Adrenal and Metabolic Hormonal Axes Shape Anti-Tuberculosis Immune Responses in Human Immunodeficiency Virus-Tuberculosis Coinfection

Abstract

Background

Tuberculosis (TB) remains a leading cause of mortality worldwide among infectious agents, and HIV increases the risk of developing into active disease. HIV-TB coinfection impairs immune responses, while chronic inflammation and infection-associated stress activate neuroendocrine pathways that deeply impact immune homeostasis. Adrenal steroids such as cortisol, dehydroepiandrosterone (DHEA) and its metabolites, along with metabolic hormones like leptin and adiponectin, have emerged as critical regulators of immune function, although their role in TB pathogenesis, particularly in co-infected individuals, remains underexplored.

Summary

This review navigates over current evidence on the neuroendocrine-immune crosstalk in HIV-TB coinfection, focusing on adrenal and metabolic hormonal axes. We first summarize how HIV-driven CD4⁺ T cell depletion, chronic immune activation, and altered granuloma dynamics predispose individuals to TB reactivation. We then examine findings indicating that TB and HIV disrupt hypothalamic-pituitary-adrenal (HPA) axis homeostasis, leading to elevated cortisol levels, reduced DHEA and its metabolites, and an unfavorable cortisol/DHEA ratio, which correlated with poor immune control and disease severity. Preclinical studies highlight immunomodulatory properties of DHEA derivatives, such as 7-oxo-DHEA (7-OD), which restore Th1 responses, limit Treg expansion, and enhance macrophage antimicrobial activity. Metabolic hormones, particularly leptin and adiponectin, further shape host immunity and energy allocation; their dysregulation in coinfection contributes to wasting, impaired granuloma formation, and increased immune reconstitution inflammatory syndrome (IRIS) risk. Despite compelling preclinical findings, clinical studies on hormonal modulation remain scarce, emphasizing the need for translational research that links endocrinology and infectious disease immunology.

Key Messages

HIV-TB coinfection creates a neuroendocrine-immune imbalance, with dysregulation of the HPA axis and metabolic hormones contributing to impaired immune control and accelerated disease progression. Adrenal hormones such as DHEA and its metabolite 7-oxo-DHEA show potential as immunomodulatory agents, capable of restoring Th1 responses, limiting Treg expansion, and supporting host-directed therapies. Additionally, leptin and adiponectin emerge as crucial metabolic players that integrate nutritional status and immune activity and may serve as potential biomarkers for TB management. Altogether, integrating endocrine profiling into TB research and advancing the clinical evaluation of hormonal immunomodulators may unlock novel avenues for precision medicine, improving treatment strategies for populations affected by the HIV and TB epidemics.

Introduction

Tuberculosis (TB) has reemerged as the leading cause of death from a single infectious agent worldwide, following 3 years of COVID-19 predominance. Currently, it affects one-quarter of the world’s population. Despite its high burden, TB remains a preventable and curable disease with standard treatment regimens (a course of anti-TB drugs for 4–6 months), achieving cure rates of up to 85% [1]. TB is caused by Mycobacterium tuberculosis (Mtb), an intracellular pathogen characterized by its strategies to evade the immune system [1]. As a chronic disease, its impact on the endocrine system is undeniable [2]. Similarly, human immunodeficiency virus (HIV) remains a major global public health concern; in 2023, approximately 39.9 million people were living with HIV globally with approximately 630,000 deaths attributed to HIV/AIDS [3]. In this context, the WHO has prioritized the development and adoption of shorter, more effective treatment regimens for TB. The incorporation of immunomodulatory strategies is central to this aim, especially for immunocompromised individuals [4].

We, along with other researchers, have been advancing the study of novel strategies to enhance immune responses against Mtb. Our findings underscore the relevance of adrenal hormones and their derivatives, as well as the role of metabolic hormones such as insulin, leptin, and others, to TB pathogenesis and disease progression. Here, we will review our most recent results, analyze them in the context of the latest discoveries in the field, and discuss the potential use of adrenal and metabolic hormones as therapeutic tools for the management of TB infection and disease.

Immune Response to Mtb and the Impact of HIV Infection

Immunity against Mtb Infection and TB Disease

Mtb primarily establishes primarily in alveolar macrophages, following inhalation of aerosolized droplets expelled by individuals with active disease. The immune response to Mtb is complex, involving many cell types. The early innate response, meditated by resident macrophages, dendritic cells, neutrophils, and NK cells, can occasionally clear Mtb before the activation of adaptive immunity. However, the mycobacteria employ multiple evasion strategies to prevail, including inhibition of phagosome-lysosome fusion and delayed initiation of a specific immune response in the draining lymph nodes, occurring at 4–6 weeks after the infection [5]. When bacilli gain access to the draining lymph nodes, T cells are primed, and effector cells are released to the periphery to return to the lung and orchestrate protective immune responses against the bacteria [6]. Thus, the adaptive immune system mounts a T helper 1 (Th1)-skewed response characterized by IL-12, IFN-γ, and TNF-α, crucial for macrophage activation and granuloma formation [7]. In this process, monocytes, macrophages, neutrophils, and lymphocytes are attracted to the site of infection, likely in response to chemokine and cytokine signals released by infected cells, initiating granuloma formation [6, 7]. Within the granuloma, Mtb can persist in both intracellular and extracellular forms. Disease reactivation may occur following a triggering event that disassembles granuloma, thus releasing the mycobacteria to disseminate and start active disease. Understanding this complex interplay between host immunity and bacterial survival mechanisms is essential to guide novel interventions [8, 9].

Immunity during HIV Infection and Immune Interactions in HIV-TB Coinfection: A Life-Threatening Combination

HIV imposes a new scenario for bacterial immunopathogenesis. In Mtb infection, the cellular nature of antimycobacterial response foresees a profound impact of viral infection over TB development and presentation. In fact, HIV is the main factor, both at the individual and population level, which increases the likelihood of progression to active TB disease [10]. HIV infection depletes CD4⁺ T cells and decreases lymphocyte function at the early stages of viral infection, predisposing to TB disease, the most prevalent opportunistic infection in previously asymptomatic individuals [11]. Hence, HIV depletes key lymphocyte populations that produce both IL-2, IFN-γ and TNF-α simultaneously (the so-called polyfunctional T cells), which are at the forefront of antitubercular immunity [11]. Consequently, while HIV undermines cellular immunity against Mtb, the adrenal and metabolic hormonal axes also play a pivotal role in shaping host responses. Importantly, during HIV-TB coinfection, both axes undergo profound dysregulation, further exacerbating immune dysfunction.

Physiology of Adrenal and Metabolic Hormones and the Impact of Infection on These Axes

The nervous, endocrine, and immune systems interact closely to maintain homeostasis, with the hypothalamic-pituitary-adrenal (HPA) axis playing a central role. Neural circuits innervating the hypothalamic paraventricular nucleus initiate this response through the release of the corticotropin-releasing hormone, which stimulates pituitary secretion of the adrenocorticotropic hormone which in turn, promotes the production of glucocorticoids (GCs) in the zona fasciculata and dehydroepiandrosterone (DHEA) in the zona reticularis of the adrenal cortex – two hormones with distinct immunomodulatory properties [12, 13]. GCs, acting through the GC receptor, suppress immune responses by inducing lymphocyte apoptosis, inhibiting monocyte and macrophage functions, and reducing the production of pro-inflammatory mediators [12, 14, 15]. They also impair mitochondrial function, thereby disrupting energy-dependent immune processes (e.g., cell migration, phagocytosis, and antigen presentation) [16, 17]. In contrast, DHEA enhances immune defenses and counteracts GC-induced immunosuppression. Age-related declines have been linked to various physiological dysfunctions, including metabolic dysregulation and neuroendocrine imbalance [18, 19].

To exert its pleiotropic effects, it is proposed that DHEA may interact with different receptors and/or be converted into other biologically active metabolites [18, 20]. So far, no specific nuclear receptor for this hormone has been identified, although it has been shown to exert a direct action as a neurosteroid and to activate certain transcriptional pathways, including nitric oxide synthesis, expression of inflammatory factors, adhesion molecules and reactive oxygen species [21]. Conversely, DHEA can be metabolized into additional biologically active compounds through enzymatic actions occurring in diverse tissues. DHEA is primarily secreted by the adrenal cortex; however, it is also produced within the gastrointestinal tract, gonadal tissues, and the central nervous system [18]. Its biosynthesis involves cytochrome P450 and 3β-HSD enzymes, starting with the conversion of cholesterol to pregnenolone (via CYP11A1), followed by CYP17-mediated transformation into DHEA. This pathway may also generate the formation of oxygenated derivatives, including 7α- and 7β-hydroxy-DHEA, synthesized via CYP and 11β-HSD enzymes through the intermediate 7-oxo-DHEA (7-OD). Additionally, 17β-HSD catalyzes the formation of androstenediol (AET) and androstenetriol (AED) from DHEA and 7-OH-DHEA (shown in Fig. 1). Emerging evidence suggests that several immunologic effects previously attributed to DHEA may be mediated by these oxygenated metabolites [22].

Fig. 1.

Metabolism of DHEA and its oxygenated derivatives. Cholesterol is converted into pregnenolone, which subsequently leads to the synthesis of DHEA. The enzymatic activities of cytochrome P450 (CYP) and hydroxysteroid dehydrogenase (HSD) complexes facilitate the production of 7-oxygenated metabolites, including androstenediol (AED), androstenetriol (AET), 7-hydroxy-DHEA (7-OH-DHEA), and 7-oxo-DHEA (7-OD). Carbon atom numbering is indicated on the cholesterol molecule.

DHEA has garnered considerable attention for its immunomodulatory potential, particularly in immunocompromised individuals. However, its administration may induce androgenic and estrogenic side effects. The metabolites AET and AED have shown protective antiviral effects and ability to enhance T cell responses, although AED retains estrogenic activity [22–24]. Notably, 7-OD lacks sex hormone receptor binding [22] and exhibits thermogenic, neuroprotective and potential immunomodulatory effects [25–27]. Preliminary studies suggest it may regulate hormone and lipid levels without inducing adverse endocrine effects. It also appears to inhibit 11β-HSD activity, thereby potentially counteracting GC-mediated immunosuppression [28]. These findings support the notion that 7-OD and its related metabolites may offer safer and more targeted therapeutic alternatives to DHEA for enhancing immune responses.

During infection, pro-inflammatory cytokines (e.g., TNF-α, IL-1, IL-6) activate the HPA axis, leading to alterations in GC and DHEA levels and disrupting immune balance as the host responds to the pathogen while limiting tissue damage [29]. In individuals with HIV, this is further exacerbated by viral proteins and antiretroviral therapy (ART), resulting in elevated cortisol, reduced DHEA-S levels, and enhanced GC sensitivity [30, 31]. These hormonal imbalances impair cellular immunity, mirror the decline in CD4⁺ T cell counts [32], and promote a Th2-dominant response, contributing to disease progression [31, 33]. A comparable neuroendocrine-immune disruption is observed in TB, where persistent inflammation activates adrenal steroidogenesis [34–37]. Individuals with active TB exhibit increased circulating cortisol and pro-inflammatory mediators [2, 37]; together with reduced DHEA, this results in an unfavorable cortisol/DHEA ratio, which has been associated with disease severity. Interestingly, anti-TB treatment has been linked to partial restoration of endocrine homeostasis, potentially contributing to improved immune responses [38, 39]. Data on adrenal steroid regulation during HIV-TB coinfection remain limited. Elevated cortisol and cortisol/DHEA ratios in untreated HIV-TB patients correlated with increased uTregs-unconventional regulatory T cells, CD4⁺CD25⁻FoxP3⁺- and reduced Mtb-specific IFN-γ, suggesting impaired immune control [40–42]. During combination therapy, DHEA and DHEA-S levels rise, while cortisol concentrations decline, coinciding with improvements in CD4⁺ T cell counts, CD4/CD8 ratios, and reductions in viral load [41]. Notably, higher plasma levels of AET and 7-OD have been observed in some HIV-TB patients, with 7-OD positively correlating with CD4⁺ counts and associated with restricted rather than disseminated TB [43]. Activation of the HPA axis appears to contribute to disease progression by impairing protective immune responses. Clinically, adrenal insufficiency and the resulting cortisol/DHEA imbalance may exacerbate immune dysfunction in co-infected patients. Elevated cortisol suppresses Th1-mediated immunity, inhibits macrophage activation, and increases susceptibility to opportunistic infections, whereas reduced DHEA levels further weaken antimicrobial defenses and contribute to systemic inflammation [41]. Altogether, these alterations in adrenal function and steroid balance could contribute to immune dysregulation in coinfected patients, potentially influencing disease severity and treatment outcomes. Therefore, monitoring adrenal function and hormonal ratios may provide valuable insights into host immune status and guide future host-directed therapeutic strategies.

Impact of Adrenal Hormones on Anti-TB Immune Responses in People with HIV

Antitubercular medications are generally ineffective at eliminating Mtb from all infection sites due to their limited efficacy against semi-dormant or persistent bacteria, especially those residing within lung granulomas [44]. Immunomodulators can either enhance or suppress the immune activity, offering therapeutic potential as adjunctive treatments in infectious diseases by restoring or boosting immunity to reduce infection severity and duration [45]. Corticosteroids, potent anti-inflammatory agents, have been widely used in inflammatory and autoimmune diseases [16]. However, elevated cortisol levels correlate with impaired Mtb-specific immunity and worse prognosis [41]. Therefore, corticosteroids are reserved for necessary cases (e.g., severe CNS symptoms in HIV-immune reconstitution inflammatory syndrome) and used short-term to minimize risks of opportunistic infections and steroid-related complications [46–48]. Although adjunctive corticosteroids may be beneficial in certain TB cases, such as tuberculous meningitis [49], their use requires caution. Interactions with pyrazinamide and rifampicin complicate co-administration [48], and their immunosuppressive effects may hinder Mtb clearance, despite potential anti-inflammatory benefits in specific disease stages [50].

Alternatively, DHEA appears to exert dual immunomodulatory effects. It promotes dendritic cell activation, induces IL-12 and IFN-γ production, suppresses TGF-β secretion, and enhances antimicrobial peptide expression, all of which are essential for TB control [51–54], while also displaying anti-inflammatory properties that may be advantageous in chronic infections [55, 56]. Therefore, the dual and sometimes opposing effects attributed to DHEA on the immune system may reflect context-dependent regulation involving indirect pathways or the action of specific metabolites, rather than a single receptor-mediated mechanism [57, 58]. A broader group of oxygenated DHEA metabolites is being considered as adjuvants to improve infection control and potentially reduce treatment duration [43]. AED was more potent than DHEA in protecting against similar viral, bacterial and parasitic challenges and exhibited modest anti-GC effects by reducing TNF-α secretion [59]. In murine models of TB, AED reduced bacterial burden, prolonged survival, and enhanced early pro-inflammatory responses and granuloma formation [60]. Additionally, AET counteracted GC-induced suppression of TNF-α and IL-1, attenuated acute inflammation, reversed immune senescence, and promoted context-dependent immune homeostasis without engaging nuclear hormone receptors or causing systemic toxicity [61]. It also supported the recovery of CD4⁺ and CD8⁺ T cells, essential for effective cellular immunity in HIV and TB [59].

Nevertheless, in the context of HIV-TB coinfection, the DHEA metabolite 7-OD proved more effective in restoring Mtb-specific immune responses [62]. HIV-TB individuals displayed impaired Th1 responses upon Mtb in vitro stimulation. Notably, 7-OD treatment enhanced lymphoproliferation and promoted a cytokine profile favoring IFN-γ and TNF-α production. Moreover, it reduced the frequency of Treg and increased the proportion of CD4⁺ T-bet⁺ cells, a phenotype associated with improved clinical outcomes [62]. Recent evidence from our group indicates that 7-OD exerted bacteriostatic effects on Mtb, enhanced macrophage-mediated bacterial clearance, reduced bacterial burden, and mitigated lung pneumonia in an experimental mouse model of progressive TB [63]. Importantly, 7-OD has been previously tested in humans for other indications and demonstrated a favorable safety profile, with no significant impact on sex hormone levels [25]. These findings highlight the potential of 7-OD to restore Th1/regulatory balance and enhance immune control while limiting tissue damage, supporting its role as a host-directed immunomodulatory adjuvant in TB therapy. In addition, HE2000, a synthetic DHEA derivative that bypasses sex steroid pathways, demonstrated therapeutic efficacy in a murine TB model and synergized with antibiotics to enhance bacillary clearance [64]. Although its mechanism remains unknown, it was safe in HIV-infected patients, reducing viral load [65] and lowering TB coinfection rates by 42.2% in ART-naïve individuals [66]. Taken together, these considerations highlight both the potential and the current constraints of 7-OD administration in experimental TB. While first-line anti-TB drugs target defined bacterial processes such as mycolic acid biosynthesis, RNA transcription, or cell wall assembly, and ART effectively controls viral replication, these treatments do not fully restore immune or endocrine homeostasis [67, 68]. Given that 7-OD acts through distinct host-directed mechanisms, it may exert complementary rather than redundant effects. However, its potential as an adjunctive agent remains to be investigated in combination with standard anti-TB or ART regimens.

Effects of Metabolic Hormones on HIV-TB Coinfection

The hypothalamic-peripheral axis orchestrates immunometabolic responses through hormonal mediators such as leptin, adiponectin, and insulin, among others, thus regulating energy distribution between immune function and tissue maintenance [69]. Adipose tissue serves as both a metabolic and immunological hub [69]. Chronic infections like HIV and TB disrupt this balance, leading to pathological immunometabolic reprogramming [70].

Immunocompromised patients often develop chronic inflammation and recurrent infections [70]. Effective immunity requires significant energy, making nutritional status critical for infection control. Malnutrition impairs innate and adaptive immunity, increasing susceptibility to infections and perpetuating immune-metabolic dysfunction [71]. HIV, TB, and their coinfection hijack host metabolism and drive wasting through fat/protein depletion – a hallmark of both diseases that worsens clinical outcomes [72]. While HIV broadly disrupts energy metabolism, TB specifically impairs protein balance. Coinfection synergistically exacerbates protein hypoalbuminemia [72].

As was already mentioned, in infectious diseases, pro-inflammatory cytokines activate the HPA axis, leading to elevated cortisol levels. This cortisol surge profoundly reshapes metabolism by stimulating hepatic gluconeogenesis and increasing hepatic glucose output, while simultaneously antagonizing insulin action in skeletal muscle and adipose tissue to reduce glucose uptake. These combined hepatic and peripheral effects promote systemic insulin resistance and hyperglycemia, ensuring fuel availability for vital organs. This metabolic shift is part of a critical bidirectional circuit, as insulin signaling itself modulates the response: in the periphery, insulin exerts anti-inflammatory effects by suppressing NF-κB and inflammasome signaling, thereby tempering cytokine production. [73]. In chronic infections, a vicious cycle can ensue where cytokines raise cortisol, cortisol induces insulin resistance and hyperglycemia, and this metabolic dysregulation, compounded by central insulin resistance, further fuels inflammation and HPA activation, ultimately influencing infection outcomes and glycemic control [73].

Hyperglycemia and insulin resistance are common features of active TB that reshape host immunity [74, 75]. This relationship is bidirectional: active TB is associated with altered insulin-glucose homeostasis and immune-metabolic disturbances that may contribute to disease pathogenesis. Human and experimental studies support this link, showing that TB is accompanied by inflammation-driven metabolic derangement, impaired glucose tolerance, and immune transcriptomic reprogramming that compromises adaptive responses. [76–78]. The interplay becomes even more complex in the context of coinfection, as both TB and HIV disrupt glucose metabolism-TB through transient infection-induced hyperglycemia, and HIV, together with ART, through sustained insulin resistance [79, 80]. Consequently, co-infected patients exhibit high rates of dysglycemia and poorer TB outcomes, yet mechanistic understanding and targeted therapeutic strategies for this intertwined condition remain critically limited [81–83].

The hypothalamic melanocortin system regulates energy balance through antagonistic POMC (anorexigenic) and AgRP/NPY (orexigenic) neurons, modulated by leptin and ghrelin [84]. Leptin serves dual metabolic and pro-inflammatory roles, activating STAT3/mTOR pathways to link nutritional status with immune responses [85]. Conversely, adiponectin counteracts leptin’s effects through insulin-sensitizing and anti-inflammatory mechanisms, despite its paradoxical reduction in obesity [86]. Together, these adipokines create a dynamic endocrine equilibrium: leptin facilitates energy expenditure and immune activation during the fed state, whereas adiponectin restrains inflammation and enhances metabolic adaptability. Dysregulation of these pathways disrupts both energy homeostasis and immune competence, particularly in chronic inflammatory conditions. [85]. Moreover, leptin serves as both a metabolic gatekeeper (via hypothalamic energy balance control) and an immunometabolic switch (via T-cell glycolytic activation), bridging adipose reserves with inflammatory capacity [87].

Active TB infection increases energy demands, resulting in catabolic wasting (weight loss, muscle atrophy) and reduced leptin production [88], which impairs Th1 responses, and weakens bacterial clearance [89, 90]. HIV infection lowers leptin levels, which is associated with insulin resistance and metabolic dysfunction [91]. TB/HIV coinfection worsens this scenario, accelerating wasting, hypercatabolism and leptin dysregulation, impairing immune control of M. tuberculosis [92]. Co-infected patients often exhibit micronutrient deficiencies [92], high inflammation, poor granuloma formation [93], and increased risk of immune reconstitution inflammatory syndrome upon ART initiation [94].

Adiponectin, similar to leptin, functions dually as a hormone and cytokine, with emerging roles in disease pathogenesis and, under certain conditions, may cross-regulate each other [95]. Adiponectin circulates in three major isoforms, where the multimeric HMW form enhances insulin sensitivity, glucose uptake, and lipid metabolism. Its expression is regulated by adipogenic transcription factors, including PPAR-γ [96]. Adiponectin isoforms play distinct roles in disease pathogenesis, functioning as acute-phase reactants that regulate inflammatory responses in both acute and chronic conditions. Dysregulated isoform formation has been associated with metabolic disorders. Notably, adiponectin exhibits context-dependent duality: although it often acts as an anti-inflammatory mediator in metabolic diseases, some studies have reported pro-inflammatory effects mediated through NF-κB activation and IL-1 and IL-6 induction [97, 98]. This functional dichotomy remains unresolved, highlighting the need for further mechanistic studies.

Chronic inflammation and adipose tissue depletion are hallmarks of both HIV and TB. In metabolic health, adiponectin improves glucose metabolism by antagonizing fatty acid-induced insulin resistance [99]. However, HIV infection disrupts this physiology through adipocyte dysfunction. ART-naïve HIV individuals demonstrate loss of subcutaneous adipose tissue, lowering adiponectin production. Proposed mechanisms include HIV protein R-mediated PPAR-γ suppression, though pathways that require further elucidation [91, 100]. However, HIV infection disrupts this physiology through adipocyte dysfunction. ART-naïve HIV individuals demonstrate loss of subcutaneous adipose tissue, lowering adiponectin production. Proposed mechanisms include HIV protein R-mediated PPAR-γ suppression, though pathways that require further elucidation [91, 100].

In TB, plasma adiponectin levels are augmented [89, 101], and tend to rise during treatment, correlating with wasting and systemic inflammation, and reduced leptin concentrations. However, Moideen et al. [95] reported decreased adiponectin levels in active TB that normalized following treatment completion. The role of adiponectin in TB-HIV coinfection remains poorly understood despite well-documented evidence of metabolic disruptions and the absence of conclusive studies to date.

Beyond leptin and adiponectin, other adipokines like resistin and visfatin remain understudied in coinfection. Both mediators may exacerbate inflammatory cascades [102] and metabolic dysregulation [103], yet their specific roles in HIV-TB synergy are poorly characterized. Resistin’s pro-inflammatory effects on macrophage activation [102] and visfatin’s involvement in NAD+ biosynthesis [104] could influence disease progression and therapeutic outcomes. However, the absence of clinical studies correlating their circulating levels with coinfection severity represents a critical knowledge gap in current knowledge. Systematic investigation of these adipokines may uncover novel biomarkers or therapeutic targets for addressing the intersecting metabolic and inflammatory disturbances in HIV-TB comorbidity.

Clinical and Therapeutic Implications, Challenges, and Future Perspectives

Hormonal profiling, measuring cortisol/DHEA ratios or 7-OD levels, shows potential as a prognostic tool and for monitoring immune competence in HIV-TB coinfection. Adipokines like leptin and adiponectin may complement this approach, given their dual metabolic and immunological roles. Such biomarkers could help identify patients at higher risk of disease progression or treatment failure, enabling more personalized management.

Therapeutically, targeted modulation of adrenal and metabolic hormones, particularly through agents such as 7-OD, represents a promising host-directed strategy to restore immune balance, enhance antimycobacterial activity, and control tissue damage. When administered alongside standard anti-TB and ARV treatments, such interventions may shorten treatment duration. However, translation into clinical practice is limited due to the small number of studies.

Future research should prioritize integrative approaches that combine hormonal and adipokine profiling with immune functional and clinical data to achieve a more comprehensive understanding of neuroendocrine-immune interactions in TB and HIV-TB coinfection. In parallel, the development of rapid, field-adapted assays for hormone and adipokine measurements, together with the clinical evaluation of hormonal immunomodulators, will be crucial to translate these insights into practice. Progress will depend on bridging endocrinology, immunology, and global health to design appropriate interventions suitable for the epidemiological and socioeconomic realities of HIV-TB.

Conclusion

HIV-TB coinfection creates a unique landscape of immune-endocrine dysfunction that accelerates disease progression and challenges clinical management. Far from being passive modulators, adrenal and metabolic axes are active determinants of anti-TB immunity. Harnessing these pathways for biomarker identification and host-directed interventions could significantly improve outcomes, provided that future research addresses current gaps in knowledge and translates findings into context-appropriate clinical strategies.

Acknowledgments

We would like to thank Mr. Sergio Mazzini for his assistance with editing and proofreading during manuscript preparation.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions

M.B.V., N.S., and M.F.Q. drafted the manuscript and contributed previously published and unpublished data from their research groups. D.A.G. and M.V.A. contributed with data and insightful critics. All authors reviewed the final manuscript.

Funding Statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.