Endocrine Abstracts

Introduction: Available clinical literature raises the possibility that stress-responsive mechanisms differ by gender, especially in older individuals; however the accompanying evidence is both limited and discrepant. We hypothesize that gender determines the degree of ACTH inhibition by and recovery after an experimental cortisol clamp in older subjects.

Subjects and design: We conducted a prospectively randomized, double-blind, placebo-controlled, crossover study in 10 older men and 10 post-menopausal women (age group 50–80 years) in the clinical research unit of a tertiary medical center.

Methods: Volunteers received oral placebo or ketoconazole (KTCZ), to inhibit adrenal steroidogenesis, along with 8-h i.v. infusions of saline or a low (2.5 mg/m²) vs. high (10 mg/m²) physiological dose of i.v. cortisol. ACTH and cortisol concentrations were measured every 10 min during the last 4 h of the saline and cortisol infusions (feedback-clamp phase) and for 10 h thereafter (recovery phase).

Primary outcomes measure: Plasma ACTH concentrations.

Results: Gender did not determine mean ACTH concentrations during the feedback-clamp phase of saline or cortisol infusions. However, compared with men, women had markedly impaired mean (and peak) ACTH recovery from experimental cortisol infusion (P=0.005, KTCZ/low-dose cortisol arm; P=0.006, KTCZ/high-dose cortisol arm). Non-linear regression of ACTH on time confirmed attenuated ACTH recovery in women. Decreased ACTH recovery was accompanied by lower mean cortisol concentrations, pointing to attenuated feedforward drive of ACTH secretion rather than reduced cortisol clearance as the sex-related mechanism.

Conclusion: Gender determines the recovery of the hypothalamic–pituitary–ACTH unit from cortisol-induced feedback, with attenuated responses in post-menopausal women. The gender differences may have relevance to stress-related adaptations in the sexes.