Theodore M. Jackanicz

Polylactic acid as a biodegradable carrier for contraceptive steroids

Abstract d-Norgestrel was incorporated into a solid matrix of poly-L-lactic acid and its rate of release measured in in vitro and in vivo. The release rate in vitro from films containing 33 percent norgestrel was approximately 3 micrograms per day per cm 2 of surface area and was relatively constant over 80 days. Release rates when similar films were implanted subcutaneously in rats were initially about 5.5 micrograms per day per cm 2 of surface and declined by 80 days to about 3 micrograms per day. The polylactic acid matrix was broken down, but relatively less rapidly than the rate of norgestrel release. Tissue reactions were minimal.

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.

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

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.

Ovarian function during use of vaginal rings delivering three different doses of Nestorone

Contraceptive vaginal rings delivering various progestins alone or in combination with estrogen have been previously studied, showing adequate steroid vaginal absorption and acceptability by the users. Nestorone progestin (NES) is a potent 19-nor-progesterone derivative, inactive by the oral route, but an excellent option for vaginal delivery. The purpose of this study was to evaluate ovarian function during 6 months of continuous use of progestin-only vaginal rings delivering 3 different doses of NES: 50, 75, and 100 microg per day. Blood samples were taken twice a week for 5 consecutive weeks during a control cycle and on months 1, 3 and 6 of use, for the measurement of estradiol (E2), progesterone (P), and NES. A total of 87 volunteers randomly received each of the 3 doses. After an initial peak, NES serum levels remained fairly constant throughout the duration of the study at about 125, 200 and 250 pmol/L, respectively, decreasing slightly with time. Luteal activity occurred very rarely (1.2-2.6% of sampling periods) with no apparent difference between doses. Low E2 levels (< or =100 pmol/L) in all samples of a run were rare (5%) and only with the high dose ring (100 microg/day). E2 remained within normal levels (101-1500 pmol/L) in most of the segments studied. We conclude that the 50 and 75 microg/day NES rings provide adequate ovulation inhibition without hypoestrogenism, while the 100 microg/day ring may deliver an unnecessarily high dose.

Evaluation of four different contraceptive vaginal rings: Steroid serum levels, luteal activity. bleeding control and lipid profiles

Four different models of contraceptive vaginal rings were tested during three cycles for luteal activity, bleeding control, plasma lipoproteins and serum levels of the contraceptive steroids. Two progestins, levonorgestrel acetate (LNGA) and ST 1435, alone or in combination with ethynyl-estradiol (EE) were tested. The rings released 100 ug/day of the progestins and 30 ug/day of EE. Luteal activity was detected among users of the progestin-only rings: 4 of 8 cycles with ST 1435 and 2 of 10 with LNGA. Only one of the 18 cycles studied with the two combined rings showed luteal activity, but the measurement of contraceptive steroid in plasma suggested that this subject delayed reinsertion of the ring for about one week in that particular cycle. Breakthrough bleeding was observed in 12 of 30 cycles of use of the progestin-only rings, and in only 2 of 27 cycles with the combined models. No significant changes in total cholesterol or its HDL-fraction were observed. However, the only reduction observed in HDL-cholesterol was among users of the LNGA-only ring. It is concluded that the two combined CVR models offer good possibilities of high effectiveness and bleeding control and merit further development.

Levonorgestrel and estradiol release from an improved contraceptive vaginal ring

Abstract A contraceptive vaginal ring containing levonorgestrel and estradiol was designed in which the drug is located in a 0.15-mm layer beneath a 0.25-mm overcoat at the rings surface which controls the rate of steroid release. This design has been termed the “shell” ring. In-vitro studies were carried out on the shell ring and also on two types of rings of earlier design, a homogeneous ring and a shell ring without the rate-controlling overcoat. Levonorgestrel and estradiol were released In vitro at a constant rate of about 500 μg per day and 300 μg per day, respectively, from shell rings of 9.2-mm cross-sectional diameter and 58-mm overall diameter. In the other two types of rings, a burst of steroid release was seen followed by a rapid fall in diffusion rates. Individual shell rings were used in clinical trials for six or seven consecutive 21-day cycles with a 7-day non-use interval between cycles. At the end of the study they were returned to allow analysis and calculation of average steroid loss in vivo . In vivo , rings of 58-mm diameter were found to release levonorgestrel and estradiol at rates of 293 ± 54μg per day and 183 ± 34μg per day, respectively. Rings of 50-mm diameter had levonorgestrel and estradiol release rates of 252 ± 34 μg per day and 152 ± 21μg per day, respectively. The release characteristics of the shell ring are such that it is expected to find a role in fertility control. All the studies reported in this issue of Contraception have used the same design of shell ring.

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.

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 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.

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.