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.

Estradiol delivery by vaginal rings: potential for hormone replacement therapy.

OBJECTIVES: To determine if delivery of estradiol from elastomeric vaginal rings gives estradiol blood levels in the range associated with effective estrogen replacement therapy and to determine the relation between in vitro estradiol release from the rings and blood levels in vivo. Secondary objectives related to changes in lipoprotein cholesterol, changes in climacteric symptoms, and evaluation of acceptability to users. METHODS: Three ring variants releasing approximately 100, 150 and 200 micrograms/day of estradiol in vitro were used through 22 days in 21 postmenopausal women, 7 on each dose levels. Blood samples for measurement of estradiol were taken at 3-4 day intervals. Lipoprotein cholesterol was measured before and at the end of treatment. Women were questioned about climacteric symptoms and about their satisfaction with the ring. RESULTS: Mean serum estradiol levels for the three groups of rings were 63 +/- 6, 94 +/- 5 and 136 +/- 13 pg/ml for the 100, 150 and 200 micrograms/day rings, respectively. FSH levels declined during ring use and the maturation values of cells collected on vaginal swabs markedly increased. Total and LDL cholesterol were significantly reduced and HDL cholesterol was not significantly changed. All women reported relief of postmenopausal symptoms. Vaginal discomfort during the first 3 days of use was reported by 12 women but overall satisfaction with the method was high. CONCLUSIONS: Women using the vaginal rings attained estradiol blood levels compatible with control of climacteric symptoms and bone loss. The relation between in vitro estradiol release and blood levels in vivo was essentially identical for all 3 doses. The use of vaginal rings to deliver estradiol for hormone replacement therapy is judged to merit further evaluation.

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.

Contraception in hypertensive women using a vaginal ring delivering estradiol and levonorgestrel.

Contraception with a vaginal ring (CVR) that delivers estradiol and levonorgestrel was used during a mean of 15.6 menstrual cycles in 12 hypertensive women. Blood pressure (BP) was measured 5 times on each visit during 2 pretreatment control cycles; during the 1st, 2nd, 4th, 6th, and from the 9th to 12th cycles of CVR use; and again after a 1-month recovery period. No significant change in BP occurred during CVR use in any of the subjects. Plasma renin substrate and antithrombin III activity did not vary significantly, which suggests the utility of administering natural estradiol via the vagina, thus avoiding the first pass effect that occurs with oral contraceptives. Significant decreases in plasma sex hormone-binding globulin, cholesterol, high density lipoprotein cholesterol, phospholipids, and triglycerides occurred, indicating an androgenic effect of levonorgestrel. We conclude that the CVR is a method of contraception that does not elevate BP in hypertensive women.

PIP: Contraception with a vaginal ring (CVR) that delivers estradiol and levonorgestrel was used during a mean of 15.6 menstrual cycles in 12 hypertensive women. Blood pressure (BP) was measured 5 times on each visit during 2 pretreatment control cycles; during the 1st, 2nd, 4th, 6th, and from cycles 9-12 of CVR use; and again after a 1-month recovery period. No significant change in BP occurred during CVR use in any of the subjects. Plasma renin substrate and antithrombin III activity did not vary significantly, which suggests the utility of administering natural estradiol via the vagina, thus avoiding the 1st pass effect that occurs with oral contraceptives. Significant decreases in plasma sex hormone-binding globulin, cholesterol, high density lipoprotein cholesterol, phospholipids, and triglycerides occurred, indicating an androgenic effect of levonorgestrel. The authors conclude that the CVR is a method of contraception which does not elevate BP in hypertensive women.

Fertility regulation in nursing women: VIII. Progesterone plasma levels and contraceptive efficacy of a progesterone-releasing vaginal ring.

The objectives of this trial were to test the contraceptive efficacy and measure progesterone plasma levels of women using progesterone-releasing rings during lactation. Two types of rings delivering an average of about 5 mg or 10 mg of progesterone per day were tested in 128 healthy nursing women. A control group was formed by 127 Copper T users. Rings were inserted at day 60 postpartum and replaced every 3 months with a new one. Initially progesterone plasma levels were around 10 nmol/l and 15 nmol/l for rings releasing 5 and 10 mg per day, respectively, and decreased slightly after 30 days. Levels observed in subsequent segments of use approximated those of the first segment. These levels are within the range shown to inhibit fertility in lactating women. One pregnancy was diagnosed in 739 woman-months of progesterone ring use, and none occurred in 794 woman-months of Copper T use, which contrasts with the high incidence of pregnancy in a group of untreated nursing women where 19 pregnancies resulted during 677 woman-months. No deleterious effects were detected lactation and infant growth or maternal and infant health. It is concluded that the vaginal rings releasing progesterone are a suitable contraceptive method for lactating women.

Ovarian function, bleeding control and serum lipoproteins in women using contraceptive vaginal rings releasing five different progestins.

Ovarian function, bleeding patterns and serum lipoproteins were studied in women using contraceptive vaginal rings (CVRs) of dimethyl-polysiloxane impregnated with steroids. The different CVRs were used for about 10 cycles each. The following groups were studied, with the daily steroid dosage given in parentheses. Women using CVRs delivering levonorgestrel (290 micrograms), norethisterone (850 micrograms), medroxyprogesterone acetate (700 micrograms) or megestrol acetate (1.9 mg), all of which were in combination with estradiol (200 ug). Women using CVRs delivering progesterone (5.2 mg). Women taking megestrol acetate orally (15 mg/day) for three weeks. In all women except those using the levonorgestrel CVR, there were indications of incomplete suppression of ovarian activity as shown by elevated levels of progesterone and/or estradiol peaks. Bleeding control seemed to be good with the levonorgestrel CVR and rather poor with the others. Levonorgestrel treatment was associated with a decrease in high density lipoprotein cholesterol (32%) and triglycerides (25%) and a 16% decrease in apolipoprotein A-I. Norethisterone induced a 10% decrease in A-I and a reduction of cholesterol in very low density lipoprotein. All other lipid and apolipoprotein B, A-I and A-II values were unaltered with the administration of the CVRs and with oral megestrol acetate. Levonorgestrel was given in a higher dose than the other progestins, but the absence of effects of the high oral dose of megestrol acetate on the serum lipoproteins indicates that the progesterone-derived progestins in adequate doses probably would not alter the lipoprotein metabolism. Higher doses of progestins are needed to achieve acceptable control of ovarian activity and bleeding patterns than seen with these CVRs.

A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. I-Use effectiveness. An international comparative trial.

PIP: Contraceptive vaginal rings (CVRs), with approximate daily release rates of 250-290 mcg of levonorgestrel and 150-180 mcg of estradiol and manufactured in a shell design, were studied for effectiveness and acceptability in multicentered trials involving 1103 ring users in Brazil, Chile, Dominican Republic, Sweden, U.S., Denmark/Finland, and Nigeria. A comparison group of 533 women used the oral contraceptive Nordette. Both 1st and all segment 1 year gross pregnancy rates among CVR users were less than 3/100, rates similar to Nordette users. Continuation at 1 year was 50/100 users of the ring (all segments) and 38/100 among Nordette users, more of whom were lost to follow-up. Gross 1 year rates of termination for medical reasons ranged from 25-29/100. Ring users were more likely to terminate for vaginal problems and pill users for headache, nausea, and associated reasons. These trials indicate that CVRs of this design are as effective and have continuation rates equal to and possibly superior to Nordette under the same study conditions.^ieng

A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. II-Subjective and objective measures of effects. An international comparative trial.

Comparative clinical trials of 2 sizes of contraceptive vaginal rings and of an oral contraceptive were undertaken at 8 investigational sites (9 clinics). More than 500 women enrolled on each of the 3 study regimens. Side effects of the rings and of Nordette, the oral contraceptive, were evaluated by noting spontaneous complaints, by recording medications taken and by physical examination. Inquiries about changes in the frequency of specific conditions were made at the end of the subjects participation in the first year of the study. The incidence of spontaneous complaints was similar among users of the 2 different-sized rings and of the pill.

A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. III-Menstrual patterns. An international comparative trial.

Menstrual events among users of contraceptive vaginal rings (CVRs), releasing levonorgestrel and estradiol, were studied in comparison with a combined oral contraceptive, Nordette, in multicentered trials. CVRs were made with outside diameters of 50 and 58 mm and released about 250 micrograms and 290 microgram of levonorgestrel and 150 microgram and 180 microgram of estradiol per day, respectively. The CVRs were used continuously for 3 weeks and then removed for 1 week. Both the CVRs and Nordette were perceived to reduce menstrual flow and days of menstrual bleeding. Twenty to 25% of CVR users perceived increased intermenstrual bleeding or spotting. Diaries indicate, however, that on average, CVR users experienced about 1 day per month of bleeding or spotting with the ring in place. CVRs and Nordette produced approximately the same total number of bleeding and spotting days during 6 cycles of use, 27-29, but the small (50-mm OD) ring was associated with somewhat more spotting. This ring was also associated with somewhat more prolonged bleeding and spotting runs and with more prolonged nonbleeding intervals than reported by users of the larger (58-mm OD) ring or of Nordette. Differences among regimens, however, tended to be small even when statistically significant. Evidence from menstrual diaries indicates that these CVRs, and in particular 58-mm ring, provide control over the menstrual cycle comparable to the Nordette.

Vaginal progesterone for contraception.

Silastic vaginal rings impregnated with progesterone (P) or progesterone and estradiol (E) were used in nine women for thirty 21-day cycles to study the effect on ovarian function. The average daily rates of release of P and E from the rings were 2.2 mg/day and 220 microgram/day, respectively. In anovulatory treatment cycles the mean plasma level of P was 0.9 ng/ml. E levels fluctuated in the range seen in normally cycling women due to endogenous E production. In a menopausal woman the E levels increased to 50 to 100 pg/ml during treatment and FSH levels declined. Ovulation occurred in 18 (60%) of the treated cycles, and resulted in one pregnancy. Although the results rule out the use of these rings for contraceptive purposes, they indicate that at higher dosages the Silastic vaginal ring offers a mode of administration of natural steroids to be used in hormonal contraception.

PIP: This study was conducted to determine whether a relatively low dose of P (progesterone) alone or in combination with estradiol (E) administered from silastic vaginal rings would suppress ovulation, thus providing a safe contraceptive form women. 9 healthy fertile women with regular menstrual cycles were studied for a total of 30 21-day cycles. 4 women used a ring with a P dose while the other 4 used the combination ring. 1 65 year old menopausal woman used both types of ring for 2 weeks. Venous blood samples were collected 2-3 times a week from the subjects and were analyzed for E, P, and FSH levels using radioimmunoassay and radioimmunosorbent technique. The average daily rate of release for P from the rings was 2.2 mg/day and 220 ug/day for E. Mean plasma level of P in anovulatory treatment cycle was 0.9 ng/ml. E levels fluctuated in the range seen in normal women because of endogenous E production. The E levels for the menopausal woman increased from 50 to 100 pg/ml during treatment. Ovulation was observed in 18 (60%) of the treated cycles, resulting in 1 pregnancy. The pregnancy which occurred in this series suggests that P does not provide the 'local' protective effect of synthetic gestagens used in low dose gestagen contraceptive pills. However, the pregnancy may also be attributed to the passage of spermatozoa 7 days after the ring was removed. Further studies should be done on P-releasing contraceptive rings.

Release of contraceptive steroids from sustained release dosage forms and resulting plasma levels.

The correlations of plasma levels of levonorgestrel, megestrol acetate and norgestrienone with the doses delivered from subdermal implants and contraceptive rings have been examined. Differences in plasma levels as large as three-fold between different subjects receiving nearly identical doses were observed with all three steroids. The relative plasma levels seen from one subject to another showed high consistency over time. Part of the explanation may lie in differing levels of sex hormone binding globulin, but additional factors must be operative since megestrol acetate binds only weakly with this carrier.

Intravaginal contraception with the synthetic progestin, R2323.

PIP: A Silastic intravaginal ring (IVR) containing R2323 (17 alpha-ethinyl-17 beta-hydroxy-18-methyl-4,9,11-estrien-3-one) in its center core was tested in vitro and in 4 women for 1 cycle each. Initially 330 mg of drug was released/day from the IVR in vitro, and after 150 days the value had declined to about 230 mg. Ovulation was inhibited in the 4 subjects due to the constant release of R2323 as evidenced by the steroid blood levels of 1-3 ng/ml. When the IVR was removed, R2323 blood levels quickly fell to zero. All the women had normal withdrawal bleeding, and 2 subjects followed during a recovery cycle had ovulatory levels of progesterone.^ieng

Biodegradable polylactate as a steroid-releasing polymer: intrauterine administration of d-norgestrel.

Polylactate film containing 30 per cent or 4.5 mg. of d-norgestrel was fixed around a plain T-IUD and the device was inserted into the uterine cavity. Norgestrel was gradually released into the systemic circulation, blood levels being highest during menstruation. Plasma estradiol and progesterone determinations revealed that cyclic ovarian function was maintained during the intrauterine administration of norgestrel; however, marked local effects on the endometrium resulted. The amount of menstrual bleeding was reduced.

PIP: Biodegradable polylactate as a steroid-releasing polymer for the intrauterine administration of d-norgestrel was investigated. Polylactate film containing 30% or 4.5 mg of d-norgestrel was fixed around a plain T-intrauterine device and inserted into the uterine cavity of 5 healthy women, aged 25-33 years. Norgestrel was gradually released into the systemic circulation and the blood levels were highest during menstruation. Plasma estradiol and progesterone determination revealed that cyclic ovarian function was maintained during the administration of norgestrel. Cyclic endometrial changes were markedly reduced, and menstrual bleeding decreased. The women ovulated during the treatment cycle. Normal sexual activities were carried on and no pregnancy occurred.