Determining the Exposure Threshold for Levonorgestrel Efficacy Using an Integrated Model Based Meta-Analysis Approach.

Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g., levonorgestrel (LNG)) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug-drug interactions (DDIs) and obesity (women with body mass index (BMI) ≥ 30 kg/m2 ) are prime suspects for decreased LNG efficacy. Therefore, we developed an integrated physiologically-based pharmacokinetic modeling and model-based meta-analysis approach to determine LNG's efficacy threshold concentrations and to evaluate the impact of DDIs and obesity on the efficacy of LNG-containing hormonal contraceptives (HCs). Based on this approach, co-administration of strong CYP3A4 inducers and LNG-containing HCs (LNG150: LNG 150 µg + EE 30 µg and LNG100: LNG 100 µg + EE 20 µg) resulted in a predicted clinically relevant decrease of LNG plasma exposure (women with BMI < 25 kg/m2 : 50-65%; obese women: 70-75%). Following administration of LNG150 or LNG100 in the presence of a CYP3A4 inducer, there was an increase in mean Pearl Index of 1.2-1.30 and 1.80-2.10, respectively, in women with BMI < 25 kg/m2 (incidence rate ratios (IRRs): 1.7-2.2), whereas it ranged from 1.6-1.80 and 2.40-2.85 in obese women (IRR: 2.2-3.0), respectively. Our results suggest that the use of backup or alternate methods of contraception is not necessarily required for oral LNG + EE formulations except within circumstances of both obesity and strong CYP3A4 inducer concomitance following administration of LNG100.

Low dose combined oral contraceptives induced thrombotic anterior wall myocardial infarction: a case report.

BACKGROUND: Combined oral contraceptive pills are associated with an established risk for venous thrombosis; however, their risk for arterial thrombosis remains uncertain, especially with the development of low dose new generations of combined oral contraceptive. Arterial thrombosis is less likely to occur with the use of oral contraceptive pills in the absence of cardiovascular risk factors. CASE PRESENTATION: We report a 35-year old female with no cardiovascular risk factors who presented with thrombotic anterior wall myocardial infarction 6 months after using a third generation low dose combined oral contraceptive pills (Marvelon; ethinylestradiol 30 mcg and desogestrel 150 mcg). CONCLUSION: Third generation low dose combined oral contraceptives may lead to myocardial infarction in young women, even in the absence of other cardiovascular risk factors.

Norethindrone is superior to combined oral contraceptive pills in short-term delay of menses and onset of breakthrough bleeding: a randomized trial.

BACKGROUND: To determine whether oral norethindrone acetate is superior to combined oral contraceptives (OCP) in delaying menstruation and preventing breakthrough bleeding when started late in the cycle. METHODS: This article comprises of a case control study followed by a pilot randomized controlled study. In the first study, four women who presented late in their cycle and desired avoiding vaginal bleeding within 10 days before a wedding were started on norethindrone 5 mg three times daily and compared to age matched controls started on OCPs. Subsequently, a randomized controlled pilot study (n = 50) comparing OCPs to norethindrone for the retiming of menses was conducted. Percentage of women reporting spotting were compared with level of statistical significance set at p < 0.05. RESULTS: Of the norethindrone treated group, only 2 women (8%) reported spotting compared with 10 women (43%) in the control group (p < 0.01). Norethindrone recipients experienced significant weight gain, which resolved after cessation of therapy and had heavier withdrawal bleed (p < 0.04) when compared to controls. Patient satisfaction was significantly higher in the norethindrone group, with 80% willing to choose this method again. Time to conceive was significantly shorter in the norethindrone group (p < 0.03). CONCLUSIONS: Norethindrone, begun on or before cycle day 12, is superior for women who desire to avoid breakthrough bleeding and maintain fertility when compared to OCPs. It is an ideal approach in patients presenting late in their cycle and who desire delaying menses as well as in circumstances when even minute amounts of breakthrough bleeding cannot be tolerated. TRIAL REGISTRATION: Clinicaltrials.gov NCT03594604 , July 2018. Retrospectively registered.

Estradiol modulation of the renin-angiotensin system and the regulation of fear extinction.

Post-traumatic stress disorder (PTSD) is more prevalent in women than men, yet much remains to be determined regarding the mechanism underlying this sex difference. Clinical and preclinical studies have shown that low estradiol levels during extinction of fear conditioning in rodents (i.e., cue exposure therapy in humans) leads to poor extinction consolidation and increased fear during extinction recall. The renin-angiotensin system (RAS) is also associated with stress-related pathologies, and RAS antagonists can enhance extinction consolidation in males. However, less is known about how estradiol and the RAS converge to alter fear extinction consolidation in females. Since estradiol downregulates the RAS, we determined the role of surgically (via ovariectomy [OVX]) and pharmacologically (via the hormonal contraceptive [HC], levonorgestrel) clamping estradiol at low levels in female rats on fear-related behavior, serum estradiol and angiotensin II (Ang II) levels, and angiotensin II type I receptor (AT1R) binding in the brain. We then tested whether the AT1R antagonist losartan would alter fear-related behavior in an estradiol-dependent manner. We found that both OVX and HC treatment produced extinction consolidation deficits relative to intact female rats in proestrus (when estradiol levels are high), and that losartan treatment mitigated these deficits and reduced freezing. OVX, but not HC, altered AT1R ligand binding, though HC reduced estradiol and increased Ang II levels in plasma. These findings have significant clinical implications, indicating that administration of an AT1R antagonist, especially if estradiol levels are low, prior to an exposure therapy session may improve treatment outcomes in females.

Preparation and Characterization of an Oral Norethindrone Sustained Release/Controlled Release Nanoparticles Formulation Based on Chitosan.

Norethindrone has short half-life and low bioavailability. The objective was to prepare an oral Sustained Release/Controlled Release (SR/CR) Liquid Medicated Formulation (LMF) to enhance bioavailability and improve patient compliance. Norethindrone was solubilized in HP-ß-CD then complexed with different concentrations of Low Molecular Weight Chitosan (LMWC) (mucoadhesive). PolyElectrolyte Complexes (PECs) were homogenized with oleic acid using different concentrations of tween 80 to form LMFs (nanoemulsions). PECs and LMFs were characterized using different techniques. LMF 2 (optimum formula containing 2.5% w/v LMWC 11 kDa) was administered orally to dogs and mice for pharmacokinetic and adhesion evaluation. DSC, FTIR spectroscopy and SEM images indicated complex formation. Mean diameters of PECs were 183-425 nm, mean zeta potentials were + 18.6-+ 31 mV, and complexation efficiencies were 18.0-20.6%. Ten to fifteen percent tween was needed to prepare homogenous LMFs. Mean diameter of LMF 2 was 10.5 ± 0.57 nm, mean zeta potential was - 11.07 ± - 0.49 mV, encapsulation efficiency was 95.28 ± 1.75%, and each mL contained 145.5 µg norethindrone. SEM images showed spherical homogeneous oil droplets. All of these parameters were affected by molecular weight and concentration of chitosan. Norethindrone release from LMFs was controlled (zero order) for 96 h. It was little affected by molecular weight and concentration of chitosan but affected by concentration of tween 80. LMF 2 adhered to GIT for 48 h and enhanced the bioavailability. It showed no cytotoxicity after considering dilution in GIT and was stable for 3 months refrigerated. In conclusion an effective SR/CR LMF was prepared.

Limited evidence guides empiric Tx of female chronic pelvic pain.

This article reviews the limited evidence for treating chronic pelvic pain and offers recommendations for the primary care physician on providing symptomatic relief in the absence of diagnosed pathology.

Shifting from Oral Contraceptives to Norethisterone Acetate, or Vice Versa, because of Drug Intolerance: Does the Change Benefit Women with Endometriosis?

BACKGROUND/AIMS: Oral contraceptives (OC) and norethisterone acetate (NETA) are among first-line medical therapies for symptomatic endometriosis, but their use is sometimes associated with intolerable side effects. We investigated whether shifting from low-dose OC to NETA (2.5 mg/day), or vice versa, improved tolerability. METHODS: Sixty-seven women willing to discontinue their treatment because of intolerable side effects despite good pain relief, were enrolled in a self-controlled study, and shifted from OC to NETA (n = 35) or from NETA to OC (n = 32). The main study outcome was satisfaction with treatment 12 months after the change. Tolerability, pain symptoms, health-related quality of life, psychological status, and sexual functioning were also evaluated. RESULTS: After treatment change, good tolerability was reported by 37% of participants who shifted to NETA, and by 52% of those who shifted to OC. At 12-month assessment, 51% of women intolerant to OC were satisfied with NETA, and 65% of those intolerant to NETA were satisfied with OC (intention-to-treat analysis). Other study variables did not vary substantially. CONCLUSIONS: In selected endometriosis patients, shifting from OC to NETA, or vice versa, because of side effects, improved tolerability. Better results were observed when substituting NETA with OC rather than the other way round.

Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study.

OBJECTIVE: Women with ovarian cancer have poor survival rates, which have proven difficult to improve; therefore primary prevention is important. The levonorgestrel-releasing intrauterine system (LNG-IUS) prevents endometrial cancer, and recent studies suggested that it may also prevent ovarian cancer, but with a concurrent increased risk of breast cancer. We compared adjusted risks of ovarian, endometrial, and breast cancer in ever users and never users of LNG-IUS. METHODS: Our study cohort consisted of 104,318 women from the Norwegian Women and Cancer Study, 9144 of whom were ever users and 95,174 of whom were never users of LNG-IUS. Exposure information was taken from self-administered questionnaires, and cancer cases were identified through linkage to the Cancer Registry of Norway. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated with Poisson regression using robust error estimates. RESULTS: Median age at inclusion was 52years and mean follow-up time was 12.5 (standard deviation 3.7) years, for a total of 1,305,435 person-years. Among ever users of LNG-IUS there were 18 cases of epithelial ovarian cancer, 15 cases of endometrial cancer, and 297 cases of breast cancer. When ever users were compared to never users of LNG-IUS, the multivariable RR of ovarian, endometrial, and breast cancer was 0.53 (95% CI: 0.32, 0.88), 0.22 (0.13, 0.40), and 1.03 (0.91, 1.17), respectively. CONCLUSION: In this population-based prospective cohort study, ever users of LNG-IUS had a strongly reduced risk of ovarian and endometrial cancer compared to never users, with no increased risk of breast cancer.

Anordrin Eliminates Tamoxifen Side Effects without Changing Its Antitumor Activity.

Tamoxifen is administered for estrogen receptor positive (ER+) breast cancers, but it can induce uterine endometrial cancer and non-alcoholic fatty liver disease (NAFLD). Importantly, ten years of tamoxifen treatment has greater protective effect against ER+ breast cancer than five years of such treatment. Tamoxifen was also approved by the FDA as a chemopreventive agent for those deemed at high risk for the development of breast cancer. The side effects are of substantial concern because of these extended methods of tamoxifen administration. In this study, we found that anordrin, marketed as an antifertility medicine in China, inhibited tamoxifen-induced endometrial epithelial cell mitosis and NAFLD in mouse uterus and liver as an anti-estrogenic and estrogenic agent, respectively. Additionally, compared with tamoxifen, anordiol, the active metabolite of anordrin, weakly bound to the ligand binding domain of ER-α. Anordrin did not regulate the classic estrogen nuclear pathway; thus, it did not affect the anti-tumor activity of tamoxifen in nude mice. Taken together, these data suggested that anordrin could eliminate the side effects of tamoxifen without affecting its anti-tumor activity.

The Effects of Gonadotropin-Releasing Hormone Agonist Combined with Add-Back Therapy on Quality of Life for Adolescents with Endometriosis: A Randomized Controlled Trial.

STUDY OBJECTIVE: Use of gonadotropin-releasing hormone agonists (GnRHa) to treat endometriosis can cause mood and vasomotor side effects. "Add-back therapy," the combination of low-dose hormones, limits side effects but research is limited to adults. We sought to characterize quality of life (QOL) before treatment and to compare an add-back regimen of norethindrone acetate (NA) with conjugated estrogens (CEE) to NA alone for preventing side effects of GnRHa therapy in female adolescents with endometriosis. DESIGN: Twelve-month double-blind, placebo-controlled trial. SETTING: Pediatric Gynecology clinic in Boston, Massachusetts. PARTICIPANTS: Fifty female adolescents (aged 15-22 years) with surgically confirmed endometriosis initiating treatment with GnRHa. INTERVENTIONS: Subjects were randomized to: NA (5 mg/d) with CEE (0.625 mg/d) or NA (5 mg/d) with placebo. All subjects received leuprolide acetate depot every 3 months. MAIN OUTCOME MEASURES: The Short Form-36 v2 Health Survey, Beck Depression Inventory II, and Menopause Rating Scale were completed at repeated intervals. RESULTS: At baseline, subjects reported impaired physical health-related QOL compared with national norms (all P < .0001). Over 12 months, these Short Form-36 v2 scores improved (all P < .05). Subjects receiving NA with CEE showed greater improvements in the pain, vitality, and physical health subscales (Pbetween groups < .05) than those receiving NA alone, as well as better physical functioning (P < .05). There were no changes in depression or menopause-like symptoms in either group. CONCLUSION: Female adolescents with endometriosis initiating GnRHa therapy have impaired QOL. Treatment with GnRHa combined with add-back therapy led to improved QOL, with no worsening of mood or menopausal side effects. NA with CEE was superior to NA alone for improving physical health-related QOL.

Effect of BMI and body weight on pregnancy rates with LNG as emergency contraception: analysis of four WHO HRP studies.

OBJECTIVE: To estimate the effect of increased body weight and body mass index (BMI) on pregnancy rates with levonorgestrel (LNG) 1.5mg used as emergency contraception (EC). METHODS: The study reviewed data from 6873 women in four WHO-HRP randomized trials on EC conducted between 1993 and 2010. Participants took either 1.5mg of LNG as a single dose or in two doses 12h apart, up to 120h of unprotected intercourse. Contraceptive efficacy (pregnancy rates) at different weight and BMI categories was evaluated. RESULTS: Overall pregnancy rate was low at 1.2%. Pregnancy rates were also low in women weighing over 80kg (0.7%) and who were obese (BMI over 30kg/m2) (2.0%). The pooled analyses for pregnancy demonstrated that BMI over 30kg/m2 decreased efficacy significantly (odds ratio 8.27, 95% confidence interval = 2.70-25.37) when compared to women in lower BMI categories, mainly influenced by pregnancies in obese women from one study site. Sensitivity analyses excluding that site showed that obesity was no longer a risk factor; however, the other studies included too few obese women in the sample to exclude a substantial decrease in efficacy. CONCLUSIONS: Pregnancy rates with use of LNG 1.5mg for EC were low at less than 3% across different weight and BMI categories. Pooled analyses showed an increase in pregnancy rates among obese women (BMI more than 30kg/m2) compared to women with normal BMI levels, influenced by pregnancies all coming from one study site. IMPLICATIONS: Access to LNG as EC should still be promoted to women who need them, and not be restricted in any weight or BMI category, with additional attention for counselling and advice for obese women.

Preparation and in vitro/in vivo evaluation of gestodene (GEST) intravaginal ring.

Preparation and in vitro/in vivo evaluation of gestodene (GEST) intravaginal ring (IVR) formulations which can release a constant dose of GEST during 3 weeks were investigated. In present study a reservoir gestodene intravaginal ring, including a gestodene silicone elastomer core and the non-active silicone layer, was reported, which was manufactured by reaction injection moulding at 80°C for 20 min. The raw materials compatibility experiments showed that the silicone elastomer core carrier wouldn't interact with drugs. In vitro release samples were determined by HPLC and the experiment was performed under sink conditions. The equation of cumulative release verse time was Y=64.76χ+5.44 (r=0.9998), performing zero-order release at about the target dose of 60 µg/day over 21 days. Drug release increased with temperature elevating from 45 to 55°C, which could be attributed to optimizing the prescription. In addition, the pharmacokinetic and safety studies of gestodene intravaginal ring were evaluated in female New Zealand White rabbits. The GEST in plasma was analyzed by LC-MS/MS and the results proved that the correlation between in vitro and in vivo was relatively well.

Choice of Emergency Contraceptive and Decision Making Regarding Subsequent Unintended Pregnancy.

OBJECTIVES: To prospectively evaluate (1) pregnancy desirability, (2) stated intentions should pregnancy occur among emergency contraception (EC) users, and (3) explore differences between women selecting the copper T380 intrauterine device (Cu IUD) or oral levonorgestrel (LNG) regarding hypothetical pregnancy plans and actual pregnancy actions during subsequent unintended pregnancies. STUDY DESIGN: In this prospective observational trial, women received the Cu IUD or oral LNG for EC without cost barriers. At baseline, participants completed a visual analogue scale measuring pregnancy desirability (anchors: 0, "trying hard not to get pregnant"; 10, "trying hard to get pregnant") and self-reported plans (abortion, adoption, parenting, and unsure) if the pregnancy test were to come back positive. Pregnancies were tracked for 12 months, and actions regarding unintended pregnancies were compared between EC method groups. RESULTS: Of 548 enrolled women, 218 chose the Cu IUD and 330 the oral LNG for EC. Pregnancy desirability at baseline was low, with no difference between EC groups (IUD group: 0.51, SD ± 1.60; LNG group: 0.68, SD ± 1.74). Fifty-four (10%) women experienced unintended pregnancies. Pregnancy plans from baseline changed for 27 (50%) women when they became pregnant. EC groups did not differ in hypothetical pregnancy intention (p = 0.15) or in agreement of hypothetical pregnancy intention with actual pregnancy action (p = 0.80). CONCLUSIONS: Women presenting for EC state high desire to prevent pregnancy regardless of method selected. When considering a hypothetical pregnancy, half of women had a plan for how they would respond to that situation, but when confronting an actual unintended pregnancy, half altered their plan. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov identifier NCT00966771.

A 12-month multicenter, randomized study comparing the levonorgestrel intrauterine system with the etonogestrel subdermal implant.

OBJECTIVE: To compare the levonorgestrel intrauterine system (LNG-IUS 8), which has an average levonorgestrel release rate of ∼8 µg/24 hours during the first year (total levonorgestrel content 13.5 mg; Jaydess/Skyla), with the etonogestrel (ENG) subdermal implant (total content, 68 mg) with regard to the 12-month discontinuation rate (primary outcome). DESIGN: Randomized, open-label, phase III study. SETTING: Thirty-eight centers in six European countries. PATIENT(S): Study population of 766 healthy nulliparous and parous women aged 18-35 years. INTERVENTION(S): The LNG-IUS 8 or the ENG implant. MAIN OUTCOME MEASURE(S): Discontinuation rate, by treatment group, at Month 12. RESULT(S): The 12-month discontinuation rates were 19.6% and 26.8% in the LNG-IUS 8 and ENG implant groups, respectively. The -7.2% difference was statistically significant (95% confidence interval -13.2%, -1.2%). Fewer women in the LNG-IUS 8 group than in the ENG implant group discontinued because of increased bleeding (3.2% vs. 11.3%) or adverse events (14.3% vs. 21.8%). At 12 months, more women in the LNG-IUS 8 group than in the ENG implant group were "very/somewhat satisfied" with their bleeding pattern (60.9% vs. 33.6%) and reported a preference to use their study treatment after study completion (70.1% vs. 58.5%). CONCLUSION(S): The LNG-IUS 8 was associated with a significantly lower 12-month discontinuation rate compared with the ENG implant; mainly because ENG implant users frequently discontinued due to increased bleeding. More LNG-IUS 8 users than ENG implant users reported being "very/somewhat satisfied" with their bleeding pattern, and reported a preference to continue using their study treatment after the study. CLINICAL TRIAL REGISTRATION NUMBER: NCT01397097.

Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing.

OBJECTIVE: To determine if differences exist in the pharmacokinetics (PK) of levonorgestrel-based emergency contraception (LNG-EC) in obese and normal body mass index (BMI) users and test whether doubling the dose of LNG-EC in obese women increases total and free (active) LNG serum concentrations. STUDY DESIGN: Healthy, reproductive-age women with obese and normal BMIs received 1.5mg LNG orally (ECx1) and then in a subsequent menstrual cycle, the obese group also received 3mg LNG (ECx2). Dosing occurred during the follicular phase. Total and free LNG PK parameters were obtained via serum samples through an indwelling catheter at 0, 0.5, 1, 1.5, 2, and 2.5h. The primary outcome was the difference in total and free LNG concentration maximum (Cmax) between ECx1 and ECx2 in the obese group. RESULTS: A total of 10 women enrolled and completed the study (normal BMI=5, median 22.8kg/m(2), range 20.8-23.7; obese BMI=5, 39.5kg/m(2), range 35.9-46.7). The total LNG Cmax for obese subjects following ECx1 (5.57±2.48ng/mL) was significantly lower than the level observed in normal BMI women (10.30±2.47, p=.027). Notably, ECx2 increased the Cmax significantly (10.52±2.76, p=.002); approximating the level in normal BMI subjects receiving ECx1. Free LNG Cmax followed a similar pattern. CONCLUSION: Obesity adversely impacts both the total and free Cmax levels of LNG EC and this likely explains its lack of efficacy in obese women. Doubling the dose appears to correct the obesity-related PK changes but additional research is needed to determine if this also improves EC effectiveness in obese women. IMPLICATIONS: This study demonstrates that obesity interferes with the pharmacokinetics of LNG EC, and that doubling the dose may be an effective strategy to improve its efficacy in obese women.

Population-based evaluation of the effectiveness of two regimens for emergency contraception.

OBJECTIVE: To estimate and compare the effectiveness of the levonorgestrel and Yuzpe regimens for hormonal emergency contraception in routine clinical practice. METHODS: A retrospective population-based study included women who accessed emergency contraceptives for immediate use prescribed by community pharmacists in British Columbia, Canada, between December 2000 and December 2002. Linked administrative healthcare data were used to discern the timings of menses, unprotected intercourse, and any pregnancy-related health services. A panel of experts evaluated the compatibility of observed pregnancies with the timing of events. The two regimens were compared with statistical adjustments for potential confounding. RESULTS: Among 7493 women in the cohort, 4470 (59.7%) received levonorgestrel and 3023 (40.3%) the Yuzpe regimen. There were 99 (2.2%) compatible pregnancies in the levonorgestrel group and 94 (3.1%) in the Yuzpe group (P=0.017). The estimated odds ratio for levonorgestrel compared with the Yuzpe regimen after adjusting for potential confounders was 0.64 (95% confidence interval 0.47-0.87). Against an expected pregnancy rate of approximately 5%, the relative and absolute risk reductions were 56.0% and 2.8%, respectively, for levonorgestrel and 36.7% and 1.8% for the Yuzpe regimen. CONCLUSION: The levonorgestrel regimen is more effective than the Yuzpe regimen in routine use. The data suggest that both regimens are less effective than has been observed in randomized trials.

A prospective, open-label, single arm, multicentre study to evaluate efficacy, safety and acceptability of pericoital oral contraception using levonorgestrel 1.5 mg.

STUDY QUESTION: Will the use of levonorgestrel (LNG) 1.5 mg taken at each day of coitus by women who have relatively infrequent sex be an efficacious, safe and acceptable contraceptive method? SUMMARY ANSWER: Typical use of LNG 1.5 mg taken pericoitally, before or within 24 h of sexual intercourse, provides contraceptive efficacy of up to 11.0 pregnancies per 100 women-years (W-Y) in the primary evaluable population and 7.1 pregnancies per 100 W-Y in the evaluable population. WHAT IS KNOWN ALREADY: LNG 1.5 mg is an effective emergency contraception following unprotected intercourse. Some users take it repeatedly, as their means of regular contraception. STUDY DESIGN, SIZE, DURATION: This was a prospective, open-label, single-arm, multicentre Phase III trial study with women who have infrequent coitus (on up to 6 days a month). Each woman had a follow-up visit at 2.5, 4.5 and 6.5 months after admission or until pregnancy occurs if sooner, or she decided to interrupt participation. The study was conducted between 10 January 2012 and 15 November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 330 healthy fertile women aged 18-45 years at risk of pregnancy who reported sexual intercourse on up to 6 days a month, were recruited from four university centres located in Bangkok, Thailand; Campinas, Brazil; Singapore and Szeged, Hungary to use LNG 1.5 mg pericoitally (24 h before or after coitus) as their primary method of contraception. The participants were instructed to take one tablet every day she had sex, without taking more than one tablet in any 24-h period, and to maintain a paper diary for recording date and time for every coital act and ingestion of the study tablet, use of other contraceptive methods and vaginal bleeding patterns. Anaemia was assessed by haemoglobin evaluation. Pregnancy tests were performed monthly and pregnancies occurring during product use were assessed by ultrasound. At the 2.5-month and final visit at 6.5 months, acceptability questions were administered. MAIN RESULTS AND THE ROLE OF CHANCE: There were 321 women included in the evaluable population (which includes all eligible women enrolled), with 141.9 woman-years (W-Y) of observation and with a rate (95% confidence interval [CI]) of 7.1 (3.8; 13.1) pregnancies per 100 W-Y of typical use (which reflects use of the study drug as main contraceptive method, but also includes possible use of other contraceptives from admission to end of study) and 7.5 (4.0; 13.9) pregnancies per 100 W-Y of sole use. In the primary evaluable population (which includes only eligible enrolled women <35 years old), the rate was 10.3 (5.4; 19.9) pregnancies per 100 W-Y of typical use, and 11.0 (5.7; 13.1) pregnancies per 100 W-Y of sole use. There were three reported severe adverse events and 102 other mild adverse events (most common were headache, nausea, abdominal and pelvic pain), with high recovery rate. The vaginal bleeding patterns showed a slight decrease in volume of bleeding and the number of bleeding-free days increased over time. There was only one case of severe anaemia, found at the final visit (0.4%). The method was considered acceptable, as over 90% of participants would choose to use it in the future or would recommend it to others. LIMITATIONS, REASONS FOR CAUTION: This was a single-arm study with small sample size, without a control group, designed as a proof of concept study to explore the feasibility of this type of contraception. WIDER IMPLICATIONS OF THE FINDINGS: A larger clinical study evaluating pericoital contraception with LNG is feasible and our data show that this method would be acceptable to many women. STUDY FUNDING/COMPETING INTERESTS: This study received partial financial support from the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR) and the World Health Organization. Gynuity and the Bill and Melinda Gates Foundation (BMGF) provided financial support for project monitoring. HRA Pharma donated the LNG product. N.K. was the initial project manager when she was with WHO/HRP and was employed by HRA Pharma, which distributes LNG for emergency contraception. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: This study was registered on ANZCTR, Trial ID ACTRN12611001037998. TRIAL REGISTRATION DATE: 4 October 2011. DATE OF FIRST PATIENT'S ENROLMENT: 10 January 2012.