Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men.

Abstract

It is well recognized that aging in men is accompanied by a decline in the serum levels of some adrenal and testicular steroids, but little or no attention has focused on the multiple steroid metabolites that are formed by steroid-converting enzymes in target tissues. In the present study, we have examined in detail the serum concentrations of a large series of adrenal and testicular steroids and their most significant metabolites produced in intracrine peripheral tissues. The serum concentrations of 26 conjugated and unconjugated C21-, C19-, and C18-steroids were measured in 2423 men aged 40-80 yr. The serum concentrations of the major circulating adrenal C19-steroids, namely dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), androst-5-ene-3 beta, 17 beta-diol and its sulfate, and androstenedione, decreased by about 60% between the ages of 40-80 yr. The small decrease in the serum concentrations of progesterone and pregnenolone in the presence of increased levels of cortisol and markedly decreased levels of DHEA, androst-5-ene-3 beta, 17 beta-diol, and their polar metabolites suggests that adrenal 17,20-lyase is particularly affected by aging. In addition to a marked decline in the serum concentrations of adrenal C19-steroids, a smaller, but significant, decrease occurred in serum testosterone. However, serum dihydrotestosterone levels remained constant, but the glucuronidated derivatives of dihydrotestosterone metabolites (androstane-3 alpha, 17 beta-diol glucuronide, androstane-3 beta, 17 beta-diol glucuronide, and androsterone glucuronide) were reduced by 45-50%, suggesting that 5 alpha-reductase activity in peripheral tissues may show a compensatory increase during aging. Analysis of the fatty acid esters of DHEA (DHEA-FA) also revealed that these nonpolar steroids markedly decrease between 40-80 yr of age, although such a decrease in DHEA-FA levels was smaller than that in DHEA and DHEA-S, suggesting that the formation of DHEA-FA may be specifically increased during aging. In summary, the present study suggests that in contrast to the marked decline in activity of steroidogenic enzymes in the adrenals and the small decrease in the testis, the activity of the steroid-converting enzymes present in peripheral tissues does not decrease during aging. In fact, the marked decrease in DHEA formation by the adrenals leads to a decrease of about 50% in total androgens in men between the ages of 40-80 yr. Such a decrease probably affects many physiological processes during aging.

Dehydroepiandrosterone inhibits microglial nitric oxide production in a stimulus-specific manner

“…DHEA is commonly believed to suppress immune activity (Rom and Harkin, 1991;Mohan and Jacobson, 1993;DiSanto et al, 1996;Padgett and Loria, 1998); although some studies have indicated that DHEA may activate immune cells, including macrophages (McLachlan et al, 1996;Delpedro et al, 1998). DHEA is of particular interest in Alzheimer disease because the levels of this steroid hormone decrease dramatically with age (Belanger et al, 1994;Thomas et al, 1994;Berr et al, 1996). In addition, DHEA levels are lower in Alzheimer patients than age-matched individuals, suggesting that DHEA may play a role in inhibiting the development of this disease (Nasman et al, 1991).…”

“…DHEA circulates in a sulfated form (DHEA-S) at a high concentration relative to steroid hormones. Humoral DHEA/DHEA-S, however, peaks in young adulthood in humans and drops significantly during aging (Belanger et al, 1994;Thomas et al, 1994;Berr et al, 1996). Even greater declines have been noted in certain disease conditions, notably Alzheimer disease (Nasman et al, 1991).…”

Dehydroepiandrosterone Stimulates Phosphorylation of FoxO1 in Vascular Endothelial Cells via Phosphatidylinositol 3-Kinase- and Protein Kinase A-dependent Signaling Pathways to Regulate ET-1 Synthesis and Secretion

“…DHEA (100 nM, 30 min) and ␤-estradiol (20 nM, 5 min) both stimulated phosphorylation of FoxO1 when compared with vehicle-treated control cells (Fig. 2, A and B, lanes [1][2][3]. Pretreatment of cells with ICI182780 only blocked the effect of ␤-estradiol, but not DHEA, to stimulate phosphorylation of FoxO1 (Fig.…”

“…Pretreatment with either wortmannin (PI 3-kinase inhibitor) or H89 (PKA inhibitor) completely blocked DHEA-stimulated phosphorylation of FoxO1 (Fig.2, C and D, lanes [1][2][3][4]. By contrast, pretreatment with PD98059 (MEK inhibitor), PP2 (Src inhibitor), or SB203580 (p38 MAPK inhibitor) did not significantly impair the ability of DHEA to stimulate phosphorylation of FoxO1 (Fig.…”

“…When compared with a control scrambled siRNA (Fig. 3A, third panel, lanes [1][2][3], siRNA targeting PKA specifically reduced PKA protein expression in transfected HAECs (Fig. 3A, third panel, lanes 4 -6).…”