Effects of aging on adrenal function in the human: Responsiveness and sensitivity of adrenal androgens and cortisol to adrenocorticotropin in premenopausal and postmenopausal women

We sought to determine the effects of aging on several aspects of adrenal steroidogenesis in the hopes of characterizing the possible causes of adrenal androgen deficiency in elderly women. To this end, we quantified basal morning concentrations of cortisol (F), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DS), and androstenedione (A4) and then evaluated the effects of overnight dexamethasone (DEX) suppression followed by adrenal responses to graded hourly infusions of ACTH, ranging from 20 -1280 ng/1.5 m²·h. Finally, we performed a standard 0.25-mg ACTH bolus stimulation test, with sampling at 1 h thereafter. Basal serum levels ofDHEA, DS, and A4 were significantly reduced (∼50% each) in a group of 35 healthy postmenopausal women, 55-68 yr old, compared to those in 30 healthy, regularly menstruating women, 20-25 yr old. Post-DEX levels of these C₁₉ steroids also were significantly lower in the older women than in the younger women; the percent decrease after DEX for A4 was greater in the older women, whereas those in DHEA and DS were not age related. Basal and post-DEX levels off were similar in both groups. Secretory responses of DS to ACTH were not informative due to its large plasma pool and slow clearance rate. The maximally stimulated levels of DHEA after ACTH bolus were significantly lower in the older women than in younger women; those of A4 were similar in both age groups, and the maximally achieved levels of F were higher in the older women than in the younger women. The sensitivity of adrenal DHEA, A4, and F to ACTH (defined as the minimal dose of ACTH required to significantly increase the steroid levels above basal post-DEX values) was similar in older and younger women. The responsiveness of the steroids of interest to ACTH (defined as the slope of the dose-response curve over the linear portion of the dose-response curve) also was similar among younger and older women. These data demonstrate that the deficiency in adrenal androgen production in women is restricted to the Δ⁵-pathway steroid products (DHEA and DS), whereas there is no reduction in the capacity of the adrenal to produce A4 or cortisol. As DHEA and DS are likely to be produced mainly in the zona reticularis of the adrenal cortex, we propose that these data point to an alteration in that cortical zone as the cause of adrenal androgen deficiency in aging. The reductions in A4 in aging are probably due to reduced ovarian secretion after menopause.