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

  • Britt-Marie Landgren
  • Elisabeth Johannisson
  • Britt Masironi
  • E. Diczfalusy


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.


Medroxyprogesterone Acetate Atrophic Change Vaginal Ring Contraceptive Steroid Zero Order Release 
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  1. Aedo AR, Landgren BM, Cekan Z, Diczfalusy E: (1976) Studies on the pattern of circulating steroids in the normal menstrual cycle. 2. Levels of 20a-dihydroprogesterone, 17-hydroxyprogesterone and 17-hydroxypregnenolone and the assessment of their value for ovulation prediction. Acta Endocrinol (Kbh) 82: 600Google Scholar
  2. Akinla O, Lähteenmäki P, Jackanicz TM (1976) Intravaginal contraception with the synthetic progestin, R2323, Contraception 14: 671PubMedCrossRefGoogle Scholar
  3. Aso T, Guerrero R, Cekan Z, Diczfalusy E (1975) A rapid 5-hour radioimmunoassay of progesterone and oestradiol in human plasma. Clin Endrocrinol (Oxf) 4: 173CrossRefGoogle Scholar
  4. Bedolla-Tovar N, Rahman SA, Cekan S, Diczfalusy E (1978) Assessment of the specificity of norethisterone radioimmunoassays. J Steriod Biochem 9: 561CrossRefGoogle Scholar
  5. Benagiano G (1977) Long-acting systemic contraceptives. In: Diczfalusy E (ed) Regulation of human fertility. WHO Symposium, Moscow 1976. Scriptor, Copenhagen, pp 323–360Google Scholar
  6. Burton FG, Skiens WE, Gordon NR, Veal JT, Kalkwarf DR, Duncan GW (1978) Fabrication and testing of vaginal contraceptive devices designed for release of prespecified dose levels of steroids, Contraception 17: 221PubMedCrossRefGoogle Scholar
  7. Guerrero R, Aso T, Brenner PF, Cekan Z, Landgren BM, Hagenfeldt K, Diczfalusy E (1976) Studies on the pattern of circulating steroids in the normal menstrual cycle. 1. Simultaneous assays of progesterone, pregnenolone, dehydroepiandrosterone, testosterone, dihydrotestosterone, androstenedione, oestradiol and oestrone. Acta Endocrinol (Kbh) 81: 133PubMedGoogle Scholar
  8. Henzl MR, Mishell Dr jr, Giner Velazquez J, Leitch WE (1973) Am J Obstet Gynecol 115: 101Google Scholar
  9. Hiroi M, Stanczyk FZ, Goebelsmann U, Brenner PF, Lumkin ME, Mishell DRJr (1975) Radioimmunoassay of serum medroxyprogesterone acetate ( Provera) in women following oral and intravaginal administration. Steroids 26: 373PubMedCrossRefGoogle Scholar
  10. Johansson EDB, Luukkainen T, Vartiainen E, Victor A (1975) The effect of progestin R2323 released from vaginal rings on ovarian function. Contraception 12: 299PubMedCrossRefGoogle Scholar
  11. Mishell DR Jr, Lumkin ME (1970) Contraceptive effect of varying dosages of progestogen in silastic vaginal rings. Fertil Steril 21: 99PubMedGoogle Scholar
  12. Mishell DR Jr, Lumkin M (1975) Initial clinical studies of intravaginal rings containing norethindrone and norgestrel. Contraception 12: 253PubMedCrossRefGoogle Scholar
  13. Mishell DR Jr, Talas M, Parlow AF, Moyer DL (1970) Contraception by means of a silastic vaginal ring impregnated with medroxyprogesterone acetate. Am J Obstet Gynecol 107: 100PubMedGoogle Scholar
  14. Mishell DR Jr, Lumkin M, Stone S (1972) Inhibition of ovulation with cyclic use of progestogen-impregnated intravaginal devices. Am J Obstet Gynecol 114: 927Google Scholar
  15. Mishell DR Jr, Roy S, Moore DE, Brenner PF, Page MA, Gentzschein E, Fisk PD (1977) Clinical performances and endocrine profiles with contraceptive vaginal rings containing d-norgestrel. Contraception 16: 625PubMedCrossRefGoogle Scholar
  16. Mishell DR Jr, Moore DE, Roy S, Brenner PF, Page MA (1978) Clinical performance and endocrine profiles with contraceptive vaginal rings containing a combination of estradiol and d-norgestrel. Am J Obstet Gynecol 130: 55PubMedGoogle Scholar
  17. Noyes RW, Hertig AT, Rock I (1950) Dating the endometrial biopsy. Fertil Steril 1: 3Google Scholar
  18. Stanczyk FZ, Hiroi M, Goebelsmann U, Brenner PF, Lumkin ME, Mishell DRJr (1975) Radioimmunoassay of serum d-norgestrel in women following oral and intravaginal administration. Contraception 12: 279PubMedCrossRefGoogle Scholar
  19. Thiery M, Vandekerckhove D, Dhont M, Vermeulen A, Decoster JM (1976) The medroxyprogesterone acetate intravaginal silastic ring as a contraceptive device, Contraception 13: 605PubMedCrossRefGoogle Scholar
  20. Victor A, Johansson EDB (1976a) Pharmacokinetic observations on medroxyprogesterone acetate administered orally and in trav agin ally. Contraception 14: 319PubMedCrossRefGoogle Scholar
  21. Victor A, Johansson EDB (1976b) Plasma levels of d-norgestrel and ovarian function in women using intravaginal rings impregnated with dl-norgestrel for several cycles. Contraception 14: 215PubMedCrossRefGoogle Scholar
  22. Victor A, Edqvist LE, Lindberg P, Elamsson K, Johansson EDB (1975) Peripheral plasma levels of d-norgestrel in women after oral administration of d-norgestrel and when using intravaginal rings impregnated with d-norgestrel. Contraception 12: 261PubMedCrossRefGoogle Scholar
  23. Victor A, Nash HA, Jackanicz TM, Johansson EDB (1977) Collagen bands: A new vaginal delivery system for contraceptive steroids. Contraception 16: 125PubMedCrossRefGoogle Scholar
  24. Viinikka L, Victor A, Janne O, Raynaud J-P (1975) The plasma concentration of a synthetic progestin, R 2323, released from polysilastic vaginal rings. Contraception 12: 309PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1980

Authors and Affiliations

  • Britt-Marie Landgren
  • Elisabeth Johannisson
  • Britt Masironi
  • E. Diczfalusy

There are no affiliations available

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