Vaginal epithelial surface appearances in women using vaginal rings for contraception.

Vaginal inspections using colposcopy before insertion of contraceptive vaginal rings and at 2-month intervals during ring use were conducted on 169 users of four different formulations. The rings studied released Nestorone alone (50, 75, 100 g daily over 6 months); ethinyl estradiol: Nestorone (30:100 and 15:150 g daily over 6 months); ethinylestradiol:norethindrone acetate (20:1000 and 15:1000 g daily over 4 months); and ethinyl estradiol:norethindrone acetate (20:1000 g daily over 12 months). A total of 88 altered or atypical conditions of the vaginal surface appearance were recorded in 507 inspections (17.4% of inspections). Many of these atypical appearances were quite subtle. The incidence was significantly higher (p <0.01) than in the single pretreatment examinations (11 in 158 inspections; 7.0%), but closely matched that of a "control group" of sexually active women who were the subject of an earlier study by the same investigators. In that study, the incidence was 18% (57 atypical conditions in 317 inspections). In all, 83% of atypical conditions identified in the vagina during ring use had disappeared by the next scheduled colposcopy despite continued ring use. Findings of potential significance were conservatively defined as all ulcerations, those abrasions and ecchymoses that were >0.5 cm in any direction, and fields of five or more petechiae. Findings fitting those criteria comprised 30% of atypical conditions in ring users, 33% in the control group, and 27% pretreatment. The corresponding incidence as a percentage of inspections were 5.3%, 6. 0%, and 2.5% in the ring users, control groups, and pretreatment groups, respectively. These differences were not statistically significant. The findings suggest that the vaginal rings included in the studies contributed little, if at all, to clinically significant lesions or to total lesion incidence. Further definition would require a larger and longer-term study with matched controls.

Preliminary safety and acceptability of a carrageenan gel for possible use as a vaginal microbicide.

OBJECTIVE: We sought to determine the safety and acceptability of vaginal gel formulation PC-503 among low risk, abstinent women. The active ingredient was 2% pharmaceutical grade lambda carrageenan, a sulphated polymer that is generally recognised as safe by the US Food and Drug Administration. METHODS: 35 women in five sites applied 5 ml of the PC-503 gel vaginally once a day for 7 days while abstaining from sexual intercourse. Visual vaginal examinations were performed on days 1, 4, and 8. STI testing and vaginal pool Gram stain preparations were done on days 1 and 8. Participants were asked about product acceptability. RESULTS: 34 of the 35 women enrolled completed 7 days' use. Following product use, five reported mild symptoms including "bladder fullness," "genital warmth," or discomfort, and lower abdominal pain, and one had moderate pale yellow cervical discharge. Using the Nugent criteria, three women had bacterial vaginosis (BV) before and after use; three had BV before but not after, and two had BV after but not before. Most of the women found PC-503 to be pleasant or neutral in feel and smell and considered extra lubrication to be an advantage; however, one third found it to be messy. CONCLUSIONS: Vaginal use of PC-503 gel did not cause significant adverse effects in a small number of low risk, sexually abstinent women. Further testing in larger numbers of sexually active women is planned. A smaller volume of gel may be more acceptable to some women.

A comparative study of two contraceptive vaginal rings releasing norethindrone acetate and differing doses of ethinyl estradiol.

Two combined contraceptive vaginal rings (CVR) each releasing approximately 1 mg norethindrone acetate (NET-Ac) and either 20 micrograms or 15 micrograms ethinyl estradiol over 24 h were tested at three clinic sites in Los Angeles, San Francisco, and Sydney. A total of 61 women were enrolled to use the ring on a schedule of 3 weeks in/1 week out for four treatment cycles. Serum estradiol, progesterone, norethindrone (NET), and ethinyl estradiol (EE) levels were assayed twice weekly in all four treatment cycles. Both CVR performed well, with no pregnancies occurring and only one cycle of luteal activity suggestive of ovulation (serum progesterone > 32 nmol/L) occurring with each ring (0.9% of cycles with the 1/15 ring and 1.2% of cycles with the 1/20 ring). Although there was significantly more luteal activity in women using the 1/15 CVR (5.9% compared with 1.2% of cycles), only three cycles with a marked degree of luteal activity (progesterone > 10 nmol/L) occurred among compliant women. Serum levels of NET and EE were consistently elevated during use of both rings. There was no significant difference between serum levels with the two rings because of wide interindividual variations, although both NET and EE levels tended to be higher with the 1/20 ring. However, there was a significant difference in EE levels between the women in Los Angeles and Sydney using the same dose rings. Total cholesterol, HDL, and LDL cholesterol values were not significantly changed during treatment. Triglycerides increased but remained within the normal range. Overall cycle control was good with both formulations, but there was slightly more cycle disturbance with the lower dose ring. There was no change in mean body weight during the study, and individual weight changes appeared to be idiosyncratic. Side effects were infrequent and similar to those reported with other steroidal contraceptive methods. Three women complained of vaginal discharge, one with accompanying itch and one with a vaginal Candida infection in cycle 1. Overall, both of these EE/NET-Ac rings performed well, with only minor and mainly nonsignificant differences in effect on serum EE, NET, E2, and progesterone levels and lipids, and on vaginal bleeding patterns.

PIP: This study compares the performance of 2 combined contraceptive vaginal rings (CVRs) releasing 1 mg norethindrone acetate (NET-Ac) and either 20 or 15 mcg ethinyl estradiol (EE) over 24 hours. 61 women selected at 3 clinic sites in Los Angeles, San Francisco and Sydney were included. The performance of the 2 CVRs was determined by luteal activity, menstrual bleeding patterns, sum levels of EE and NET-Ac, and effects on serum lipoproteins. Results showed that both CVRs worked effectively: no pregnancies occurred, and there was only 1 cycle of luteal activity suggestive of ovulation (serum progesterone 32 nmol/l) with each ring (0.9% of cycles with the 1/15 ring and 1.2% of cycles with the 1/20 ring). Although there was more luteal activity in 1/15 CVR users, only 3 cycles with a significant level of luteal activity (progesterone 10 nmol/l) occurred among compliant users. Consistent elevation in serum levels of NET and EE was observed during use of both rings. A significant difference in EE levels was observed between women in Los Angeles and Sydney using the same dose of rings. There were no significant changes in the total cholesterol, HDL and LDL cholesterol values during treatment. The increase in triglycerides remained within the normal range while mean body weight showed no change. Side effects were infrequent and were similar to those associated with other steroidal contraceptives. Overall, both CVRs performed well, showing only minor and mainly nonsignificant differences in effect on serum EE, NET, E2, on progesterone levels and lipids, and on vaginal bleeding patterns.

Efficacy, bleeding patterns, and side effects of a 1-year contraceptive vaginal ring.

A combined contraceptive vaginal ring designed to last 12 months was tested at three clinic sites. This ring released approximately 1 mg of norethindrone acetate (NET-Ac) and 20 micrograms of ethinyl estradiol (EE) daily. A total of 60 women were enrolled to use the ring in a schedule of 3 weeks in/1 week out. Serum norethindrone (NET) and ethinyl estradiol (EE) levels were assayed twice weekly in cycles 6, 9, and 13. Mean NET concentrations between cycles 6 and 9 were relatively stable between 13 and 19 nmol/L but showed a 10%-21% decrease in all centers between cycles 9 and 13. Mean EE concentrations ranged from 75 to 103 pmol/L, but did not have the same decrease as NET between cycles 9 and 13. Cycles with progesterone peaks (> 9.6 nmol/L) compatible with some luteal activity occurred in 4% of cycles sampled in Sydney, 3% in Santo Domingo, and 26% in Los Angeles. Half of these cycles exhibited at least one progesterone value > 32 nmol/L with three of 18 occurring in noncompliant cycles. Heavier body weight was associated with increased probability of luteal activity. Based on serum estradiol peaks > 400 pmol/L, eight of 81 cycles appeared to have marked follicular activity with no luteal activity. No pregnancies occurred. Nausea was reported by about half the subjects in approximately 10% of the visits (mainly in the first 1-2 days in the first cycle immediately after ring insertion). Vomiting was reported by 20% of subjects early in the first cycle only. Headache was reported on occasion by nearly 50% of the women, but the relationship to ring use was uncertain. Vaginal discharge was reported by 17 women (82% of these were from one clinic). Of 60 women, 14 discontinued before completing the study, but only two discontinuations were for medical reasons. Small but statistically significant changes occurred in lipid levels in two of the three centers. All changes remained within normal limits and were similar to those seen with many oral contraceptives. It appears that this ring may perform slightly differently in different populations, but is a highly satisfactory method of contraception for many women. Minor modifications in design could provide higher levels of steroid release and in the later months of the ring life span would assure continuing high levels of contraceptive protection for heavier women.

PIP: This study determines the ovarian effects, contraceptive efficacy, and effects on serum levels of norethindrone acetate (NET-Ac) and ethinyl estradiol (EE) among women using a single contraceptive vaginal ring (CVR) cyclically over a period of 1 year. A total of 60 women were enrolled and used the ring according to a schedule of 3 weeks "in" and 1 week "out." Assays of serum norethindrone acetate (NET-Ac) ethinyl estradiol (EE) levels were taken twice weekly in cycles 6, 9, and 13. Despite luteal activity in some cycles, no pregnancies were noted within the 12-month study period. Heavier body weight was associated with increased probability of luteal activity. Mean serum levels decreased over the last 3 months of CVR use, accounting for the increase in luteal activity and possible ovulations in cycle 13. Among women in Sydney, by contrast with women in the other centers, a difference in the effect on lipids was seen. However, the changes in lipid levels were very small. The side effects were a little different from those experienced by women using a combined pill. Nausea and vomiting were largely confined to early cycles and most common in the first days of the first cycle. Weight gain was also not a problem, although there was a small mean increase in body weight over the 12-month treatment period. This study indicates that use of a single CVR releasing EE and NET-Ac over a period of 12 months constitutes an acceptable, safe and effective contraceptive method.

Variations in vaginal epithelial surface appearance determined by colposcopic inspection in healthy, sexually active women.

A total of 107 sexually active women, aged 18-35 years, was recruited through family planning clinics in four centres in different countries. Each woman underwent two or three gentle but thorough and systematic vaginal inspections using a consistent technique with colposcopic magnification over a 4-6 month period to look for changes in vaginal and cervical appearance which might be related to sexual intercourse, tampon use, contraceptive method used, cigarette smoking or other environmental factors. Obvious changes in appearance were photographed at x10 magnification. These 'appearances' or 'conditions' were classified according to a modification of the recommendations of a workshop sponsored by the World Health Organization, the Population Council and the Conrad Program. Most of these alterations in the appearance of the vaginal epithelium were judged to be of such minor clinical importance that they have been termed 'conditions' or 'changes in appearance' rather than 'lesions'. In all, 56 'conditions' or 'appearances' were noted in 314 inspections, the commonest being petechiae (53.6%). Potentially significant conditions justifying the term 'lesions' (three microulcerations, two ecchymoses, five abrasions and one mucosal tear; 3.5% of inspections) usually healed spontaneously and disappeared rapidly. The incidence of these conditions was highest when the inspections followed intercourse in the previous 24 h (25.2 versus 14.2%; P < 0.0008), or tampon use (32.4 versus 15.9%; P < 0. 0001). These processes may be regarded as a reflection of regular minor trauma to the vaginal epithelium.

A medical method of early pregnancy termination using tamoxifen and misoprostol.

A study was undertaken to determine whether ingestion of the selective estrogen receptor modulator tamoxifen followed by vaginal administration of the prostaglandin misoprostol would be an effective medical method of elective termination of early pregnancy. A clinical trial was conducted with a study group of 100 healthy women with pregnancies of 56 days gestational age or less who desired elective pregnancy termination. Each subject ingested 20 mg of tamoxifen once daily for 4 days followed 4 days later by intravaginal placement of four 200 micrograms tablets of misoprostol. If abortion did not occur within the next 24 h a second dose of 800 micrograms of misoprostol was given. The main outcome measures were incidence of complete abortion, hemoglobin levels, duration of vaginal bleeding, and incidence of side effects. Complete abortion occurred in 92 (92%, 95% CI 86.7, 97.3%) of 100 subjects. Of these 92 women, four aborted after ingesting tamoxifen without use of misoprostol, 84 within 24 h after receiving a single dose of misoprostol, one 21 days following a single dose of misoprostol, and three after a second dose of misoprostol was administered. There were six (6.0%) complete treatment failures and two (2%) incomplete abortions that required a dilatation and curettage. The mean duration of uterine bleeding was 8.1 days (range 1-34 days) and there was a median decrease in hemoglobin level of 0.50 g/dL (+2.2 to -4.7 g/dL). Vomiting occurred in 28% of subjects and diarrhea in 8%. These initial data suggest that ingestion of tamoxifen followed by intravaginal misoprostol may be an effective, easily administered, and inexpensive method to electively induce complete abortion in pregnancies of 56 days gestational age or less. Additional studies are necessary to determine whether the addition of tamoxifen increases the success rate compared with that obtained with the use of vaginally administered misoprostol by itself.

Contraception with two levonorgestrel rod implants. A 5-year study in the United States and Dominican Republic.

A 5-year trial of a two-rod contraceptive implant, which releases the progestin levonorgestrel (LNG rod), was conducted at four clinics with 594 women. Mean age and weight at admission were 25.5 years and 62.4 kg, respectively. Consent to continue through 5 years was sought and obtained when the 3-year cumulative pregnancy rate proved to be 0.8 per 100. No pregnancies occurred in the fourth or fifth years. The 5-year cumulative pregnancy rate was, therefore, 0.8 per 100 with an annual average pregnancy rate below 2 per 1000 women. Prolonged bleeding/spotting (8.2% of subjects) and irregular bleeding (5.6%) were the most frequently cited medical reasons for removal. Removals for headache (4.7%) and weight change (4.0%) were the next most frequent medical reasons. Between 1% and 2% of subjects during the 5-year trial sought removals for each of the following conditions: mood changes, lower abdominal pain, depression, or pain at the implant site. The mean annual continuation rate during the study was 77 per 100. Use per woman averaged 2.96 years. Mean removal time was 5.9 +/- 0.6 min. These data indicate that, for a 5-year period, the two LNG rod implants are equivalent to the six Norplant capsule implants with respect to safety and efficacy parameters, but permit easier and more rapid implant removal.

PIP: The newly developed 2-rod levonorgestrel (LNG) implant system has a surface area only 44% that of Norplant yet provides LNG release rates and blood levels similar to the 6-capsule Norplant system. Clinical trials of the 2-rod implant system initiated in 1990 demonstrated an exceptionally low cumulative pregnancy rate (0.8/100) in the first 3 years of use. This paper reports on an extension of the original study for an additional 2 years. 594 women at 4 study sites in the US and the Dominican Republic completed 5 years of method use. No pregnancies occurred in the fourth and fifth years of use. Thus, the 5-year cumulative pregnancy rate was 0.8/100, with an average annual pregnancy rate below 2/1000 women. The mean annual continuation rate during the 5-year study period was 77/100 women, with an average duration of use of 2.96 years. The most frequent reasons for medical removal were prolonged bleeding/spotting (8.2% of women), irregular bleeding (5.6%), headache (4.7%), and weight gain (4.0%). Mean removal time was 5.9 minutes and complications occurred in only 2.3% of removals. Overall, these findings confirm that the 2-rod LNG implant contraceptive has an effectiveness equivalent to the 6-capsule implant for a 5-year period, with good acceptability and a substantially improved ease of removal.

Effect of different insertion regimens on side effects with a combination contraceptive vaginal ring.

The study population included 159 women aged 18 to 37 years requiring contraception (60 in Sydney, 99 in Los Angeles). The design consisted of a 6 month study of a contraceptive vaginal ring (CVR) releasing 20 micrograms ethinyl estradiol and 1 mg of norethindrone acetate daily over two successive cycles with a new ring on each of three different insertion regimens. A total of 831 woman-months of exposure were recorded, and 129 women completed the study. The overall incidence of side effects was similar in the two centers and differences between the insertion regimens were not observed. Transient nausea following insertion of a new ring (mainly lasting 0.5 to 48 h) was the most prominent side effect, with no significant difference between the insertion regimens (although the incidence tended to be highest with bedtime insertion [34%] and lowest with early evening insertion and temporary removal during the first night [27%]). Transient vomiting occurred in about 10% of women in the first 24 h after first insertion of a new ring. The incidence and severity of nausea was greatly reduced in cycle 2 with each regimen (6% to 9% of women). Nausea could be prevented by overnight soaking of the ring in water before use. Other side effects such as headache, dizziness, uterine cramps, breakthrough bleeding, weight gain, and ring expulsion occurred with similarly low frequency in all three insertion groups. One pregnancy occurred with probable ovulation between cycles 5 and 6, the only pregnancy recorded to date in studies with this ring. The study demonstrated that this effective and generally well tolerated CVR causes a relatively high incidence of transient nausea after insertion of a new ring, which is probably due to accumulation of ethinyl estradiol on the ring surface during storage. Acceptability is still high, and this particular CVR merits further development.

PIP: A cross-sectional study involving 60 women from Sydney, Australia, and 99 women from Los Angeles, California (US), evaluated the impact of three different insertion regimens on the transient nausea associated with the contraceptive vaginal ring. The ring released 20 mcg of ethinyl estradiol and 1 mg of norethindrone acetate per day. 128 women completed the 6-month study, providing 831 woman-months of exposure. The one pregnancy recorded during the 6-month study occurred during the 7-day break between cycles 5 and 6. 53% of women experienced nausea in at least one cycle. No significant differences in side effects were noted based on insertion group: 1) early evening (5-7 p.m.); 2) late night (10 p.m. to midnight); and 3) early evening insertion, removal at bedtime, and reinsertion the next morning. In each insertion group, the incidence of nausea was greatly reduced (to 6-9%) in the second cycle of use. 9% of women experienced transient vomiting in the 24 hours after first insertion of a new ring. The remaining side effects--headache, dizziness, uterine cramps, breakthrough bleeding, weight gain, and expulsion--were rare and occurred with equal frequency in all three insertion groups. Women at both study sites expressed a high degree of satisfaction with the vaginal ring, primarily because of its convenience and effectiveness. Overnight soaking of the ring before first use has the potential to reduce the side effect of transient nausea, presumed attributable to the accumulation of ethinyl estradiol on the ring surface during storage.

Contraceptives for lactating women: a comparative trial of a progesterone-releasing vaginal ring and the copper T 380A IUD.

From approximately one week before normal ovulation resumes, lactating women require protection against pregnancy by a contraceptive that is safe for both infant and mother in a multicenter one-year study, the natural hormone, progesterone, delivered vaginally by a sequence of four contraceptive rings designed for continuous use, was evaluated as a contraceptive for nursing mothers in comparison with the Copper T 380A IUD. Individual rings release in effective average dose of 10 mg day for a 3 month period. Evaluation included measures of lactational performance as well as of contraceptive efficacy and safety to mother and child. Nine participating clinics enrolled 802 ring users and 734 IUD acceptors between postpartum days 29 and 63. Life table analyses were performed with parallel decrements for ring and IUD subjects. Continuation in the study and analysis required that subjects not stop breastfeeding. The ring, with a one-year pregnancy rate of 1.5 per 100, did not differ significantly from the IUD with respect to contraceptive effectiveness (p > 0.05). More than half of the ring subjects were continuing at 6 months post admission and a quarter (23.5 per hundred) were still using the ring and breastfeeding one year after admission. Women with the IUD, however, had higher continuation rates (p < 0.001) at both time points. The largest single decrement for each method was that for weaning. Ring users had more complaints of vaginal problems but had fewer vaginal disorders on examination. At 12 months postpartum, 46 per 100 continuing ring users remained in amenorrhea. Lactation performance and the health and weight gain of the infants were similar among users of either regimen.

PIP: A multicenter trial conducted in nine clinics in Asia, Latin America, North Africa, and the US indicated the progesterone-releasing vaginal ring (PVR) is a safe, effective contraceptive method for lactating women. Study participants, enrolled 4-9 weeks postpartum, agreed to fully or nearly fully breast feed for at least 3 months after admission. The ring released an average of 10 mg of progesterone per day for a 3-month period. The Copper T 380A IUD served as the non-hormonal control. A total of 431 and 533 woman-years of observation were accumulated in the PVR and IUD groups, respectively. After 12 months of use, the cumulative pregnancy rate was 1.5 per 100 in the PVR group and 0.5 per 100 in the IUD group. In the year following admission, 3.4% of PVR acceptors complained of heavy and/or prolonged bleeding. At 12 months postpartum, 46.2% of ring users compared with only one-sixth of IUD users remained amenorrheic. Although PVR acceptors reported more vaginal problems (e.g., discharge or leukorrhea), pelvic examinations were more likely to detect abnormalities in IUD users. The 6- and 12-month continuation rates were 52.5% and 23.5%, respectively, in the PVR group and 74.8% and 34.5%, respectively, in the IUD group. The predominant reason for discontinuation was weaning. Breast feeding performance and infant growth were within normal limits for the PVR and IUD. Both methods are highly effective and appropriate for use by lactating women from the second postpartum month forward; the PVR has the additional advantage of being user-controlled.

Levonorgestrel concentrations during use of levonorgestrel rod (LNG ROD) implants.

In a three-year randomized trial that included 398 women, blood samples were collected for the purpose of assaying levonorgestrel concentrations in women using a new two-rod contraceptive implant system or an earlier implant formulation, Norplant-2 implants. Sample collection was at 1, 3, 6, 9, and 12 months after placement and semiannually thereafter through three years. Resulting assays and analyses showed that levonorgestrel concentrations of each implant formulation decreased significantly with time after placement, with increasing body weight, and with ponderal index. In the third year, several measures indicated that concentrations of the contraceptive drug were higher in women using the LNG ROD implants than in users of the original formulation. No pregnancies occurred among women in either group in the three years. This study provides evidence that the minimum levonorgestrel concentration needed to protect against pregnancy is below 200 pg/ml, and possibly is below 175 pg/ml.

Colposcopic evaluation of a vaginal gel formulation of iota-carrageenan.

There is an urgent need to develop safe, effective, and acceptable vaginal products for the prevention of sexually transmitted infections. Preliminary in vitro results suggest that vaginal formulations of sulfated polysaccharides, including iota-carrageenan, have the potential to block mucosal transmission of human immunodeficiency virus (HIV). Twenty-five women in five sites participated in Phase I trials to evaluate the safety of a formulation containing iota-carrageenan (PC 213). The results of this study indicate that a 5 mL 2% gel formulation of iota-carrageenan is not associated with significant irritation of the female reproductive tract when administered once daily in the absence of sexual intercourse. Given the small number of participants in this initial study, careful observation for potential irritation must also be included in larger studies of this and other vaginal formulations.

PIP: Preliminary in vitro results suggest that vaginal formulations of sulfated polysaccharides have the potential to block mucosal HIV transmission. Reported in this paper are the results of a 1995 Phase I trial of the safety of a formulation containing 2% iota-carrageenan (PC 213). Enrolled were 25 women at 5 sites (Australia, Chile, Dominican Republic, Finland, and US). Study participants self-administered 5 ml of PC 213 gel intravaginally for 7 days, during which time they abstained from sexual intercourse. 18 women had completely normal colposcopic examinations both at baseline and at 1 week of follow-up. 3 of the 4 women who had signs of minor cervical irritation at baseline had normal exams after product use. Colposcopy indicated new cervical or vaginal lesions after PC 213 use in 3 women, but only 1 such case (cervical erythema) could be attributed to product use. Participants considered the product easy to apply, not messy, and easily disposable. Both the safety and acceptability of this preparation should be re-examined in larger populations and under conditions of use during sexual intercourse.

First week drug concentrations in women with levonorgestrel rod or Norplant capsule implants.

Forty-two healthy women volunteered to have blood samples drawn at 2, 4, 8, 24, 48, and 168 h (7 days) following placement of levonorgestrel-releasing rod (LNG rod) or of Norplant capsule implants to permit measurement of drug concentrations. Three clinics recruited 10 women each, half of whom used each type of implant. Twelve additional subjects were later enrolled at one site to provide greater detail for the capsule implants. Throughout the week, women with Norplant implants had apparently higher mean drug concentrations than did women with LNG rod implants, but the differences were significant only in the first 48 h after placement (p < 0.05). Maximum levels for capsule implants were found at the 24-h sample (mean, 1358 to 1474 pg/mL) and for the LNG rod implants at 48 h (772 pg/mL). Body weight was negatively correlated with levonorgestrel concentrations at all times (p < 0.05). For several sampling times, differences between clinics in mean concentrations were statistically significant after weight adjustment. Despite differences by implant type, weight, or clinic location, drug concentrations compatible with contraceptive effect were attained within 24 h in users of LNG rod or of Norplant implants, insofar as all women had levonorgestrel concentrations above 250 pg/mL at the 24-h sample.

PIP: To establish the minimum times required for contraceptive implants to achieve serum concentrations compatible with contraceptive action, drug concentrations were measured in blood samples collected from 42 women at 2, 4, 8, 24, and 168 hours after implant insertion. 15 volunteers from three centers (US, Chile, and the Dominican Republic) were fitted with a levonorgestrel (LNG)-releasing rod and 27 received Norplant implants. An LNG concentration of 250 pg/ml and above was considered indicative of contraceptive action. By 8 hours, all Norplant subjects but only 40% of the LNG rod subjects had achieved this serum level. By 24 hours, however, all women in both groups had LNG concentrations above 250 pg/ml. The maximum mean LNG level was recorded in the 24-hour sample (1358 pg/ml) in the Norplant group and at 48 hours (772 pg/ml) in the LNG rod group. Consistent with earlier investigations, LNG concentrations demonstrated strong and significant negative correlations with body weight at all time points. The paucity of pregnancies recorded in large-scale clinical trials in the first month of use of contraceptive implants supports the rapid attainment of effective LNG concentrations. It remains unclear, however, precisely how late in the menstrual cycle implants can be inserted and still prevent follicular development or halt ovulation. Until more information is available, continuation of the policy of implant placement in the first few days after the onset of menstruation is recommended.

The acceptability of a combined oestrogen/progestogen contraceptive vaginal ring.

The acceptability of a vaginal ring releasing ethinyl oestradiol 20 mcg per day and norethindrone acetate 1 mg per day was assessed during a six-month phase II trial comparing three different regimens, which was carried out simultaneously in Los Angeles and Sydney. Sixty women were enrolled in Sydney and 90 in Los Angeles. On admission into the study, the women were asked to complete a questionnaire which gave details of age, last contraceptive method used, contraceptive methods used in the past and their reason for liking or disliking previous contraceptive methods, as well as their reason for stopping the last method. On completion of the study or leaving the study for any reason, each woman was asked to complete an acceptability questionnaire which included her experiences with the ring and the rating of the method. The responses to these two questionnaires form the basis of this report. The overall rating of the ring was similar in both the Sydney and Los Angeles groups. Sixty-nine percent of women rated the method as very good. Seventy-two percent of women in Los Angeles and 62% of women in Sydney liked the ring much more than their most liked previous method. In both groups the method they liked best apart from the ring was the pill (62% in Sydney and 53% in Los Angeles). The major reasons for liking the ring were convenience of use, effectiveness and no requirements for taking medication daily. Most women in both studies would recommend the ring to others (92% in Sydney and 89% in Los Angeles).

A contraceptive vaginal ring releasing norethindrone acetate and ethinyl estradiol.

A core design contraceptive vaginal ring (CVR) releasing 650 mcg of norethindrone acetate (NA) and 10, 20, 30 or 65 mcg of ethinyl estradiol (EE) daily was developed and tested in 99 women. The CVR inhibited ovulation well with 30 or 65 mcg EE. Vaginal bleeding was better controlled than in 23 control women using NA/EE oral contraceptives. Side effects were comparable to controls for the 20 and 30 mcg EE CVR. The 65 mcg EE CVR resulted in an unacceptably high level of nausea. The 20 and 30 mcg EE CVR caused an increase in serum HDL cholesterol and triglycerides. Total cholesterol was unchanged. Angiotensinogen and sex hormone binding globulin-binding capacity were increased in a subgroup of the 20 and 30 mcg EE CVR subjects, similar to that of 20 controls using EE/gestodene oral contraceptives. This new CVR offers an excellent contraceptive alternative with the best performance provided by the 30 mcg EE dose.

Dose-finding study of a contraceptive ring releasing norethindrone acetate/ethinyl estradiol.

A core design contraceptive vaginal ring (CVR) with average daily release of 650 mcg of norethindrone acetate (NA) and 30 mcg of ethinyl estradiol (EE) inhibited ovulation and controlled vaginal bleeding well, but caused some nausea. This study was designed to minimally alter the dose of steroid to see if nausea could be reduced without loss of contraceptive efficacy. This 30/650 CVR was compared to a CVR releasing 20 mcg of EE and 1000 mcg of NA (20/1000) and another releasing 25 mcg of EE and 650 mcg of NA (25/650) in 69 subjects. Twenty-three subjects using an oral contraceptive containing NA/EE served as controls. Ovulation inhibition was excellent and comparable to the OC for all formulations. The CVR provided better control of vaginal bleeding than did the OC. Side effects were equivalent to the OC with the exception of a slight increase in nausea in CVR users. Lipid changes and globulin increases were comparable to oral contraceptive users. The 20/1000 CVR increased sex hormone binding globulin-binding capacity less than the other two CVRs. The performance of the three CVRs was not significantly different, but the 25/650 showed a trend of reduced performance relative to the other two formulations.

Ovulation and follicular development associated with three low-dose oral contraceptives: a randomized controlled trial.

OBJECTIVE: To address the hypothesis that multiphasic oral contraceptives (OCs) increase rather than decrease the risk of functional ovarian cysts. METHODS: In this single-center, randomized controlled study, women were assigned to a multiphasic pill, a lower-dose monophasic pill, a higher-dose monophasic pill, or nonsteroidal contraception. Forty volunteers were randomized (ten each) to three different pill regimens or to nonsteroidal contraception. During 6 months of treatment, follicular development was measured by vaginal ultrasonography and ovulation was indicated by serum progesterone levels. RESULTS: The relative risk (RR) of developing a follicular structure greater than 30 mm in diameter during a cycle with the higher-dose monophasic pill was 0.5 (95% confidence interval [CI] 0.1-1.9; P = .49) compared with the multiphasic pill. The risk with the lower-dose monophasic pill was comparable to that with the multiphasic pill (RR 1.3, 95% CI 0.5-3.6; P = .56). With the multiphasic pill, the maximum ovulation rate over 60 cycles was 1.7 per 100 cycles (95% CI 0.0-8.9). CONCLUSION: This multiphasic pill more closely resembled the lower-dose monophasic pill than the higher-dose monophasic pill in its suppression of follicular development.

Rates and outcomes of planned pregnancy after use of Norplant capsules, Norplant II rods, or levonorgestrel-releasing or copper TCu 380Ag intrauterine contraceptive devices.

OBJECTIVES: The objectives were to measure rates of planned pregnancy and factors affecting these rates after use of very-long-acting contraceptive methods (Norplant or Norplant II implants, a levonorgestrel-releasing intrauterine contraceptive device, or the copper T (model TCu 380Ag) intrauterine contraceptive device. STUDY DESIGN: The design was a concurrent, multicenter prospective study of 372 women who stopped contraception for planned pregnancy. Analysis was by life-table, log-rank, and standard chi 2 methods. RESULTS: Pregnancy rates 12 and 24 months after cessation of contraceptive use were 82 and 89 per 100, respectively. Age at removal and family planning intentions at initiation of contraception were both significantly correlated with pregnancy rates (p less than 0.05), but former contraceptive regimen and duration of contraceptive use were not. Pregnancy outcomes did not deviate from normal limits and did not differ by contraceptive formerly used. CONCLUSION: Contraceptive implants releasing 30 micrograms/day of levonorgestrel or intrauterine contraceptive devices releasing 20 micrograms/day of levonorgestrel or having copper surface areas of 380 mm2 are associated with normal fertility after use for women seeking pregnancy at termination. Durations of use do not affect pregnancy rates.

PIP: A Norplant capsule releasing 30 mcg/day of levonorgestrel (LNG), Norplant II rods releasing 30 mcg/day LNG, an IUD releasing 20 mcg/day LNG, and a model TCu 380Ag model copper T IUD were used in trials by 2748 women at 7 centers during 1882-90. 372 women requested removal by the end of 1990. 10-12% of implant subjects and 17-20% years and mean parity was 1.75. The 12-month life-table rate of pregnancy was 82/100 for those planning pregnancy. 2 years later the rate was 89/100 achieved for in the first years before age 30; and 93/100 of younger women got pregnant 2 years after removal. Duration of use for or= 3 years resulted in a pregnancy rate of 84/100, while use 3 years yielded 81/100. The rates were 85/100 at 1 year and 92/100 at 2 years for women desiring more children compared with the 70 and 81/100 rate of family limiters. Age was a major factor: under 30 years with or= 37 months of contraceptive use the pregnancy rate was 93/100, while age or= 30 years and use of 37 months produced a rate of 58/100 at 1 year. 58% of former users of Norplant II rods, 34% of LNG-releasing IUD users. 43% of copper T IUD, and 37% of Norplant capsules became pregnant within 3 months. Amenorrhea of 90 days occurred in LNG IUD users at removal with 1st month pregnancy of 5/100, but the conception rate reached 80- 92/100 at 1 year. 88% of pregnancies ended with live births: 2 newborns with weight of 2500 gm and tubal pregnancy in a former Norplant II rod user. Female neonates made up 50.5% of births. The recovery of fertility outcomes were not adversely affected by these methods.

Characteristics of ovarian follicular development in Norplant users.

Daily transvaginal ultrasound (US) scanning of the ovaries to assess follicular development and daily blood sampling were performed on 19 Norplant (Leiras, Turku, Finland) subdermal contraceptive implant users who had regular menstrual cycles and on 10 normally cycling women. Three groups were identified in the implant users based on US finding. Six (31.6%) of the implant users had US findings that were consistent with a normal ovulatory pattern. However, their mean peak luteinizing hormone levels and peak midluteal phase progesterone (P) levels were significantly lower than control values. Eleven (57.9%) users had persistent follicles, and 2 users (10.5%) had no follicular development. These data suggest that after 2 to 4 years of use, about one third of Norplant users with regular bleeding patterns may ovulate but most have deficient luteal P levels. In this small study, the presence of persistent follicular enlargement in implant users was common.

Mifepristone (RU 486) failure in an ovarian heterotopic pregnancy.

A patient treated with mifepristone (RU 486), which successfully induced abortion of an intrauterine pregnancy, was discovered to have a heterotopic ovarian pregnancy resistant to this antiprogesterone. The ovarian pregnancy was removed with operative laparoscopy. This case demonstrates for the first time that an ovarian pregnancy may be resistant to treatment with RU 486 at a dose adequate to abort an intrauterine pregnancy.

Predictors of failed attempted abortion with the antiprogestin mifepristone (RU 486).

The experience of 271 patients who received mifepristone (RU 486) in experimental protocols from July 1984 to January 1989 was analyzed by logistic regression methods. The regimen used was the strongest predictor of failure, followed by Quetelet's index and initial beta-human chorionic gonadotropin level. The relative risk of failure was 2.3 times with 7-day regimens and 6.3 times with the other regimens that obtained with regimens of 600 mg given once or twice. The relative risk of failure increased with increasing Quetelet's index; women in the top quartile were 2.9 times more likely to fail to abort than were women in the bottom quartile. The risk of failure increased with increasing initial beta-human chorionic gonadotropin level; those with an initial level greater than 19,800 mIU/ml were 2.8 times more likely to fail to abort than were women with an initial value less than or equal to 6350 mIU/ml. Body mass appears to influence the likelihood of abortion with mifepristone.