Polycystic ovarian syndrome: Evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone
Polycystic ovarian syndrome: Evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone
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DOI：
10.1210/jc.85.11.4047
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发表时间：
2000-11-01
影响因子：
5.8
通讯作者：
Marshall, JC
中科院分区：
文献类型：
--
作者：
Eagleson, CA;Gingrich, MB;Marshall, JC
多囊卵巢综合征（PCOS）是一种复杂的疾病，有多种异常，包括雄激素过多、排卵功能障碍和促性腺激素分泌改变。大多数患者血浆中LH水平升高，且持续快速的促黄体生成素（GnRH）脉冲分泌频率，其机制尚不清楚。早期的研究表明，GnRH脉冲发生器对卵巢类固醇抑制的敏感性受损。我们进行了一项研究，以确定氟他胺抗雄激素治疗是否可以增强雌二醇（E(2)）和黄体酮(P)对PCOS女性的反馈抑制作用。10名无排卵的PCOS女性和9名正常中心（周期8-10天）进行了三次研究。每次入院时，每10分钟检测一次LH和FSH，每2小时检测一次E(2)、P和睾酮(T)，持续13小时。12小时后，静脉给予GnRH （25 ng/kg）。首次入院后，患者开始服用氟他胺（250 mg，每日2次），并持续整个研究。第二次入院发生在正常对照组的下一个月经周期的第8-10天，多囊卵巢综合征患者的第28天。然后经皮给予受试者E(2)（平均血浆E(2), 106 +/- 18 pg/mL）和阴道栓剂给予P，以获得不同的血浆P浓度（平均P， 4.4 +/- 0.5 ng/mL；范围，0.6-9.0 ng/mL）， 7天后进行第三次研究。在基线时，PCOS女性的LH脉搏幅值较高，对GnRH、T、雄烯二酮和胰岛素的反应较高，性激素结合球蛋白浓度较低（P < 0.05）。服用氟他胺4周后，除了对照组的T和PCOS患者的E(2)和FSH较低外，大多数激素参数没有改变。值得注意的是，氟他胺单独对LH脉冲频率或幅度、平均血浆LH或LH对外源性GnRH的反应性没有影响。在添加E(2)和P 7天后，PCOS患者和正常对照者的LH脉冲频率都有相似的降低（分别为4.0 +/- 0.7和5.8 +/- 0.7脉冲/12 h）。这与我们之前在不使用氟他胺的情况下的结果形成对比，其中血浆P水平低于10 ng/mL对PCOS女性LH脉冲频率的影响很小，但对对照组有效。这些结果表明，尽管PCOS患者LH脉冲频率升高可能部分反映了对E(2)和P的敏感性受损，但高雄激素血症的持续作用对于维持下丘脑对卵巢类固醇反馈抑制的异常敏感性是重要的。
Polycystic ovarian syndrome (PCOS) is a complex disorder with multiple abnormalities, including hyperandrogenism, ovulatory dysfunction, and altered gonadotropin secretion. The majority of patients have elevated LH levels in plasma and a persistent rapid frequency of LH (GnRH) pulse secretion, the mechanisms of which are unclear. Earlier work has suggested that the sensitivity of the GnRH pulse generator to inhibition by ovarian steroids is impaired. We performed a study to determine whether antiandrogen therapy with flutamide could enhance feedback inhibition by estradiol (E(2)) and progesterone (P) in women with PCOS. Ten anovulatory women with PCOS and nine normal centrals (days 8-10 of the cycle) were studied on three occasions. During each admission, LH and FSH were determined every 10 min and E(2), P, and testosterone (T) every 2 h for 13 h. After 12 h, GnRH (25 ng/kg) was given iv. After the first admission, patients were started on flutamide (250 mg twice daily), which was continued for the entire study. The second admission occurred on days 8-10 of the next menstrual cycle for normal controls and on study day 28 for PCOS patients. Subjects were then given E(2) transdermally (mean plasma E(2), 106 +/- 18 pg/mL) and P by vaginal suppository to obtain varied plasma concentrations of P (mean P, 4.4 +/- 0.5 ng/mL; range, 0.6-9.0 ng/mL), and a third study was performed 7 days later.At baseline women with PCOS had higher LH pulse amplitude, response to GnRH, T, androstenedione, and insulin and lower sex hormone-binding globulin concentrations (P < 0.05). Most hormonal parameters were not altered by 4 weeks of flutamide, except T in controls and E(2) and FSH in PCOS patients, which were lower. Of note, flutamide alone had no effect on LH pulse frequency or amplitude, mean plasma LH, or LH responsiveness to exogenous GnRH. After the addition of E(2) and P for 7 days, both PCOS patients and normal controls had similar reductions in LH pulse frequency (4.0 +/- 0.7 and 5.8 +/- 0.7 pulses/12 h, respectively). This contrasts with our earlier results in the absence of flutamide, where a plasma P level of less than 10 ng/mL had minimal effects on LH pulse frequency in women with PCOS, but was effective in controls. These results suggest that all though the elevated LH pulse frequency in PCOS may in part reflect impaired sensitivity to E(2) and P, continuing actions of hyperandrogenemia are important for sustaining the abnormal hypothalamic sensitivity to feedback inhibition by ovarian steroids.