They are endogenous hormones synthesized and excreted mainly by the reticular zone of the adrenal cortex in response to the adrenocorticotropic hormone.
Epidemiological data indicate an inverse relationship between the serum levels of DHEA, DHEAS and the frequency of cancer, cardiovascular disease (only in men), Alzheimer’s disease and other disorders related to age, immune function and progression of HIV infection.
Studies in animals (mainly rodents) have suggested many beneficial effects of DHEA, including improved immune function and memory and the prevention of atherosclerosis, cancer, diabetes and obesity.
Many of the benefits observed in animal studies have not yet been demonstrated in humans.
Dehydroepiandrosterone (DHEA) clinically justified (albeit controversial) uses include replacement therapy in patients with low DHEA levels.
Also in serum secondary to chronic disease, adrenal exhaustion or corticosteroid therapy, treat systemic lupus erythematosus (SLE), improve bone density in postmenopausal women, improve the symptoms of severe depression.
Also to improve the depressed mood and fatigue in patients with HIV infection and the increased rate of reepithelialization in patients undergoing autologous skin grafts for burns.
Other possible uses (with some supporting clinical studies) include the improvement of the immune response and the sense of well-being in the elderly, the decrease of certain cardiovascular risk factors and the treatment of male erectile dysfunction.
The use of DHEA to delay or reverse the aging process, improve cognitive function, promote weight loss, increase muscle mass or slow down the progression of Parkinson’s disease and Alzheimer’s disease clinically is not proven
In women, the synthesis of DHEA and DHEAS occurs almost exclusively in the adrenal cortex, while in men the testes secrete approximately 5% DHEAS and 10-25% DHEA.
The minimum amounts are synthesized again in the brain. In young adults, the adrenal cortex secretes approximately 4 mg of DHEA and 25 mg of DHEAS per day.
During pregnancy, the fetal adrenal glands secrete large amounts of DHEA and DHEAS. At birth, production decreases to insignificant amounts in both sexes and remains so until five or seven years of age.
At the beginning of adrenarche, the adrenal glands gradually resume the production of DHEA and DHEAS, which accelerates during puberty.
The production of DHEA and DHEAS is maximum between the ages of 20 and 30 years and then begins a decrease of approximately 2% per year, leaving a residual of 10-20% of the maximum production in the eighth or ninth decade of life
DHEA and DHEAS are interconvertible by sulfohydrolases in the peripheral and adrenal tissues.
Approximately 64-74% of the DHEAS produced each day is converted to DHEA, but only 13% of the DHEA produced is metabolized to DHEAS.
In humans, the brain-plasma ratio for DHEA and DHEAS are 4-6.5 and 8.5, respectively, indicating a neuroendocrine role for these hormones.
They serve as precursors of approximately 50% of androgens in men, 75% of active estrogens in premenopausal women and 100% of active estrogens after menopause.
There seems to be a specific sexual response to DHEA replacement therapy in humans.
In postmenopausal women (ages 50-65), supraphysiological doses of 100 mg of DHEA per day have predominantly androgenic effects, increasing testosterone levels approximately 300% above baseline levels.
In older men (mean ± SD, 58.8 ± 5.1 years), 100 mg / day did not affect the levels of testosterone or dihydrotestosterone, but 17 levels of beta-estradiol and estrone increased above the baseline level by 37% and 225%, respectively (p <0.0001 for both).
It has been hypothesized that the increase in serum estrogens may provide a mechanism for beneficial cardiovascular effects in men; however, clinical studies that address the possible cardioprotective effects of DHEA have not been conclusive.
Several mechanisms of action of DHEA and DHEAS other than their role as precursors of sex hormones have been proposed. In the central nervous system, both DHEA and DHEAS appear to affect neurotransmitter receptors.
In rodents, DHEAS binds to the acid-amino-butyric complex (GABA) / benzodiazepine receptor (GABA-RC) and acts as a non-competitive negative modulator of GABA-RC.
DHEA, on the other hand, appears to have GABA agonist effects in GABA-RC. DHEA selectively improves the neuronal response to N-methyl-D-aspartate.
In addition, DHEA and DHEAS appear to have neurotrophic effects, increasing the number of positive neurofilaments and regulating the motility and growth of corticothalamic projections in cultured brain cells from mouse embryos.
It has been found that supraphysiological oral doses of DHEA (100-300 mg / day) in humans inhibit the synthesis of thromboxane A 2 in activated platelets.
Reduced plasminogen activator inhibitor plasminogen type 1 and tissue plasminogen activator antigen, increase serum insulin levels growth factor 1 (IGF-1), and increase the cyclic synthesis of guanosine monophosphate and nitric oxide (either directly or through higher levels of IGF-1).
These effects suggest that DHEA may be beneficial to improve circulation in the microvasculature and regulation of some of the risk factors for cardiovascular diseases, such as platelet aggregation and ischemia .
Clinical studies in this area have been misleading, with a majority showing an inverse relationship between DHEA or DHEAS levels and cardiovascular morbidity and mortality in men, but not in women.
However, a recently published five-year epidemiological cohort study did not find a statistically significant correlation between serum levels of DHEA or DHEAS and the development of atherosclerosis in men or women.
DHEA can play a positive role in the modulation of the immune response.
Clinical studies in older people have shown that oral DHEA doses of 50 mg / day increase IGF-1 levels (p <0.01) and cause functional activation of T cells (increase CD8 + and CD56 + cells [ natural killer cells] and increase cytotoxic activity).
Serum levels of interleukin (a proinflammatory cytokine involved in the pathogenesis of osteoporosis, rheumatoid arthritis , atherosclerosis , Alzheimer’s disease, Parkinson’s disease and beta cell neoplasms) increase significantly with age and inversely correlated with serum levels of DHEA and DHEAS (p <0.001).
In addition, DHEA, DHEAS and androstenedione inhibit the production of interleukin-6 by peripheral blood mononuclear cells in a concentration-dependent manner (p <0.001)
Oral absorption of DHEA is excellent. The volume of distribution is 17.0-38.5 L for DHEA and 8.5-9.3 L for DHEAS. DHEA and DHEAS are converted into several active metabolites, including androstenedione, testosterone, estrone, estradiol and estriol.
The elimination half-life of DHEA is 15-38 minutes, while the half-life of DHEAS is 7-22 hours. Renal excretion represents 51-73% of the elimination of DHEAS and its metabolites
To date, clinical studies of DHEA in patients with specific diseases have yielded generally inconclusive results. Most of the studies were open label or had very small samples.
Most of the studies discussed below were randomized, double-blind, placebo-controlled trials in which the oral dose was 300 mg / day.
Tummala and Svec showed that incremental increases in serum levels of DHEA and DHEAS appear to be stabilized at an oral DHEA dose of 300 mg / day and infer that higher doses have little additional therapeutic value.
Postmenopausal Bone Density:
In a randomized, double-blind, placebo-controlled study conducted by Baulieu et al., 280 healthy men and women between 60 and 79 years of age received DHEA 50 mg / day orally for 12 months.
Increases in bone mineral density (p <0.05) and decreases in biochemical markers of bone turnover were observed (p <0.01 for serum C-terminal peptide and p <0.05 for serum bone alkaline phosphatase) at 12 months in older women 70 but not in any other subgroup.
Systemic lupus erythematosus (SLE):
Supplementation with DHEA has shown promise for the treatment of SLE.
In a randomized, double-blind trial, women with SLE received DHEA 200 mg / day for three months.
In the DHEA group, the SLE disease activity index score and general assessments of disease activity of patients and physicians decreased, while small increases were observed in the placebo group.
However, the significance was achieved only for the visual analog scale component of the index (p = 0.022).
Outbreaks of lupus occurred less frequently in the treatment group than in the placebo group (three versus eight exacerbations, p = 0.053), and a non-significant decrease in prednisone requirements was observed in the treatment group (from one dose mean ± SD from 12.4 ± 3.2 mg to 9.1 ± 2.3 mg, compared to an increase from 5.3 ± 1.37 mg to 7.3 ± 2.9 mg in the placebo group).
The serum titers of antibodies against the double-stranded DNA and the levels of the complement components C3 and C4 did not change significantly between the groups.
Wellbeing and cognition:
In a randomized, placebo-controlled, crossover trial, 30 patients aged 40-70 years received 50 mg of DHEA orally daily.
In two weeks, this dose restored serum DHEA levels in men and women to those found in young adults.
With treatment with DHEA, 67% of men and 84% of women perceived an increase in physical and psychological well-being. However, the study has been criticized for its use of an open questionnaire for self-assessment of well-being.
At present, there are no rigorous data to support an improvement in memory or other aspects of cognitive function after DHEA replacement therapy. The low endogenous levels of DHEA and DHEAS do not seem to be associated with an increased risk of dementia.
The possible relationship between depression and serum levels of DHEA and DHEAS is intriguing; however, more research is needed.
Some authors have suggested that abnormal diurnal variations in serum levels of DHEA and DHEAS, as well as the abnormally high proportions of cortisol to DHEA, may be causative factors of depression in adults and depression with comorbid panic or phobic disorders in adolescents .
In a randomized, double-blind trial of Wolkowitz, 22 patients with major depression (Hamilton Rating Scale for Depression [HAM-D] of 16 or more) and who had no medication or were stabilized on antidepressant regimens received DHEA ( 30 mg / day for weeks 1 and 2, 60 mg / day for weeks 3 and 4, and 90 mg / day for weeks 5 and 6) or placebo.
At the end of the six weeks, the average decrease in the HAM-D score was 30.5% in the treatment group and 5.3% in the placebo group (p <0.04).
Five of 11 patients in the treatment group were considered responders (at least a 50% decrease in the HAM-D score), compared to none of the 11 patients in the placebo group.
Effects on patients infected with HIV:
In a recent open-label trial evaluating the effect of DHEA on depressed mood and fatigue, 45 HIV-positive patients (39 men and 6 women) received oral DHEA doses of 200-500 mg / day for eight weeks.
Of the 32 patients who completed the trial, 23 (72%) had an improvement in mood and 26 (81%) had a reduction in fatigue.
There was a significant increase in body cell mass and libido, but there was no effect on CD4 + lymphocyte counts or testosterone levels in men.
The positive effects on mood, fatigue and body cell mass continued for an additional four weeks in a subsequent double-blind phase of the study.
Christeff and others have noted an inverse relationship between serum levels of DHEA and DHEAS and immune impairment in patients with HIV, suggesting a role for DHEA and other androgens in the normal functioning of the immune system.
Effects on physical variables:
A randomized, double-blind, placebo-controlled trial by Morales examined the effects of oral DHEA 100 mg / day in 16 subjects 50-65 years of age.
The basal levels of serum DHEA, DHEAS, androstenedione, testosterone and dihydrotestosterone were in the lowest or lowest range for young adults.
In both sexes, DHEA 100 mg / day restored the DHEAS serum to levels equal to or slightly above the upper limit of the young adult range.
In women, androstenedione, testosterone and dihydrotestosterone increased to three to five times the baseline levels (p <0.001 for each hormone), or to levels higher than the sex-specific ranges for young adults, whereas in men only androstenedione increased significantly above the start (p <0.05).
Physiological doses of oral DHEA replacement in healthy people older than 40 years are in the range of 20-50 mg / day for men and 10-30 mg / day for women.
These doses are generally adequate to increase DH-EAS serum to levels found in adults 20-30 years of age and to provide the reported benefits of a greater sense of well-being in both sexes, increased bone mineral density in postmenopausal women, and the improvement of erectile dysfunction in men.
Higher doses may be necessary to increase levels of DHEA and DHEAS suppressed secondary to chronic diseases, adrenal exhaustion and corticosteroid therapy.
DHEA replacement doses are usually taken once a day in the morning
An increase in the production of facial sebum, acneiform dermatitis and mild hirsutism has been reported in women taking DHEA in physiological or supraphysiological doses (25-200 mg / day).
Hepatitis was reported in a postmenopausal woman with pre-existing high titers of antinuclear antibodies who received a single oral dose of 150 mg of DHEA; causality could not be established.
It was shown that a supraphysiological dose of DHEA (100 mg / day) increases the levels of androstenedione, testosterone and dihydrotestosterone three to five times in postmenopausal women.
The long-term effects of these increases in androgen levels in women are unknown.
A nested Dorgan case-control study found that postmenopausal women (who do not take DHEA or hormone replacement therapy) whose endogenous DHEAS levels were in the highest quartile had a significantly higher risk of breast cancer (risk index , 2.8 [95% confidence interval 1.1-7.4]).
More so than women whose endogenous DHEAS levels were in the lowest quartile.
Calcium channel blockers and metformin increase the levels of endogenous DHEAS, while corticosteroids and insulin significantly reduce them.
The supraphysiological doses of DHEA may increase serum levels of triazolam due to an inhibition of metabolism.
Theoretically, aromatase inhibitors, such as chrysin (5.7-dihydroxyflavone), an extract of the Passiflora coerula plant, can increase androgen levels, including DHEA and DHEAS, in both men and women.
Kroboth et al. Published an excellent review of the effects of disease, diet, exercise and medications on the endogenous levels of DHEA and DHEAS
Clinical data suggest that DHEA may have a role in hormone replacement therapy in patients with low levels of endogenous DHEA and DHEAS due to chronic diseases, adrenal exhaustion, corticosteroid therapy, and advanced age.
However, as a potent steroid precursor, DHEA can significantly increase androgen levels in women and can improve the progression of cancers sensitive to estrogen and testosterone.
Supplementation with DHEA should never be done without direct medical supervision. The long-term effects of DHEA supplementation are unknown.