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.

The use of sex hormones in women with rheumatological diseases.

A number of rheumatological diseases predominantly affect women of reproductive age. There has always been concern that the use of oestrogen-containing agents such as combined hormonal contraception and hormone therapy might aggravate these conditions. This article reviews the up-to-date evidence regarding the safety of using these agents in women with various rheumatological diseases, with emphasis on systemic lupus erythematosus and rheumatoid arthritis. In the absence of antiphospholipid antibody or other prothrombotic risk factors, combined hormonal contraception is not contra-indicated in most rheumatological conditions including inactive systemic lupus erythematosus. Moreover, hormone therapy is generally not contra-indicated except for women with active systemic lupus erythematosus disease where its effect on disease flare is less clear and individual judgement is required.

Pregnancy during breastfeeding in rural Egypt.

BACKGROUND: Breastfeeding does not reliably protect against pregnancy except during the first 6 months postpartum and only then if accompanied by amenorrhea. Reluctance to use other methods of contraception during lactation may result in unplanned pregnancy. The aims of this study were to describe, among women in rural Egypt attending for antenatal care the prevalence of pregnancy during breastfeeding, contraceptive practice and unintended pregnancy. Finally, the study assessed women's impressions of the effect of conception during breastfeeding on breast milk and on the health of the breastfed infant. STUDY DESIGN: A descriptive study using an interviewer-administered structured questionnaire for 2617 parous women attending a hospital in Egypt for antenatal care. RESULTS: More than 95% of women breastfed the child before their current pregnancy; 25.3% conceived while breastfeeding. Conception occurred during the first 6 months postpartum in 4.4%, before resumption of menstruation in 15.1% and while exclusively or almost exclusively breastfeeding in 28.1%. Only 10 pregnancies (1.5%) occurred when all the prerequisites of the lactational amenorrhea method of contraception (LAM) were present. Twenty-nine percent of pregnancies conceived during breastfeeding were unintended, 10% of women had considered terminating their pregnancy while 4.4% of them reported trying to do so. CONCLUSIONS: Pregnancy during breastfeeding is common in Egypt and is often unintended. There is great potential for using LAM, but it must be properly taught, and women should be encouraged to start using effective contraception as soon as any of the prerequisites of LAM expires.

Changes in vaginal morphology, steroid receptor and natural antimicrobial content following treatment with low-dose mifepristone.

BACKGROUND: We have previously shown that the antigestagen mifepristone is contraceptive when given in a daily dose of 5 mg, po. Epidemiological studies suggest that gestagen-only contraceptives may increase the risk of transmission of human immunodeficiency virus (HIV) due to effects on the vaginal defenses to infection. We investigate the effects of mifepristone on vaginal thickness, steroid receptor and natural antimicrobial content and pharmacokinetics of mifepristone. METHODS: In a pilot study, eight women were given mifepristone 5 mg/day for an average of 33 days. Ovarian function was assessed by measurement of estradiol and progesterone in blood and their metabolites in urine and by serial ultrasound of their ovaries. Vaginal biopsies were collected before (late proliferative) and after taking mifepristone. RESULTS: All subjects showed a similar pattern of descending serum concentrations of mifepristone. The elimination phase half-life was 18+/-5.1 h (mean+/-SD). Mean Cmax measured at 1 h was 641.7 nmol/L (range, 502-740 nmol/L). All eight women reported amenorrhea for the duration of treatment and seven of eight women showed biochemical and ultrasound evidence of anovulation. There was no significant change in vaginal thickness following treatment [342+/-40 microm pretreatment, 303+/-69 microm posttreatment (mean+/-SEM); p>.05]. Estrogen (ERalpha, ERbeta) and androgen receptor were expressed in both vaginal epithelium and subepithelial stroma, whereas progesterone receptor was expressed predominantly in the subepithelial stroma. There was no change in receptor content and distribution following mifepristone treatment. Natural antimicrobial mRNA [secretory leukocyte protease inhibitor, human beta defensins mRNA (HBD1, HBD2, HBD3, HBD5), granulysin and elafin] was extracted from the vaginal tissues, and the content was unaffected by mifepristone treatment. CONCLUSION: The absence of changes in vaginal thickness, steroid receptor and natural antimicrobial content and its distribution in this preliminary study suggests that in contrast to other estrogen-free contraceptives, mifepristone is unlikely to be associated with the increased risk of transmission of HIV and other sexually transmitted infections.

Comparison of a transdermal continuous combined and an interrupted progestogen HRT.

OBJECTIVES: Pilot study to compare the effects of a continuous combined hormone replacement therapy (HRT) regimen with an interrupted progestogen regimen administered transdermally, upon the endometrium of postmenopausal women, the incidence of amenorrhoea and relief of menopausal symptoms. METHODS: Fifty-nine postmenopausal women aged 50-63 years were randomised to either (i) continuous combined regimen: combined oestrogen/progestogen skin patches (releasing continuous 50 microg estradiol and 20 microg levonorgestrel/day) or (ii) interrupted regimen: oestrogen-only patches (releasing 80 microg estradiol/day) for 4 days followed by combined oestrogen/progestogen patches (releasing continuous 50 microg estradiol and 20 microg levonorgestrel/day) for 3 days, for 6 months. An endometrial biopsy was performed at end of treatment for histological analysis. RESULTS: Thirty-three women (56%) completed the study. Significantly higher rates of amenorrhoea were observed with the interrupted than continuous combined regimen (P<0.0001; 25% versus 7% at 6 months). The interrupted regimen was also associated with fewer days of bleeding overall (total 20 versus 44 days during months 4-6; P=0.001). Both regimens improved vasomotor symptoms. No endometrial hyperplasia or atypical changes were observed in endometrial biopsies. CONCLUSIONS: Although significantly less bleeding was observed with the interrupted regimen, it did not have a sufficiently high incidence of amenorrhoea to render it clinically useful.

Continuation rates of Implanon in the UK: data from an observational study in a clinical setting.

BACKGROUND: Long-acting reversible methods of contraception can potentially reduce unintended pregnancy. There are few data on "real-life" continuation rates of the contraceptive implant Implanon. MATERIALS AND METHODS: Three hundred twenty-four women choosing Implanon in a community family planning clinic in Scotland were followed up by case note review (n=236) or postal questionnaire (n=87) 3 years after insertion of the implant (1 woman chose not to disclose her home address). RESULTS: Data were available for 85% of the women. Continuation rates were 89% (CI 84-91) at 6 months, 75% (CI 69-79) at 1 year, 59% (CI 52-63) at 2 years and 47% (CI 40-52) at 2 years and 9 months. Of the 68 women who discontinued Implanon within 1 year, 62 (91%) did so because of unwanted side effects, the most common being frequent and/or unpredictable bleeding (n=42, 62%). Almost half changed to a less-effective method of contraception; however, one third (n=99, 39%) chose to use a second implant when the first one expired. CONCLUSIONS: Continuation rates of Implanon in this clinic setting in the UK make it a cost-effective method of contraception and justify its widespread provision.

Combined hormonal contraception and bone health: a systematic review.

This systematic review examined whether women who use combined hormonal contraception experience changes in risk of fracture or bone mineral density (BMD) that differ from nonusers. We identified 86 articles from PubMed and EMBASE (published 1966 to August 2005) that reported on fracture or BMD outcomes by use of combined hormonal contraceptives. The evidence relating to combined oral contraceptives (COCs) and fracture is inconclusive, as results from the available studies conflict. Studies of adolescent and young adult women generally found lower BMD among COC users than nonusers. Evidence for premenopausal adult women suggested no differences in BMD between COC users and nonusers. COC use in perimenopausal and postmenopausal women preserved bone mass, while nonusers lost BMD, but BMD among former COC users in this age group was the same as for never-users. Evidence for other combined hormonal methods was very limited, with one study indicating no effect of combined hormonal injectable use among premenopausal women on BMD and one study suggesting lower BMD among premenopausal users of the NuvaRing than in nonusers.

Administration of an antiprogesterone up-regulates estrogen receptors in the endometrium of women using Norplant: a pilot study.

OBJECTIVE: To determine the effect of a single dose of mifepristone (200 mg) on endometrial estrogen and progesterone receptors in Norplant users. DESIGN: A prospective single-blind placebo-controlled pilot study. SETTING; Women were recruited from a large family planning clinic and were studied either at the clinic or in a clinical research unit attached to a teaching hospital gynecology department. PATIENT(S): Eight women using Norplant and experiencing vaginal bleeding more often than once every 24 days. All completed the study. INTERVENTION(S): Endometrial biopsies were taken after treatment with both placebo and 200 mg of mifepristone, both given at the start of a bleeding episode. MAIN OUTCOME MEASURE(S): Expression of endometrial progesterone (PR) and estrogen (ER) receptors, ovulation, and vaginal bleeding. RESULT(S): Mifepristone administration was associated with down-regulation of PR receptor subtype B and up-regulation of ER. Women treated with mifepristone showed a tendency to increased ovulation rates and reduced vaginal bleeding. CONCLUSION(S): The effect of mifepristone on endometrial steroid receptors was consistent with functional inhibition of progesterone. The findings warrant further investigation of this regimen as a strategy to reduce frequent bleeding.

Effects of onapristone on postmenopausal endometrium.

The progesterone antagonist mifepristone (RU486, Exelgyn) has been shown to exert a paradoxical agonist effect on postmenopausal endometrium. We conducted a study to investigate the effects of the 'pure' antiprogestin onapristone (ZK 98 299, Schering AG) on postmenopausal endometrium. Seventeen postmenopausal subjects (45-62 years), took 2 mg of oestradiol and either placebo, 1 mg onapristone or 10 mg of onapristone, daily for 56 days. An endometrial biopsy was performed during the final week of treatment and assessed for histology and immunohistochemistry for oestrogen receptors (ER), progesterone (PR), androgen receptors (AR) and the cell proliferation marker Ki 67. FSH fell in all 14 subjects who completed the study, consistent with the effect of oestradiol treatment. There was a dose-dependent additive effect of onapristone on suppression of gonadotrophins. All endometrial biopsies showed proliferative endometrium. A similar pattern and intensity of immunostaining of ER, PR and Ki 67 was observed in all groups, with positive immunoreactivity in both glands and stroma. AR immunostaining was observed in both glands and stroma from all subjects, but there was an increase in intensity of immunostaining within the glandular epithelium of women receiving 10 mg onapristone. The antiprogestin onapristone, in contrast to mifepristone, is not agonistic on postmenopausal endometrium and does not exert obvious antiproliferative effects. It does however cause a dose dependent suppression of FSH and LH release.

Effect of advanced provision of emergency contraception on women's contraceptive behaviour: a randomized controlled trial.

BACKGROUND: Emergency contraception (EC) can prevent pregnancy but is under-used. Advanced provision increases use but the effect on contraceptive behaviour varies. METHODS: Women aged 18-45 years, using less effective contraceptives, were randomized to either advanced provision of three courses of EC (intervention) or to obtaining each course from clinic (control). EC use and contraceptive behaviour were monitored for 1 year. RESULTS: In all, 1030 women were recruited in 6 months. The mean+/-SD number of courses of EC used in intervention versus control group was 0.56+/-1.2 versus 0.20+/-0.6 (P<0.001). In the intervention group, 47% women aged <26 years used at least one course of EC compared with 23% of older women (P<0.001). The majority of women used condoms before (intervention 89%, control 91%) and during the study (89% for both groups). Consistency of contraceptive use was higher during the study (65 versus 60% of women in both groups) (P<0.001). There were 17 unplanned pregnancies, eight in the intervention group, six of whom did not use EC in the conception cycle. CONCLUSIONS: Advanced provision increases EC use especially among young women in Hong Kong. Contraceptive choice and consistency of use remains the same even among young women.