Relationship of Bioassayable and Immunoassayable Plasma ACTH and Cortisol Concentrations in Normal Subjects and in Patients with Cushing's Disease

Abstract

Plasma ACTH and cortisol concentrations were determined at 5-min intervals over a 3- or 4-h sampling period in 2 normal subjects. Time spans studied were 10:00 AM-1:00 PM, 4:00 PM-8:00 PM, 8:00 PM-11:00 PM, and 4:00 AM-8:00 AM. Similar sampling for 3 h, (onset 9:00-9:30 AM) was performed on 4 patients with Cushing's disease, 3 untreated and 1 in remission following pituitary irradiation. Two of these patients were studied on 2 separate occasions. Plasma ACTH was determined by both immunoassay (I) and bioassay (B). Although in general, these studies demonstrated significant correlation between I-ACTH or B-ACTH concentrations and those of plasma cortisol, a striking finding in both subject categories was the presence of 30- to 50-min episodes during which marked rises in both I- and B-ACTH concentrations occurred without concomittant, or markedly diminished, increments in plasma cortisol concentrations. This could not be explained by biological inactivity of the ACTH, since a highly significant correlation was present between I- and B-ACTH concentrations at all times; r values ranged between 0.86 and 0.98 for normal subjects, and 0.76 and 0.96 for patients with Cushing's disease. The lack of correlation in these episodes also does not appear to be secondary to an 11-beta-hydroxylase block, differences in the rate of change of plasma ACTH concentrations, lack of adrenal "priming" by prior ACTH or incapacity of the adrenal gland to further increase secretion. I/B ACTH ratios were similar in the normal subjects (1.42-1.64) and in the patients with Cushing's disease (1.27-1.47). "Apparent" ACTH half lives calculated from "peaks" of ACTH secretion were 7-12 min for I-ACTH and 3-9 min for B-ACTH in the normal subjects; and 9-13 min and 7-9 min respectively, in the patients with Cushing's disease. Mean plasma ACTH I-and B-concentrations at comparable time periods were higher in patients with active Cushing's disease than in normal subjects. These studies also indicate that in Cushing's disease, the abnormality present resides in ACTH regulatory mechanisms, not in the nature of the ACTH secreted. Approximation of the total amount of immunoassayable ACTH secreted in one normal subject over a 24-h period yielded a value of 73 mug. Total mug/h secreted in the 2 normal subjects were highest in the hour preceding awakening (6:30-7:30 AM; 12.9 and 12.2 mug/h); were 5.3 and 4.0 mug/h between 10:00-11:00 AM, and 1.4 and 1.7 mug/h between 9:00-10:00 PM. In the 3 patients with clinically active Cushing's disease, apparent ACTH secretion between 10:00-11:00 AM varied from 19.2-34.3 mug/h, the magnitude of such secretion being positively correlated with the extent of increased adrenal cortical activity present.

Evidence for an Ultradian Secretion of Adrenocorticotropin, β-Endorphin and α-Melanocyte-Stimulating Hormone by the Ovine Anterior and Intermediate Pituitary

“…The finding that one-third of all the cortisol pulses were not preceded by a significant rise in ACTH is consistent with previous studies in man and in the dog [3,19,30], and may be explained by postulating the existence of high-frequency ACTH pulses which remain undetected by a 10-min samp ling interval. Indeed, the pulse frequencies of all the measured substances were increased 3-to 7-fold when blood samples were withdrawn at 2-min intervals and, to our knowledge, these data provide the first in vivo evidence for the existence of high-frequency POMC-peptide and cor tisol pulses in any species.…”

“…However, when blood samples are taken at 10-min intervals, it may be ob served that the rise in plasma cortisol commences within 10 min of the secretion of ACTH [ 10,19).…”

Effect of Histamine Depletion on Circadian Variations of Corticotropin and Corticosterone in Rats

“…HA depletion also had a similar effect on the circadian ACTH rhythm: namely, the amplitude of the circadian rhythm of plasma ACTH decreased and it did not show a peak at the onset of darkness or a trough at the onset of the light period. The results were not so clear as those on the CS level, but fluctuation of the plasma ACTH level is reported to show a more irregular variation than that of plasma CS [14]; this may be partly because samples for ACTH must be obtained from different individual rats.…”

Enhanced cortisol production rates, free cortisol, and 11β-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss

“…The 24-h cortisol profile demonstrated that the higher total cortisol levels in men with greater visceral obesity occurred during the hours from late morning to early evening, but not during the "trough" period between midnight and 0200 typically associated with Cushing's disease (20,28). Wallerius et al (47) described a similar pattern, using salivary FC measurements in men with higher vs. lower WHR during a limited daytime sampling period.…”