Gender determines ACTH recovery from hypercortisolemia in healthy older humans

Abstract

Objective: Available clinical data raise the possibility that stress-adaptive mechanisms differ by gender. However, this notion has not been rigorously tested in relation to cortisol-mediated negative feedback.

Materials/methods: Degree of ACTH inhibition during and recovery from an experimental cortisol clamp was tested in 20 healthy older subjects (age 60±2.2 y). Volunteers received oral placebo or ketoconazole (KTCZ) to inhibit adrenal steroidogenesis along with i.v. infusions of saline or a low vs high physiological dose of cortisol in a prospectively randomized double-blind, placebo-controlled design. ACTH and cortisol concentrations were measured every 10 min during the feedback-clamp phase and thereafter (recovery or escape phase). Corticosteroid-binding globulin (CBG) was measured, and free cortisol concentrations were calculated.

Results: Gender did not determine mean ACTH concentrations during the saline or cortisol feedback-clamp phases per se. However, women had markedly impaired ACTH recovery after stopping both low- and high-dose cortisol infusions compared with men (P=0.005, KTCZ/low-dose cortisol arm; and P=0.006, KTCZ/high-dose cortisol arm). Decreased ACTH recovery in women was accompanied by lower total and free cortisol concentrations, pointing to heightened feedback inhibition of hypothalamo-pituitary drive of ACTH secretion as the main mechanism.

Conclusions: In summary, gender or a factor related to gender, such as sex steroids or body composition, determines recovery of ACTH secretion from cortisol-enforced negative feedback. Attenuated ACTH recovery in post-menopausal women may have relevance to sex differences in stress-related adaptations.

Keywords: ACTH; AVP; Aging; CRH; Cortisol; E(2); Feedback; Human; KTCZ; T; adrenocorticotropic hormone; arginine vasopressin; corticotropin-releasing hormone; estradiol; ketoconazole; testosterone.

© 2013.

Figures

Fig. 1

Schema of experimental design. Ten healthy older men and ten postmenopausal women each received successive oral doses of either KTCZ (steroidogenesis inhibitor) or placebo at regular intervals during 4 separate randomly ordered inpatient study sessions. To create a feedback clamp, saline or cortisol as a low dose (LDC) or a high dose (HDC) was infused continuously i.v. over 8 h (1800–0200 h). This paradigm yielded 4 intervention types: placebo/saline (control), KTCZ/saline, KTCZ/LDC, and KTCZ/HDC. The infusion was stopped abruptly at 0200 h to permit ACTH recovery. In each session, 10-min blood sampling was conducted over a total of 14 h, divided into an initial (4-h) feedback clamp phase (last 4 h of the 8-h saline or cortisol infusion, viz. 2200–0200 h), and a later (10-h) ACTH recovery phase (2200–1200 h). Time is represented in clock hours.

Fig. 2

Fourteen-h profiles of median gender-categorized concentrations of ACTH (left panel) and cortisol (right panel). Analyses were divided into an earlier 8-h feedback clamp phase, with sampling over the last 4 h of this interval (Fig. 1) and a later 10-h recovery phase. Each panel shows an individual interventional group (placebo/saline, KTCZ/saline, KTCZ/LDC, KTCZ/HDC). Data from men (closed circles) and women (open circles) are displayed separately. To convert ACTH ng/L to pmol/L multiply by 0.2202, and cortisol μg/dL to nmol/L multiply by 27.6.

Fig. 3

Absence of gender effect on mean ACTH (top) and cortisol (bottom) concentrations in older men and women during the last 4 h of the 8-h KTCZ-saline/cortisol feedback clamp in the 4 interventions. Overall infusion effects were significant by ANCOVA at P < 0.001 for both ACTH and cortisol. Paired bar graphs surmounted by brace brackets with unique (unshared) boldface capital letters are significantly different independently of gender. Individual P values by post hoc testing under each bracket show the lack of gender effects within intervention. Data are mean ± SEM (N = 10 men, N = 10 women). Post hoc testing was by Tukey’s HSD multiple-comparison test.

Fig. 4

Effects of gender on 10-h mean ACTH concentrations during the post-infusion recovery phase segmented into before and after the objective breakpoint in each of the 4 interventions. Different (unshared) upper-case letters within KTCZ/LDC as well as within KTCZ/HDC signify significantly different mean (± SEM) ACTH concentrations measured pre- vs post-breakpoints. Different lower-case letters in the KTCZ/HDC arm denote significant gender effects on mean ACTH concentrations both before and after the breakpoint. Analysis is based upon ANCOVA and Tukey’s post hoc HSD testing.

Fig. 5

Time course of median ACTH (top) and cortisol (bottom) concentrations during recovery phase in the KTCZ/LDC arm (left) and KTCZ/HDC arm (right) in older men (blue) and women (red) evaluated via a 4-parameter sigmoidal-curve model. The analysis yields estimates of the minimum (floor) and maximum (plateau) concentration along with 95% confidence bands (interrupted lines). Time is shown in min. Zero time (x-axis) denotes 0200 h.

Appendix Figure 1

Linear-segmental regression of 10-h individual ACTH concentrations on time during recovery in 10 men (left) and 10 women (right) in each of the 4 treatment arms. ACTH recovery overtime is segmented by a calculated breakpoint into a pre- (ACTH escape) and post- (return to baseline) phase. Time is shown in min with zero denoting 0200 h.