IN-VIVO CONVERSION OF NORETHISTERONE AND NORETHISTERONE ACETATE TO ETHINYL ESTRADIOL IN POSTMENOPAUSAL WOMEN

Previous studies with postmenopausal women receiving oral doses of nor ethisterone-containing preparations have shown that a small fraction o f the dose is converted metabolically to ethinyl estradiol and may be detected in the peripheral blood. To investigate the extent and the do se dependence of this conversion in more detail, we performed a study with 24 postmenopausal women who received single oral doses of 5 mg no rethisterone as well as 5 and 10 mg norethisterone acetate with a wash out phase of 2 weeks between each treatment. After each treatment, blo od was collected at regular intervals and the concentrations of noreth isterone 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 conversi on 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 corres ponded to an oral dose equivalent of about 6 mu g ethinyl estradiol pe r milligram of norethisterone acetate. For norethisterone, a conversio n ratio of 0.4 +/- 0.4% was found at a dose of 5 mg, which corresponde d to an oral dose equivalent of about 4 mu g ethinyl estradiol per mil ligram of norethisterone. Although it cannot be excluded that in indiv idual cases, even higher doses of ethinyl estradiol may be produced by conversion, it is concluded that at therapeutic doses of the progesto gens, the exposure to metabolically derived ethinyl estradiol is proba bly of little clinical significance not only in fertile women using or al contraceptive combination preparations containing norethisterone an d ethinyl estradiol, but also in postmenopausal women who receive oral doses of estradiol for estrogen replacement. The estrogenic effects o f metabolically derived ethinyl estradiol on the liver (eg, synthesis of transport proteins) are very likely more than compensated due to th e androgenic activity of norethisterone. (C) 1997 Elsevier Science Inc . All rights reserved.