Passaro Maureen D, Piquion Johann, Mullen Nancy, Sutherland Dorette, Zhai Suoping, Figg William D, Blye Richard, Nieman Lynnette K
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Hum Reprod. 2003 Sep;18(9):1820-7. doi: 10.1093/humrep/deg342.
Progesterone receptor modulators have potential therapeutic use in progesterone-dependent conditions such as endometriosis, fibroids and induction of labour. The synthetic steroid CDB-2914 binds to the progesterone and glucocorticoid receptors. In animals it has antiprogestational activity at doses 50-fold less than those required for antiglucocorticoid effects.
We evaluated the biological activity, blood levels and safety of CDB-2914 at escalating single doses, in 36 normally cycling women at mid-luteal phase. CDB-2914 at doses of 1-100 mg did not change luteal phase length, but after 200 mg, all women had early endometrial bleeding. Four women with early menses had concurrent functional luteolysis (one at 10, 50, 100 and 200 mg). There were no biochemical or clinical signs of toxicity, and no effect on urinary cortisol or circulating thyroxine, prolactin, adrenocorticotrophic hormone or renin levels. Higher serum equivalents of CDB-2914 were observed by radioimmunoassay than by high performance liquid chromatography detection, indicating a considerable contribution of metabolites.
Mid-luteal administration of CDB-2914 antagonizes progesterone action on the endometrium, in a dose-dependent fashion, without apparent antiglucocorticoid effects. Further study of CDB-2914 is needed to determine its clinical role.
孕激素受体调节剂在诸如子宫内膜异位症、子宫肌瘤及引产等依赖孕激素的病症中具有潜在治疗用途。合成类固醇CDB - 2914可与孕激素受体和糖皮质激素受体结合。在动物实验中，其抗孕激素活性的剂量比产生抗糖皮质激素效应所需剂量低50倍。
我们评估了在黄体中期对36名月经周期正常的女性递增单次剂量使用CDB - 2914后的生物活性、血药浓度及安全性。1 - 100毫克剂量的CDB - 2914未改变黄体期长度，但200毫克剂量后，所有女性均出现早期子宫内膜出血。4名出现早期月经的女性同时伴有功能性黄体溶解（分别为10毫克、50毫克、100毫克和200毫克剂量各1例）。未出现生化或临床毒性迹象，对尿皮质醇或循环甲状腺素、催乳素、促肾上腺皮质激素或肾素水平也无影响。通过放射免疫测定法观察到的CDB - 2914血清等效物水平高于高效液相色谱检测结果，表明代谢产物有相当大的贡献。
黄体中期给予CDB - 2914可拮抗孕激素对子宫内膜的作用，呈剂量依赖性，且无明显抗糖皮质激素效应。需要对CDB - 2914进行进一步研究以确定其临床作用。
