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Ti trovi in Medicina Antiaging,Antiaging,Menopausa,Andropausa,Ormoni Bioidentici | Abstract presentato al congresso di medicina antiaging di parigi-11-13 marzo 2008-what's the future of dhea's replacement therapy?

Abstract presentato al congresso di medicina antiaging di parigi-11-13 marzo 2008-what's the future of dhea's replacement therapy?

26/04/2008

ASCANIO POLIMENI M.D.--NEUROENDOCRINOLOGIST--

What’s the future of dhea’s replacement therapy?
Future perspectives of dhea therapy used alone and in combination with other therapies in HRT of menopause, in chronic inflammatory and autoimmune diseases, in immunedeficiency-immunesenescence and in the prevention of cardiovascular death.

Estrogen therapy (oral estrogen specially) alone or combined with synthetic progesterone can promote breast cancer in users of HRT for menopause’s complaints. Tamoxifen and other SERM (selective estrogen receptor modulators) are the most effective treatments for breast cancer through its ability to antagonize estrogen-dependent growth by binding estrogen receptors (ERs) and inhibiting proliferation of breast epithelial cells.
In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation. In clinical studies, DHEA has been found to increase bone mineral density and to stimulate vaginal maturation without affecting the endometrium, while improving well-being and libido with no significant side effects. To avoid the concerns about the use of traditional hormone replacement therapy, dhea (a tissue-targeted precursor of sex steroid formation) offers hope of a physiological tissue-targeted hormone replacement that, combined with a SERM, would simultaneously prevent breast and uterine cancer.
The natural concomitant secretion of DHEA with glucocorticoid (GC) probably enables the latter to protect the body from ill-effects of stress without exerting their deleterious potency.GC are widely used as key therapy in chronic inflammatory and autommune disease. Long-term GC administration may result in some deleterious side-effects, such as muscular weakness, atrophy and necrosis, diabetes, fattiness, osteopenia, osteoporosis and avascular necrosis and susceptibility to infections. DHEA ameliorates some deleterious effects of GC, such as diabetes, amino acid deamination, fattiness, hypertension and susceptibility to viraemia. By its anabolic effects in muscles, bones and endothelium, DHEA may diminish the severity of GC-induced catabolic effects like myopathy, osteopenia, osteoporosis and avascular necrosis. On the other hand, administration of GC inhibits ACTH secretion, involutes the adrenal cortex and results in further DHEA deficiency, particularly harmful in chronic autoimmune diseases (i.e. RA, SLE). Therefore, the deleterious side-effects of chronic administration of GC emerges from both their direct catabolic activity and the suppression of DHEA production. The viewpoint presented in an Italian study claims that under chronic GC supplementation, DHEA replacement therapy may reduce damage caused by GC administration.
The progression of HIV infection is accompanied by complex alterations in the production of adrenal steroids. Cortisol levels are increased in HIV infection whereas those of dehydroepiandrosterone (DHEA), a physiologic antagonist of the immunoregulatory activities of cortisol, decrease. The progression of HIV infection to AIDS is also characterised by a shift from a type 1 to type 2 cytokine production. The type 1 to type 2 shift and the altered Dhea/Cortisol ratio are negatively correlated with the in vivo CD4 T-cell counts, with the malnutrition markers, such as body-cell mass and fat mass, and with the increased circulating lipids (cholesterol, triglycerides, and apolipoprotein B) associated to the lipodystrophy syndrome. The observations of an Italian research group, show that the cortisol/DHEA ratio is dramatically altered in HIV-infected men, particularly during the syndromes of malnutrition and lipodystrophy, and this ratio remains elevated whatever the antiretroviral treatment, including HAART. These findings have practical clinical implications, since manipulation of this ratio could prevent metabolic (protein and lipid) perturbations and improve nutritional and immunological status as shown by an Italian research group.
The dampening of cortisol and DHEA circadian fluctuation and the progressive decrease of DHEA/cortisol ratio are at the basis of multiple clinical implications of immunesenescence: the shift from anabolic to catabolic status, the activation of atherosclerosis progression, the deterioration of immune competence, the impairment of cognitive and affective performances and the glico- and lipometabolic disorders. The hypothesis of a DHEA supplementation strategy comes out from these premises,as shown in some Italian studies.
Several epidemiological studies indicate an inverse correlation between DHEA/DHEAS plasma concentration and mortality, particularly due to cardiovascular disease. The analysis of the Rancho Bernardo population was the first to correlate DHEAS levels with cardiovascular risk in males over 50 yr of age. Afterward, a number of studies extended this observation to young men as well as to premenopausal and postmenopausal women. Low DHEAS levels have been also associated with cardiovascular events, with the extent of angiographic coronary stenosis, as well as with allograft vasculopathy, suggesting a role for DHEAS in delaying coronary disease.
However, other studies have questioned the association between DHEA/DHEAS and cardiovascular disease, and a later reanalysis of the Rancho Bernardo cohort showed a much weaker correlation . The prospective PAQUID study has recently renewed the interest in this issue, showing higher mortality in male patients with lower DHEAS concentrations.
Animal studies indicate a protective role of DHEA for atherosclerotic disease in primates and rabbits, but in vitro studies explaining the mechanisms are largely missing.
Steroid hormones regulate vascular function in part through general metabolic modifications, but mostly through actions exerted directly on the vessel wall. Endothelial cells are primary targets of steroids that regulate endothelial function through transcriptional as well as rapid nontranscriptional mechanisms. For instance, estradiol stimulates nitric oxide (NO) synthesis via the induction of endothelial NO synthase (eNOS) expression as well as through nongenomic enhancement of its activity .
The mechanisms of action of DHEA are not clear. Part of the effects of DHEA depends on the conversion to estrogens and androgens and on the recruitment of the respective receptors. However, there is suggestive evidence that DHEA may have a dedicated receptor. In a new italian study was shown that DHEA directly regulates human endothelial cells, activating eNOS through both genomic and nongenomic mechanisms.
To conclude we can claim that, endothelial NO induction by DHEA provides a rationale for some of the vascular protective effects of this steroid.
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