Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback

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Abstract
To explore the mechanisms of homeostatic adaptation of the hypothalamo-pituitary-adrenal axis to an experimental low- feedback condition, we quantitated pulsatile (ultradian), en- tropic (pattern-sensitive), and 24-h rhythmic (circadian) ACTH secretion during high-dose metyrapone blockade (2 g orally every 2 h for 12 h, and then 1 g every 2 h for 12 h). Plasma ACTH and cortisol concentrations were sampled concur- rently every 10 min for 24 h in nine adults. The metyrapone regimen reduced the amplitude of nyctohemeral cortisol rhythm by 45% (P 0.0013) and delayed the time of the cortisol maximum (acrophase) by 7.1 h (P 0.0002). Attenuated cor- tisol negative feedback stimulated a 7-fold increase in the mean (24-h) plasma ACTH concentration, which rose from 24 1.6 to 169 31 pg/ml (ng/liter) (P < 0.0001). Augmented ACTH output was driven by a 12-fold amplification of ACTH secretory burst 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 pulses (53 3.5 vs. 92 1.3%; P < 0.0001). There were minimal elevations in basal (nonpul- satile) ACTH secretion (by 50%; P 0.0049) and ACTH secre- tory burst frequency (by 36%; P 0.031). The estimated half- life of ACTH (median, 22 min) and the calculated ACTH secretory burst half-duration (pulse event duration at half- maximal amplitude) (median, 23 min) did not change. Hypo- cortisolemia evoked remarkably more orderly subordinate patterns of serial ACTH release, as quantitated by the approx- imate 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 alteration in serial ACTH interpulse-interval (waiting-time) regularity. At the level of 24-h ACTH rhythmicity, cortisol withdrawal en- hanced the daily rhythm in ACTH secretory burst mass by 29-fold, elevated the mesor by 16-fold, and delayed the ac- rophase by 3.4 h from 0831 h to 1154 h (each P < 103). In summary, short-term glucocorticoid feedback depriva- tion primarily (>97% of effect) amplifies pulsatile ACTH se- cretory burst mass, while minimally elevating basal/nonpul- satile ACTH secretion and ACTH pulse frequency. Reduced cortisol feedback paradoxically elicits more orderly (less en- tropic) patterns of ACTH release due to emergence of more regular ACTH pulse mass sequences. Cortisol withdrawal con- currently heightens the amplitude and mesor of 24-h rhythmic ACTH release and delays the timing of the ACTH acrophase. In contrast, the duration of underlying ACTH secretory epi- sodes is not affected, which indicates that normal pulse ter- mination may be programmed centrally rather than imposed by rapid negative feedback. Accordingly, we hypothesize that adrenal glucocorticoid negative feedback controls hypo- thalamo-pituitary-adrenal axis dynamics via the 3-fold dis- tinct mechanisms of repressing the mass of ACTH secretory bursts, reducing the orderliness of the corticotrope release process, and modulating the intrinsic diurnal rhythmicity of the hypothalamo-corticotrope unit. (J Clin Endocrinol Metab 86: 5554 -5563, 2001)

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