Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Centre for Human Drug Research, Leiden, The Netherlands.
Br J Clin Pharmacol. 2020 Aug;86(8):1575-1584. doi: 10.1111/bcp.14265. Epub 2020 Mar 9.
Growth hormone (GH) secretion is pulsatile and secretion varies highly between individuals. To understand and ultimately predict GH secretion, it is important to first delineate and quantify the interaction and variability in the biological processes underlying stimulated GH secretion. This study reports on the development of a population nonlinear mixed effects model for GH stimulation, incorporating individual GH kinetics and the stimulation of GH by GH-releasing hormone (GHRH).
Literature data on the systemic circulation, the median eminence, and the anterior pituitary were included as system parameters in the model. Population parameters were estimated on data from 8 healthy normal weight and 16 obese women who received a 33 μg recombinant human GH dose. The next day, a bolus injection of 100 μg GHRH was given to stimulate GH secretion.
The GH kinetics were best described with the addition of 2 distribution compartments with a bodyweight dependent clearance (increasing linearly from 24.7 L/h for a 60-kg subject to 32.1 L/h for a 100-kg subject). The model described the data adequately with high parameter precision and significant interindividual variability on the GH clearance and distribution volume. Additionally, high variability in the amount of secreted GH, driven by GHRH receptor activation, was identified (coefficient of variation = 90%).
The stimulation of GH by GHRH was quantified and significant interindividual variability was identified on multiple parameters. This model sets the stage for further development of by inclusion of additional physiological components to quantify GH secretion in humans.
生长激素（GH）的分泌呈脉冲式，个体间的分泌差异很大。为了理解并最终预测 GH 的分泌，首先明确和量化刺激 GH 分泌的基础生物学过程的相互作用和可变性非常重要。本研究报告了一种用于 GH 刺激的群体非线性混合效应模型的开发，该模型结合了个体 GH 动力学和 GH 释放激素（GHRH）对 GH 的刺激。
将文献中关于全身循环、中脑和垂体前叶的数据作为模型的系统参数进行了纳入。对 8 名健康正常体重和 16 名肥胖女性接受 33μg 重组人生长激素剂量的数据进行了群体参数估计。第二天，给予 100μg GHRH 冲击注射以刺激 GH 分泌。
通过增加 2 个分布室并使清除率与体重相关（从 60kg 受试者的 24.7L/h 线性增加到 100kg 受试者的 32.1L/h），GH 动力学得到了最佳描述。该模型能够充分描述数据，具有较高的参数精度和 GH 清除率和分布容积的显著个体间可变性。此外，还确定了由 GHRH 受体激活驱动的分泌 GH 量的高度可变性（变异系数=90%）。
对 GHRH 刺激 GH 的作用进行了量化，并确定了多个参数的显著个体间可变性。该模型为进一步发展包括其他生理成分以定量人体 GH 分泌奠定了基础。
