BACKGROUND: Recent analyses in small cohorts suggest that pituitary hormones exert time-varying (viz., initial and delayed) dynamic dose-responsive effects on target glands, wherein down-regulating dynamics are inferable on a time scale of single pulses. HYPOTHESIS: Age, body mass index (BMI), and sex modulate the rapid potency-down-regulating dynamics of pulsatile pituitary ACTH-adrenal cortisol coupling overnight. LOCATION: The study was conducted at a clinical translational research unit. SUBJECTS: Subjects included healthy adults (48 women, 63 men; aged 18-77 yr; BMI 18-42 kg/m(2)). OUTCOMES: Outcomes included analytical dose-response estimates of endogenous ACTH efficacy, dynamic ACTH potency, and adrenal sensitivity from overnight 10-min ACTH-cortisol profiles. RESULTS: Stepwise backward-elimination, multivariate-regression analysis revealed that in the combined cohorts (n = 111), age was associated with enhanced initial ACTH potency (R = 0.265, P = 0.005). Moreover, age and BMI jointly attenuated adrenal sensitivity (R = 0.334, P = 0.0017) and augmented down-regulated ACTH potency (R = 0.321 and P = 0.0028). Exploratory gender-segmented analyses showed that these outcomes might be explained by: (1) a negative effect of age in men on adrenal sensitivity (R = 0.270, P = 0.034) and (2) positive effects of age in men (R = 0.332, P = 0.0019) and BMI in women (R = 0.331, P = 0.024) on initial ACTH potency. CONCLUSIONS: In healthy adults, adrenal sensitivity to endogenous ACTH pulses, ACTH efficacy, and ACTH potency is associated with age, BMI, and gender. These findings may explain conflicting data in earlier literature and introduce the need to control all three of age, BMI, and sex in future studies of the stress-adaptive axis.