Article

Prospective measurements of dehydroepiandrosterone sulfate in a cohort of elderly subjects: Relationship to gender, subjective health, smoking habits, and 10-year mortality

Institut National de la Santé et de la Recherche Médicale U330, Epidémiologie, Santé Publique et Développement, Université de Bordeaux II, 146, Rue Léo Saignat, 33076 Bordeaux Cedex, France.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 08/2001; 98(14):8145-50. DOI: 10.1073/pnas.121177998
Source: PubMed

ABSTRACT The decrease with age of the adrenal-secreted dehydroepiandrosterone sulfate (DHEAS) in serum has suggested that it may be causally related to longevity. For the PAQUID [People (Personnes) Aged (Agées) About What (Quid, in Latin)] cohort of elderly subjects, we have previously reported higher DHEAS in men than in women, a decrease with age and, among men, a negative correlation between the DHEAS level and mortality at 2 and 4 years. Here, with an 8-year followup in 290 subjects, we show a global decrease of 2.3% per year for men and 3.9% per year for women. However, in approximately 30% of cases, there was an increase of DHEAS. We observed no relationship between the evolution of DHEAS level and functional, psychological, and mental status, possibly because of selection by death. In women, no association was found between mortality and DHEAS level. In men, the relative risk (RR) of death was higher for the lowest levels of DHEAS (RR = 1.9, P = 0.007), with RR = 6.5, P = 0.003 for those under 70 years old, a result indicating heterogeneity of the population. There was an effect of subjective health on mortality that disappeared after adjustment of DHEAS levels, suggesting its relation with these DHEAS levels. Death RR was much higher in smokers with a low DHEAS level than in nonsmokers with high DHEAS (RR = 6.7, P = 0.001). We submit that the involvement of DHEAS is possibly different according to gender, that association between low DHEAS level and mortality only for men under 70 years old possibly reflects heterogeneity of the population, and that DHEAS level is a reliable predictor of death in male smokers.

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    • "During the third decade of life, blood DHEA levels rise and peak at around 10 mM. This is followed by an age-dependent decline of around 2–5% per year, leaving a residual production of 10–20% of the peak production by the eighth or ninth decade of life [22] [23]. This progressive diminution in the human adult suggests that a decrease in 17,20-lyase activity (Fig. 1B) may be responsible for the dramatic age-related reduction in DHEA and DHEA-S secretion [4] "
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    ABSTRACT: Dehydroepiandrosterone (DHEA) is a steroid hormone derived from cholesterol synthesized by the adrenal glands. DHEA and its 3β-sulphate ester (DHEA-S) are the most abundant circulating steroid hormones. In human, there is a clear age-related declined in serum DHEA and DHEA-S and this has suggested that a relative deficiency in these steroids may be causally related to the development of a series of diseases associated with aging including cardiovascular diseases (CVD). This commentary aims to highlight the action of DHEA in CVD and its beneficial effect in therapy. We thus discuss the possible impact of serum DHEA decline and DHEA supplementation in diseases such as hypertension, coronary artery disease, atherosclerosis… More specifically, we provide evidence for a beneficial action of DHEA in the main disease of the pulmonary circulation: pulmonary hypertension. We also examine the potential cellular mechanism of action of DHEA in terms of receptors (membrane/nuclear) and associated signalling pathways (ion channels, calcium signalling, PI3K/AKT/eNos pathway, cGMP, RhoA/RhoK pathway). We show that DHEA acts as an anti-remodelling and vasorelaxant drug. Since it is a well tolerated and inexpensive drug, DHEA may prove to be a valuable molecule in CVD but it deserves further studies both at the molecular level and in large clinical trials.
    Biochemical pharmacology 12/2012; 85(6). DOI:10.1016/j.bcp.2012.12.004 · 4.65 Impact Factor
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    • "This large decline in DHEA has led to interest in the possibility that development of DHEA deficiency may play a role in the deterioration in physiological and metabolic functions with aging and in the development of aging-related disease processes. In support of this possibility, it has been reported that DHEA level is negatively correlated with mortality and that lower levels of DHEA are associated with a higher risk of developing cardiovascular disease (CVD) in elderly people (Barrett-Connor et al., 1986; Berr et al., 1996; Mazat et al., 2001). "
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    ABSTRACT: Serum dehydroepiandrosterone (DHEA) concentrations decrease approximately 80% between ages 25 and 75 year. Aging also results in an increase in arterial stiffness, which is an independent predictor of cardiovascular disease (CVD) risk and mortality. Therefore, it is conceivable that DHEA replacement in older adults could reduce arterial stiffness. We sought to determine whether DHEA replacement therapy in older adults reduces carotid augmentation index (AI) and carotid-femoral pulse wave velocity (PWV) as indices of arterial stiffness. A randomized, double-blind trial was conducted to study the effects of 50 mg day(-1) DHEA replacement on AI (n = 92) and PWV (n = 51) in women and men aged 65-75 year. Inflammatory cytokines and sex hormones were measured in fasting serum. AI decreased in the DHEA group, but not in the placebo group (difference between groups, -6 ± 2 AI units, P = 0.002). Pulse wave velocity also decreased (difference between groups, -3.5 ± 1.0 m s(-1) , P = 0.001); however, after adjusting for baseline values, the between-group comparison became nonsignificant (P = 0.20). The reductions in AI and PWV were accompanied by decreases in inflammatory cytokines (tumor necrosis factor α and IL-6, P < 0.05) and correlated with increases in serum DHEAS (r = -0.31 and -0.37, respectively, P < 0.05). The reductions in AI also correlated with free testosterone index (r = -0.23, P = 0.03). In conclusion, DHEA replacement in elderly men and women improves indices of arterial stiffness. Arterial stiffness increases with age and is an independent risk factor for CVD. Therefore, the improvements observed in this study suggest that DHEA replacement might partly reverse arterial aging and reduce CVD risk.
    Aging cell 06/2012; 11(5):876-884. DOI:10.1111/j.1474-9726.2012.00852.x · 5.94 Impact Factor
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    • "In cardiovascular epidemiological studies in men, it was found that elevated levels of DHEA-S were associated with lower mortality rates from cardiovascular or any other diseases (Barrett-Connor et al., 1986; Barrett-Connor & Goodman-Gruen, 1995a; Berr et al., 1996; Mazat et al., 2001; Trivedi & Khaw, 2001). Although this suggests that DHEA supplementation might improve cardiovascular outcomes, prospective controlled studies have not yet been conducted. "
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    ABSTRACT: This review describes the cellular and molecular mechanism heterogeneity of dehydroepiandrosterone (DHEA) and its putative therapeutic role in vascular remodeling diseases such as pulmonary artery hypertension (PAH). PAH is characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation, constriction and resistance to apoptosis, all of which contribute to increase the pulmonary artery wall thickness, resistance and therefore pressure. The etiology of PAH remains elusive. Nonetheless, the implications of endothelial dysfunction (decreased nitric oxide generation and increased endothelin production etc), PASMC K(+) channel/mitochondrial axis disruption (voltage-gated K(+) channel (Kv1.5) downregulation and mitochondrial membrane potential hyperpolarization) and the activation of survival pathways such as PI3K/Akt are now accepted. Therefore, a drug able to target all of these abnormalities would be of a great therapeutic interest for the treatment of PAH. We and others have demonstrated that DHEA, a clinically available drug with a low adverse effect profile, is able to achieve these effects. In several animal models of vascular remodeling diseases such as PAH, DHEA has been demonstrated to be a good anti-proliferative and pro-apoptotic drug, decreasing vascular remodeling, and a potent vasodilator. A better understanding of the DHEA mechanisms of action may allow the development of new and better therapies to treat vascular remodeling diseases such as pulmonary hypertension.
    Pharmacology [?] Therapeutics 03/2010; 126(2):186-99. DOI:10.1016/j.pharmthera.2010.02.003 · 7.75 Impact Factor

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