Gender determines ACTH recovery from hypercortisolemia in healthy older humans.
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.


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.
Endocrine Research Unit, Mayo School of Graduate Medical Education, Center for Translational Science Activities, Mayo Clinic, Rochester, MN 55905, USA.
Animesh
A
Sharma
Paul
P
Aoun
Jean
J
Wigham
Sue
S
Weist
Johannes D
JD
Veldhuis
D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000368:Aged; D000369:Aged, 80 and over; D001823:Body Composition / Q000502:physiology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D007118:Immunoassay; D007262:Infusions, Intravenous; D007654:Ketoconazole; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D012727:Sex Characteristics
D000324:Adrenocorticotropic Hormone; D007654:Ketoconazole; D006854:Hydrocortisone
ACTH; AVP; Aging; CRH; Cortisol; E(2); Feedback; Human; KTCZ; T; adrenocorticotropic hormone; arginine vasopressin; corticotropin-releasing hormone; estradiol; ketoconazole; testosterone