Do inflammatory cytokines suppress ovarian and adrenal sex-steroid production?

Pro-inflammatory cytokines act as potent endocrine disruptors by directly targeting the enzymatic machinery responsible for sex-steroid production in both ovarian and adrenal tissues.

Suppression of steroidogenic pathways

• Enzymatic downregulation: Pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6), suppress the expression and activity of critical steroidogenic enzymes, including CYP19A1 (aromatase), CYP17A1, and steroidogenic acute regulatory (StAR) protein.
• Impact on steroid output: In ovarian tissues, the downregulation of CYP19A1 in granulosa cells directly limits the conversion of androgens to estrogens, resulting in reduced estradiol output. Concurrently, the inhibition of CYP17A1 in theca cells and the StAR protein restricts androgen precursor availability.
• Adrenal consequences: In adrenal glands, chronic inflammatory states suppress ACTH-driven steroidogenesis and downregulate CYP11A1, StAR, and CYP17A1. This shifts synthesis away from sex-steroid precursors like dehydroepiandrosterone (DHEA), compounding the systemic sex-steroid deficit.

Mechanistic signaling pathways

• NF-κB activation: Cytokine signaling triggers downstream NF-κB pathway activation within target steroidogenic tissues.
• Receptor blunting: The activation of NF-κB directly suppresses key steroidogenic enzymes, such as CYP19A1, while blunting gonadotropin receptor responsiveness to further impair hormone synthesis.

Bottom line

• Chronic inflammation directly drives endocrine insufficiency by activating NF-κB pathways to suppress essential ovarian and adrenal enzymes (StAR, CYP19A1, and CYP17A1), ultimately reducing downstream estradiol and androgen output.