DHEA : Is replacement therapy needed?

DHEA is secreted in humans, but not in rodents. So results of rodent studies cannot be translated into human effects. Animal studies show improved neuronal function and memory with increased glial survival. Human clinical studies in ageing subjects have been performed using 50mg or 100mg DHEAS for maximum of 6 months. DHEA increases estrogen in men and testosterone in women!

In normal humans, adrenals produce DHEA, which is converted (by 3βHSD) to androstenedione, which is in turn converted (by 17βHSD) to testosterone and estradiol. Note that DHEA does not bind to androgen receptors. A specific DHEA receptor has not yet been cloned. (as of 2004). Androgenic metabolites of DHEA (androstanediol glucuronide-metabolite of DHT; and androsterone glucuronide) increase after DHEA administration resulting in tissue specific action depending on expression of 3βHSD, 17βHSD, 5alpha reductase and P450 aromatase.
Also note that DHEA is inactivated into DHEAS (by steroid sulfatase), or activated via conversion to sex steroids as above (by sulfotransferase). Continuous interconversion is the rule. Chronic disease shifts the intra-adrenal biosynthesis away from DHEAS towards Cortisol secretion.

Epidemiological studies:
An inverse correlation has been shown between serum DHEAS and cardiovascular deaths in men >50 years age, but not in women. Numbers in these cohort studies have ranged from 600 to 1000 men, with ages of up to 90-106 year-olds  having been studied. Overall, low DHEAS levels have been shown to be a non-specific marker of poor health status resulting in increased mortality.

Studies assessing effect of DHEA replacement in ageing patients with lower DHEA levels have not demonstrated significant benefit, although this could be interpreted to be the result of selection bias, due to recruitment of relatively healthy subjects in whom demonstration of further improvement might have been less likely anyway. Positive effects on IGF-1 have been variable in studies.

Patients with Adrenal Insufficiency have severe loss of DHEA production in contrast to the mild decreases with ageing. The only trial from the UK (abstract from Cambridge) in adrenal insufficient men and women [for 12 months using 50 mg DHEA] has shown improved physiological function with improved femoral neck BMD.

DHEA might prove to be a better way of treating female hypo-androgenism, than the presently used dose adjusted testosterone delivery with its accompanying  pharmacokinetic problems. BMD rise with DHEA has mostly been restricted to elderly women. DHEA might  prove to be a potential addition to the  therapeutic armamentarium for osteoporosis or osteopenia.

Concerns:
Significant HDL decrease on DHEA therapy has been demonstrated, although total cholesterol also decreased. Lack of benefit of DHEA administration demonstrated in a recent 9-month study in 39 adrenal insufficient patients J Clin Endocrinol Metab. 2003 Mar;88(3):1112-8 seems to have been due to an underpowered study and hence the potential for benefits from DHEA replacement remains.

In conclusion, at all times, the difference between replacement of a severely depleted DHEA levels-as in hypoadrenal patients-has to be contrasted against the supplementation in mild decreases of ageing or in prospective body builders with normal DHEA levels.

What needs to be known? Further research:
DHEA receptor cloning
Larger Phase III trials of DHEA replacement
Tissue specificity of DHEA action needs to be elucidated
Regulatory mechanisms of adrenopause!!

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