Couzinet B, Young J, Brailly S, Chanson P, Thomas J L, Schaison G
Service d'Endocrinologie et des Maladies de la Reproduction, Hopital Bicetre, Kremlin, France.
J Clin Endocrinol Metab. 1996 Dec;81(12):4218-23. doi: 10.1210/jcem.81.12.8954018.
To further study the mechanism of the antigonadotropic activity of progestins, the effects of a 19-nortestosterone derivative, norethisterone acetate (NETA), and a 19-norprogesterone derivative, nomegestrol acetate (NOMA), were compared. The aim was to assess whether their action is exerted via the androgen receptor. Ten healthy postmenopausal women were treated for five monthly periods of 24 days separated by 10 days in a randomized cross-over design. Transdermal estradiol, Estraderm TTS (25 micrograms; one patch every 3 days), was given from days 1-24 during the five periods. On the last 12 days, of each estradiol treatment, they all received a placebo, NOMA (5 mg/day), NOMA in association with the nonsteroidal antiandrogen, flutamide (FLU; 250 mg, twice a day), NETA (10 mg/day), or NETA plus FLU. On the other hand, three castrated patients with complete androgen insensitivity (CAI) received NOMA and NETA for two periods of 12 days separated by 3 weeks. In postmenopausal women, the effects of NOMA and NETA on metabolic parameters were studied. Only NETA decreased high density lipoprotein cholesterol. Plasma LH, FSH, and estradiol were measured during each treatment period. A significant decrease in mean plasma LH and FSH levels and their responses to exogenous GnRH was observed with NOMA and NETA treatments compared to placebo (P < 0.001). The pulsatile frequency, but not the amplitude, of LH was significantly decreased during both treatments. Interestingly, the effects of both progestins on gonadotropins were not antagonized by FLU administration. In the patients with CAI, the pulsatile study of gonadotropins was performed before and on day 12 of NOMA and NETA treatments. As in postmenopausal women, both progestins induced similar decreases in LH and FSH. In conclusion, a 19-nortestosterone derivative, NETA, and a 19-norprogesterone derivative, NOMA, have similar antigonadotropic activities. This effect, not antagonized by FLU and observed in patients with CAI, is not mediated via the androgen receptor. The absence of deleterious effects of 19-norprogesterone derivatives on metabolic parameters should favor the therapeutic use of these compounds.
为进一步研究孕激素抗促性腺激素活性的机制，比较了19-去甲睾酮衍生物醋酸炔诺酮（NETA）和19-去甲孕酮衍生物醋酸诺美孕酮（NOMA）的作用。目的是评估它们的作用是否通过雄激素受体发挥。10名健康绝经后女性采用随机交叉设计，接受5个为期24天、间隔10天的疗程治疗。在5个疗程的第1 - 24天给予经皮雌二醇，即雌二醇透皮贴剂（25微克；每3天贴一片）。在每个雌二醇治疗周期的最后12天，她们均接受安慰剂、NOMA（5毫克/天）、与非甾体类抗雄激素药物氟他胺（FLU；250毫克，每日两次）联合使用的NOMA、NETA（10毫克/天）或NETA加FLU。另一方面，3名完全雄激素不敏感的去势患者（CAI）接受NOMA和NETA治疗，分两个疗程，每个疗程12天，间隔3周。在绝经后女性中，研究了NOMA和NETA对代谢参数的影响。只有NETA降低了高密度脂蛋白胆固醇。在每个治疗周期测量血浆促黄体生成素（LH）、促卵泡生成素（FSH）和雌二醇水平。与安慰剂相比，NOMA和NETA治疗后观察到平均血浆LH和FSH水平及其对外源性促性腺激素释放激素（GnRH）的反应显著降低（P < 0.001）。在两种治疗期间，LH的脉冲频率显著降低，但幅度未降低。有趣的是，两种孕激素对促性腺激素的作用并未因给予FLU而受到拮抗。在CAI患者中，在NOMA和NETA治疗前及治疗第12天进行促性腺激素的脉冲研究。与绝经后女性一样，两种孕激素均使LH和FSH出现类似程度的下降。总之，19-去甲睾酮衍生物NETA和19-去甲孕酮衍生物NOMA具有相似的抗促性腺激素活性。这种作用不受FLU拮抗且在CAI患者中也观察到，并非通过雄激素受体介导。19-去甲孕酮衍生物对代谢参数无有害影响，这应有利于这些化合物的治疗应用。
