Katsuki Y, Sasagawa S, Takano Y, Shibutani Y, Aoki D, Udagawa Y, Nozawa S
Toxicology Laboratory, Mochida Pharmaceutical Co., Shizuoka, Japan.
Drugs Exp Clin Res. 1997;23(2):45-62.
Dienogest is an orally active synthetic steroid that is used for contraception and is currently being studied for the possible treatment of endometriosis. Earlier we demonstrated that dienogest had therapeutic effects on experimental endometriosis in rats and that its mechanisms of action were different from those of drugs currently on the market for the treatment of endometriosis. We also reported preclinically that dienogest showed a potential anticancer action against hormone-dependent cancers that was different from that of progestins. Accordingly, we obtained preclinical background data for the above-described clinical applications and extension of the clinical use of the drug in the near future by investigating the endocrinological profile of dienogest in rabbits and rats. Dienogest was characterized by having a moderate binding affinity for progesterone receptors and by progestational activities: it stimulated endometrial proliferation (> or = 0.01 mg/kg) that was only partially inhibited by RU-486, and induced carbonic anhydrase activity in endometrium (> or = 0.01 mg/kg). Also, it was slightly uterotrophic (> or = 1 mg/kg) with very low binding affinity for oestrogen receptors but without biological androgenic and anabolic activities (100 mg/kg), with neither glucocorticoid activity nor mineralocorticoid activity (100 mg/kg), and with very slight binding affinity for human sex hormone-binding globulin. These findings suggest that dienogest is not a pure progestin and appears to induce fewer side effects than drugs currently on the market for the treatment of endometriosis.
地诺孕素是一种口服活性合成甾体，用于避孕，目前正在研究其对子宫内膜异位症的可能治疗作用。我们之前证明地诺孕素对大鼠实验性子宫内膜异位症有治疗作用，且其作用机制与目前市场上用于治疗子宫内膜异位症的药物不同。我们还在临床前报告称，地诺孕素对激素依赖性癌症显示出与孕激素不同的潜在抗癌作用。因此，我们通过研究地诺孕素在兔和大鼠体内的内分泌特征，获得了上述临床应用的临床前背景数据以及该药物在不久的将来临床应用扩展的相关数据。地诺孕素的特点是对孕激素受体具有中等结合亲和力并具有孕激素活性：它刺激子宫内膜增殖（≥0.01mg/kg），这种增殖仅被RU-486部分抑制，并且在子宫内膜中诱导碳酸酐酶活性（≥0.01mg/kg）。此外，它有轻微的子宫营养作用（≥1mg/kg），对雌激素受体的结合亲和力非常低，但没有生物学雄激素和同化活性（100mg/kg），既没有糖皮质激素活性也没有盐皮质激素活性（100mg/kg），对人性激素结合球蛋白的结合亲和力非常轻微。这些发现表明地诺孕素不是一种纯粹的孕激素，并且似乎比目前市场上用于治疗子宫内膜异位症的药物引起的副作用更少。
