Dehydroepiandrosterone acetate: a natural hormone

Dehydroepiandrosterone acetate (DHEA) is a hormone that your body naturally produces in the adrenal gland. DHEA helps produce other hormones, including testosterone and estrogen. Natural Dehydroepiandrosterone acetate levels peak in early adulthood and then slowly fall as you age.

Determination of dehydroepiandrosterone acetate in human plasma

Regarding Mtb-infected individuals, it was reported that patients exhibit altered plasma levels of cortisol, prolactin, growth hormone, thyroid hormone, testosterone and Dehydroepiandrosterone acetate (DHEA). Together, the endocrine disturbances found in TB patients are related with worsened clinical status and unfavorable disease outcome. Despite these data, reports about HPA imbalance during HIV-TB co-infection are very scarce. In HIV-TB individuals, an increased cortisol/DHEA ratio might lead to infection progression by inducing a shift from Th1 to Th2 immunologic responses. Dehydroepiandrosterone acetate is a hormone secreted mainly by the adrenal cortex, but also by the gastrointestinal tract, gonads, and brain. It serves several functions in the human body, which are classically associated with age-related changes such as metabolism alterations, cardiovascular disease, fertility and neuronal function. However, it is now clear that DHEA is a regulator of immune functions, as it modulates the production of inflammatory cytokines, increases resistance to infections, exhibits antiviral activity and counteracts the immune-suppressive effects of glucocorticoids. In previous studies, we demonstrated that Dehydroepiandrosterone acetate modulates the immune response against Mtb, enhancing the cytotoxic Th1 and CD8+ T cell responses and negatively regulating the expression of transcription factor FoxP3. In line with this, we observed that DHEA enhanced Mtb-specific Th1 responses from human dendritic cells in vitro.[1]

The assay developed allowed us to determine the concentrations of Dehydroepiandrosterone acetate, AED, AET and 7-oxo-DHEA in human plasma samples. We used HD samples to evaluate the performance of the novel HPLC–MS/MS approach compared with RIA, a validated radioimmunoassay. The results showed correspondence between both methodologies, obtaining a statistically significant Spearman’s rank correlation coefficient of 0.8095. Considering the results from this analysis, we conclude that the values in the secondary laboratory were similar to those acquired in the laboratory of reference. In contrast, the curve slopes of DHEA and AED were <1.0 (0.4540 and 0.6090, respectively), indicating that the values from the secondary laboratory were lower. It was previously observed that Dehydroepiandrosterone acetate plasma levels measured by RIA are significantly diminished in HIV,TB and HIV-TB patients, compared to HD. Moreover, antituberculous therapy seems to increase DHEA in plasma, restoring its concentration to the levels observed in healthy individuals. Nevertheless, as shown before, we observed that the HIV-TB cohort exhibited not only higher Dehydroepiandrosterone acetate plasma levels, but also higher AET and 7-oxo-DHEA concentrations compared with HD.

As discussed above, HIV-TB co-infection is a chronic inflammatory condition which dysregulates the production of cytokines and other compounds secreted by cells and tissues, as hormones or acute-phase proteins. Therefore, we propose that the discrepancy between plasma Dehydroepiandrosterone acetate concentration obtained by HPLC-MS/MS and RIA might be caused by differences in extraction efficiency due to matrix complexities, which can be solved with the use of an IS. As the radioimmunoassays used in clinical practice do not take advantage of including standards in their methodology, this generates a problem in sample preparation which cannot be solved. To the best of our knowledge, this is the first report showing the simultaneous measurement of Dehydroepiandrosterone acetate, AED, AET and 7-oxo-DHEA in plasma from HIV-TB individuals using HPLC-MS/MS technology. Our findings about 7-oxo-DHEA suggest that this Dehydroepiandrosterone acetate metabolite with weak estrogenic and androgenic activities may be involved in the development of an effective immune response against Mtb and/or HIV in co-infected individuals.

Dehydroepiandrosterone acetate, Cancer, and Aging

The biological significance of dehydroepiandrosterone acetate (DHEA) which, in the form of its sulfated ester is the most abundant steroid hormone in human plasma, is an enigma. Over the past years, numerous investigators have reported preclinical findings that dehydroepiandrosterone acetate has preventive and therapeutic efficacy in treating major age-associated diseases, including cancer, atherosclerosis, diabetes, obesity, as well as ameliorating the deleterious effects of excess cortisol exposure. Epidemiological studies have also found that low DHEA(S) levels predict an increased all-cause mortality. However, clinical trials, in which oral doses of dehydroepiandrosterone acetate at 50 mg-100 mg have been administered to elderly individuals for up to two years, have produced no clear evidence of benefit in parameters such as body composition, peak volume of oxygen consumption, muscle strength, or insulin sensitivity. I discuss why clinical trials, which use doses of dehydroepiandrosterone acetate in the 100 mg range, which are the human equivalent of about 1/20th the doses used in animal studies, are an inadequate test of DHEA’s therapeutic potential. I also discuss three mechanisms of dehydroepiandrosterone acetate action that very likely contribute to its biological effects in animal studies. Lastly, I describe the development of a DHEA analog which lacks dehydroepiandrosterone acetate’s androgenic and estrogenic action and that demonstrates enhanced potency and is currently in clinical trials. The use of such analogs may provide a better understanding of DHEA’s potential therapeutic utility.[2]

The mechanism of the anti-GC effect of dehydroepiandrosterone acetate is not known. DHEA does not bind to the GC receptor and is not a competitive inhibitor. dehydroepiandrosterone acetate, both in vitro in cultured adipocytes and in vivo in mouse adipose tissue and liver, down regulates the expression and oxoreductase activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme which locally reactivates GC’s. 11β-HSD1 knockout mice are resistant to GC-induced side effects, such as hyperglycemia, myopathy, thinning of skin, etc. However, inhibition of 11β-HSD1 by itself cannot account for DHEA’s protection against Dex-induced thymic and splenic atrophy, since Dex does not require activation by 11β-HSD1, and 11-keto Dex is as potent a glucocorticoid receptor agonist as is Dex. The receptor mediating the anti-GC action of dehydroepiandrosterone acetate, as well as its mechanism of action, has not been identified.

Pharmacological Effects and Potential Therapeutic Application

Dehydroepiandrosterone acetate (DHEA) is the most abundant steroid hormone in primates, which is predominantly synthesized in the adrenal cortex. A characteristic curve of growth and decline of its synthesis during life was observed, together with the corresponding formation of its sulphate ester (DHEAS). High levels of plasma circulating DHEA are suggested as a marker of human longevity, and various pathophysiological conditions lead to a decreased DHEA level, including adrenal insufficiency, severe systemic diseases, acute stress, and anorexia. More recent studies have established the importance of dehydroepiandrosterone acetate in the central nervous system (CNS).[3]

A specific intranuclear receptor for dehydroepiandrosterone acetate has not yet been identified; however, highly specific membrane receptors have been detected in endothelial cells, the heart, kidney, liver, and the brain. Research shows that DHEA and DHEAS, as well as their metabolites, have a wide range of effects on numerous organs and organ systems, which places them in the group of potential pharmacological agents useful in various clinical entities. Their action as neurosteroids is especially interesting due to potential neuroprotective, pro-cognitive, anxiolytic, and antidepressant effects. Evidence from clinical studies supports the use of dehydroepiandrosterone acetate in hypoadrenal individuals and in treating depression and associated cognitive disorders. However, there is also an increasing trend of recreational dehydroepiandrosterone acetate misuse in healthy people, as it is classified as a dietary supplement in some countries. This article aims to provide a critical review regarding the biological and pharmacological effects of DHEA, its mechanism of action, and potential therapeutic use, especially in CNS disorders.

References

[1]Vecchione MB, Eiras J, Suarez GV, Angerami MT, Marquez C, Sued O, Ben G, Pérez HM, Gonzalez D, Maidana P, Mesch V, Quiroga MF, Bruttomesso AC. Determination of dehydroepiandrosterone and its biologically active oxygenated metabolites in human plasma evinces a hormonal imbalance during HIV-TB coinfection. Sci Rep. 2018 Apr 27;8(1):6692.

[2]Schwartz AG. Dehydroepiandrosterone, Cancer, and Aging. Aging Dis. 2022 Apr 1;13(2):423-432.

[3]Nenezic N, Kostic S, Strac DS, Grunauer M, Nenezic D, Radosavljevic M, Jancic J, Samardzic J. Dehydroepiandrosterone (DHEA): Pharmacological Effects and Potential Therapeutic Application. Mini Rev Med Chem. 2023;23(8):941-952.