Pigment Epithelium-Derived Factor (PEDF) as an Anti-Inflammatory Mediator in Polycystic Ovary Syndrome (PCOS)

PCOS is a common endocrine disorder in women. Whereas its etiology remains elusive, evidence indicates that chronic, systemic inflammation is a significant component of PCOS. The relationship between inflammation and hyperandrogenism, hallmark of PCOS, is not well understood. PCOS patients have increased expression of ovarian VEGF and IL6/8; associated with ovarian hyperstimulation-syndrome (OHSS). We showed that PEDF, a potent anti-angiogenic, anti-inflammatory factor, which counteracts VEGF and IL6/8, plays fundamental role in the pathogenesis and treatment of OHSS. We demonstrated, in a model of PCOS-mice, that the level of ovarian VEGF increases whereas that of PEDF mRNA decreases. Our aim is to elucidate the role of PEDF in PCOS pathogenesis.

We cultured human granulosa cells (GCs): KGN-cell-line and human-primary-granulosa-cells (hpGC) from follicular fluids aspirated from woman undergoing IVF treatments.

Stimulation of GCs with DHT decreased PEDF mRNA expression (~70%), concomitantly with significant increase of IL6/8 mRNAs expression. Co-stimulation with recombinant (r)PEDF restrained this increase (P<0.05). Stimulation of hpGC with IL8 increased the expression of VEGF and decreased that of PEDF mRNA; whereas co-stimulation with rPEDF restrained VEGF upregulation (P<0.04). The level of IL6/8 mRNAs increased in lysophosphatidic acid-stimulated cells; co-stimulation with (r)PEDF decreased it (P<0.05) and GW (specific inhibitor of PPAR-g) abolished this anti-inflammatory effect, suggesting that this effect of PEDF in GCs involves the PPAR-g pathway.

Our findings suggest that low level of ovarian PEDF lies at the core of PCOS pathogenesis where the impaired angiogenic/inflammatory balance, induced by increased levels of androgens and cytokines, can be restored by PEDF.