Effects of d-norgestrel-releasing intracervical devices in the nonhuman primate, Erythrocebus patas.

Primates (Erythrocebus patas) were implanted with intracervical devices which slowly released d-norgestrel at either of two rates: 38 +/- 12 microgram/day (high dose, 4 animals) or 14 +/- 10 microgram/day (low dose, 3 animals). An additional 8 animals received placebo devices or were untreated controls. All animals were studied for 3 months of exposure, at which time they were necropsied and evaluated. The uterus in all of the high dose primates had endometrial stromal and epithelial hyperplasia and, in two primates, suppurative endometritis. Similar, but less severe, uterine changes were present in animals of the low dose group. Systemic effects included evidence of diminished menstrual cycling and an absence of corpora lutea at both dose levels. Our results indicate that local application of these levels of d-norgestrel for contraception produces effects similar to those from systemically administered d-norgestrel.

Low-level, progestogen-releasing vaginal contraceptive devices.

Silicone rubber vaginal contraceptive devices of four different formulations, which release predetermined, controlled doses of three progestogens at four distinct levels, were designed and fabricated, and tested in 90-day clinical trials. Data obtained with 70 of the devices indicated that in vivo release rates (microgram/day +/- S.D.) for the formulations were: progesterone, 1400 +/- 30; norethindrone (two levels), 49.4 +/- 2.4, 196 +/- 21; d-norgestrel, 21.6 +/- 1.4. Clinical studies with these devices indicate that the women usually ovulate (with the exception of the high-dose norethindrone-releasing devices) while sperm penetration of the cervix was inhibited by all four fromulations, most consistently by the norgestrel-releasing devices.

PIP: 4 different formulations, which released predetermined, controlled doses of 3 progestogens at 4 distinct levels, were incorporated into newly designed and fabricated silicone rubber vaginal contraceptive devices. 90-day clinical trails tested in vivo release rates of 70 devices; the rates were: progesterone, 1400+ or -30 mcg/day; norethindrone (2 levels), 49.4+ or -2.4 and 196+ or -21 mcg/day; and d-norgestrel, 21.6+ or -1.4 mcg/day. Clinical studies with these devices indicated that the women usually ovulated (with the exception of the high-dose norethindrone-releasing device), whereas sperm penetration of the cervix was inhibited by all 4 formulations, most consistently by the norgestrel-releasing device. Data from a shelf-life study indicated that there were no significant differences between the amount of progestogen in freshly fabricated devices and that in devices stored at room temperature for 2 years.

Fabrication and testing of vaginal contraceptive devices designed for release of prespecified dose levels of steroids.

PIP: Polydimethylsiloxane (Silastic) intravaginal devices of 3 different designs were tested both in vivo and in vitro as delivery systems for d-norgestrel, norethindrone, and progesterone. The devices were toroids measuring 55.6 mm in diameter and 9.5 mm in cross-section. In vitro release rates were determined by placing the devices in a stirred stream of isotonic saline for 30-60 days, and certain others were tested following in vivo use. 78 devices used in clinical trials for an average 92.5 days formed the basis for in vivo data. In vitro relase rates at 10 days did not differ significantly from those at the end of testing, and they accorded closely with the in vivo release rates. 1 design problem encountered was the reduction in release rate once a certain portion of the dose had been expended.^ieng