Dose-response downregulation within the span of single interpulse intervals.
Pituitary ACTH drives adrenal glucocorticoid (cortisol) pulses via a time-delayed asymptotic dose-response process. To test the postulate that ACTH stimulates cortisol secretion dynamically (unequally during the initiation and termination of a cortisol secretory burst), a mathematical formalism was developed in which dose-response hysteretic shifts were allowed, but not required, within the time evolution of ACTH-cortisol pulse pairs. A dual-waveform deconvolution model was used to quantify cortisol secretion rates and reconstruct ACTH concentration profiles in 28 healthy adults previously sampled every 10 min for 24 h in the unstressed state (8,120 measurements). ACTH concentration-cortisol secretion dose-response functions were then estimated in each subject 1) without hysteresis (base model) and with allowances for possible hysteresis in 2) ACTH potency, 3) adrenal sensitivity, and 4) ACTH efficacy. Model residual error was 40% lower in the potency and sensitivity models and 20% lower in the efficacy model than in the base model (P < 0.001). Mean time shifts for inferable hysteretic inflection were model-independent, i.e., grand mean (95% confidence interval) 22 (12-39) min after the onset of a cortisol secretory burst. Half-maximally effective ACTH concentrations (EC(50)) differed before and after hysteretic inflection within individual pulses: 1) 9.4 and 54 ng/l in the potency model (P < 0.001) and 2) 8.9 and 123 ng/l in the sensitivity model (P < 0.001) compared with 16 ng/l in the no-hysteresis model (P < 0.001). In the efficacy-shift model, estimated maximal ACTH drive varied by 17-fold within cortisol secretory bursts (from 22 to 1.3 nmol.l(-1).min cortisol secretion(-1), P < 0.001). The collective results introduce the basis for modeling the dynamics of rapid, reversible physiological downregulation within the span of single interpulse intervals in vivo. This construct should have utility in parsing mechanisms of physiological regulation in other integrative systems.
Keenan
Daniel M
DM
Department of Statistics, University of Virginia, Charlottesville, Virginia, USA.
Roelfsema
Ferdinand
F
Veldhuis
Johannes D
JD
D000311:Adrenal Glands / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000328:Adult; D015536:Down-Regulation; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological
D005938:Glucocorticoids; D006728:Hormones; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone
Endocr Rev. 2006 Apr;27(2):101-40
16434512
J Clin Endocrinol Metab. 1998 Feb;83(2):688-92
9467594
Vitam Horm. 2005;70:265-79
15727807
Peptides. 2009 Aug;30(8):1448-55
19416745
Proc Natl Acad Sci U S A. 1989 Jul;86(13):4978-81
2544885
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4028-33
11274427
Biochem Biophys Res Commun. 1991 Apr 15;176(1):94-101
1708253
Peptides. 2000 Feb;21(2):309-24
10764961
Horm Metab Res. 1998 Jun-Jul;30(6-7):311-4
9694555
Am J Physiol Regul Integr Comp Physiol. 2003 Nov;285(5):R950-61
12842865
Endocr Rev. 2008 Dec;29(7):823-64
18940916
Endocrinology. 2009 Apr;150(4):1941-51
19022882
Endocrinology. 1988 Dec;123(6):2605-10
3197637
Mol Cell Endocrinol. 2001 Feb 14;172(1-2):147-55
11165048
J Clin Invest. 1994 Apr;93(4):1828-33
8163681
Mol Cell Endocrinol. 1987 Aug;52(3):243-9
2820814
Endocrinology. 1996 Dec;137(12):5311-8
8940351
Endocrinology. 1998 Feb;139(2):443-50
9449609
Endocrinology. 1984 Mar;114(3):1041-7
6365522
Endocr Rev. 1988 Feb;9(1):3-37
3286234
Horm Metab Res. 2000 Jul;32(7):265-8
10965931
Endocrinology. 1989 Sep;125(3):1711-7
2759041
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6740-5
15090645
Endocrinology. 1983 Jan;112(1):315-20
6291918
FEBS Lett. 1985 May 6;184(1):6-9
2985448
J Physiol. 1989 Sep;416:557-69
2607463
Endocrinology. 1990 Jul;127(1):218-26
2163311
Horm Metab Res. 1998 Jun-Jul;30(6-7):341-5
9694560
Mol Endocrinol. 1997 Apr;11(4):400-14
9092792
Life Sci. 1995;57(9):833-7
7630311
Mol Endocrinol. 2002 Dec;16(12):2746-53
12456795
Mol Pharmacol. 2003 Jul;64(1):132-42
12815169
Mol Cell Endocrinol. 1984 Jun;36(1-2):43-51
6086424
PLoS One. 2009 Oct 07;4(10):e7309
19809495
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12795-800
12237400
Am J Physiol Endocrinol Metab. 2004 Oct;287(4):E652-61
15186998