Exploratory pilot trial of astaxanthin supplementation in PCOS patients at risk of OHSS with focus on RAGE–NFκB pathway

Polycystic ovary syndrome (PCOS) is a major risk factor for ovarian hyperstimulation syndrome (OHSS) during controlled ovarian stimulation (COS). Oxidative stress and inflammation, mediated by the advanced glycation end products (AGE)-receptor for AGE (RAGE)-nuclear factor kappa-B (NFκB) pathway, contribute to OHSS development and impaired oocyte quality. Astaxanthin (AST), a potent antioxidant, may modulate this pathway. In this exploratory pilot trial using a triple‑blind, randomized, placebo‑controlled design, 44 PCOS patients at high risk for OHSS were assigned to receive AST (n = 22) or placebo (n = 22) adjunct to the COS regimen. COS was performed using a gonadotropin-releasing hormone (GnRH) antagonist protocol with individualized gonadotropin dosing. Stimulation characteristics, gonadotropin dose, and follicle distribution were comparable between groups. The mean number of retrieved oocytes was slightly higher with AST, and the oocyte maturity rate (OMR) was significantly greater. Estradiol and progesterone levels on trigger day were lower in the AST group, though not statistically significant. Molecular analyses showed reduced RAGE expression, a lower phosphorylated inhibitor of kappa-B (pIκB)/inhibitor of kappa-B (IκB) ratio in granulosa cells (GCs), and significantly decreased interleukin-6 (IL-6) in follicular fluid (FF), with vascular endothelial growth factor (VEGF) showing a downward trend. These findings suggest that AST supplementation may improve COS outcomes and favorably modulate inflammatory pathways, with potential to reduce OHSS risk in high-risk PCOS patients. However, this pilot trial was not powered enough to confirm the primary OHSS endpoint, and larger studies are required for validation.Trial registration: Registration ID: IRCT20231028059882N2; Registration date: 2024-06-15; Update date: 2025-03-16; Direct Access Link: https://irct.behdasht.gov.ir/trial/77250 .