Veldhuis Johannes D, Iranmanesh Ali
Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate School of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Clin Endocrinol Metab. 2004 Sep;89(9):4474-9. doi: 10.1210/jc.2004-0203.
The present study tests the hypothesis that iv infusion of discrete pulses of recombinant human (rh)LH after overnight GnRH-receptor blockade can restore midphysiological concentrations of testosterone (Te) in normal young men. In a pilot time-course analysis, injection of the GnRH antagonist ganirelix (2.0 mg sc) at 2200 h lowered LH concentrations (mean +/- sem) from 3.4 +/- 0.7 to 0.8 +/- 0.1 IU/liter (P < 0.01) and Te concentrations from 416 +/- 48 to 107 +/- 16 ng/dl (P < 0.01) (to convert to nmol/liter, multiply by 0.0347) at 0800 h the next morning. LH and Te concentrations remained suppressed thereafter for an additional 15 h (interval, 10-25 h after ganirelix administration) at mean values of 1.2 +/- 0.1 IU/liter and 67 +/- 10 ng/dl, respectively (P < 0.005 vs. baseline). Based on these data and earlier dose-finding studies, eight men received a single ganirelix injection followed by seven consecutive iv pulses of rhLH (15.3 IU Second International Reference Preparation) each delivered over 6 min every 2 h beginning at 0800 h. Recurrent rhLH stimuli restored mean LH concentrations (IU/liter of homologous standard) to 4.8 +/- 0.3, LH peak maxima to 7.1 +/- 0.6, incremental LH peak amplitudes to 3.7 +/- 0.4, and interpeak nadir LH concentrations to 3.3 +/- 0.3 (each P < 0.01 vs. saline infusion after ganirelix). These values were indistinguishable from the normal 95% range established in 23 young adults of comparable age. Injected LH pulses increased total Te concentrations (ng/dl) to 440 +/- 52, Te peak maxima to 552 +/- 64, incremental Te amplitudes to 188 +/- 23, and interpeak nadir Te concentrations to 366 +/- 43 (each P < 0.01 vs. saline addback; P value not significant vs. untreated men). Under combined ganirelix inhibition and pulsatile rhLH drive, Te concentrations rose from a nadir of less than 120 ng/dl to an asymptotic plateau of 611 ng/dl with an estimated half-time of 97 +/- 9.1 min. Cross-correlation analysis of paired serial LH and Te concentrations verified that infused LH pulses stimulate Te elevations within 40-70 (median 50) min (P < 0.001). Kinetic estimates of the half-life of exogenous rhLH averaged 107 +/- 3.8 min, which value exceeded that of secreted LH monitored after pharmacological GnRH stimulation (83 +/- 12 min; P = 0.012). We conclude that intermittent iv pulses of rhLH delivered over 12 h under selective GnRH-receptor blockade can restore young adult-like pulsatile LH and Te concentrations with an appropriate time delay coupling the lutropic stimulus to the steroidogenic response. Whether a comparable near-physiological paradigm can maintain human Leydig-cell testosterone production for a more extended interval is not known.
在夜间GnRH受体被阻断后，静脉输注离散脉冲的重组人（rh）LH能够恢复正常年轻男性睾酮（Te）的生理浓度。在一项初步的时间进程分析中，于22:00皮下注射GnRH拮抗剂加尼瑞克（2.0 mg），可使第二天上午08:00时的LH浓度（均值±标准误）从3.4±0.7降至0.8±0.1 IU/升（P<0.01），Te浓度从416±48降至107±16 ng/dl（P<0.01）（换算为nmol/升时，乘以0.0347）。此后，LH和Te浓度在接下来的15小时内（加尼瑞克给药后10 - 25小时的时间段）仍被抑制，均值分别为1.2±0.1 IU/升和67±10 ng/dl（与基线相比，P<0.005）。基于这些数据和早期的剂量探索研究，8名男性接受了单次加尼瑞克注射，随后从08:00开始每2小时静脉注射7个连续脉冲的rhLH（15.3 IU第二国际参考制剂），每个脉冲持续6分钟。反复给予rhLH刺激使平均LH浓度（同源标准品的IU/升）恢复到4.8±0.3，LH峰值最大值恢复到7.1±0.6，LH峰值增量幅度恢复到3.7±0.4，峰间LH最低浓度恢复到3.3±0.3（与加尼瑞克后输注生理盐水相比，各P<0.01）。这些值与23名年龄相仿的年轻成年人建立的正常95%范围无差异。注射的LH脉冲使总Te浓度（ng/dl）增加到440±52，Te峰值最大值增加到552±64，Te增量幅度增加到188±23，峰间Te最低浓度增加到366±43（与加回生理盐水相比，各P<0.01；与未治疗男性相比，P值无统计学意义）。在加尼瑞克抑制和脉冲式rhLH驱动的联合作用下，Te浓度从低于120 ng/dl的最低点升至611 ng/dl的渐近平台期，估计半衰期为97±9.1分钟。对配对的系列LH和Te浓度进行互相关分析证实输注的LH脉冲在40 - 70（中位数50）分钟内刺激Te升高（P<0.001）。外源性rhLH半衰期的动力学估计平均值为107±3.8分钟，该值超过了药理学GnRH刺激后监测到的分泌型LH的半衰期（83±12分钟；P = 0.012）。我们得出结论，在选择性GnRH受体阻断下，12小时内间歇性静脉注射rhLH脉冲能够恢复类似年轻成年人的脉冲式LH和Te浓度，并在促黄体生成素刺激与类固醇生成反应之间有适当的时间延迟耦合。尚不清楚类似的近生理模式能否在更长时间内维持人类睾丸间质细胞睾酮的产生。
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