Monroe S E, Blumenfeld Z, Andreyko J L, Schriock E, Henzl M R, Jaffe R B
J Clin Endocrinol Metab. 1986 Dec;63(6):1334-41. doi: 10.1210/jcem-63-6-1334.
To determine if treatment with the GnRH agonistic analog nafarelin could reliably block ovulation while only partially disrupting ovarian estrogen production, three degrees of pituitary-ovarian inhibition were investigated. Thirty-two women with ovulatory menstrual cycles were given 125 micrograms (group (Gp) I), 250 micrograms (Gp II), or 1000 micrograms (Gp III) nafarelin daily by intranasal spray. Twenty-seven women completed 6 months of treatment. Basal serum FSH concentrations decreased (P less than 0.01) in all groups. Suppression of serum LH was dose dependent and significant (P less than 0.01) only in Gps II and III. Pituitary desensitization to nafarelin developed in all groups. Peak LH responses to nafarelin decreased by about 70% (Gps I and II) and 95% (Gp III). Basal serum estradiol levels after 1 month of treatment were approximately 70 pg/ml (Gp I) and 25 pg/ml (Gps II and III). Serum estradiol levels increased acutely in Gps I and II, but not in Gp III, in response to each dose of nafarelin. Thus, average daily estradiol levels in Gp II were higher than those in Gp III. Serum testosterone and androstenedione levels decreased slightly (P less than 0.05; Gp II) or by 50% (P less than 0.01; Gp III) during treatment. The effects of nafarelin on ovulatory function also were dose-dependent. In Gp I there were four ovulations (progesterone, greater than 4 ng/ml) and seven instances of luteinization (progesterone, 2-4 ng/ml) during 73 months of nafarelin administration. In contrast, there were no ovulations during 58 and 44 months in Gps II and III, respectively. After discontinuance of nafarelin, ovulatory menstrual function returned rapidly in all women. In summary, inhibition of pituitary-ovarian function by daily intranasal nafarelin administration is dose dependent. Gonadotroph sensitivity to 125 micrograms is variable, and there is inconsistent inhibition of ovulation. Daily doses of 250 or 1000 micrograms analog reliably inhibit ovulation, but are associated with either moderate (Gp II) or marked (Gp III) reduction of ovarian estradiol secretion. The effects of these reduced levels of circulating estradiol on bone are not known. Further investigation, with dosage adjusted according to individual patient sensitivity, may lead to the development of a clinically acceptable contraceptive which consistently inhibits ovulation while maintaining serum estradiol levels sufficient to prevent osteoporosis.
为了确定促性腺激素释放激素（GnRH）激动剂类似物那法瑞林治疗能否在仅部分干扰卵巢雌激素生成的同时可靠地阻断排卵，研究了三种程度的垂体 - 卵巢抑制情况。32名月经周期有排卵的女性通过鼻内喷雾每日给予125微克（I组）、250微克（II组）或1000微克（III组）那法瑞林。27名女性完成了6个月的治疗。所有组的基础血清促卵泡激素（FSH）浓度均下降（P<0.01）。血清促黄体生成素（LH）的抑制呈剂量依赖性，且仅在II组和III组有显著意义（P<0.01）。所有组均出现了对那法瑞林的垂体脱敏。对那法瑞林的LH峰值反应在I组和II组下降约70%，在III组下降95%。治疗1个月后的基础血清雌二醇水平在I组约为70 pg/ml，在II组和III组约为25 pg/ml。I组和II组在每次给予那法瑞林后血清雌二醇水平急剧升高，但III组没有。因此，II组的平均每日雌二醇水平高于III组。治疗期间血清睾酮和雄烯二酮水平略有下降（P<0.05；II组）或下降50%（P<0.01；III组）。那法瑞林对排卵功能的影响也呈剂量依赖性。在I组给予那法瑞林的73个月中有4次排卵（孕酮>4 ng/ml）和7次黄体化（孕酮2 - 4 ng/ml）。相比之下，II组和III组在58个月和44个月期间分别无排卵。停用那法瑞林后，所有女性的排卵月经功能迅速恢复。总之，每日鼻内给予那法瑞林抑制垂体 - 卵巢功能是剂量依赖性的。对125微克那法瑞林的促性腺激素敏感性存在差异，且排卵抑制不一致。每日250或1000微克类似物可可靠地抑制排卵，但分别与卵巢雌二醇分泌的中度（II组）或显著（III组）减少有关。这些循环雌二醇水平降低对骨骼的影响尚不清楚。根据个体患者敏感性调整剂量的进一步研究可能会开发出一种临床上可接受的避孕药，既能持续抑制排卵，又能维持足以预防骨质疏松症的血清雌二醇水平。
