Can chronic inflammation suppress HPG signaling and lower LH, testosterone, and DHEA-S?

Chronic inflammation impairs systemic endocrine function by targeting both central signaling pathways and peripheral steroidogenesis.

Mechanistic pathways of endocrine suppression

• Central HPG Axis Inhibition: Chronic systemic cytokines (IL-1β, TNF-α, IL-6) act on the hypothalamus and anterior pituitary to disrupt GnRH neuronal firing and gene expression. This diminishes GnRH pulse frequency and amplitude, directly blunting pituitary LH synthesis and secretion.
• Testicular Impairment: Decreased LH reduces the vital tropic stimulation of Leydig cells. Locally, TNF-α and IL-6 bind Leydig cell receptors (TNFR and gp130), triggering MAPK/JNK and JAK-STAT3 cascades that transcriptionally repress steroidogenic acute regulatory (StAR) protein, leading to lower testosterone production.
• Adrenal Steroidogenic Blockade: Cytokines drive NF-κB and JAK/STAT pathways in the adrenal zona reticularis, downregulating CYP17A1 expression and impairing its 17,20-lyase activity via the loss of cytochrome b5 (CYB5A). Additionally, transcriptional repression of SULT2A1 inhibits the sulfation of DHEA into DHEA-S, redirecting cholesterol substrates toward glucocorticoid production.

Bidirectional feedback loops

• Endocrine-Immune Counter-Regulation: Both testosterone and DHEA-S act as natural negative feedback regulators of the immune system. Testosterone replacement is shown to reduce levels of IL-6 and TNF-α, while DHEA-S modulates and inhibits the production of these same inflammatory cytokines. Consequently, cytokine-induced androgen suppression removes these anti-inflammatory checks, perpetuating chronic inflammation.

Bottom line

• Chronic inflammation directly drives a state of secondary hypogonadism and adrenal androgen depletion. Pro-inflammatory cytokines suppress central HPG signaling (reducing LH and testosterone) while programmatically downregulating adrenal CYP17A1 and SULT2A1 (reducing DHEA-S). This suppression dismantles crucial anti-inflammatory feedback loops, creating a self-sustaining cycle of inflammation and hormone deficiency.