madman
Super Moderator
* The findings from TTrials, TRAVERSE, T4DM and other recent studies have provided high-quality evidence of the metabolic benefits and low risk of serious adverse events associated with testosterone therapy. Reflecting this new evidence, the FDA revised its black box warning regarding testosterone and cardiovascular risks in 2025.
* Testosterone treatment can also produce erythrocytosis; however, the incidence of erythrocytosis with physiological doses of testosterone replacement was low and not associated with cardiovascular events in randomized trials105
* Concurrently, the discovery and cloning of the AR, ERα and ERβ, CYP19A1 aromatase and steroid 5α-reductases, along with the identification of testosterone’s rapid extranuclear signalling mechanisms, have expanded our understanding of testosterone’s diverse actions and its critical role as a metabolic messenger.
Fig. 3 | Summary of testosterone’s effects as a metabolic messenger in men and male rodents. In men and male rodents, testosterone promotes metabolic homeostasis as a hormone that binds to the AR and following its conversion to DHT. Testosterone is also a prohormone that undergoes conversion to oestradiol (E2) by aromatase; oestradiol then binds to ERα or ERβ and is a critical messenger of testosterone’s action in metabolic homeostasis.
Testosterone, discovered during the endocrine gold rush of the 1930s, was the first hormone chemically synthesized for replacement therapy. In both men and women, testosterone functions directly through the androgen receptor (AR) and indirectly as a prohormone, converted by aromatase into 17β-oestradiol (oestradiol), which activates the oestrogen receptors ERα and ERβ. Testosterone is also metabolized to dihydrotestosterone—a potent, non-aromatizable AR agonist—through steroid 5α-reductases. Testosterone and its metabolites signal through AR- and ER-mediated genomic and rapid non-genomic actions. Long recognized for its role as a sex hormone, mounting evidence underscores the importance of testosterone in the regulation of systemic metabolism in both male and female organisms. Here, we highlight key milestones in the history of testosterone’s discovery and therapeutic applications. Additionally, we synthesize the current understanding of testosterone as a key messenger promoting metabolic homeostasis in preclinical models and humans.
Tissue-specific metabolic effects of testosterone in men and male rodents
Here, we synthesize the current understanding of testosterone as an important messenger that regulates metabolic homeostasis. Figure 3 summarizes the tissue-specific metabolic effects of testosterone in humans and rodents.
Skeletal muscle
Testosterone dose-dependently increases skeletal muscle mass, strength and power in both hypogonadal13 and eugonadal14 men. Administration of supraphysiological doses of testosterone further enhances muscle size and strength in eugonadal men, even without exercise; these anabolic effects are augmented by resistance training15. In men, testosterone induces hypertrophy of both oxidative (mitochondria-rich) and glycolytic (mitochondria-poor, type II) muscle fibres and increases the numbers of myonuclei and satellite cells16
Testosterone also increases muscle mass by enhancing postprandial protein synthesis in men17. Although both testosterone and DHT promote muscle mass and strength, the conversion of testosterone to DHT is not required for its anabolic effects in men18
Adipose tissue
In men, testosterone deficiency promotes whole-body and abdominal adipose tissue accumulation, contributing to the development of metabolic syndrome38. Conversely, chronic—but not acute—testosterone treatment increases energy expenditure and lipid oxidation39 ,40 Therefore, the ability of testosterone to decrease whole-body and abdominal adipose tissue probably involves a delayed metabolic effect through increased muscle mass.
Pancreatic β cells
Testosterone also modulates β cell function. Human and rodent male β cells express 5α-reductase type 1 and aromatase53. After its conversion to DHT and oestradiol, testosterone enhances glucose-stimulated insulin secretion.
Bone
Testosterone contributes to bone mass, strength and microarchitecture, and its systemic metabolic benefits may be partially mediated through its actions on the bone. Testosterone therapy improves bone density, trabecular microarchitecture and mechanical strength59. These effects are mediated through aromatization to oestradiol (which acts on ERα) and direct AR signalling60,61. Men who are oestradiol resistant or deficient due to inactivating mutations in ERα or the aromatase gene exhibit impaired skeletal development and early-onset osteoporosis45,62. In men, oestradiol primarily prevents bone resorption, while both oestradiol and testosterone stimulate bone formation63. Oestradiol suppresses osteoclastogenesis by inhibiting RANKL, sclerostin, interleukin-1β (IL-1β) and tumour necrosis factor (TNF) through ERα, while promoting both trabecular and cortical bone formation59. Testosterone enhances trabecular bone formation through AR-mediated induction of insulin-like growth factor 1 (IGF-1) and TGFβ59. In parallel, testosterone-induced increases in muscle mass and strength may secondarily support skeletal loading and enhance bone strength.
Blood vessels
Testosterone is a potent vasodilator in men, acutely increasing coronary flow72 by relaxing vascular smooth muscle cells (VSMCs) and stimulating NO production in endothelial cells. Thus, testosterone improves flow-mediated dilation (FMD)—a NO-dependent marker of endothelial function73,74. These effects are partially mediated by testosterone’s aromatization to oestradiol. In healthy men, circulating oestradiol, but not testosterone, correlates positively with FMD75 while aromatase inhibition reduces FMD76. Low doses of oestrogens in men promote endothelium-dependent vasodilation and lower blood pressure8. In both men and male mice, these vasodilatory effects occur through non-genomic, membrane-initiated ERα signalling that promotes endothelial NO synthase phosphorylation and NO production8 The early onset of endothelial dysfunction and coronary artery disease n a man with an inactivating ERα mutation further supports the critical role of ERα in testosterone’s vascular actions77 ,78
Testosterone also binds to L-type voltage-gated calcium channels in VSMCs, producing vasorelaxation independent of the AR or ERs, similar to nifedipine—a drug used to treat hypertension12
Testosterone may also exert anti-atherogenic effects by modulating lipids and inflammation.
Heart
Sex differences in cardiac physiology and failure reflect both chromosomal and hormonal influences92. Under physiological conditions, testosterone generally supports cardiac health. In rats, it enhances myocardial contractility by increasing intracellular calcium through L-type calcium channels93, as well as promotes cardiomyocyte glucose uptake through CaMKII and AMPK activation94
Many cardioprotective effects of testosterone are dependent on oestradiol, as suggested by studies in women and female mice. Menopause is associated with an increased risk of heart failure, myocardial fibrosis and cardiac dysfunction95. In mice, oestradiol limits cardiac hypertrophy, fibrosis, apoptosis and oxidative stress while improving mitochondrial function92. Anti-hypertrophic effects are mediated by mitochondrial and membrane ERβ96, whereas anti-apoptotic effects involve PI3K–AKT activation through ERα97. Oestradiol also promotes cardiac mitochondrial biogenesis through G-protein-coupled ER signalling98
By contrast, in male hearts, testosterone acting through the AR may promote pathological remodelling under certain conditions92 Clinical trials suggest a potentially beneficial role of testosterone in men with heart failure, leading to improved lean mass, muscle strength and aerobic capacity but without noticeable effects on cardiac function99. Testosterone also shortens the age-related prolongation of the QT interval in men100, reducing arrhythmia risk through rapid non-genomic AR signalling that suppresses L-type calcium channels and delays rectifier potassium currents101
Haematopoiesis
In men, testosterone increases red blood cell production and corrects unexplained anaemia102. Testosterone stimulates erythropoiesis by increasing the number of haematopoietic progenitors in the bone marrow, stimulating erythropoietin production, and by suppressing hepcidin transcription through AR signalling in hepatocytes, thereby enhancing iron availability and erythrocyte iron incorporation103. Testosterone also increases 2,3-diphosphoglycerate levels in erythrocytes, shifting the oxygen dissociation curve to enhance oxygen delivery to tissues104. Together, these effects may improve aerobic capacity in individuals with heart failure. Testosterone treatment can also produce erythrocytosis; however, the incidence of erythrocytosis with physiological doses of testosterone replacement was low and not associated with cardiovascular events in randomized trials105
In male mice, testosterone expands myeloid progenitor populations and promotes neutrophil release from the bone marrow106. In men, testosterone treatment increases circulating neutrophils and monocytes within the physiological range107
Testosterone therapy and prevention of metabolic dysfunction in hypogonadal men
A mediation analysis from the T4DM trial concluded that testosterone’s anti-diabetic effect is primarily driven by a reduction in fat mass113. However, the testosterone-induced increase in skeletal muscle mass—along with the associated alterations in muscle fibre types, enhanced insulin-mediated glucose uptake and fatty acid oxidation—as well as testosterone’s insulinotropic effect on pancreatic β cells probably also contribute to its anti-diabetic effect.
Role of testosterone in female metabolic homeostasis
In conclusion, a physiological window of testosterone seems to amplify the beneficial effects of oestradiol on metabolic health in women, probably through direct AR actions, although the contribution of aromatization to oestradiol cannot be excluded.
Conclusion and future perspectives
Testosterone exerts pleiotropic effects on cardiometabolic physiology. Testosterone and its metabolites act on ERs and the AR expressed in endothelial cells, VSMCs and cardiomyocytes, modulating vascular tone, endothelial function, lipid handling and myocardial performance. Testosterone also directly binds to calcium channels in VSMCs, producing vasorelaxation independent of the AR or ERs. Clinically, these actions may contribute to the improvements in arterial stiffness, endothelial-dependent vasodilation and exercise capacity observed in testosterone-treated individuals and experimental subjects.
Testosterone’s actions through ERs and the AR also regulate key metabolic tissues—including skeletal muscle, adipose tissue, the liver and pancreatic β cells—where it enhances muscle mass and bioenergetics, improves insulin sensitivity and lipid oxidation, reduces visceral adiposity and cholesterol export, and enhances β cell function. Testosterone also signals in macrophages to suppress chronic low-grade inflammation. These metabolic and immunological effects may collectively reduce cardiometabolic risk over time.
The integrated in vivo effects of testosterone are context dependent and influenced by dose, treatment duration, age, sex and underlying metabolic status, which explains the variability in clinical outcomes. Although recent randomized controlled trials have confirmed the cardiometabolic safety and efficacy of testosterone therapy in hypogonadal men, the mechanistic basis—particularly the cell-specific genomic and non-genomic signalling through the AR and ERs in metabolic, immune and vascular cells—remains incompletely defined. Elucidating these pathways offers a roadmap for developing receptor- and tissue-selective androgen-based therapies that preserve metabolic and vascular benefits while minimizing risks. Such an approach could enable precision hormone therapy targeting age-related cardiometabolic diseases in both men and women.
* Testosterone treatment can also produce erythrocytosis; however, the incidence of erythrocytosis with physiological doses of testosterone replacement was low and not associated with cardiovascular events in randomized trials105
* Concurrently, the discovery and cloning of the AR, ERα and ERβ, CYP19A1 aromatase and steroid 5α-reductases, along with the identification of testosterone’s rapid extranuclear signalling mechanisms, have expanded our understanding of testosterone’s diverse actions and its critical role as a metabolic messenger.
Fig. 3 | Summary of testosterone’s effects as a metabolic messenger in men and male rodents. In men and male rodents, testosterone promotes metabolic homeostasis as a hormone that binds to the AR and following its conversion to DHT. Testosterone is also a prohormone that undergoes conversion to oestradiol (E2) by aromatase; oestradiol then binds to ERα or ERβ and is a critical messenger of testosterone’s action in metabolic homeostasis.
Testosterone, discovered during the endocrine gold rush of the 1930s, was the first hormone chemically synthesized for replacement therapy. In both men and women, testosterone functions directly through the androgen receptor (AR) and indirectly as a prohormone, converted by aromatase into 17β-oestradiol (oestradiol), which activates the oestrogen receptors ERα and ERβ. Testosterone is also metabolized to dihydrotestosterone—a potent, non-aromatizable AR agonist—through steroid 5α-reductases. Testosterone and its metabolites signal through AR- and ER-mediated genomic and rapid non-genomic actions. Long recognized for its role as a sex hormone, mounting evidence underscores the importance of testosterone in the regulation of systemic metabolism in both male and female organisms. Here, we highlight key milestones in the history of testosterone’s discovery and therapeutic applications. Additionally, we synthesize the current understanding of testosterone as a key messenger promoting metabolic homeostasis in preclinical models and humans.
Tissue-specific metabolic effects of testosterone in men and male rodents
Here, we synthesize the current understanding of testosterone as an important messenger that regulates metabolic homeostasis. Figure 3 summarizes the tissue-specific metabolic effects of testosterone in humans and rodents.
Skeletal muscle
Testosterone dose-dependently increases skeletal muscle mass, strength and power in both hypogonadal13 and eugonadal14 men. Administration of supraphysiological doses of testosterone further enhances muscle size and strength in eugonadal men, even without exercise; these anabolic effects are augmented by resistance training15. In men, testosterone induces hypertrophy of both oxidative (mitochondria-rich) and glycolytic (mitochondria-poor, type II) muscle fibres and increases the numbers of myonuclei and satellite cells16
Testosterone also increases muscle mass by enhancing postprandial protein synthesis in men17. Although both testosterone and DHT promote muscle mass and strength, the conversion of testosterone to DHT is not required for its anabolic effects in men18
Adipose tissue
In men, testosterone deficiency promotes whole-body and abdominal adipose tissue accumulation, contributing to the development of metabolic syndrome38. Conversely, chronic—but not acute—testosterone treatment increases energy expenditure and lipid oxidation39 ,40 Therefore, the ability of testosterone to decrease whole-body and abdominal adipose tissue probably involves a delayed metabolic effect through increased muscle mass.
Pancreatic β cells
Testosterone also modulates β cell function. Human and rodent male β cells express 5α-reductase type 1 and aromatase53. After its conversion to DHT and oestradiol, testosterone enhances glucose-stimulated insulin secretion.
Bone
Testosterone contributes to bone mass, strength and microarchitecture, and its systemic metabolic benefits may be partially mediated through its actions on the bone. Testosterone therapy improves bone density, trabecular microarchitecture and mechanical strength59. These effects are mediated through aromatization to oestradiol (which acts on ERα) and direct AR signalling60,61. Men who are oestradiol resistant or deficient due to inactivating mutations in ERα or the aromatase gene exhibit impaired skeletal development and early-onset osteoporosis45,62. In men, oestradiol primarily prevents bone resorption, while both oestradiol and testosterone stimulate bone formation63. Oestradiol suppresses osteoclastogenesis by inhibiting RANKL, sclerostin, interleukin-1β (IL-1β) and tumour necrosis factor (TNF) through ERα, while promoting both trabecular and cortical bone formation59. Testosterone enhances trabecular bone formation through AR-mediated induction of insulin-like growth factor 1 (IGF-1) and TGFβ59. In parallel, testosterone-induced increases in muscle mass and strength may secondarily support skeletal loading and enhance bone strength.
Blood vessels
Testosterone is a potent vasodilator in men, acutely increasing coronary flow72 by relaxing vascular smooth muscle cells (VSMCs) and stimulating NO production in endothelial cells. Thus, testosterone improves flow-mediated dilation (FMD)—a NO-dependent marker of endothelial function73,74. These effects are partially mediated by testosterone’s aromatization to oestradiol. In healthy men, circulating oestradiol, but not testosterone, correlates positively with FMD75 while aromatase inhibition reduces FMD76. Low doses of oestrogens in men promote endothelium-dependent vasodilation and lower blood pressure8. In both men and male mice, these vasodilatory effects occur through non-genomic, membrane-initiated ERα signalling that promotes endothelial NO synthase phosphorylation and NO production8 The early onset of endothelial dysfunction and coronary artery disease n a man with an inactivating ERα mutation further supports the critical role of ERα in testosterone’s vascular actions77 ,78
Testosterone also binds to L-type voltage-gated calcium channels in VSMCs, producing vasorelaxation independent of the AR or ERs, similar to nifedipine—a drug used to treat hypertension12
Testosterone may also exert anti-atherogenic effects by modulating lipids and inflammation.
Heart
Sex differences in cardiac physiology and failure reflect both chromosomal and hormonal influences92. Under physiological conditions, testosterone generally supports cardiac health. In rats, it enhances myocardial contractility by increasing intracellular calcium through L-type calcium channels93, as well as promotes cardiomyocyte glucose uptake through CaMKII and AMPK activation94
Many cardioprotective effects of testosterone are dependent on oestradiol, as suggested by studies in women and female mice. Menopause is associated with an increased risk of heart failure, myocardial fibrosis and cardiac dysfunction95. In mice, oestradiol limits cardiac hypertrophy, fibrosis, apoptosis and oxidative stress while improving mitochondrial function92. Anti-hypertrophic effects are mediated by mitochondrial and membrane ERβ96, whereas anti-apoptotic effects involve PI3K–AKT activation through ERα97. Oestradiol also promotes cardiac mitochondrial biogenesis through G-protein-coupled ER signalling98
By contrast, in male hearts, testosterone acting through the AR may promote pathological remodelling under certain conditions92 Clinical trials suggest a potentially beneficial role of testosterone in men with heart failure, leading to improved lean mass, muscle strength and aerobic capacity but without noticeable effects on cardiac function99. Testosterone also shortens the age-related prolongation of the QT interval in men100, reducing arrhythmia risk through rapid non-genomic AR signalling that suppresses L-type calcium channels and delays rectifier potassium currents101
Haematopoiesis
In men, testosterone increases red blood cell production and corrects unexplained anaemia102. Testosterone stimulates erythropoiesis by increasing the number of haematopoietic progenitors in the bone marrow, stimulating erythropoietin production, and by suppressing hepcidin transcription through AR signalling in hepatocytes, thereby enhancing iron availability and erythrocyte iron incorporation103. Testosterone also increases 2,3-diphosphoglycerate levels in erythrocytes, shifting the oxygen dissociation curve to enhance oxygen delivery to tissues104. Together, these effects may improve aerobic capacity in individuals with heart failure. Testosterone treatment can also produce erythrocytosis; however, the incidence of erythrocytosis with physiological doses of testosterone replacement was low and not associated with cardiovascular events in randomized trials105
In male mice, testosterone expands myeloid progenitor populations and promotes neutrophil release from the bone marrow106. In men, testosterone treatment increases circulating neutrophils and monocytes within the physiological range107
Testosterone therapy and prevention of metabolic dysfunction in hypogonadal men
A mediation analysis from the T4DM trial concluded that testosterone’s anti-diabetic effect is primarily driven by a reduction in fat mass113. However, the testosterone-induced increase in skeletal muscle mass—along with the associated alterations in muscle fibre types, enhanced insulin-mediated glucose uptake and fatty acid oxidation—as well as testosterone’s insulinotropic effect on pancreatic β cells probably also contribute to its anti-diabetic effect.
Role of testosterone in female metabolic homeostasis
In conclusion, a physiological window of testosterone seems to amplify the beneficial effects of oestradiol on metabolic health in women, probably through direct AR actions, although the contribution of aromatization to oestradiol cannot be excluded.
Conclusion and future perspectives
Testosterone exerts pleiotropic effects on cardiometabolic physiology. Testosterone and its metabolites act on ERs and the AR expressed in endothelial cells, VSMCs and cardiomyocytes, modulating vascular tone, endothelial function, lipid handling and myocardial performance. Testosterone also directly binds to calcium channels in VSMCs, producing vasorelaxation independent of the AR or ERs. Clinically, these actions may contribute to the improvements in arterial stiffness, endothelial-dependent vasodilation and exercise capacity observed in testosterone-treated individuals and experimental subjects.
Testosterone’s actions through ERs and the AR also regulate key metabolic tissues—including skeletal muscle, adipose tissue, the liver and pancreatic β cells—where it enhances muscle mass and bioenergetics, improves insulin sensitivity and lipid oxidation, reduces visceral adiposity and cholesterol export, and enhances β cell function. Testosterone also signals in macrophages to suppress chronic low-grade inflammation. These metabolic and immunological effects may collectively reduce cardiometabolic risk over time.
The integrated in vivo effects of testosterone are context dependent and influenced by dose, treatment duration, age, sex and underlying metabolic status, which explains the variability in clinical outcomes. Although recent randomized controlled trials have confirmed the cardiometabolic safety and efficacy of testosterone therapy in hypogonadal men, the mechanistic basis—particularly the cell-specific genomic and non-genomic signalling through the AR and ERs in metabolic, immune and vascular cells—remains incompletely defined. Elucidating these pathways offers a roadmap for developing receptor- and tissue-selective androgen-based therapies that preserve metabolic and vascular benefits while minimizing risks. Such an approach could enable precision hormone therapy targeting age-related cardiometabolic diseases in both men and women.
