The bidirectional communication between the neuroendocrine and immune systems has been widely evidenced, both in humans and in experimental models. Immune compounds are likely to modify the functioning of the endocrine system. Conversely, adrenal steroids can alter the functioning of immune cells and therefore the course of diseases exhibiting an immune-inflammatory component, mostly autoimmune or infectious. This interconnection between the immune and the neuroendocrine systems is partly due to the stimulatory action of inflammatory cytokines on the Hypothalamic-Pituitary-Adrenal axis. Cytokines such as IL-6, IL-1β, and TNF-α stimulate the production of CRH by the hypothalamus with the subsequent release of ACTH in the pituitary gland further promoting the secretion of steroid hormones at the level of the adrenal cortex: glucocorticoids, in humans mainly cortisol, and DHEA (1, 2).

DHEA is an androgen synthesized by the adrenal cortex. Many endogenous factors can influence its synthesis, i.e., CRH, ACTH, growth factors, and cytokines. While sulfated steroids were considered metabolic end-products, additional research showed that sulfated steroids, such as DHEA-S, can act as circulating reservoirs for the peripheral formation of bioactive. Therefore, DHEA synthesized in the adrenal gland, is transformed into DHEA-S to be released into the bloodstream (3). In turn, desulfation, through steroid sulfatase, predominates in the mammary gland, ovary, prostate, testicles, placenta, and uterus wherein produced DHEA serves as a precursor of sex hormones. However, in the liver, a so-called “futile-loop” of DHEA/DHEA-S is present, as well as for other steroids, challenging the view that the pathway can only go one way (3).

As well as being the physiological precursor for the synthesis of androgens and estrogens DHEA can also be metabolized into oxygenated derivatives in non-steroidogenic tissues, especially in the human liver (4). There is evidence that DHEA can be converted into oxygenated derivatives such as 3β, 17β-androstenediol (AED) and 3β, 16β, 17β-androstentriol by monocyte-derived macrophages (5).

Concerning their metabolic functions, both DHEA and its metabolites carry out biological actions through the activation of various receptors, such as estrogen receptors, the receptor for activated peroxisome proliferators (PPAR), and the pregnane X receptor, as well as other membrane-associated receptors (6). The full range of biologically active forms of DHEA is a pending issue. Since DHEA is metabolized intracellularly to other steroids, including estradiol, androstenediol (7, 8), among others, its multiple actions may be mediated by different metabolites and receptors, including differential effects on alpha and beta estrogen receptors. Although the mechanism of action of DHEA is not fully elucidated, the hormone would exert its action indirectly on the peripheral target tissues after its conversion to androgens and/or estrogens; or directly, as a neurosteroid (9). The same holds for macrophages (10–12).

Animal studies showed that DHEA increases immune function protecting animals from viral, bacterial, and parasitic infections (13, 14). This hormone also has antiglucocorticoid effects both at the level of macrophage (10) and lymphocyte functions (15).

Studies in human cells indicate that DHEA favors a Th1 cytokine profile by acting as a transcriptional activator of the CD4+ cell IL-2 gene (16, 17). DHEA-S, in turn, has immunomodulatory functions with low levels of this hormone being associated with changes in the repertoire of immune cells, such as a decrease in the main T cell subsets, together with increased numbers of NK cells, and T cells exhibiting an activated phenotype (18, 19). Furthermore, during septic shock or multiple traumas, low levels of DHEA-S seem to be a marker of poor outcomes (20, 21).

The immunoregulatory actions of DHEA are also tissue-dependent. As stated above, after biosynthesis, DHEA circulates primarily in its sulfated form. At the tissue level, target cells express transmembrane organic anion transporting polypeptides (OATPs) that facilitate cellular uptake of the sulfated steroid. Once inside the cell, sulfatases hydrolyze this steroid sulfate ester to active, unconjugated DHEA. This and its metabolites must bind to the corresponding receptors to carry out their biological functions. Sulfation and desulfation are thus fundamental pathways, for which tissue distribution and regulation of these processes are essential for steroid functions (3, 22).

In this sense, at the lymphoid level, Daynes et al. observed that, although recirculating T lymphocytes have the inherent potential to produce both IL-2 and IL-4, in DHEA challenged mice, lymphocyte isolates from peripheral lymph nodes, spleen, and Peyer’s patches showed an increased ability to produce IL-2 and IFNγ after activation. At variance with these results, the challenge with DHEA sulfate was only active on lymphocytes from peripheral lymph nodes and spleen; with lymphocytes obtained from Peyer’s patches continuing to produce IL-4 and IL-5 (23, 24).

As well as lymph nodes contain one of the highest levels of sulfatase activity, macrophages exhibit the main DHEAS sulfatase activity within secondary lymphoid tissue. In this context, macrophages play a fundamental role, since when exposed to microbial stimulants produce mediators with paracrine or autocrine action (TNF-α and IFN-α) capable of inhibiting their ability to metabolize DHEAS. Chronic infections, including the one induced by Mycobacterium tuberculosis, result in elevated circulating levels of several cytokines, including TNF-α and type 1 interferon, as well as low levels of DHEA that correlate negatively with the severity of lung disease (25).

A decrease in DHEA plasma concentrations also occurs during severe infections, such as African trypanosomiasis, cysticercosis, AIDS, TB (26–29), as well as autoimmune disturbances or other chronic diseases (30). This dysregulated adrenal response may be partly due to the presence of inadequate concentrations of TNF-α (31, 32); reinforced by the fact that increased levels of TNF-α and IL-6 during chronic inflammation are also accompanied by a drop in circulating levels of DHEA-S and DHEA (33).

Turning to the infectious context, immune-mediated protective effects of both DHEA and AED were observed in mice inoculated with lethal doses of Pseudomonas aeruginosa or Enterococcus faecalis (14). It has also been shown that DHEA supplementation in Trypanosoma cruzi infected mice enhanced the immune response, resulting in lower parasitemia (34). In dexamethasone-immunosuppressed mice undergoing an experimental infection by Cryptosporidium parvum, treatment with DHEA reduced both the elimination of fecal oocysts and the parasitic colonization of the ileum along with higher amounts of splenic CD4+ and CD8+ T cells (35). Another study in mice infected with avirulent C. parvum or Toxoplasma gondii also showed that DHEA administration reduced mortality along with a significant reduction in the cryptosporidium oocyst count in feces and intestinal villi or brain toxoplasma cysts (36).

In a cross-sectional study about Plasmodium falciparum parasitemia in 12-18-year-old schoolgirls from an area of ​​intense transmission in Kenya, DHEA levels were associated with a decrease in parasitemia, even after age adjustment. People with low levels of DHEA had significantly higher parasite densities than those with higher amounts of DHEA (37).

DHEA exhibited favorable effects in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease (60–63).

Replacement DHEA studies also pointed out an encouraging role in the elderly (17, 56, 58, 64) wherein DHEA therapy may be an effective approach for preserving bone and muscle mass in women. In turn, DHEA treatment (50 mg/day for 3 months) improves self-reported well-being: sleep quality, general mood, vital energy, and stress management (65). At the immunological level, DHEA improved the plasma levels of monocytes (CD14), and NK cells (CD16, CD57), doubled the number of T gamma/delta cells, and the levels of the soluble IL2 receptor in plasma (66).

Women with Addison’s disease in whom DHEA was added to standard treatment showed a reduction in the number of circulating regulatory T cells as well as NK and NKT cells in presence of an increased lymphoproliferation and levels of IFN-γ, IL-5, IL-10, and TGF-β, along with a significant clinical improvement (67).

DHEA may be also beneficial in women’s infertility by augmenting fecundity and fertility (68–70), although some metanalysis failed to demonstrate a difference in pregnancy and miscarriage rates among those pretreated with DHEA and those who did not receive such treatment (71, 72).

Data from two randomized, double-blind, placebo-controlled studies on the effect of DHEA supplementation in women with systemic lupus erythematosus were consistent with the beneficial effects of DHEA (56, 61, 68, 73). One study reported that DHEA treatment (200 mg/d) improved the patient’s global assessment of disease activity (61); whereas in the other one the same DHEA dose served to reduce the dose of corticosteroids without affecting disease stability or even reducing its activity (73).

In a randomized, double-blind, placebo-controlled, small-scale study of 12-week duration, DHEA treatment improved the oxidative imbalance induced by hyperglycemia, downregulated the TNF-α/TNF-α receptor system, and prevented advanced glycation end-product formation, suggesting a beneficial effect on the onset and/or progression of chronic complications in type 2 diabetic patients (74).

As in many pharmacological developments, the issue of DHEA implementation in the clinical field should be carried out paying attention to its safety profile. Partly because of the possibility of DHEA conversion to testosterone, or estradiol, which might favor the development of prostate, ovary, or uterine neoplasms, particularly in elderly people (75–77). Although there are encouraging studies regarding the use of DHEA in the treatment of inflammatory pathologies and even neoplasms (78, 79).

The use of the above-mentioned synthetic DHEA analog may serve to circumvent some of these constraints. It is worth commenting that studies carried out a few years ago indicate that HE2000, exerted beneficial effects on HIV infection, at the level of the specific immune response, or a decreased TB coinfection in parallel with a fewer occurrence of opportunistic infections (54, 56, 80). In essence, the bulk of reviewed data set the basis for carrying out exploratory clinical studies aimed at assessing the potential benefit of adjuvant DHEA therapy in TB patients. Since two months of specific treatment in TB patients improves DHEA values to normality (41, 42), the length of adjuvant DHEA therapy would not be longer than at doses well established in other pathological settings [i.e., fertility stimulation studies in women 25-75 mg/day] (68, 69). Given our results in M. tuberculosis-infected macrophages, wherein the effect of DHEA seems to be related to mycobacterial elimination (49) it may be assumes that beneficial effects of DHEA will be apparent in the initial stages of therapeutical intervention.

Adjuvant therapy may offer a better way of treating tuberculosis not only in the field of drug resistance but also in non-adherence to chemotherapy and reducing the length of modern short-course chemotherapy, provided this approach turns out to be useful.

All authors have written and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

This research was supported by Fondo para la Investigación Científica y Tecnológica –FONCyT (PICT 2018- 02375), Argentina; Facultad de Ciencias Médicas –Universidad Nacional de Rosario, Argentina and Consejo Nacional de Ciencia y Tecnología, México, CONACyT, Grant/Award Number: 433346 and FC2015-1/115.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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