How does testosterone reduce inflammation?

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Last updated: May 10, 2026 • View editorial policy

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How Testosterone Reduces Inflammation

Testosterone reduces inflammation primarily by downregulating pro-inflammatory cytokines (TNF-α, IL-17, IL-6), decreasing Fc gamma receptor expression on macrophages, suppressing inflammatory chemokines (CXCL-9, CXCL-10), and reducing Toll-like receptor 4 (TLR4) expression—the key trigger for innate immune activation.

Mechanisms of Anti-Inflammatory Action

Direct Effects on Immune Cells

Testosterone acts through multiple pathways to dampen inflammatory responses:

Macrophage Modulation:

  • Testosterone decreases TLR4 expression on macrophages, which is the primary receptor triggering innate immunity and inflammation 1. Orchidectomized mice show significantly higher TLR4 expression and increased susceptibility to endotoxic shock, effects reversed by testosterone replacement 1.
  • Both testosterone and estradiol reduce expression of Fc gamma receptors IIa and III on human macrophages—the two main receptors responsible for antibody-mediated inflammatory responses 2. This mechanism is particularly relevant in conditions where immune complexes drive inflammation.

Cytokine Profile Shifts:

  • Testosterone treatment significantly reduces TNF-α production while increasing IL-10 (an anti-inflammatory cytokine), creating a favorable IL-10-to-TNF-α ratio 3. In renal ischemia-reperfusion injury models, low-dose testosterone (20 μg/kg) increased intrarenal IL-10 while reducing TNF-α 3.
  • In hepatic inflammation, testosterone suppresses IL-17, CXCL-9, and CXCL-10 expression 4. Serum testosterone levels negatively correlate with these inflammatory markers 4.
  • Human macrophages treated with physiologic testosterone levels show significant reductions in TNF and IFN-γ production when exposed to viral stimuli and immune complexes 2.

T-Cell Regulation

Testosterone reduces inflammatory T-cell responses through several mechanisms:

  • Decreases intrarenal CD4+ and CD8+ T-cell infiltration following injury 3
  • Reduces effector T helper 17 (Th17) cells, which produce pro-inflammatory IL-17 3
  • Attenuates group 2 innate lymphoid cell (ILC2)-mediated airway inflammation by decreasing IL-5 and IL-13 expression 5

Dose-Dependent Effects

Critical caveat: The anti-inflammatory effects of testosterone are dose-dependent and biphasic 3:

  • Low-dose testosterone (20 μg/kg): Protective, reduces plasma creatinine, increases IL-10, reduces TNF-α
  • Medium-dose (50 μg/kg): Increases IL-10 but fails to reduce TNF-α or provide protection
  • High-dose (100 μg/kg): Increases both IL-10 AND TNF-α, fails to provide protection

This demonstrates that supraphysiologic doses may paradoxically increase inflammation rather than suppress it.

Nitric Oxide Pathway

Low-dose testosterone's anti-inflammatory effects partially depend on nitric oxide production 3. When nitric oxide synthesis is blocked with low-dose L-NAME, testosterone loses its protective effects against ischemia-reperfusion injury and fails to increase intrarenal IL-10 3.

Clinical Implications

Sexual Dimorphism in Inflammation: The anti-inflammatory effects of testosterone explain several clinical observations:

  • Women have increased circulating ILC2 numbers compared to men in moderate-to-severe asthma 5
  • Female mice develop marked cholangitis while male mice are resistant; castration renders males susceptible, while testosterone treatment completely suppresses liver inflammation in females 4
  • Men with low testosterone have increased systemic immune-inflammation index (SII) and pan immune inflammation value (PIV), both correlating with increased inflammatory markers 6, 7

Testosterone Deficiency and Inflammation: Low testosterone levels are associated with increased inflammatory burden 6, 7. The highest quartile of PIV shows a 51% increased risk of testosterone deficiency compared to the lowest quartile 6. This bidirectional relationship suggests testosterone deficiency may both result from and contribute to chronic inflammation.

Practical Considerations

When considering testosterone's anti-inflammatory effects, recognize that:

  • Physiologic replacement doses are necessary for anti-inflammatory benefits; supraphysiologic doses may be counterproductive 3
  • The anti-inflammatory effects occur through multiple redundant pathways (cytokine modulation, receptor downregulation, T-cell suppression), making the overall effect robust
  • These mechanisms are distinct from testosterone's effects on cardiovascular risk, which existing evidence suggests are neutral or possibly beneficial 8, 9

The evidence consistently demonstrates that testosterone at physiologic levels functions as an endogenous anti-inflammatory hormone through direct effects on innate and adaptive immune cells, providing a mechanistic explanation for sex differences in inflammatory and autoimmune diseases.

References

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