Pharmacokinetic and Pharmacodynamic Effects of Small Doses of Norethisterone Released from Vaginal Rings Continuously During 90 Days

Abstract

The pharmacokinetic and pharmacodynamic effects of norethisterone (17 α-ethinyl-17β-hydroxy-4-estren-3-one; NET) released continuously from vaginal devices at a rate of 50 μg/24 h and 200 μg/24 h, respectively, were investigated during a 90-day period in two groups of seven women each with regular menstrual periods. Blood samples were taken three times weekly (mondays, Wednesdays, and fridays) during a control cycle and during the entire study period for the estimation of estradiol, progesterone, and NET levels, and hourly blood samples were collected throughout a 24-hour period after 6 weeks of exposure to assess the short term variation in NET levels. In addition, an endometrial biopsy was taken on days 21–23 of the control cycle and after 6 and 10 weeks with the device in situ.

There was little, if any, initial “burst” effect on the plasma levels of NET following the insertion of the devices, and a statistically significant linear relationship was found in each case when the NET levels were plotted against the 90 days of exposure. However, the average slope of the regression lines with the 50 μg releasing devices (-0.44) was significantly flatter than that with the 200 μg releasing devices (-1.63). Also the mean plasma level in the former group 283 pg/ml) was significantly lower than that (666 pg/ml) observed in the latter group. The average daily decline in plasma NET levels was 0.16% and 0.24%, respectively, and the 95% confidence limits of the hour-to-hour variation in NET levels were at 92% and 106%.

All control cycles were of normal length (26–35 days) and exhibited a normal luteal activity. There were a total of 16 cycles with normal luteal function among the seven subjects with 50 μg releasing devices; each of them had a minimum of two such cycles. However, 11 of these 16 cycles were of abnormal length, indicating a significant effect of NET on the follicular phase. Only nine cycles were found with a normal luteal activity in the group with the devices releasing 200 μg/24 h; three of the seven subjects in this group had anovulation throughout the entire study and two of them had prolonged anovulatory periods alternating with normal cycles.

Thirteen of the 14 biopsies taken with the 50 μg releasing devices in situ after 6 and 10 weeks of exposure showed normal cyclic changes, whereas 11 of the 14 biopsies taken in the group exposed to a release rate of 200 μg/24 h indicated predecidual and atrophic changes. These were associated with a significantly diminished number of endometrial glands per microscopic field and with a significant increase in the number of days will bleeding and spotting. Hence, the increased frequency of intermenstrual bleeding may be associated with the predecidual and atrophic changes induced by the administration of NET.

No correlation was found between the individual plasma levels of NET and the following parameters: weight, height and ponderal index of the subjects, individual release rate of NET from the devices, effects on ovarian function, the appearance of the endometrium, and the number of days with bleeding and spotting.

It is concluded that the vaginal rings studied provide a near zero order release of NET and represent an ideal experimental model for the study of the effects of constant blood levels of contraceptive steroids.