Uncovering Common Anti-Inflammatory Targets of DHEA, 5-AED, Progesterone, and Gestobutanoyl

Androstenes and progestogens possess strong anti-inflammatory and immunomodulatory properties, as well as cytostatic and anti-proliferative effects on certain hormone-dependent tumors. While these steroids have distinct nuclear and membrane receptors, their targets may overlap, influencing immune and inflammatory pathways. The binding affinities of these steroids to shared molecular targets remain insufficiently characterized. This study aimed to identify and compare common binding targets of selected androstenes and progestogens relevant to immune regulation and inflammation.

Molecular docking analyses were performed to evaluate the binding affinities of Dehydroepiandrosterone (DHEA), 5-Androstenediol (5-AED), Progesterone (P4), and Gestobutanoyl (GB) to receptors and proteins involved in immune and inflammatory processes.

Docking results revealed several common targets for both androstenes and progestogens, including Interleukin-6 (IL-6), Constitutive Androstane Receptor (CAR), Pregnane X Receptor (PXR), Progesterone Receptor Membrane Component 1 (PGRMC1), Peroxisome Proliferator-Activated Receptor Alpha (PPARα), and Toll-Like Receptor 4 (TLR4), consistent with their known anti-inflammatory activities. Unexpectedly, progestogens also bind to glucose-6-phosphate dehydrogenase (G6PD), a metabolic enzyme previously considered a specific DHEA target. GB did not bind to nuclear progesterone receptors but promoted IL-6 production in Peripheral Blood Mononuclear Cells (PBMCs) while inhibiting macrophage luminol-dependent chemiluminescence. This suggests that the rapid, non-genomic effects are likely mediated by membrane targets of GB such as PGRMC1 and TLR4.

These findings indicate substantial overlap in the molecular targets of androstenes and progestogens, supporting their shared anti-inflammatory effects. The unique binding profile of GB, including IL-6 upregulation alongside oxidative burst suppression, highlights its potential to modulate immune responses through non-genomic mechanisms.

Combined use of androstenes and progestogens may provide therapeutic benefits for acute and chronic inflammatory conditions, with possible additive or synergistic effects when used sequentially or simultaneously.