Testosterone, a cornerstone of endocrinology first isolated and synthesized in the 1930s, has long been recognized as the quintessential male sex hormone. However, recent advances in biomedical research have begun to reshape this classical view, revealing a far more expansive and intricate role for testosterone in metabolic regulation across both sexes. Emerging evidence suggests that testosterone operates not merely as a reproductive hormone but as a critical metabolic messenger, interfacing with multiple signaling pathways to maintain homeostasis in energy balance, glucose metabolism, and lipid regulation. This paradigm shift is poised to revolutionize therapeutic strategies for metabolic diseases, leveraging testosterone’s multifaceted modes of action.
The chemical synthesis of testosterone marked a watershed moment in hormone replacement therapy, laying the groundwork for decades of clinical application. Testosterone exerts its biological effects primarily through binding to the androgen receptor (AR), a nuclear receptor that, upon activation, modulates gene transcription. Yet, the picture is far more complex. Testosterone is metabolized enzymatically by aromatase into 17β-estradiol, an estrogen receptor (ER) agonist, and converted by 5α-reductases into dihydrotestosterone (DHT), a more potent AR agonist incapable of aromatization. These metabolites broaden the spectrum of testosterone’s physiological impacts, enabling both genomic and rapid non-genomic signaling cascades.
Central to understanding testosterone’s systemic impact is its dualistic signaling. Genomic actions involve AR and ER-mediated modulation of target gene expression, a process that unfolds over hours to days, profoundly influencing cellular differentiation, proliferation, and metabolism. In parallel, testosterone and its derivatives can engage in non-genomic signaling, triggering rapid cellular responses through membrane-bound receptors and intracellular signaling pathways that influence ion fluxes, kinase activation, and second messenger systems. This combination of long- and short-term signaling mechanisms allows testosterone to fine-tune metabolic processes in a context-dependent fashion.
The metabolic roles of testosterone extend beyond reproductive tissues. In adipose tissue, testosterone influences lipolysis and adipogenesis, often opposing the accumulation of visceral fat associated with metabolic syndrome. It enhances insulin sensitivity in skeletal muscle, promoting glucose uptake and mitochondrial function. These anabolic effects contribute to the maintenance of lean body mass and overall metabolic vigor. Notably, testosterone deficiency correlates with increased risk of type 2 diabetes and cardiovascular diseases, underlining its importance in systemic metabolic health.
In females, testosterone serves equally vital metabolic functions, although these roles are less often emphasized in clinical discourse. The androgen receptor is expressed in multiple metabolic tissues, including liver, muscle, and adipose compartments, where testosterone modulates energy expenditure and substrate utilization. Emerging research indicates that perturbations in androgen signaling can contribute to metabolic dysfunctions observed in conditions such as polycystic ovary syndrome (PCOS), highlighting the hormone’s critical influence beyond reproductive physiology.
Therapeutically, testosterone replacement has traditionally been employed to treat hypogonadism and related symptoms. However, burgeoning data advocate for a broader therapeutic potential targeting metabolic derangements. Clinical trials suggest that testosterone supplementation can improve insulin sensitivity, reduce adiposity, and ameliorate lipid profiles, especially in hypogonadal men. Yet the balance is delicate; supraphysiological doses or inappropriate administration routes may exacerbate adverse outcomes, typifying the need for precision medicine approaches tailored to individual metabolic phenotypes.
At the molecular level, the interplay between testosterone and its metabolites with AR and ER subtypes orchestrates a symphony of metabolic gene regulation. The distinct but complementary actions of AR and ERα/β mediate tissue-specific responses, tuning metabolic pathways such as glycolysis, gluconeogenesis, and lipid biosynthesis. This coupling of androgenic and estrogenic signals illustrates the sophisticated endocrine crosstalk that testosterone navigates, offering a more integrated understanding of hormonal control over metabolism.
Preclinical models have been instrumental in delineating testosterone’s metabolic functions. Rodent studies reveal that androgen depletion leads to increased adiposity, insulin resistance, and impaired mitochondrial biogenesis, while restoration confers protective metabolic profiles. Genetically engineered models lacking AR or aromatase provide compelling evidence for the receptor-mediated mechanisms underlying these phenotypes, laying a mechanistic foundation for translating findings into human medicine.
In humans, observational studies fortify the link between endogenous testosterone levels and metabolic health indices. Lower testosterone concentrations associate with increased visceral fat, dyslipidemia, and impaired glucose handling. Conversely, physiological testosterone levels correspond with favorable metabolic parameters, underscoring the hormone’s role as a sentinel of metabolic integrity. However, age-associated declines complicate this relationship, prompting ongoing investigation into optimizing testosterone-based therapies in aging populations.
Advances in molecular endocrinology have also uncovered rapid, non-genomic actions of testosterone that modulate metabolic enzyme activity and hormone secretion. These effects occur within minutes, independent of gene transcription, and involve activation of kinase cascades such as MAPK and PI3K/AKT pathways. The non-genomic mechanisms contribute to acute regulation of insulin secretion, mitochondrial respiration, and nutrient uptake, highlighting an additional layer of metabolic control imparted by testosterone.
Clinical application of these insights demands a nuanced understanding of testosterone’s pleiotropic effects. The heterogeneity in androgen receptor polymorphisms, enzyme expression levels (e.g., aromatase and 5α-reductase), and tissue-specific receptor distribution necessitates personalized approaches to testosterone therapy. Future directions include selective androgen receptor modulators (SARMs) that aim to harness metabolic benefits while minimizing androgenic side effects, representing a promising frontier in metabolic disease intervention.
Moreover, the bidirectional relationship between testosterone and metabolism suggests feedback mechanisms whereby metabolic states influence androgen biosynthesis and signaling. Obesity and insulin resistance can suppress hypothalamic-pituitary-gonadal axis activity, leading to hypogonadism and further metabolic deterioration. This vicious cycle underscores the importance of integrated therapeutic strategies addressing both hormonal and metabolic dysfunctions simultaneously.
Testosterone’s role as a metabolic messenger also intersects with inflammatory pathways that underlie chronic metabolic diseases. Androgen signaling modulates immune cell function and inflammatory cytokine production, influencing the low-grade inflammation characteristic of obesity and type 2 diabetes. By tempering inflammatory responses, testosterone may confer protective effects beyond classical metabolic pathways, opening new avenues for research and therapy.
In sum, testosterone is emerging as a multifaceted metabolic regulator with far-reaching implications for both male and female physiology. Its intricate signaling networks span genomic and non-genomic domains, involving androgenic and estrogenic pathways that collectively orchestrate energy homeostasis. Appreciating these complex interrelations positions testosterone at the nexus of endocrine and metabolic health, with transformative potential for future clinical innovation.
As the landscape of metabolic research advances, re-evaluating testosterone’s role beyond reproduction holds transformative promise. Bridging basic science discoveries with clinical practice could foster the development of therapeutic interventions that leverage testosterone’s metabolic signaling to combat obesity, diabetes, and associated co-morbidities. This expanding horizon not only enriches our understanding of hormone biology but also underscores the importance of androgens as pivotal orchestrators of systemic metabolic resilience.
Subject of Research: Testosterone as a metabolic regulator and messenger.
Article Title: Metabolic Messengers: testosterone.
Article References: Mauvais-Jarvis, F., Bhasin, S. Metabolic Messengers: testosterone. Nat Metab (2026). https://doi.org/10.1038/s42255-025-01431-6
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s42255-025-01431-6
