In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women.
Previous studies with postmenopausal women receiving oral doses of norethisterone-containing preparations have shown that a small fraction of the dose is converted metabolically to ethinyl estradiol and may be detected in the peripheral blood. To investigate the extent and the dose dependence of this conversion in more detail, we performed a study with 24 postmenopausal women who received single oral doses of 5 mg norethisterone as well as 5 and 10 mg norethisterone acetate with a washout phase of 2 weeks between each treatment. After each treatment, blood was collected at regular intervals and the concentrations of norethisterone and ethinyl estradiol were analyzed in the serum samples by a specific radioimmunoassay and by gas chromatography/mass spectrometry, respectively. Ethinyl estradiol was present in the serum samples of all women following treatment with norethisterone acetate and, except for four cases, also after treatment with norethisterone. The conversion ratio of norethisterone acetate to ethinyl estradiol was 0.7 +/- 0.2% and 1.0 +/- 0.4% at doses of 5 and 10 mg, respectively. This corresponded to an oral dose equivalent of about 6 micrograms ethinyl estradiol per milligram of norethisterone acetate. For norethisterone, a conversion ratio of 0.4 +/- 0.4% was found at a dose of 5 mg, which corresponded to an oral dose equivalent of about 4 micrograms ethinyl estradiol per milligram of norethisterone. Although it cannot be excluded that in individual cases, even higher doses of ethinyl estradiol may be produced by conversion, it is concluded that at therapeutic doses of the progestogens, the exposure to metabolically derived ethinyl estradiol is probably of little clinical significance not only in fertile women using oral contraceptive combination preparations containing norethisterone and ethinyl estradiol, but also in postmenopausal women who receive oral doses of estradiol for estrogen replacement. The estrogenic effects of metabolically derived ethinyl estradiol on the liver (eg. synthesis of transport proteins) are very likely more than compensated due to the androgenic activity of norethisterone.
Kuhnz
W
W
Research Laboratories, Schering Aktiengesellschaft, Berlin, Germany.
Heuner
A
A
Hümpel
M
M
Seifert
W
W
Michaelis
K
K
D000284:Administration, Oral; D019540:Area Under Curve; D001682:Biological Availability; D015331:Cohort Studies; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D045166:Estradiol Congeners / Q000097:blood*; D015914:Estrogen Replacement Therapy; D004997:Ethinyl Estradiol / Q000097:blood*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D000077563:Norethindrone Acetate; D017698:Postmenopause / Q000378:metabolism*; D045167:Progesterone Congeners / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D045166:Estradiol Congeners; D045167:Progesterone Congeners; D004997:Ethinyl Estradiol; D000077563:Norethindrone Acetate; D009640:Norethindrone