Human Corticotropin-Releasing Factor in Man: Pharmacokinetic Properties and Dose-Response of Plasma Adrenocorticotropin and Cortisol Secretion

Abstract

The responses of plasma immunoreactive ACTH (IR-ACTH), cortisol, GH, PRL, and LH to a single iv injection of 0.01-5 micrograms/kg human corticotropin-releasing factor (hCRF) were investigated in healthy volunteers. The lowest effective dose of hCRF was 0.5 micrograms/kg. hCRF caused brief pulse-like elevations of plasma IR-ACTH and cortisol without any effect on the plasma concentrations of GH, PRL, and LH. By contrast, ovine CRF (oCRF), given for comparison, produced long-lasting stimulation of the human pituitary-adrenal axis. The difference in duration of effect between hCRF and oCRF may be attributed to an approximately 3-4 times higher MCR of hCRF [7.9 +/- 1.2 (+/- SE) ml/kg min; n = 14] than oCRF (1.9 +/- 0.1 ml/kg min; n = 9) in man. No serious side effects occurred at any of the doses of hCRF tested. The highest dose (5 micrograms/kg) caused a slight increase of heart rate that was not associated with significant changes in arterial blood pressure. All subjects receiving 5 micrograms/kg and one third of the subjects receiving 1 micrograms/kg hCRF experienced a transient facial flush. We conclude that hCRF causes brief plasma ACTH and cortisol secretory episodes in man, similar to the physiological plasma ACTH and cortisol secretory episodes. This is in contrast to oCRF, which causes prolonged ACTH and cortisol secretion. These differences between the two peptides may be explained by the higher MCR of hCRF than oCRF.

Dose Response of Adrenocorticotropin and Cortisol to the CCK-B Agonist Pentagastrin

“…The present data can shed only limited light on mediating mechanisms, but pentagastrin elicited much more rapid ACTH responses than are reported with human CRH infusions [7 min to peak vs. about 30 min (Schürmeyer et al 1984)], which argues against a CRHmediated mechanism in our subjects and may support a direct anterior pituitary effect. Pentagastrin effects are also differentiated from CRH-induced ACTH release in that responses to CRH are inversely related to basal levels of cortisol (De Cherney et al 1985;Hermus et al 1984) because of negative feedback inhibition; but we could not detect evidence of similar negative feedback regulation of pentagastrin-induced ACTH release.…”

Large Molecular Weight Immunoreactive Corticotrophin‐Releasing Hormone has Bioactivity on Superfused Ovine Pituitary Cells

“…However, the binding protein-attenuated ACTH release was still higher than the basal release reported, indicating that the binding protein did not eliminate all hCRH bioactivity. Data from in vivo studies in man (17,18) showed that the presence of the specific high affinity plasma binding protein for CRH did not prohibit the pituitary response to low doses of infused hCRH,, (0.05 to 0.1 pg, equivalent to 10.5 to 21 pmol/kg body wt).…”

“…However, 20% increases in ACTH release have been reported (17,18) suggesting that bound CRH may still be capable of evoking a pituitary response. Our gel filtration data indicate that the ovine pituitary appears to store mainly oBLpH, while both oBLpH and the smaller oBEP-IR materials are secreted basally and 15 min after by CRH-IR (Fig.…”

Peri‐operative steroid supplementation

“…Ovine CRH has a prolonged action, possibly due to its longer half-life, but may cause side-effects such as flushing (20% patients) or, rarely, tachypnoea. Human CRH causes shorter periods of ACTH and cortisol secretion similar to the physiological response of these hormones [81]. Nevertheless, ovine CRH has been preferred to human CRH because of its longer duration of action and because many of the initial studies were performed with oCRH before hCRH became available [82].…”