Pulsatile Cortisol Feedback on ACTH Secretion Is Mediated by the Glucocorticoid Receptor and Modulated by Gender

Abstract

Context: Factors that regulate physiological feedback by pulses of glucocorticoids on the hypothalamic-pituitary unit are sparsely defined in humans in relation to gluco- or mineralocorticoid receptor pathways, gender, age, and the sex steroid milieu.

Objective: The objective of the study was to test (the clinical hypothesis) that glucocorticoid (GR) and mineralocorticoid (MR) receptor-selective mechanisms differentially govern pulsatile cortisol-dependent negative feedback on ACTH output (by the hypothalamo-pituitary unit) in men and women studied under experimentally defined T and estradiol depletion and repletion, respectively.

Setting: The study was conducted at the Mayo Center for Translational Science Activities.

Subjects: Healthy middle-aged men (n = 16) and women (n = 25) participated in the study.

Interventions: This was a randomized, prospective, double-blind, placebo- and saline-controlled study of pulsatile cortisol infusions in low cortisol-clamped volunteers with and without eplerenone (MR blocker) and mifepristone (GR blocker) administration under a low and normal T and estradiol clamp. During frequent sampling, a bolus of CRH-arginine vasopressin was infused to assess corticotrope responsiveness. Analytical Methods and Outcomes: Deconvolution and approximate entropy of ACTH profiles were measured.

Results: Infusion of cortisol (but not saline) pulses diminished ACTH secretion. The GR antagonist, mifepristone, interfered with negative feedback on both ACTH burst mass and secretion regularity. Eplerenone, an MR antagonist, exerted no detectable effect on the same parameters. Despite feedback imposition, CRH-arginine vasopressin-stimulated ACTH secretion was also increased by mifepristone and not by eplerenone. Withdrawal vs addback of sex steroids had no effect on ACTH secretion parameters. Nonetheless, ACTH secretion was greater (P = .006) and more regular (P = .004) in men than women.

Conclusion: Pulsatile cortisol feedback on ACTH secretion in this paradigm is mediated by the glucocorticoid receptor, in part acting at the level of the pituitary, and influenced by sex.

Figure 1.

Schematic presentation of overall study design. See Materials and Methods for full details. Abbreviations are defined in text.

Figure 2.

Plasma ACTH concentration profiles in healthy men and women. All subjects were treated with ketoconazole and received either saline (placebo) or pulsed cortisol infusions. Sequential cortisol or placebo pulses each of 8 minutes of duration were injected at 90-minute intervals, overnight for none pulses in total, during exposure to oral placebo or eplenerone or mifepristone. After 8 hours of 10 minutes of blood sampling, an injection of CRH/AVP was given and sampling continued for 2 more hours. Data are shown as mean ± SEM.

Figure 3.

ACTH secretion parameters quantified by deconvolution of 8-hour plasma ACTH profiles. Black bars represent men and open bars women. Data are shown as the mean ± SEM. Overall significance between the four infusion experiments by GLM was P < .0001 in all four panels. In the unrestrained state (ketoconazole and saline infusion only), ACTH secretion was larger than in the three other conditions in which cortisol was infused. ACTH secretion is larger in men than in women, except for basal (nonpulsatile) ACTH secretion. Individual P values are shown in the panels. Treatment with sex steroids had no effect. Contrasts between cortisol infusion alone and cortisol infusion together with mifepristone are indicated by the horizontal lines.

Figure 4.

ACTH secretory-burst mass calculated by deconvolution analysis of 2-hour ACTH time series observed after injection of CRH/AVP. Black bars represent men and gray bars, women. Data are shown as the mean ± SEM. Overall GLM significance is P < .0001. Selected contrasts between different infusion protocols are as follows: saline vs cortisol and cortisol with eplerenone, P < .0001; cortisol vs cortisol with mifepristone, P = .018; and cortisol vs cortisol with eplerenone, P = .92. ACTH secretion was larger in men than women, but treatment with sex steroids had no significant effects (see inserted text in the figure).

Figure 5.

ACTH ApEn, a measure of feedback differences. Black bars represent men and gray bars, women. Data are shown as the mean ± SEM. Overall GLM significance is P < .0001. ApEn of saline, cortisol + placebo, and cortisol + eplerenone did not differ (P = .17). Addition of mifepristone caused a significant decrease in ACTH ApEn compared with placebo (P < .001), indicating more orderly, less irregular, ACTH secretion patterns. ApEn was larger in women than men in all four infusion sessions (P = .004), signifying greater process randomness in the regulation of ACTH secretion in women.