Can inflammatory cytokine signaling lower testosterone?

Systemic and central inflammatory signaling acts at multiple levels of the hypothalamic-pituitary-gonadal (HPG) axis to suppress reproductive hormone production and lower testosterone.

Central suppression of the HPG axis

Inflammatory cytokine signaling disrupts the central drivers of the reproductive axis:

• Hypothalamic GnRH suppression: Pro-inflammatory cytokines, particularly interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), suppress gonadotropin-releasing hormone (GnRH) pulse generator activity. They directly downregulate kisspeptin expression and KNDy (kisspeptin/neurokinin B/dynorphin) neuron activity, which are essential for driving pulsatile GnRH release.
• Pituitary LH suppression: Cytokines act on pituitary gonadotropes to directly suppress luteinizing hormone (LH) secretion. Specifically, IL-1β downregulates GnRH receptor (GnRHR) expression and decreases LHβ subunit mRNA, weakening pituitary responsiveness to central signaling.

Direct Leydig cell impairment

In addition to reducing upstream trophic drive, cytokines directly arrest the biosynthetic machinery within the testes:

• Transcriptional repression: TNF-α, IL-1β, and IL-6 activate NF-κB pathways to repress crucial nuclear receptors, including steroidogenic factor 1 (SF-1) and Nur77. This blocks the transcription of key steroidogenic enzymes, including CYP11A1 and CYP17A1.
• Inhibition of rate-limiting transport: Cytokines directly suppress the expression of the steroidogenic acute regulatory (StAR) protein. Because StAR is the rate-limiting mediator of cholesterol transport into the inner mitochondrial membrane, its downregulation prevents the initiation of steroidogenesis, resulting in a proportional drop in serum testosterone.

Bottom line

• Inflammatory cytokines lower testosterone through a dual central and peripheral mechanism: they suppress hypothalamic GnRH and pituitary LH secretion by inhibiting KNDy neurons and gonadotrope receptors, while simultaneously arresting testicular Leydig cell steroidogenesis by transcriptionally repressing the rate-limiting StAR protein and key biosynthetic enzymes.