Growth hormone (GH) secretion is pulsatile and highly variable between individuals. However, we commonly reduce the outcomes of the complex GH axis to summary statistics (mean/median) in order to quantify the pituitary activity. In reality, the pulsatile GH profile contains much more information (e.g. number of pulses) and there is a high level of variability in the GH kinetics and in an individual’s response to pharmacological treatment. In order to quantify what mechanisms are affected in disease states (e.g. acromegaly), we need to first be able to quantify the underlying mechanistic interactions in healthy individuals. This study reports on the semi-mechanistic model development of the feed-forward regulation of GH, driven by GH releasing hormone (GHRH), in women and men.

In this study, 100mU recombinant human GH (rhGH) was given to 8 healthy and 16 obese women. The next day, a bolus injection of 100µg GHRH was given to stimulate GH secretion. A population pharmacokinetic (PK) model was developed to study the individual GH kinetics which was used as basis for the mechanistic model. Additionally, information from literature was obtained on the systemic circulation, median eminence, and the anterior pituitary, which were included as system parameters in the model. This model was then used to assess similarity of the response in men (n=6, 1 µg/kg GHRH).

The PK of rhGH were best described with a 2-compartment model with a bodyweight dependent clearance. The semi-mechanistic model was able to adequately fit the PK and the stimulated GH response with high parameter precision. The application of the developed model on the data in men underpredicted the observations and suggested a slower dissociation phase.

This model enabled us to quantify the feed-forward regulation of GH by GHRH and the variability in this population. This model provides a basis on which the endogenous secretion of GH and the negative feedback from somatostatin can be implemented, after which the model can be used for translation to other populations.