Pharmacological aspects of corticotrophinergic and vasopressinergic function tests for HPA axis activation

Jacobs, G.E. (2010)

Doctoral Thesis

This thesis focuses on the quantification of hypothalamus-pituitary-adrenal (HPA) axis activation in healthy volunteers by applying pharmacological function tests with distinct pharmacodynamic (PD) mechanisms. Its main objective is to contribute to the validation of different function tests for the two most well-characterized HPA axis activation routes. To realize this objective, different experiments were executed in which specific principles that have been proposed to optimize the reliability of pharmacological function tests were observed. Human corticotrophin-releasing hormone (corticorelin - hCRH) and the direct serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) were applied for the corticotrophinergic (CRH-mediated) route while the synthetic analogue of arginine-vasopresin (AVP) desmopressin (dDAVP)and the D2 receptor antagonist metoclopramide were used for the vasopressinergic (AVP-mediated) pathway. Additionally, the application of these function tests was expected to contribute to a better understanding of the respective contributions of the corticotrophinergic and vasopressinergic pathways to HPA axis activation in health. Finally, an extra dimension was added to the validation process by applying proton magnetic resonance spectroscopy (MRS)to measure changes in hypothalamic metabolites during pharmacological stimulation.

• HPA axis
• Pharmacological function test/challenge test
• Corticotrophin-releasing hormone (CRH)
• Vasopressin (CRH)
• Serotonin (5-HT)
• Adrenocorticotrophic hormone (ACTH)
• Cortisol (CORT)
• PK-PD model

• All authors: Jacobs, G.E.
• Supervisor: Gerven, J.M.A. van; Zitman, F.G.; Cohen, A.F.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2010-12-15