Handelsman D J, Jansen R P, Boylan L M, Spaliviero J A, Turtle J R
J Clin Endocrinol Metab. 1984 Oct;59(4):739-46. doi: 10.1210/jcem-59-4-739.
Pulsatile administration of GnRH has been used to stimulate gonadal function in both hypogonadotropic men and women; however, deficient responses were observed with the sc in contrast to the iv route of hormone delivery. To clarify whether this was due to altered bioavailability, we compared the pharmacokinetics of these two routes of GnRH administration by bolus injection and steady state continuous infusion methods. Synthetic GnRH was administered by both sc and iv routes to 14 hypogonadotropic patients (11 women and 3 men) as a bolus (5 micrograms in 25, 100, or 250 microliters, sc, and 250 microliters, iv; n = 6) or by continuous iv or sc infusion (3.17 micrograms/h for 6 h; n = 11). In single dose studies, plasma immunoreactive GnRH (IR-GnRH) peaks were earlier and higher (400 vs. 93.5 pg/ml) and returned to baseline sooner (less than 60 vs. greater than 120 min) after iv than after sc bolus injection. Plasma IR-GnRH levels were lower between 1 and 5 min, but higher between 30-90 min after sc injection compared with iv bolus injection. During the continuous infusions, plateau levels of IR-GnRH between 2 and 6 h were 34% lower with sc delivery (67.5 vs. 102.4 pg/ml), indicating irreversible losses of about one third of GnRH injected sc. In patients undergoing pulsatile GnRH therapy delivered by programmed portable minipumps, plasma IR-GnRH profiles were highly damped after sc administration, but retained an intermittent pulse wave form with the iv route. These data suggest that pharmacokinetic differences in the sc and iv routes of GnRH administration are due to a combination of prolonged and delayed absorption with reduced bioavailability of GnRH via the sc route. The consequent damping of the plasma GnRH profiles with sc administration may contribute to differences in the clinical efficacy of pulsatile GnRH regimens, and specific modifications of pulsatile regimens may be required to adapt the physiological requirements of an intermittent plasma GnRH wave form to the damped and reduced bioavailability of sc GnRH therapy.
脉冲式给予促性腺激素释放激素（GnRH）已被用于刺激性腺功能减退的男性和女性的性腺功能；然而，与静脉注射途径相比，皮下注射时观察到反应不足。为了阐明这是否是由于生物利用度改变所致，我们通过推注注射和稳态连续输注方法比较了这两种GnRH给药途径的药代动力学。将合成GnRH通过皮下和静脉途径给予14例性腺功能减退患者（11名女性和3名男性），推注（皮下注射25、100或250微升中含5微克，静脉注射250微升；n = 6）或通过静脉或皮下连续输注（3.17微克/小时，共6小时；n = 11）。在单剂量研究中，静脉推注注射后血浆免疫反应性GnRH（IR-GnRH）峰值出现更早、更高（400对93.5皮克/毫升），且比皮下推注注射更快恢复到基线水平（小于60对大于120分钟）。与静脉推注注射相比，皮下注射后1至5分钟血浆IR-GnRH水平较低，但30至90分钟时较高。在连续输注期间，皮下给药时2至6小时IR-GnRH的平台水平低34%（67.5对102.4皮克/毫升），表明皮下注射的GnRH约有三分之一发生不可逆损失。在使用程控便携式微型泵进行脉冲式GnRH治疗的患者中，皮下给药后血浆IR-GnRH曲线高度衰减，但静脉途径仍保留间歇性脉冲波形。这些数据表明，GnRH皮下和静脉给药途径的药代动力学差异是由于皮下途径吸收延长和延迟以及GnRH生物利用度降低共同导致的。皮下给药导致的血浆GnRH曲线衰减可能导致脉冲式GnRH治疗方案临床疗效的差异，可能需要对脉冲式方案进行特定修改，以使间歇性血浆GnRH波形的生理需求适应皮下GnRH治疗衰减和降低的生物利用度。
