Sex defines the age dependence of endogenous ACTH-cortisol dose responsiveness

Abstract

Whether similar sex differences operate in humans is unknown. To test this notion, we estimated ACTH-cortisol dose-response properties analytically in 48 healthy adults (n ϭ 22 women, n ϭ 26 men), ages 18 -77 yr, body mass index (BMI) 18 -32 kg/m 2 , previously studied at two medical centers. Plasma ACTH and cortisol concentrations were measured every 10 min for 24 h. The 145 sample pairs were used in each subject to estimate ACTH-cortisol drive via a logistic function. Statistical analyses revealed that 24-h cortisol secretion (Ͼ82% pulsatile) fell in men (r ϭ Ϫ0.38, P ϭ 0.028) and rose in women (r ϭ ϩ0.37, P ϭ 0.045) with age (P ϭ 0.01 sex effect). The mechanisms involved decreased ACTH efficacy with age in men (r ϭ Ϫ0.35, P ϭ 0.04), and increased ACTH efficacy with age in women (r ϭ ϩ0.42, P ϭ 0.025) [P ϭ 0.009 sex effect]. ACTH potency diminished with higher BMI in men (r ϭ ϩ0.38, P ϭ 0.029) and in the cohort as a whole (r ϭ 0.34, P ϭ 0.0085). These outcomes demonstrate that sex, age, and BMI modulate selective properties of endogenous ACTHcortisol drive in humans, thereby indicating the need to control these three major variables in experimental comparisons. adrenal; aging; sex; men; women; secretion IN EXPERIMENTAL ANIMALS, ESTROGENS sensitize and androgens mute corticotropic-axis responses to stress (15,21,60,75). Data in the human are indirect and controversial. For example, in one study in eight hypogonadal men, cortisol production rates were normal (77), whereas in another study, leuprolideinduced gonadoprivation unmasked greater ACTH and cortisol responses to corticotropin-releasing hormones (CRH) in young and middle-aged men than premenopausal women (59). Analyses of young hypogonadal adults further suggest that serotoninergic agonists and psychosocial stress stimulate greater corticotropic-adrenal responses in young men than young women (49, 61). On the other hand, cortisol concentrations are reportedly higher in women than men during early sleep, dexamethasone suppression, interleukin-6 infusion, growth hormone-releasing hormone (GHRH) injection, CRH stimulation, physostigmine administration, and psychosocial stress (8,43,48,64,78).In some investigations, age appears to augment ACTH and cortisol release in both sexes after selected stressors (8,26,30,43,48). Nonetheless, other studies have reported no age or sex effects (19,29,32,46,48,53). Certain of these discrepancies could be due to ethnicity differences (14, 80), time-of-day effects (72), measurement of cortisol in plasma, saliva, or urine (41, 43, 58), nature of stressor (54, 71), basal vs. stressed states (2, 81), concurrent obesity (1,23,33,67,68,70), estrogen use (46), stage of menstrual cycle (40), dietary carbohydrate intake (65), and potential sex-by-age interactions (78). The last consideration has been assessed in untreated children (28) and in adults following sequential dexamethasone/CRH exposure (30).To date, no clinical studies have appraised the individual and interactive effects of sex and age on adrenal responses to endogenous ...

Requirement for age-specific peak cortisol responses to insulin-induced hypoglycaemia in children

“…Factors that have been demonstrated previously to affect cortisol values including gender, BMI and inhaled corticosteroid use did not influence the downward trend in peak cortisol responses in adolescence. Sexual dimorphism has been demonstrated previously with respect to cortisol production and metabolism in adolescents (30) and older adults (31,32). In our cohort, there was a non-significant tendency towards higher stimulated cortisol responses in females.…”

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…Other studies have reported no such age effect [280,283]. Interestingly, a recent study reported that 24-h cortisol levels were lower in men and higher in women with age [284]. This was attributed to decreased ACTH efficacy with age in men and increased ACTH efficacy with age in women [284].…”

“…Interestingly, a recent study reported that 24-h cortisol levels were lower in men and higher in women with age [284]. This was attributed to decreased ACTH efficacy with age in men and increased ACTH efficacy with age in women [284]. Shifts in the timing of circadian peaks at older ages with later [285] or earlier morning peaks have also been reported [282,283].…”

Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women

“…Details of the dynamic dose-response methodology were described in several earlier papers (11,16,17,18,19). The goal here was to relate time-varying ACTH concentrations (input, effector) to time-varying cortisol secretion rates (output, response) via both a classic fourparameter logistic dose-response function and a fiveparameter logistic dose-response function that contain two potencies to accommodate allowable (possible, but not obligatory) downregulation of ACTH drive.…”

“…Comparison of ACTH secretion with that of cortisol suggested diminished responsiveness of the adrenal gland in obesity (10). A recent analytical method allows noninvasive estimation of physiological (nonlinear) dose-response functions from serially sampled hormone-effector response pairs, such as LH and testosterone, or ACTH and cortisol, without injection of hormone agonists, antagonists, or labeled compounds (11). Relevant hormone pairing (i.e.…”