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We previously demonstrated that the reversible cholinesterase inhibitor, physostigmine (PHYSO), administered to normal young adult women and men (average age 35 years) at a dose that produced few or no side effects, resulted in a sex difference (sexual diergism) in hypothalamo-pituitary-adrenal cortical (HPA) axis responses: Plasma ACTH(1-39), cortisol, and arginine vasopressin (AVP) concentrations increased to a significantly greater extent in the men than in the women. To explore the effect of age on these sexually diergic hormone responses, in the present study we used the same dose of PHYSO (8 microg/kg IV) to stimulate ACTH(1-39), cortisol, and AVP secretion in normal elderly, non-estrogen-replaced women and elderly men (average ages 73 years and 70 years, respectively). The subjects underwent three test sessions 5-7 days apart: PHYSO, saline control, and a second session of PHYSO. Serial blood samples were taken for hormone analyses before and after pharmacologic challenge. As with the previously studied younger subjects, PHYSO administration produced no side effects in about half the elderly subjects and mild side effects in the other half, with no significant female-male differences. The hormone responses were 2-5 fold greater in the elderly subjects than in the younger subjects, but in contrast to the younger subjects, the elderly men did not have significantly greater hormone responses to PHYSO administration than did the elderly women. The ACTH(1-39) and AVP responses to PHYSO for the two sessions were significantly positively correlated in the men (+0.96, +0.91) but not in the women. None of the hormone responses was significantly correlated with the presence or absence of side effects in either group of subjects.These results indicate a greater sensitivity of the HPA axis to low-dose PHYSO, and a loss of overall sex differences in hormone responses, in elderly compared with younger subjects. The lack of a difference in side effects between the elderly women and men and the lack of significant correlations between presence or absence of side effects and hormone responses suggest that the increase in hormone responses with aging is due to correspondingly increased responsiveness of central cholinergic systems and/or the HPA axis, and not to a nonspecific stress response.

Sexual Diergism of Hypothalamo-Pituitary–Adrenal Cortical Responses to Low-Dose Physotigmine in Elderly vs. Young Women and Men