Decreased Hypothalamic-Pituitary Adrenal Axis Sensitivity to Cortisol Feedback Inhibition in Human Aging

Abstract

Aging-related reduction in the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis to glucocorticoid feedback inhibition has been demonstrated in rodents, but aging effects on glucocorticoid feedback inhibition in humans are unclear. This study assessed the influence of aging on the sensitivity of the human HPA axis to feedback inhibition induced by cortisol. Endogenous cortisol feedback inhibition was removed by treatment with metyrapone, which reduces cortisol synthesis by inhibiting 11β-hydroxylase. Feedback inhibition was then reintroduced by infusing exogenous cortisol. Sixteen young (26 ± 1 years old) and 16 older (70 ± 2 years old) subjects underwent three study conditions in random order. In the two cortisol infusion conditions, oral metyrapone treatment was followed by intravenous infusion of 0.03 mg/kg/h (83 nmol/kg/h) or 0.06 mg/kg/h (166 nmol/kg/h) cortisol for 150 min. Feedback sensitivity was estimated by the latency to and extent of decline of plasma ACTH concentration during and following the cortisol infusion. In a placebo condition, placebo tablets were substituted for metyrapone and normal saline infusion was substituted for cortisol. Blood samples were drawn twice prior to and at 15-min intervals for 4 h following the onset of the infusions, and plasma was assayed for 11-deoxycortisol, cortisol and ACTH. Plasma cortisol suppression and ACTH and 11-deoxycortisol elevations did not differ between age groups after metyrapone. Older subjects exhibited delayed and blunted ACTH responses to infused cortisol. Within older subjects, the ACTH response to the higher dose cortisol infusion was blunted in older women compared to older men. These data provide direct evidence for reduced responsiveness to glucocorticoid feedback inhibition in human aging.

Protective and Damaging Effects of Stress Mediators

“…20,21 The failure to turn off the HPA axis and sympathetic activity efficiently after stress is a feature of agerelated functional decline in laboratory animals, [22][23][24] but the evidence of this in humans is limited. 25,26 Stress-induced secretion of cortisol and catecholamines returns to base line more slowly in some aging animals with other signs of accelerated aging, [22][23][24] and the negative-feedback effects of cortisol are reduced in elderly humans. 26 One other sign of age-related impairment in rats is that the hippocampus fails to turn off the release of excitatory amino acids after stress, 27 and this may accelerate progressive structural damage and functional impairment (see below).…”

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…These analyses included the varying gender population as well as the health status of subjects with some using samples from males only [248,249,256,[260][261][262], others employing both men and women [252][253][254][255]257,259,262,265], some from subjects classified as 'normal healthy' [248,249,256,[260][261][262], and others from hospitalized patients [251,252,257,262]. Few studies have reported decreased [267,268], or increased [269][270][271][272][273] cortisol levels. Interestingly one report comparing the age-related changes in cortisol in men and women sug-gests that women exhibit much greater age-related increases in cortisol secretion, with postmenopausal women showing the highest increases [269].…”

“…Numerous studies have reported that diurnal rhythmicity of cortisol [254,257,[269][270][271][272][273][274][275][276][277][278][279][280] and ACTH [238,263] is also unaffected by aging in both sexes, but there are some exceptions. For example, some studies reported higher evening [251,281] and morning [278] cortisol levels at older ages; higher 24h mean cortisol concentrations at older ages have also been reported in both men and women [269,270,272,281,282].…”

Stress and the Aging Hippocampus

“…Many but not all studies show increased levels of glucocorticoids in aging rats and humans (89,125,132,144,149). The reasons for these differences are likely to relate to individual differences in brain aging and in the differences in the distribution of aging, impaired individuals in populations of animals and human subjects (89).…”

“…It is this last aspect of HPA regulation that is the most intriguing, namely, that the role of the hippocampus may be as an adrenal steroidprimed modulator of neural activity that is involved in regulating hypothalamic output of CRF and vasopressin. In other words, ''shutoff'' of the HPA stress response may be due to steroid-modulated neural input, e.g., increasing inhibitory input to the PVN (53), rather than due exclusively to rapid and delayed steroid feedback at the level of the PVN neuron or pituitary corticotroph.Many but not all studies show increased levels of glucocorticoids in aging rats and humans (89,125,132,144,149). The reasons for these differences are likely to relate to individual differences in brain aging and in the differences in the distribution of aging, impaired individuals in populations of animals and human subjects (89).…”