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.

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: contraceptive or contragestive?

Ulipristal acetate is the first selective progesterone receptor modulator approved for postcoital contraception in the US. It appears to be significantly more effective in inhibition of ovulation than other forms of emergency contraception. However, ulipristal acetate is structurally similar to mifepristone, and several lines of evidence suggest that a postfertilization mechanism of action is also operative. This mechanism of action is considered to be contragestive versus contraceptive. Ulipristal acetate administration is contraindicated in a known or suspected pregnancy; however, it could quite possibly be used as an effective abortifacient. Health-care providers should inform patients of the possibility of both mechanisms of action with use of this drug.

How do levonorgestrel-only emergency contraceptive pills prevent pregnancy? Some considerations.

Controversial opinions exist about the possible mechanisms throughout emergency contraception prevents pregnancy. Recently, the International Federation of Gynaecology and Obstetrics and the International Consortium for Emergency Contraception released a Joint Statement declaring that 'inhibition or delay of ovulation should be their primary and possibly only mechanism of action'. They still added that 'Review of the evidence suggests that LNG-ECPs cannot prevent implantation'. Concerning levonorgestrel-only emergency contraceptive pills effects on ovulation, the Statement based on seven reference papers which considered a total of only 142 patients, divided into still different subgroups. Basing on their same references we got quite different conclusions.

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.

[Ulipristal acetate: an emergency contraception extended to 5 days using a progesterone receptor modulator (Ellaone)]. / Le médicament du mois. Ulipristal acétate: une contraception d'urgence étendue à 5 jours par progesterone receptor modulator (Ellaone).

Emergency contraception is a second chance for prevention of pregnancy after unprotected intercourse. Hormonal emergency contraception with levonorgestrel 1.5 mg, only provides an effective contraception from 0 to 72 hours after intercourse with decreasing effectiveness as time elapses. It was accordingly mandatory to develop an alternative approach with a stable contraceptive efficacy and good tolerance for 5 days, knowing additionally that the estimated lifespan of sperm in the female genital tract is about 5 days. In comparative studies bearing on more than 3000 young women, the progesterone receptor modulator (PRM) ulipristal acetate, a progesterone antagonist (taken in a single dose of 30 mg), or levonorgestrel (1.5 mg) were administered. Results indicated that the PRM was as effective as levonorgestrel, or even more, kept a stable efficacy for 120 hours after an unprotected intercourse, and was well tolerated. This establishes ulipristal acetate as the new standard for hormonal emergency contraception.

[Mechanisms of action of emergency contraception]. / Mecanismos de acción de la anticoncepción hormonal de emergencia: efectos del levonorgestrel anteriores y posteriores a la fecundación.

There is still controversy regarding the mechanism of action of levonorgestrel (LNG) for emergency contraception (EC). For those who state that pregnancy starts prior to implantation, any compound able to interfere with post-fertilization and pre-implantation stages, should be considered as abortifacient. Previous research suggests that EC in humans acts predominantly after fertilization. Current evidence with LNG-only EC supports a pre-fertilization mechanisms to explain its action. There are many potential mechanisms of action, which could vary pending on the day during the fertilization window of the ovarian cycle at which the contraceptive is given. This paper reviews the evidence for each potential mechanism of action. According to the most recently statements, it is concluded that the primary and possible the only mechanism of action of LNG-only EC is preventing or delaying ovulation.

Synthesis and in vivo evaluation of 11-substituted estradiol derivatives as anti-implantation agents.

Synthesis of 11-substituted estradiol derivatives (12-17) has been carried out by the Grignard reaction with alkyl, allyl, and benzyl halides on 17beta-hydroxy-3-methoxy-11-oxo-estra-1,3,5(10),8(9)-tetraene (10). The novel compounds (10 and 12-17) were evaluated for their preliminary post-coital contraceptive (anti-implantation) activity in Sprague-Dawley rats. The tested compounds were administered orally and showed significant anti-implantation activity. Compound 13 is the most potent compound in the series which showed 100% contraceptive efficacy at 1.25 mg kg(-1).

Postcoital interceptive activity of Wrightia tinctoria in Sprague-Dawley rats: a preliminary study.

BACKGROUND: This study was aimed to investigate the pregnancy-interceptive activity of the stem bark of Wrightia tinctoria R.Br. (Family Apocynaceae) administered during the preimplantation, peri-implantation and early postimplantation periods by oral route in adult female Sprague-Dawley rats. STUDY DESIGN: The ethanolic extract of the stem bark and its serial fractions were administered to female rats on Days 1-7 or 1-5 postcoitum (Day 1: day of sperm-positive vaginal smear) by the oral route. At autopsy on Day 10 postcoitum, the number and status of corpora lutea and implantations were recorded. For estrogen-agonistic activity, immature rats ovariectomized 7 days earlier received the test extract or the vehicle once daily for 3 days and, at autopsy on Day 4, uterine weight, status of vaginal opening and extent of vaginal cornification were recorded. RESULTS: The ethanolic extract of the stem bark of W. tinctoria R.Br. inhibited pregnancy in 100% of rats when administered orally at a 250-mg/kg dose on Days 1-7 or 1-5 postcoitum. On fractionation, the hexane-soluble, chloroform-soluble, water-soluble and water-insoluble fractions showed 100% anti-implantation effect, while n-butanol-soluble fraction intercepted pregnancy in 75% of animals when administered in the Days 1-5 postcoitum schedule. In immature rat bioassay, the active ethanolic extract and its fractions exhibited moderate to potent estrogen-agonistic activity, which might be responsible for their contraceptive action in this species. CONCLUSIONS: Findings demonstrate the antifertility activity of the ethanolic extract of the stem bark of W. tinctoria and its hexane-soluble, chloroform-soluble, water-soluble and water-insoluble fractions. Studies that pursue promising natural products (to identify contraceptive agents from natural sources lacking potent estrogenic activity) towards a fruitful conclusion for development/lead generation should continue.

Synthesis and structure guided evaluation of estrogen agonist and antagonist activities of some new tetrazolyl indole derivatives.

Several regioisomeric tetrazolyl indole derivatives with structurally modified alkyl substituents at the tetracyclic indole nitrogen containing N-ethyl amino tetrazole moiety have been synthesized and screened for their ER binding affinity, agonist (estrogenic), antagonist (antiestrogenic) and anti-implantation activities. N-2 regioisomers were found to be moderately antagonists and one compound showed 100% contraceptive efficacy at 10 mg/kg dose. Molecular docking studies carried out in comparison to estradiol and raloxifene showed different binding modes of the two regioisomers to the binding site.

[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.

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.

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.

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.

Postcoital ingestion of the aqueous extract of Erythrina falcata Benth prevents pregnancy in the mouse.

AIM: We examined whether the aqueous extract of Erythrina falcata, reputed to be a contraceptive in Peruvian folklore, could prevent pregnancy in the mouse. METHODS: Female mice on Day 1 of pregnancy were given aqueous extract of E. falcata or tap water (control) orally for 4 days. On Day 4 of pregnancy, animals were killed and the embryos were flushed from oviducts and uterus to examine their developmental stage, cell number, mitotic index and micronuclei frequency. Other mice were killed on Day 12 of pregnancy to determine the number of implantation sites. RESULTS: Ingestion of E. falcata diminished the percentage of embryos that progressed to blastocyst stage, reduced the cell number and mitotic index, and increased the micronuclei frequency of early embryos. The number of implantation sites was also reduced in females treated with E. falcata. CONCLUSION: The aqueous extract of E. falcata, ingested during early pregnancy, disturbs preimplantation embryo development and implantation in the mouse. These results provide the first experimental evidence of the contraceptive properties of the aqueous extract of E. falcata.

Over-the-counter access to emergency contraception.

After years of debate, the Food and Drug Administration has granted approval for levonorgestrel (Plan B) to be sold over the counter to people ages 18 and older. The dual status of Plan B as an over-the counter drug and a prescription drug is unusual. The article reviews the drug's method of action and recommended dosage, as well as what nurses need to know to counsel patients on what to expect when taking the medication.