Effects of a novel estrogen-free, progesterone receptor modulator contraceptive vaginal ring on inhibition of ovulation, bleeding patterns and endometrium in normal women.

BACKGROUND: Progesterone receptor modulators (PRMs) delivered by contraceptive vaginal rings provide an opportunity for development of an estrogen-free contraceptive that does not require daily oral intake of steroids. The objective of this proof-of-concept study was to determine whether continuous delivery of 600-800 mcg of ulipristal acetate (UPA) from a contraceptive vaginal ring could achieve 80% to 90% inhibition of ovulation. STUDY DESIGN: This was a prospective, controlled, open-labeled, multicenter international trial to examine the effectiveness and safety of this prototype vaginal ring. Thirty-nine healthy women, 21-40 years old and not at risk of pregnancy, were enrolled at three clinic sites. Volunteers participated in a control cycle, a 12-week treatment period and a post-treatment cycle. Pharmacodynamic effects on follicular function and inhibition of ovulation, effects on endometrium, bleeding patterns and serum UPA levels were evaluated. RESULTS: Mean UPA levels during treatment were nearly constant, approximately 5.1 ng/mL throughout the study. Ovulation was documented in 32% of 111 "4-week treatment cycles." A correlation was observed between serum UPA and degree of inhibition of ovarian activity. There was no evidence of hyperplasia of endometrium, but PRM-associated endometrial changes were frequently observed (41%). CONCLUSION: In this study, the minimum effective contraceptive dose was not established. Further studies are required testing higher doses of UPA to attain ovulation suppression in a higher percentage of subjects.

Severity of infection following the introduction of new infection control measures for medical abortion.

BACKGROUND: In response to concerns about serious infections following medical abortion, in early 2006 the Planned Parenthood Federation of America changed the route of misoprostol administration from vaginal to buccal and required either routine antibiotic coverage or universal screening and treatment for chlamydia; in July 2007, the Planned Parenthood Federation of America began requiring routine antibiotic coverage for all medical abortions. We previously reported a pronounced drop in the rate of serious infections following the adoption of these new infection control measures. Our objective in this study was to assess whether the degree of severity of the serious infections differed in the three infection control groups (vaginal misoprostol and no antibiotics; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, to assess whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories. Of particular importance is whether the new infection control measures selectively reduced the least severe serious infections but did not diminish the rate of the most severe infections. METHODS: We performed a retrospective analysis assessing the degree of severity of infections before infection controls were implemented and after each of the two new measures was adopted: buccal administration of antibiotics with either screen-and-treat method or routine antibiotic coverage. We ranked the severity of infection from 1 (when treatment occurred in an emergency department) to 4 (when death occurred). We compared the distributions of the severity of serious infections in the three infection control groups (none; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, assessed whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories using the Jonckheere-Terpstra test for a doubly ordered 4 × 3 table. RESULTS: The distribution of infection by severity was the same for all three infection control groups. Likewise, when the two new infection control groups--buccal misoprostol plus either screen-and-treat method or routine antibiotics--were combined, the distribution of infection by severity was the same before and after the new measures were implemented. CONCLUSION: The pronounced decline in the rate of serious infections occurred in each category of severity.

State-of-the-art of non-hormonal methods of contraception: I. Mechanical barrier contraception.

Mechanical barriers, specifically male condoms, command renewed interest and are used today by more people. The worldwide prevalence rate of male condoms was about 6% in 2007 corresponding to 65 million cohabiting couples. The prevalence of female barrier methods, including diaphragms, cervical caps and female condoms has declined to less than 1% of women in North America and in north-west Europe. Even smaller percentages use female barriers elsewhere. First-year life table pregnancy probabilities of mechanical barrier methods range from 4 to 19 per hundred in clinical trials. The male condom is the only proved preventive tool against several sexually transmitted infections (STIs), especially HIV. The effectiveness of the diaphragm and cervical caps in this regard appears limited. Further research is needed to measure the efficacy of female condoms in disease prevention. Sponges are not known to protect against STIs. Because of their ease of use and availability, low short-term costs, relative freedom from side effects, and usefulness in combating STIs, mechanical barrier methods, especially condoms, will continue to be used on a large scale. For our literature search we used personal files, search engines such as Popline, Medline, PubMed and Google, and data bases of WHO, FHI and Cochrane Library.

State-of-the-art of non-hormonal methods of contraception: III. Intrauterine devices.

Since the 1959 revival of the IUD, non-hormonal devices have become the most widely used of all reversible contraceptives. Pregnancy rates of copper-releasing IUDs in current use range from approximately 0.5 to 1.5 per hundred continuing users in the first year, with somewhat lower annual pregnancy rates thereafter. Evidence-based research has been systematically conducted and translated into guidelines for eligibility criteria and problem management. Recent device research, beyond the T, Multiload and frameless devices has centred on improved designs such as U ,Y and Slimline shapes, or enhanced copper release, the latter through electrochemical effects or nanotechnology applications. Other IUD research foci concern devices that decrease bleeding and pain by releasing non-steroidal anti-inflammatory drugs. Yet other research lines indicate noncontraceptive benefits of copper intrauterine devices in protecting against endometrial cancer, and favourable risk-benefit analyses of IUD use by women at risk of or post HIV infection. IUD mechanisms of action and the relation of IUDs to pelvic infection and ectopic pregnancy are briefly reviewed. For our literature search we used Medline, Popline and Cochrane Library data bases, Google search, our personal files, and the references contained in articles in our files.

State-of-the-art of non-hormonal methods of contraception: IV. Natural family planning.

Despite the popularity of 'modern' contraceptives, natural family planning (NFP), including fertility awareness-based (FAB) methods and withdrawal, are practised in most countries. Worldwide FAB methods and withdrawal are used, respectively, by about 3.6% and 2.9% of all couples of reproductive age. This article describes the underpinnings of the different NFP methods, their rationales, histories, rules for use, efficacy and in broad categories their prevalence. Pregnancy rates of FAB methods with perfect use have ranged between 0.3 and 5.0 per 100 users per year, but typical use rates rises into the teens or higher. Withdrawal requires the male partner to be aware of his impending climax and to pull out of the vagina before ejaculation. Perfect use and typical pregnancy rates for withdrawal are estimated to be 4 and 27 per 100 per year, respectively. Many couples find NFP in accord with their own beliefs, satisfactory in its effectiveness and useful in planning a desired pregnancy. Many prize their self-control in practising NFP or withdrawal. In our research we used Medline, Popline and the Cochrane Library search engines in English, local institutional libraries, our own files in our native languages, the literature references contained therein, and source recommendations from colleagues.

Effectiveness of medical abortion with mifepristone and buccal misoprostol through 59 gestational days.

BACKGROUND: From 2001 to March 2006, Planned Parenthood Federation of America (Planned Parenthood) health centers throughout the United States provided medical abortions principally by a regimen of oral mifepristone, followed 24-48 h later by vaginal misoprostol. In late March 2006, analyses of serious uterine infections following medical abortions led Planned Parenthood to change the route of misoprostol administration and to employ additional measures to minimize subsequent serious uterine infections. In August 2006, we conducted an extensive audit of medical abortions with the new buccal misoprostol regimen so that patients could be given accurate information about the success rate of the new regimen. OBJECTIVES: We sought to evaluate the effectiveness of the buccal medical abortion regimen and to examine correlates of its success during routine service delivery. METHODS: In 2006, audits were conducted in 10 large urban service points to estimate the success rates of the buccal regimen. Success was defined as medical abortion without vacuum aspiration. These audits also permitted estimates of success rates with oral misoprostol following mifepristone in a subset in which 98% of the subjects stemmed from two sites. RESULTS: The effectiveness of the buccal misoprostol-mifepristone regimen was 98.3% for women with gestational ages below 60 days. The oral misoprostol-mifepristone regimen, used by 278 women with a gestational age below 50 days, had a success rate of 96.8%. CONCLUSION: In conjunction with 200 mg of mifepristone, use of 800 mcg of buccal misoprostol up to 59 days of gestation is as effective as the use of 800 mcg of vaginal misoprostol up to 63 days of gestation.

Unexpected heaping in reported gestational age for women undergoing medical abortion.

BACKGROUND: In August 2006, the Planned Parenthood Federation of America (Planned Parenthood) conducted an extensive audit of first-trimester medical abortions with oral mifepristone plus buccal misoprostol through 56 days of gestation so that patients could be given accurate information about the success rate of the new regimen. OBJECTIVES: We sought to evaluate the effectiveness of this buccal misoprostol regimen and to examine correlates of its success during routine service delivery. METHODS: Audits in 10 large urban service points were conducted in 2006 to estimate the success rates of the buccal regimen. Success was defined as medical abortion without vacuum aspiration. RESULTS: We discovered unexpected heaping of reported gestational age (GA) on days divisible by 7. CONCLUSION: Such heaping, which has not been reported in the literature, would make it more difficult to detect a modest trend in declining effectiveness with increasing GA, if there were one. High coefficients of variation of sac size and crown-rump length characterize the early gestational weeks. We suspect, but are unable to prove, that the source of the heaping found in our investigation is a tendency for operators of ultrasound machines at some sites to simplify reporting by rounding a portion of the results to a date corresponding to the nearest complete gestational week. We believe that immediate supervisory awareness and feedback may reduce the extent of the problem. However, the problem may persist in multiple-site studies given the underlying variability of ultrasound measurements with differently calibrated machines and different rules for recording data, some of which may permit acceptance of an estimate based on the stated date of the last menses, if it differs by no more than 2 or 3 days from the ultrasound result.

Rates of serious infection after changes in regimens for medical abortion.

BACKGROUND: From 2001 through March 2006, Planned Parenthood health centers throughout the United States provided medical abortion (abortion by means of medication) principally by a regimen of oral mifepristone followed 24 to 48 hours later by vaginal misoprostol. In response to concern about serious infections, in early 2006 Planned Parenthood changed the route of misoprostol administration from vaginal to buccal and required either routine provision of antibiotics or universal screening and treatment for chlamydia; in July 2007, Planned Parenthood began requiring routine treatment with antibiotics for all medical abortions. METHODS: We performed a retrospective analysis assessing the rates of serious infection after medical abortion during a time when misoprostol was administered vaginally (through March 2006), as compared with rates after a change to buccal administration of misoprostol and after initiation of additional infection-reduction measures. RESULTS: Rates of serious infection dropped significantly after the joint change to buccal misoprostol from vaginal misoprostol and to either testing for sexually transmitted infection or routine provision of antibiotics as part of the medical abortion regimen. The rate declined 73%, from 0.93 per 1000 abortions to 0.25 per 1000 (absolute reduction, 0.67 per 1000; 95% confidence interval [CI], 0.44 to 0.94; P<0.001). The subsequent change to routine provision of antibiotics led to a further significant reduction in the rate of serious infection - a 76% decline, from 0.25 per 1000 abortions to 0.06 per 1000 (absolute reduction, 0.19 per 1000; 95% CI, 0.02 to 0.34; P=0.03). CONCLUSIONS: The rate of serious infection after medical abortion declined by 93% after a change from vaginal to buccal administration of misoprostol combined with routine administration of antibiotics.

Effect of sexual intercourse on the absorption of levonorgestrel after vaginal administration of 0.75 mg in Carraguard gel: a randomized, cross-over, pharmacokinetic study.

BACKGROUND: The Population Council studied a pre-coital contraceptive microbicide vaginal product containing levonorgestrel (LNG) as active component and Carraguard gel as a vehicle (Carra/LNG gel) for couples who engage in occasional unplanned intercourse. The objective of this study was to evaluate the effect of sexual intercourse after vaginal application of Carra/LNG gel on serum levels of LNG in women and to assess LNG absorption by the male partner. STUDY DESIGN: This was a randomized, cross-over, pharmacokinetic study including an abstinence arm and an arm in which couples engaged in sexual intercourse between 2 and 4 h after gel application. In each study arm, each woman received a single application of Carra/LNG gel (0.75 mg in 4 mL gel) followed by serial blood samples taken at 0, 1, 2, 4, 8, 24 and 48 h after gel application for LNG measurements. In the intercourse arm, LNG was measured in blood samples taken from the male partner before intercourse and at 4, 8 and 24 h after gel application in the female partner. RESULTS: Time concentration curves for serum LNG levels showed a mean C(max) of 7.8+/-5.5 and 8.3+/-5.7 nmol/L, a mean T(max) of 6.2+/-5.9 and 7.5+/-5.7, and comparable area under the curve for the intercourse and abstinence arm, respectively. Pharmacokinetic parameters presented large variability between subjects, but excellent reproducibility within each subject. LNG was undetectable in 10 out of 12 male partners. CONCLUSION: Sexual intercourse does not appear to interfere with vaginal absorption of LNG after application of a Carra/LNG gel. A vaginal pre-coital contraceptive gel is feasible.

Comparison of the impact of vaginal and oral administration of combined hormonal contraceptives on hepatic proteins sensitive to estrogen.

OBJECTIVE: We evaluated the effects of a new combined hormonal contraceptive vaginal ring (CVR) delivering the nonandrogenic progestin Nestorone (NES) and ethinyl estradiol (EE) on several key estrogen-sensitive hepatic proteins that may be markers for the risk of arterial or venous disease events and on blood pressure (BP). Because the pharmacologic androgenicity of the progestin in these formulations influences the hepatic impact of EE, we selected an oral contraceptive (OC) delivering the androgenic progestin levonorgestrel (LNG) and EE as the comparator. We also investigated the effect of delivery route, which is known to modify the hepatic effects of estradiol, but has not been widely studied with EE. STUDY METHODS: Women, aged 18-34 years, with no contraindications to the use of combined OCs, were randomized to three cycles of treatment with a CVR delivering NES/EE (150/15 microg/day) or a combined OC providing LNG and EE (150/30 microg per tablet). Each cycle consisted of 21 days of active treatment, followed by 7 days without treatment. During the last weeks of the pretreatment and third treatment cycles, blood samples were obtained for determinations of plasma concentrations of angiotensinogen, an estrogen-sensitive hepatic protein, and serum concentrations of sex hormone-binding globulin (SHBG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and estrogen- and androgen-sensitive proteins. BP was also measured. RESULTS: Of 47 women randomized, 45 completed the study (CVR: 23; OC: 22). Within-group comparisons over time by repeated-measure analysis of variance demonstrated statistically significant changes over time with both treatments for all hepatic proteins (p < .02) but not for TC. The within-group effects, presented as relative percent difference [95% confidence interval (CI)], were greatest for angiotensinogen [CVR: 227% (195-262%); OC: 251.3% (218-288%)] and SHBG [CVR: 306% (237-389%); OC: 55% (30-86)]. Both treatments were associated with small changes in systolic BP and diastolic BP (DBP), but only the within-group change in DBP for the OC group was statistically significant (p = .04). Between-treatment comparisons of third treatment cycle mean values were performed by analysis of covariance (baseline values as covariate). No statistically significant between-treatment differences were found for angiotensinogen, sensitive only to estrogen, or BP. Statistically significant treatment differences were found for all estrogen- and androgen-sensitive proteins (p < or = .002) but not for TC. When presented as relative percent difference between the effects of treatment (CVR-OC/OC; 95% CI of percent difference), the difference was largest for SHBG (159% [117-210%]); smaller relative percent differences were found for HDL-C [31.9% (18.5-46.8%)], LDL-C [23.6% (33.4% to -2.4%)] and TG [39.0% (14.0-69.4%)], but not TC. CONCLUSION: Vaginal delivery of a combined hormonal contraceptive did not reduce the EE-associated changes in estrogen-sensitive hepatic proteins observed after use of a combined OC. Significant treatment differences between the NES/EE CVR and the LNG/EE OC were found for SHBG, HDL-C, LDL-C, and TG, proteins sensitive to androgen as well as estrogen. No treatment difference was observed for angiotensinogen, which is sensitive only to estrogen. The observed treatment differences were therefore most likely due to the difference in androgenicity between NES and LNG.

Utility and drawbacks of continuous use of a copper T IUD for 20 years.

This article examines interrelated questions concerning the extent of need for contraception in women 40 years and older and the degree to which that need can be served when use of collared T IUDs is initiated in women aged 25-35 years. Differentials in the impacts of intrauterine device (IUD) use on health issues in the second decade of contraception are also addressed. Although fertility of all women aged 40-44 years is below 100 per 1000 in all regions of the world today, the risk of pregnancy among married or cohabiting women who do not use contraception is estimated at 270-300 per 1000 or 27-30% per year. At ages 45-49 years, the annual risk of pregnancy to women in union who do not use contraception lies at or above 10% per year. Data from three studies show that users of collared copper IUDs who continued using the same device beyond the completion of 10 years experienced no pregnancies through the end of 15 years. A small number of women continued with the same IUD through 20 years and still experienced no pregnancies. Use of collared copper T IUDs beyond 10 years was not associated with intensification of side effects nor with an increase in the relative frequency of those effects, with the exception of the experience of perimenopausal symptoms and problems. Neither increased bleeding nor increased severity of pelvic disease was manifest in the second decade of continuous use of the same IUD, as compared with the first decade of such use. Under our current understanding of the duration of IUD effectiveness, only a small percentage of women complete 10 years of use. Even with revised understanding of the duration of effectiveness of long-acting copper devices, average annual continuation rates must be quite high in order that 20% of women aged 25-35 years initiate a second decade of continuous IUD use. Those who do so would find considerable protection against pregnancy and reasonable economic benefits in continuing to use the same device.

Local and systemic effects of intranodally injected CpG-C immunostimulatory-oligodeoxyribonucleotides in macaques.

Immunostimulatory CpG-C oligodeoxyribonucleotides (ISS-ODNs) represent a promising strategy to enhance vaccine efficacy. We have shown that the CpG-C ISS-ODN C274 stimulates macaque blood dendritic cells (DCs) and B cells and augments SIV-specific IFN-gamma responses in vitro. To further explore the potential of C274 for future vaccine studies, we assessed the in vivo effects of locally administered C274 (in naive and healthy infected macaques). Costimulatory molecules were marginally increased on DCs and B cells within cells isolated from C274-injected lymph nodes (LNs). However, cells from C274-injected LNs exhibited heightened responsiveness to in vitro culture. This was particularly apparent at the level of CD80 (less so CD86) expression by CD123(+) plasmacytoid DCs and was further boosted in the presence of additional C274 in vitro. Notably, cells from C274-injected LNs secreted significantly elevated levels of several cytokines and chemokines upon in vitro culture. This was more pronounced when cells were exposed to additional stimuli in vitro, producing IFN-alpha, IL-3, IL-6, IL-12, TNF-alpha, CCL2, CCL3, CCL5, and CXCL8. Following C274 administration in the absence of additional SIV Ag, endogenous IFN-gamma secretion was elevated in LN cells of infected animals, but SIV-specific responses were unchanged. Endogenous and SIV-specific responses decreased in blood, before the SIV-specific responses rebounded by 2 wk after C274 treatment. Elevated IFN-alpha, CCL2, and CCL5 were also detected in the plasma after C274 injection. Thus, locally administered C274 has local and systemic activities, supporting the potential for CpG-C ISS-ODNs to boost immune function to enhance anti-HIV vaccine immunogenicity.

Comparative effects of a contraceptive vaginal ring delivering a nonandrogenic progestin and continuous ethinyl estradiol and a combined oral contraceptive containing levonorgestrel on hemostasis variables.

OBJECTIVE: This study aimed to compare the effects on hemostasis variables of a contraceptive vaginal ring with those of an oral contraceptive. STUDY DESIGN: Twenty-three and 22 healthy premenopausal women were randomized to the contraceptive vaginal ring (150 microg Nestorone and 15 microg ethinyl estradiol) or Stediril 30 during 3 cycles. Analysis of covariance was performed with baseline values as covariate. RESULTS: The contraceptive vaginal ring changed most hemostasis variables similarly but raised (95% confidence intervals of percent treatment differences) Factor VIIt (28% to 49%), extrinsic activated protein C resistance (14% to 65%), and sex hormone-binding globulin (117% to 210%) and lowered Protein S (-32% to -16%) and the global activated partial thromboplastin time-based activated protein C resistance (-12% to -2%) more than the oral contraceptive. CONCLUSION: The contraceptive vaginal ring affected some measured hemostasis variables and sex hormone-binding globulin differently from the oral contraceptive, most likely because of difference in androgenicity of the progestins. The results suggest that the contraindications for oral contraceptive use would also apply to the tested contraceptive vaginal ring.

Serum Nestorone and ethinyl estradiol levels, and ovulation inhibition in women using three different dosage combinations of a Nestorone progestogen-ethinyl estradiol contraceptive vaginal ring on a bleeding-signaled regimen.

OBJECTIVES: This trial tested the hypothesis that menstrually signaled use of contraceptive vaginal rings ("rings") releasing low-dose combinations of Nestorone (NES) and ethinyl estradiol (EE) would reliably suppress luteal activity and ovulation, and prevent unintended pregnancy, while controlling the incidence of menstrual bleeding episodes and bleeding days. METHODS: Nestorone/ethinyl estradiol rings releasing 50/10, 50/20 and 150/15 mug/day were studied through 6 months. A ring was to be used continuously, until its removal was signaled by menstrual bleeding. Reinsertion was required 96 h after removal. Serum for NES, EE and progesterone were collected and assayed, and vaginal ultrasound scans were performed in three 5-week periods to examine luteal activity, follicular growth, ovulation and their correlates. In 10 subjects using the 150/15 ring, six samples were drawn in the 24-h period after ring removal to examine serum levels of NES and EE. RESULTS: One hundred sixty subjects at three doses provided blood samples. Median serum concentrations of NES and EE demonstrated dose ratios slightly below the nominal dose ratios expected. Serum NES concentrations declined 19-22% from weeks 3 to 25. Changes in EE levels depended on dose. Nestorone levels fell 81% by 24 h after ring removal and EE levels fell by 50%. Luteal activity was completely suppressed in 94-95% of cycles and in 90% of subjects. Three pregnancies occurred in subjects participating in this serum sampling study. CONCLUSION: Satisfactory serum levels of NES and EE, and a high level of ovulation suppression were achieved. Irregular ring use, however, permitted pregnancies to occur.

Clinical performance and menstrual bleeding patterns with three dosage combinations of a Nestorone progestogen/ethinyl estradiol contraceptive vaginal ring used on a bleeding-signaled regimen.

OBJECTIVE: We examined the clinical performance of contraceptive vaginal rings (rings) delivering Nestorone (NES) progestin and ethinyl estradiol (EE). Ring removal times were signaled by menstrual events. Bleeding patterns, adverse events, patterns of use and continuation rates were the principal parameters evaluated. METHODS: In a two-stage 6-month trial, subjects were randomized to use rings releasing 50 microg/day of NES and either 10 (50/10) or 20 (50/20) microg/day of EE. Subjects were to keep rings continuously in situ until menstrual bleeding or prolonged spotting-signaled removal. Reinsertion was to occur 96 h later. After the randomized stage, an open-label 6-month trial of rings releasing 150 microg/day of NES and 15 microg/day of EE (150/15) began with the same menstrually signaled regimen. RESULTS: Two-hundred forty-six subjects participated in the trial. Six-month pregnancy rates ranged by ring dose from 1.3 to 3.9 per 100. For each ring dose combination, 6-month continuation rates were above 80 per 100. Bleeding and spotting (B+S) days in women with the 50 microg/day NES rings were similar in number to those experienced by cycling women not using contraception. Nevertheless, in the initial 90 days, fewer B+S days were reported by subjects with the 50/20 ring than by subjects with the 50/10 ring (p < .05). Throughout the trial, subjects using the 150/15 ring reported significantly fewer B+S episodes than did subjects with either 50 microg/day NES ring. CONCLUSION: Combined contraceptive rings used with a bleeding-signaled regimen led to few terminations attributed to bleeding problems and to acceptable continuation rates. The 150/15 ring appeared to induce fewer bleeding problems than did the lower-dose NES combination rings, but no important difference in 6-month continuation rates among the three doses was noted.

Contraceptive vaginal rings releasing Nestorone and ethinylestradiol: a 1-year dose-finding trial.

In a multicenter 1-year trial of contraceptive vaginal rings (rings) involving 150 women, three dose combinations of the progestin Nestorone (NES) and ethinylestradiol (EE) were compared with respect to effectiveness, safety and acceptability. Mean in vitro drug release rates for the three doses were 150 and 15, 150 and 20 and 200 and 15 microg/day of NES and EE, respectively. Each ring remained in situ for 21 days, removed for 7 days and then reinserted for a total of 13 cycles of use. We studied ring performance with respect to pregnancy and other termination events, adverse events, the extent of ovulation inhibition, serum drug levels and bleeding control. We also assessed the rings' effects on the vagina using a standardized colposcopy procedure. Seventy-two percent of the women completed the 1-year (> or = 350 days) study. In studied cycles, luteal activity (progesterone > or = 10 nmol/L) was noted in 17%, 7% and 12% of subjects with monitored cycles at the 150/15, 150/20 and 200/15 doses, respectively (p = .34). Two pregnancies occurred, both in subjects using the 200/15 microg/day ring. Breakthrough bleeding during ring use averaged about 2 days/year and breakthrough bleeding and spotting averaged about 7 days/year. In the entire trial, only two women discontinued because of bleeding problems. Medical conditions, chiefly vaginal problems, personal reasons and device loss or repeated expulsion were the principal reasons given for study discontinuation. Vaginal and cervical colposcopy, conducted with standardized techniques and standardized interpretations, revealed no elevated event incidence attributable to ring use. Clinical performance and adverse event profiles indicate that each of these 1-year NES/EE rings, used on a 21-day-in and 7-day-out regimen, provided women effective, acceptable and safe long-acting contraception under their own control.