Gender determines ACTH recovery from hypercortisolemia in healthy older humans.

Author(s): Sharma A(1), Aoun P, Wigham J, Weist S, Veldhuis JD.

Affiliation(s): Author information: (1)Endocrine Research Unit, Mayo School of Graduate Medical Education, Center for Translational Science Activities, Mayo Clinic, Rochester, MN 55905, USA.

Publication date & source: 2013, Metabolism. , 62(12):1819-29

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.