What happens to the hypothalamic–pituitary–adrenal (HPA) axis with aging?
The HPA axis activity changes with aging and is different between the genders. The cortisol response to pharmacologic and psychological stressors is augmented with aging in both men and women. Interestingly, women have a more exaggerated response compared with men, suggesting that the loss of female sex hormones may contribute to alterations in HPA axis activity. However, distinguishing among the independent effects of age, declines in sex hormones, and body composition-related changes in the HPA axis is challenging. For example, morning cortisol levels tend to be lower, and stress-induced HPA axis responsiveness tends to be greater in older adults compared with younger adults, but such findings are also associated with central obesity (commonly found with aging; see above). Additionally, dynamic HPA axis responses to various stressors have been reported to be exaggerated in postmenopausal women compared with premenopausal women, with estradiol treatment attenuating the responses in postmenopausal women. However, several characteristics appear to be unique to aging per se. First, there is evidence for a phase advance characterized by an earlier morning cortisol peak. Second, the evening cortisol nadir appears to be higher in older persons, resulting in a compression of the diurnal amplitude. Third, glucocorticoid-mediated negative feedback is decreased. In total, mean 24-hour serum cortisol concentrations are 20% to 50% higher in both older women and older men, likely reflecting alterations in glucocorticoid clearance, HPA axis responsiveness to stress, and central glucocorticoid-mediated negative feedback. Finally, suppression of ovarian hormones for 20 weeks with leuprolide did not alter basal or dynamic HPA axis activity in premenopausal women, but estrogen add-back treatment reduced dynamic HPA axis activity compared with preintervention levels, suggesting that aging, as opposed to the decline in ovarian hormones, is the predominant contributing factor to increased HPA axis activity in older women. However, further research is needed to tease out the complex interaction between sex hormone changes and aging effects on the HPA axis in both women and men.
A recent meta-analysis of four large United Kingdom–based cohort studies of older adults followed up for 8 years showed no association of morning cortisol levels or diurnal cortisol slope with mental well-being. Whether an increase in the exposure to systemic and/or local tissue (via 11-beta hydroxysteroid dehydrogenase-1) glucocorticoids in the elderly contributes to such age-related changes as central obesity, insulin resistance, decreased lean body mass, increased risk for fractures, decreased sleep quality, and poor memory (all common symptoms of cortisol excess) are areas of ongoing investigation.