are partially due to lack of effective nonhormonal contraceptives; development of safe, effective topical vaginal methods will address this need. Preclinical product safety and efficacy assessment requires in vivo testing in appropriate models. The sheep is a good model for the evaluation of vaginally delivered products due to its close similarities to humans. The study objective was to develop an ovine model for efficacy testing of female nonhormonal contraceptives that target human sperm. Fresh human semen was pooled from male volunteers. Nonpregnant female Merino sheep were treated with control or vaginal contraceptive product (IgG antibody with action against sperm or nonoxynol-9 [N9]). Pooled semen was added to the sheep vagina and mixed with product and vaginal secretions. Microscopic assessment of samples was performed immediately and progressive motility (PM) of sperm was compared between treatments. Cytokines CXCL8 and IL1B were assessed in vaginal fluid after instillation of human semen. No adverse reactions or elevations in proinflammatory cytokines occurred in response to human semen. N9 produced signs of acute cellular toxicity while there were no cellular changes after IgG treatment. N9 and IgG had dose-related effects with the highest dose achieving complete sperm immobilization (no sperm with PM). Surrogate post-coital testing of vaginally administered contraceptives that target human semen was developed in an ovine model established for vaginal product preclinical testing. This expanded model can aid the development of much needed nonhormonal topical vaginal contraceptives, providing opportunities for rapid iterative drug development prior to costly, time-intensive human testing.

TRPV4 is involved in levonorgestrel-induced reduction in oviduct ciliary beating.

Previous studies revealed the increasing risk of tubal pregnancy following failure of levonorgestrel (LNG)-induced emergency contraception, which was attributed to the reduced ciliary motility in response to LNG. However, understanding of the mechanism of LNG-induced reduction in the ciliary beat frequency (CBF) is limited. The transient receptor potential vanilloid (TRPV) 4 channel is located widely in the female reproductive tract and generates an influx of Ca2+ following its activation under normal physiological conditions, which regulates the CBF. The present study aimed to explore whether LNG reduced the CBF in the Fallopian tubes by modulating TRPV4 channels, leading to embryo retention in the Fallopian tubes and subsequent tubal pregnancy. The study provided evidence that the expression of TRPV4 was downregulated in the Fallopian tubes among patients with tubal pregnancy and negatively correlated with the serum level of progesterone. LNG downregulated the expression of TRPV4, limiting the calcium influx to reduce the CBF in mouse oviducts. Furthermore, the distribution of ciliated cells and the morphology of cilia did not change following the administration of LNG. LNG-induced reduction in the CBF and embryo retention in the Fallopian tubes and in mouse oviducts were partially reversed by the progesterone receptor antagonist RU486 or the TRPV4 agonist 4α-phorbol 12,13-didecanoate (4α-PDD). The results indicated that LNG could downregulate the expression of TRPV4 to reduce the CBF in both humans and mice, suggesting the possible mechanism of tubal pregnancy. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

UPA and LNG in emergency contraception: the information by EMA and the scientific evidences indicate a prevalent anti-implantation effect.

RATIONALE AND OBJECTIVES: Emergency contraceptives pills (ECPs) are described as drugs that work by either inhibiting or delaying ovulation without affecting implantation. In our opinion, as we aim at demonstrating, both EMA documents and the experimental papers indicate that they prevalently inhibit embryo-implantation. LNG-ECPs: literature: LNG-ECPs never prevent ovulation when are taken in the most fertile days (EMA-EPAR on ellaOne® p. 9, first table). Conversely, they prevent the formation of an adequate corpus luteum. When they are taken pre-ovulatory ovulations occur regularly, but pregnancies do not appear. Taken after ovulation, they seem ineffective in preventing pregnancies. UPA-ECPs: literature: EllaOne® prevents ovulation only when is taken in the first fertile day. Thereafter, its anti-ovulatory effect drops sharply and becomes insignificant (8%) 36 h before ovulation, in the most fertile days (Brache); its decreasing anti-ovulatory effect cannot explain a consistently high effectiveness in preventing pregnancies (≥80%) that does not decrease depending on which of the 5 d it is taken after unprotected intercourse. Besides, ovulation occurs regularly in 91.7% of women taking ellaOne® weekly, for eight consecutive weeks (EMA-CHMP-Assessment Report 'EMA/73099/2015': study HRA2914-554, p. 7). Lastly, Lira-Albarrán administered ellaOne® to women in the most fertile pre-ovulatory days: they had normal ovulation, but their endometrium, evaluated through samples obtained in the implantation window, became inhospitable: the expression of 1183 genes was exactly the opposite of that observed in the receptive pro-gestational endometrium. This agrees with information by EMA-CHMP-Assessment Report 'EMEA/261787/2009' (p. 8): after UPA administration 'the proteins necessary to begin and maintain pregnancy are not synthesized'. CONCLUSIONS: Emergency Contraceptives work prevalently by preventing embryo-implantation. People shall receive correct information.

Combined oral contraceptive interference with the ability of ulipristal acetate to delay ovulation: A prospective cohort study.

OBJECTIVE: To determine if a combined oral contraceptive (COC) initiated shortly after ulipristal acetate (UPA) administration interferes with its mechanism of action. STUDY DESIGN: Healthy, reproductive-age women of normal BMI with proven ovulation (serum progesterone >3 ng/ml) were enrolled for three cycles (Cycle 1, UPA only; Cycle 2 washout; Cycle 3 UPA plus COC). During Cycles 1 and 3, subjects were monitored with transvaginal ultrasound and blood sampling for progesterone and LH every other day until a dominant follicle measuring >15 mm was visualized. In both treatment cycles, subjects received UPA (30mg) and were followed daily with similar monitoring for up to 7 days. In Cycle 3 only, subjects initiated a daily COC (0.15 mg levonorgestrel/30 µg ethinyl estradiol) 2 days after UPA. The study had 80% power to detect a 15% difference in the proportion of cycles with at least a 5-day delay in follicle rupture. We assessed follicle rupture as >50% decrease in mean size and adjudicated unclear outcomes with serum hormones. RESULTS: A total of 36 women enrolled and 33 completed all study procedures [age 28.4 years (SD 3.9); BMI 23.4 (SD 2.4)]. Compared to Cycle 1, more subjects demonstrated evidence of follicle rupture in <5 days in Cycle 3 [1/33 (3%) vs. 9/33 (27%), p = .008]. We also included data from 2 subjects who experienced rupture prior to COC dosing in the analysis. CONCLUSION: UPA's effectiveness is significantly reduced by administering COCs 2 days later. IMPLICATIONS: This study demonstrates that UPA's efficacy as an emergency contraceptive is reduced with early exposure to COCs.

[How Does Advance Provision of Emergency Contraceptives Affect Contraceptive Use and Sexual Activity Among Adolescents? Systematic Review and Meta-Analysis].

PURPOSE: The purpose of this study was to analyze the effect of emergency contraceptive pill on adolescent sexuality and contraceptive behaviors through a meta - analysis of intervention studies on advance provision of emergency contraceptives. This study aimed to provide objective data on the transition of general medicines to be discussed in relation to the reclassification of emergency contraceptive pills. METHODS: Using electronic database, 1,820 studies written in Korean or English without limitation of the year were reviewed and for analysis, 5 studies were selected, in which emergency contraceptives were provided to adolescents. RESULTS: The advance provision of emergency contraceptives has increased their use and shortened the time it takes to take contraceptive pills after unprotected sex. There was no change in the frequency of engaging in sexual intercourse and unprotected sex or in existing contraceptive behavior, pregnancy rates decreased, but there was no increase in sexually transmitted infection. CONCLUSION: The results of this study provide objective grounds for the reclassification of emergency contraceptive pills and propose effective interventional programs on contraceptive education, such as on efficacy and side effects of the contraceptive drug and its proper use among the youth who engage in sexual activity, to improve their reproductive health.

Characterization of Molecular Changes in Endometrium Associated With Chronic Use of Progesterone Receptor Modulators: Ulipristal Acetate Versus Mifepristone.

Ulipristal acetate (UPA) is a selective progesterone receptor modulator (PRM), which is used as an emergency contraceptive in women. Recent studies demonstrated the efficacy of an UPA contraceptive vaginal ring (UPA-CVR) as a blocker of ovulation. However, the endometrium of women exposed to UPA over a 6-month period display glandular changes, termed PRM-associated endometrial changes (PAECs). We, therefore, investigated whether UPA-induced PAECs are associated with altered expression of the transcription factor heart- and neural crest derivatives-expressed protein 2 (HAND2) whose downregulation is observed in endometrial epithelial hyperplasia and cancer. Our results showed that while exposure to mifepristone, a well-known PRM, leads to suppression of endometrial HAND2 expression, long-term exposure to UPA-CVR did not cause downregulation of this marker. Further studies, using human primary endometrial stromal cells, confirmed that whereas mifepristone-mediated suppression of HAND2 elevated the levels of its downstream target fibroblast growth factor 18, UPA did not significantly alter the expression of this growth factor. A rationale for the differential regulation of HAND2 by these PRMs was provided by our observation that mifepristone-bound progesterone receptors turn over at a faster rate than those bound to UPA. Collectively, these results support the selective effects of different PRMs and indicate that chronic exposure to UPA does not alter the HAND2 pathway whose dysregulation is linked to complex atypical endometrial hyperplasia and cancer. The results from this study involving a limited number of clinical samples should pave the way for a larger study to determine the safety of UPA for long-term use.

Controversias sobre el mecanismo del levonorgestrel postcoital: pruebas a partir de la disminución de embarazos / Controversies about the mechanism of postcoital levonorgestrel: evidences according to the decrease of pregnancies

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Effect of arteether and pyrimethamine coadministration on the pharmacokinetic and pharmacodynamic profile of ormeloxifene.

The study was intended to investigate the effect of concomitant administration of antimalarial drug (pyrimethamine or arteether) on pharmacokinetic and post coitus contraceptive efficacy of ormeloxifene in female Sprague-Dawley rats. A serial sampling technique coupled with LC-MS/MS detection was utilized for quantification of ormeloxifene in plasma samples collected from female rats treated with ormeloxifene only and ormeloxifene with pyrimethamine or arteether. Coitus-proven female rats were utilized to investigate the effect of pyrimethamine or arteether coadministration on contraceptive efficacy of ormeloxifene by investigating the presence or absence of implantations and status of corpora lutea on day 10 post coitum. None of the sperm-positive rats treated with ormeloxifene with or without coadministration of pyrimethamine or arteether showed any sign of pregnancy, confirming that concomitant administration of antimalarial drugs (pyrimethamine or arteether) did not affect the pharmacodynamic profile of ormeloxifene. Although there was no sign of pharmacodynamic interaction, the volume of distribution of ormeloxifene increased significantly on cotreatment with pyrimethamine. However, coadministration of arteether did not affect any of the pharmacokinetic parameters of ormeloxifene. The compiled results of preliminary study in female rats support that pyrimethamine or arteether can be prescribed with ormeloxifene.

Non-prescription dispensing of emergency oral contraceptives: recommendations from the German Federal Chamber of Pharmacists [Bundesapothekerkammer]

Background: Emergency hormonal contraceptives (EHC) are contraceptives used to prevent unintended pregnancy following unprotected sexual intercourse (USI) or contraceptive failure. The EHCs available without a prescription include medicines containing levonorgestrel (LNG) in more than 80 countries and, recently, based on an EU-switch ellaOne®, which contains ulipristal acetate (UPA). EHCs work by stopping or delaying ovulation. Those containing LNG can be used up to 72 hours after USI or contraceptive failure, while UPA can be used up to 120 hours. In the context of the UPA implementation process, Germany switched LNG to non-prescription status as well. Objectives: To develop recommendations, a protocol, and a continuing education program for pharmacists to assure quality when giving advice and dispensing EHCs in community pharmacies without a medical prescription. Methods: The recommendations were developed by an iterative process of drafting, recognizing, and discussing comments and proposals for amendments as well a seeking agreement with a number of stakeholders such as the Federal Ministry of Health (BMG), Federal Institute for Drugs and Medical Devices (BfArM), Federal Chamber of Physicians (BÄK), Drug Commission of German Physicians (AkdÄ), professional organizations/associations of gynaecologists, pharmaceutical OTC-industry as well as government-controlled, private, and church-based organizations and centres providing advice on sex education and family planning. Results: The recommendations were eventually endorsed by the BMG in consultation with the BfArM. Conclusions: The recommendations were made public, published in the professional journal and used in an uncounted number of continuing education programs based on the curriculum and provided by the State Chambers of Pharmacists (AU)

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Emergency contraception: which is the best?

INTRODUCTION: Emergency contraception is a safe and effective method to prevent an unwanted pregnancy after an unprotected or inadequately protected sexual intercourse. Several methods for emergency contraception (EC) are currently registered in many countries for use in an emergency to prevent a pregnancy following an unprotected, possibly fertile intercourse or after a contraceptive accident like condom rupture. Different methods have varying modes of action, time frame of efficacy, dosage schedule and unwanted effects. Since several methods are available it is important to decide the best method. EVIDENCE ACQUISITION: In this article the available literature on emergency contraception has been reviewed and an attempt has been made to discuss the need for emergency contraception and compare different options for emergency contraception in terms of their efficacy in pregnancy prevention, their safety profile and unwanted side effects. EC repeated use and initiating a regular method after EC use are also discussed. EVIDENCE SYNTHESIS: Emergency contraceptive methods include copper Intra-uterine devices (IUD) and different types of pills like estrogen progestin combination pill (Yuzpe Regimen), Progestin only pill (LNG), antiprogestin pill (Mifepristone), and progesterone modulator Uripristal Acetate (UPA). There is a marginal difference in the mechanism of action, efficacy including time frame and ability to protect from pregnancy with regular doses in obese women, drug interactions and side effects. These are discussed in detail. CONCLUSIONS: Copper IUD is the most effective emergency contraceptive with advantage of providing continued contraception. However, it cannot be used universally due to lack of infrastructure and a trained provider as well as not being suitable option for women at risk of sexually transmitted infections. Amongst different pills LNG is more effective with fewer side effects than Yuzpe regimen. LNG and UPA are comparable with similar efficacy and side effect profile. UPA has a wider window of efficacy, in LNG efficacy declines after 72 hours. UPA is more suitable for obese women. Mifepristone is effective but is registered as EC pill only in few countries and use is limited as it is also used as an abortion pill. Yuzpe regimen is the least effective of all contraceptive pills as EC, and works only till 72 hours of unprotected sex, but is useful in places where dedicated methods are not available, as it is easily accessible. Any combined pill can be used in this regimen except triphasic pill.

EMERGENCY CONTRACEPTION: AN OVERVIEW AMONG USERS.

BACKGROUND: Emergency contraception Pills (ECP) provides a safe and effective means of post coital treatment and prevents at least 75% of expected pregnancies resulting from unprotected intercourse. The purpose of the study was to assess the awareness regarding emergency contraception and to see the knowledge attitude and preference about emergency contraception. METHODS: This was a descriptive cross sectional study carried out at Combined Military Hospital (CMH) Khuzdar. A total of 200 married women of reproductive age group who agreed to participate in the study were interviewed using a self-reported comprehensive, structured closed ended questionnaire. RESULTS: 77% of the women were practicing some contraceptive method at the time of study. Most were using condoms for contraception. 16% of all respondents have never used any contraceptive in their life. 70% believe that religion of Islam is not a barrier in family planning. Only 7.5% of the women were aware about ECP. CONCLUSION: Knowledge about ECP is poor among the women of child bearing age. There is a room for improvement regarding the awareness and use of ECP which can contribute to prevention of unwanted pregnancies.

Ulipristal Acetate Antagonizes the Inhibitory Effect of Progesterone on Ciliary Beat Frequency and Upregulates Steroid Receptor Expression Levels in Human Fallopian Tubes.

Ulipristal acetate (UPA) is a new selective progesterone receptor (PR) modulator used for emergency contraception. However, our understanding of its mechanisms of action on oviductal cilia is limited. The present study focused on the in vitro effects of UPA (0.1, 1, and 10 µmol/L) on the cilia and steroid receptors of human fallopian tubes. The ciliary beat frequency (CBF), the ultrastructure of cilia, and the levels of steroid receptors were measured. The effects of UPA on the progesterone-induced CBF reduction were also studied. Our results show that UPA dose dependently antagonizes the progesterone-induced CBF decrease, but it does not affect the CBF or the ultrastructure of the cilia. The UPA also upregulates the expression levels of the estrogen receptor α and the PR in the fallopian tubes. The results enable us to better understand the mechanisms by which UPA works as an emergency contraceptive and provides a scientific basis for its clinical application.

Ulipristal acetate as an emergency contraceptive agent.

INTRODUCTION: Emergency contraceptive agents play a crucial role in preventing unplanned pregnancy. These agents and devices have been studied since the 1960s and have had varied results in terms of side effects and efficacy. A new oral tablet for emergency contraception (EC), ulipristal acetate (UPA) , is a selective progesterone receptor modulator and can be used up to 120 h following unprotected intercourse, without an increase in adverse effects or a decrease in efficacy. AREAS COVERED: This article reviews studies that evaluate the pharmacodynamics, pharmacokinetics, clinical efficacy, and safety profile of UPA as an emergency contraceptive agent. EXPERT OPINION: UPA, a selective progesterone receptor modulator, is administered as a single 30 mg dose for EC. This agent provides a comparable, if not better, efficacy and side effect profile than seen with levonorgestrel or mifepristone. Because it has both agonistic and antagonistic effects on the progesterone receptor, ongoing clinical trials are documenting UPA's use for patients with endometriosis and as an extended use contraceptive.

[Bias in publications about the mechanism of action of the morning-after pill]. / Sesgos en la Publicación Sobre El Mecanismo de Acción de la Píldora del Día Siguiente.

The morning-after pill or ECP (levonorgestrel) first came into use in the late 20th century, but has only become widely available in the last ten years. Its introduction has been facilitated by health policies which have led to the removal of certain obstacles hindering its use. In this context, sociological, statistical and scientific data have been employed which have often turned out to be biased or partial in nature. The reliability of the information provided by health authorities, pharmaceutical companies and other social entities has been called into question in various respects, particularly as far as the mechanism of action, side effects and pregnancy rate are concerned. This study focuses on the mechanism by which levonorgestrel acts, since a wider discussion would fall beyond the scope of a single study, and the mechanism of action is the aspect which is least understood and most controversial. It remains to be determined whether levonorgestrel is a product which only acts prior to ovulation or which has an effect on the human embryo.

[Estrogens and feminine brain maturation during adolescence: emergency contraceptive pill]. / Estrógenos y Desarrollo del Cerebro Femenino en la Adolescencia: Anticoncepción de Emergencia.

In the period between puberty and maturity takes place the process of brain maturation. Hormone levels induce changes in neurons and direct the architecture and structural functionality thus affecting patterns of development of different brain areas. The onset of puberty brings with it the invasion of the female brain by high levels of hormones, cyclic surges of estrogen and progesterone in addition to steroids produced in situ. Control centers of emotions (amygdala), memory and learning (hippocampus) and sexual activity (hypothalamus) are modified according to the cyclical concentrations of both hormones. Sex hormones stimulate multimodal actions, both short and longer terms, because neurons in various brain areas have different types of receptors, membrane, cytoplasmic and nuclear. The composition of emergency contraceptive pill (postcoital pill) with high hormonal content raises the urgency of a thorough knowledge about the possible effect that the lack of control of the menstrual cycle in a time of consolidation of brain maturation, can bring in structuring and development of brain circuitry. Changes in the availability of sex steroids during puberty and adolescence underlie psychiatric disorders whose prevalence is typically feminine, such as depression, anxiety disorders. It is a fundamental ethical duty to present scientific data about the influence of estrogen in young female brain maturation, both for full information to potential users, and also to induce the appropriate public health measures.

Emergency contraception: knowledge, attitudes and practice of the pharmacy staff in Aydin, Turkey.

OBJECTIVES: This study aimed to explore the knowledge, attitudes, and practices related to emergency contraception (EC) among pharmacy staff. METHODS: This descriptive and cross-sectional survey was conducted among 143 pharmacy staff in Aydin city centre who agreed to participate. Data was collected thorough questionnaires that were filled in by face to face interviews between April and June 2007. RESULTS: Remarkably most of the participants (n = 110) did not know the action mechanism of these pills. Forty-four participants reported that these drugs caused mostly hormonal side-effects. Only four participants knew all indications of EC pills. According to 72 participants, contraceptive pills should not be available without a prescription. The number of pharmacy staff who reported giving counseling to clients about family planning methods was low (n = 12). CONCLUSIONS: The current study revealed that pharmacy staff in the region had inadequate knowledge on EC. Pharmacy staff may play a crucial role in women's access to EC, and there is a need for new interventions to improve and update their knowledge on, and to improve their attitudes toward EC methods.

Updates in hormonal emergency contraception.

In recent years, there have been many updates in hormonal emergency contraception. Levonorgestrel emergency contraception has been available for several years to prevent pregnancy when used within 72 hours after unprotected intercourse or contraceptive failure, and it was recently approved for nonprescription status for patients aged 17 years or older. Current research suggests that the primary mechanism of action is delaying ovulation. Ulipristal is the newest emergency contraception, available by prescription only, approved for use up to 120 hours after unprotected intercourse or contraceptive failure. The primary mechanism of action is delaying ovulation. When compared with levonorgestrel emergency contraception, ulipristal was proven noninferior in preventing pregnancy. Evidence suggests that ulipristal does not lose efficacy from 72-120 hours; however, more studies are warranted to support this claim. Many misconceptions and controversies about hormonal emergency contraception still exist. Research does not support that increased access to emergency contraception increases sexual risk-taking behavior. Several studies suggest that health care providers, including pharmacists, could benefit from increased education about emergency contraception. It is important for pharmacists to remain up-to-date on the most recent hormonal emergency contraception products and information, as pharmacists remain a major point of access to emergency contraception.