D‐Chiro‐Inositol and LPS Induce a PCOS‐like hyperandrogenic response in human KGN granulosa cells

: Hyperandrogenism is a key hallmark of polycystic ovary syndrome, a prevalent endocrine disorder affecting women of reproductive age and often leading to infertility. We previously observed that high doses of D-chiro-inositol in mice reduce ovarian aromatase expression, contributing to a hyperandrogenic state. Given that similar effects have been reported in tumour-derived human KGN granulosa cells treated with bacterial lipopolysaccharide, we investigated whether D-chiro-inositol could elicit a comparable hyperandrogenic response in these cells, thereby shedding light on aberrant mechanisms potentially involved in polycystic ovary syndrome. Using lipopolysaccharide and myo-inositol as controls, we assessed KGN cells for proliferation, viability, inflammatory response, cellular and mitochondrial reactive oxygen species, expression of antioxidant enzyme genes, aromatase expression, and estradiol secretion. None of the treatments affected cell proliferation or viability. Both D-chiro-inositol and myo-inositol showed anti-inflammatory and antioxidant effects, whereas lipopolysaccharide induced inflammation and acted as a pro-oxidant. Notably, D-chiro-inositol and lipopolysaccharide downregulated aromatase gene and protein expression, resulting in reduced estradiol secretion. In contrast, myo-inositol had no significant impact on aromatase expression or oestrogen production. These findings suggest that D-chiro-inositol and lipopolysaccharide may serve as useful tools for probing the dysregulated molecular and cellular pathways associated with polycystic ovary syndrome, particularly those contributing to hyperandrogenism.