The effect of chronic hexarelin administration on the pituitary–adrenal axis and prolactin

OBJECTIVE: With the development of growth hormone (GH) releasing agents and their use in human subjects, it is clear that these agents are not specific for GH release. More recent studies in humans have demonstrated acute increases in adrenocorticotrophic hormone (ACTH), cortisol and prolactin (PRL) after boluses of intravenous or subcutaneous GHRPs. The potential adverse effects of repeated episodes of transient hyperprolactinaemia and hypercortisolaemia during long-term therapy with growth hormone releasing peptides (GHRPs) and similar agents have raised concern. We have therefore assessed the impact of chronic hexarelin administration on the pituitary-adrenal axis and serum prolactin levels. DESIGN: Each subject received twice-daily subcutaneous hexarelin therapy (1.5 micrograms/kg body weight) for 16 weeks. The ACTH, cortisol and PRL responses to the morning subcutaneous injection of hexarelin were assessed. Hexarelin was administered at time 0 and blood samples were taken at -10, 0, 10, 20, 30, 40, 50, 60, 90, 120, 170 and 180 min. The ACTH and PRL responses were assessed at baseline and after 16 weeks of therapy. The cortisol response was assessed at baseline, 16 weeks and also 4 weeks after completion of hexarelin therapy. Basal levels of cortisol binding globulin (CBG), 24-h urinary free cortisol (UFC) estimations, thyroid stimulating hormone (TSH) and total thyroxine (TT4) were performed at baseline, weeks 16 and 20. RESULTS: The mean (+/- SEM) area under the cortisol curve (AUCCORT) at baseline, week 16 and week 20 were 1506 (+/- 77) nmol/l/h, 1222 (+/- 92) nmol/l/h and 1586 (+/- 58) nmol/l/h, respectively. There was a significant change in AUCCORT over the study period (P = 0.008). Compared with baseline, AUCCOPRT had decreased significantly (P < 0.05) after 16 weeks of hexarelin therapy. Four weeks after completion of hexarelin therapy, the AUCCORT increased significantly compared with AUCCORT at week 16 (P < 0.01) and was no longer significantly different from baseline values. There were no significant changes in UFC (P = 0.3), basal cortisol measurements (P = 0.19), area under the ACTH curve (AUCACTH) (P = 0.24) or CBG (P = 0.6) over the study period. The mean (+/- SEM) area under the PRL curve (AUCPRL) at the baseline and week 16 were 624 (+/- 82) mU/l/h and 641 (+/- 83) mU/l/h, respectively. There was no significant change in AUCPRL over the study period (P = 0.35). CONCLUSION: The present study demonstrates clearly that in this hexarelin dosage regimen, over-stimulation of the pituitary adrenal axis and prolactin secretion do not occur. In fact the impact of chronic hexarelin therapy on the pituitary-adrenal axis, i.e. decreased AUCCORT, contradict the findings reported after acute hexarelin administration and cannot be explained by changes in CBG. The lack of change in UFC, however, suggests that these changes are unlikely to be of clinical significance although the underlying mechanism requires further study.