Kuhnz W, Heuner A, Hümpel M, Seifert W, Michaelis K
Research Laboratories, Schering Aktiengesellschaft, Berlin, Germany.
Contraception. 1997 Dec;56(6):379-85. doi: 10.1016/s0010-7824(97)00174-1.
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.
以往针对接受口服含炔诺酮制剂的绝经后女性的研究表明，一小部分剂量会通过代谢转化为炔雌醇，并可在外周血中检测到。为了更详细地研究这种转化的程度和剂量依赖性，我们对24名绝经后女性进行了一项研究，她们分别单次口服5毫克炔诺酮以及5毫克和10毫克醋酸炔诺酮，每次治疗之间有2周的洗脱期。每次治疗后，定期采集血液，分别通过特异性放射免疫测定法和气相色谱/质谱法分析血清样本中炔诺酮和炔雌醇的浓度。在接受醋酸炔诺酮治疗的所有女性的血清样本中均检测到炔雌醇，除4例患者外，接受炔诺酮治疗的女性血清样本中也检测到炔雌醇。醋酸炔诺酮转化为炔雌醇的转化率在5毫克和10毫克剂量时分别为0.7±0.2%和1.0±0.4%。这相当于每毫克醋酸炔诺酮的口服剂量相当于约6微克炔雌醇。对于炔诺酮，在5毫克剂量时发现转化率为0.4±0.4%，这相当于每毫克炔诺酮的口服剂量相当于约4微克炔雌醇。尽管不能排除在个别情况下，转化可能产生更高剂量的炔雌醇，但得出的结论是，在孕激素的治疗剂量下，代谢产生的炔雌醇暴露可能不仅在使用含炔诺酮和炔雌醇的口服复方避孕药的育龄女性中，而且在接受口服雌二醇进行雌激素替代的绝经后女性中，临床意义不大。由于炔诺酮的雄激素活性，代谢产生的炔雌醇对肝脏的雌激素作用（如转运蛋白的合成）很可能得到了更多的补偿。
