Corticotropin secretory dynamics in humans under low glucocorticoid feedback

To explore the mechanisms of homeostatic adaptation of the hypothalamo-pitu itary-adrenal axis to an experimental low-feedback condition, we quantitate d pulsatile (ultradian), entropic (pattern-sensitive), and 24-h rhythmic (c ircadian) ACTH secretion during high-dose metyrapone blockade (2 g orally e very 2 h for 12 h, and then 1 g every 2 h for 12 h). Plasma ACTH and cortis ol concentrations were sampled concurrently every 10 min for 24 h in nine a dults. The metyrapone regimen reduced the amplitude of nyctohemeral cortiso l rhythm by 45% (P = 0.0013) and delayed the time of the cortisol maximum ( acrophase) by 7.1 h (P = 0.0002). Attenuated cortisol negative feedback sti mulated a 7-fold increase in the mean (24-h) plasma ACTH concentration, whi ch rose from 24 +/- 1.6 to 169 +/- 31 pg/ml (ng/liter) (P < 0.0001). Augmen ted ACTH output was driven by a 12-fold amplification of ACTH secretory bur st mass (integral of the underlying secretory pulse) (21 +/- 3.1 to 255 +/- 64 pg/ml; P < 0.0001), yielding a higher percentage of ACTH secreted in pu lses (53 +/- 3.5 as. 92 +/- 1.3%; P < 0.0001). There were minimal elevation s in basal (nonpulsatile) ACTH secretion (by 50%; P = 0.0049) and ACTH secr etory burst frequency (by 36%; P = 0.031). The estimated half-life of ACTH (median, 22 min) and the calculated ACTH secretory burst half-duration (pul se event duration at half-maximal amplitude) (median, 23 min) did not chang e. Hypocortisolemia evoked remarkably more orderly subordinate patterns of serial ACTH release, as quantitated by the approximate entropy statistic (P = 0.003). This finding was explained by enhanced regularity of successive ACTH secretory pulse mass values (P = 0.032). In contrast, there was no alt eration in serial ACTH interpulse-interval (waiting-time) regularity. At th e level of 24-h ACTH rhythmicity, cortisol withdrawal enhanced the daily rh ythm in ACTH secretory burst mass by 29-fold, elevated the mesor by 16-fold , and delayed the acrophase by 3.4 h from 0831 h to 1154 h (each P < 10(-3) ). In summary, short-term glucocorticoid feedback deprivation primarily (> 97% of effect) amplifies pulsatile ACTH secretory burst mass, while minimally elevating basal/nonpulsatile ACTH secretion and ACTH pulse frequency. Reduc ed cortisol feedback paradoxically elicits more orderly (less entropic) pat terns of ACTH release due to emergence of more regular ACTH pulse mass sequ ences. Cortisol withdrawal concurrently heightens the amplitude and mesor o f 24-h rhythmic ACTH release and delays the timing of the ACTH acrophase. I n contrast, the duration of underlying ACTH secretory episodes is not affec ted, which indicates that normal pulse termination may be programmed centra lly rather than imposed by rapid negative feedback. Accordingly, we hypothe size that adrenal glucocorticoid negative feedback controls hypothalamo-pit uitary-adrenal axis dynamics via the 3-fold distinct mechanisms of repressi ng the mass of ACTH secretory bursts, reducing the orderliness of the corti cotrope release process, and modulating the intrinsic diurnal rhythmicity o f the hypothalamo-corticotrope unit.