A Pre-Phase III Efficacy Trial of the Spermicide/Contraceptive Effect of the Invisible Condom, a Non-Hormonal Vaginal Gel, in Women from Canada.

OBJECTIVES: To evaluate the spermicidal efficacy of non-hormonal vaginal gel in vitro and in a post-coital test, and to evaluate its contraceptive efficacy in Canadian women of childbearing age. METHODS: We conducted single-centre trial to assess spermicidal and contraceptive efficacy of vaginal gel. Participants were healthy, sexually active women aged 18-49 years and their regular male sexual partners (30 couples). Measured outcomes included effect of vaginal gel on sperm motility in vitro, its effect on sperm in a post-coital test, and its effect on pregnancy prevention over 3 months. RESULTS: For in vitro spermicidal effect, 98% and 67% of sperm were immotile in the presence of the gel with sodium lauryl sulfate (gel-SLS) and gel alone, respectively. For the post-coital test, 99% and 93% of sperm were immotile in the presence of gel-SLS and gel alone, respectively. In the second part of trial, a total of 410 instances of vaginal intercourse in 95 menstrual cycles were protected (during 3-month period of gel-SLS use before each sexual intercourse with probability of 24 conceptions prevented according to Wilcox's table). Four women became pregnant during the study period; 2 during unprotected vaginal intercourse around the time of ovulation, and 2 attributed to user failure. CONCLUSION: Based on our results, the vaginal gel demonstrated important spermicidal and contraceptive effect. A larger phase III contraceptive efficacy trial is warranted. The vaginal gel may represent a non-hormonal spermicide/contraceptive option for women.

Effect of body weight and BMI on the efficacy of levonorgestrel emergency contraception.

OBJECTIVES: To further evaluate the effect of weight and body mass index (BMI) on the efficacy of levonorgestrel emergency contraception. METHODS: Data from two large, multicenter, randomized controlled trials designed to assess emergency contraceptive efficacy were pooled to evaluate the effect of weight and BMI on pregnancy rates among women who received levonorgestrel. Descriptive methods (comparison of means and distributions according to pregnancy status and pregnancy rates across weight and BMI categories) as well as cubic spline modeling were used to describe the relationship between pregnancy risk and weight/BMI. RESULTS: The analysis population comprised 1731 women, among whom 38 pregnancies were reported. Women for whom levonorgestrel was not effective in preventing pregnancy had a significantly higher mean body weight and BMI than women who did not become pregnant (76.7 vs. 66.4 kg, p<.0001; 28.1 vs. 24.6 kg/m², p<.0001). The estimated pregnancy rate increased significantly from 1.4% [95% confidence interval (CI): 0.5%-3.0%] among the group of women weighing 65-75 kg to 6.4% (95% CI: 3.1%-11.5%) and 5.7% (95% CI: 2.9%-10.0%) in the 75-85 kg and >85 kg groups, respectively. Statistical modeling demonstrated a steep increase in pregnancy risk starting from a weight near 70-75 kg to reach a risk of pregnancy of 6% or greater around 80 kg. Similar results were obtained for statistical modeling of BMI as well as when the two studies were analyzed individually. CONCLUSIONS: All analyses showed a significant drop in the efficacy of levonorgestrel emergency contraception with increasing body weight, with pregnancy risk in the higher weight categories similar to expected rates in the absence of contraception. Like body weight, increasing BMI was highly correlated with increased pregnancy risk.

Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel.

BACKGROUND: Emergency contraception (EC) does not always work. Clinicians should be aware of potential risk factors for EC failure. STUDY DESIGN: Data from a meta-analysis of two randomized controlled trials comparing the efficacy of ulipristal acetate (UPA) with levonorgestrel were analyzed to identify factors associated with EC failure. RESULTS: The risk of pregnancy was more than threefold greater for obese women compared with women with normal body mass index (odds ratio (OR), 3.60; 95% confidence interval (CI), 1.96-6.53; p<.0001), whichever EC was taken. However, for obese women, the risk was greater for those taking levonorgestrel (OR, 4.41; 95% CI, 2.05-9.44, p=.0002) than for UPA users (OR, 2.62; 95% CI, 0.89-7.00; ns). For both ECs, pregnancy risk was related to the cycle day of intercourse. Women who had intercourse the day before estimated day of ovulation had a fourfold increased risk of pregnancy (OR, 4.42; 95% CI, 2.33-8.20; p<.0001) compared with women having sex outside the fertile window. For both methods, women who had unprotected intercourse after using EC were more likely to get pregnant than those who did not (OR, 4.64; 95% CI, 2.22-8.96; p=.0002). CONCLUSIONS: Women who have intercourse around ovulation should ideally be offered a copper intrauterine device. Women with body mass index >25 kg/m(2) should be offered an intrauterine device or UPA. All women should be advised to start effective contraception immediately after EC.

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.

Met909 plays a key role in the activation of the progesterone receptor and also in the high potency of 13-ethyl progestins.

Many progestins have been developed for use in contraception, menopausal hormone therapy, and treatment of gynecological diseases. They are derived from either progesterone or testosterone, and they act by binding to the progesterone receptor (PR), a hormone-inducible transcription factor belonging to the nuclear receptor superfamily. Unlike mineralocorticoid, glucocorticoid, and androgen receptors, the steroid-receptor contacts that trigger the switch of the ligand-binding domain from an inactive to an active conformation have not yet been identified for the PR. With this aim, we solved the crystal structure of the ligand-binding domain of the human PR complexed with levonorgestrel, a potent testosterone-derived progestin characterized by a 13-ethyl substituent. Via mutagenesis analysis and functional studies, we identified Met909 of the helix 12 as the key residue for PR activation by both testosterone- and progesterone-derived progestins with a 13-methyl or a 13-ethyl substituent. We also showed that Asn719 contributes to PR activation by testosterone-derived progestins only, and that Met759 and Met909 are responsible for the high potency of 19-norprogestins and of 13-ethyl progestins, respectively. Our findings provide a structural guideline for the rational synthesis of potent PR agonist and antagonist ligands that could have therapeutic uses in women's health.

Pharmacologic properties of CDB(VA)-2914.

CDB(VA)-2914 (17alpha-acetoxy-11beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione) is a synthetic steroid that demonstrates potent progesterone antagonist activity in vitro and in vivo. Its binding and antagonist potency with respect to the glucocorticoid receptor is significantly reduced compared to that of mifepristone, indicating that CDB(VA)-2914 belongs to a new class of dissociated progesterone receptor modulators that have reduced antiglucorticoid activity. The pharmacological effects of CDB(VA)-2914 have been examined in a variety of animal models, the results of which are reviewed in this paper. CDB(VA)-2914 inhibits ovulation in rats in a dose-dependent manner upon single-dose oral administration and exhibits antifertility activity during continuous low-dose administration. CDB(VA)-2914 is also effective in animal models of postcoital contraception. This paper also presents the results of metabolism studies undertaken to link the results of the animal models to potential human applications. Because of its unique pharmacological profile, CDB(VA)-2914 is a promising candidate for use in contraception as well as treatment of uterine fibroids and endometriosis.

Surfing on the morning after: analysis of an emergency contraception website.

The introduction of widespread nonprescription delivery of hormonal emergency contraception (EC) calls for development of innovative tools to provide information to and gather feedback from EC users. Individuals seeking confidential information on sexual health and contraception are increasingly turning to the Internet as the resource of choice. This study employed analytical software and manual content analysis to examine the use of a website dedicated to an EC product (www.norlevo.com) over the course of 2 years. Frequency of visits to and pageviews of the site increased consistently over the 2-year time period, and the bulk of the visitors to the site were EC users seeking responses to frequently asked questions. The most common concern raised by users was the occurrence of spotting and menstrual bleeding following EC use. This analysis reveals that within the context of nonprescription access to hormonal EC, a website can constitute a potent educational tool for health professionals and EC users and provide a valuable source of post-marketing feedback on product use.