Evidences for the Existence of a Low Dopaminergic Tone in Polycystic Ovarian Syndrome: Implications for OHSS Development and Treatment

Abstract

CONTEXT: The dopamine/dopamine receptor 2 (D2/Drd2) pathway modulates vascular endothelial growth factor (VEGF)-dependent vascular permeability and angiogenesis in the ovary. Deregulation of the VEGF/VEGF receptor (VEGFR)-2 pathway leading to increased risk of ovarian hyperstimulation syndrome has been described in the ovary of patients suffering from polycystic ovarian syndrome (PCOS). OBJECTIVE: The objective of the study was to ascertain whether deregulation of the VEGF/VEGFR-2 might a least be partially due to abnormalities of the D2/Drd2 pathway in PCOS women. DESIGN: Dated, archived ovaries from PCOs and control group patients as well as human chorionic gonadotropin-stimulated luteinized granulosa cells form PCOS and non-PCOS oocyte patients were used. SETTING: The study was conducted at a private research center. PATIENTS OR OTHER PARTICIPANTS: PCOS and nonpolycystic ovarian patients and oocyte patients participated in the study. INTERVENTION(S): Human ovarian sections were stained against the Drd2 antibody. Human chorionic gonadotropin-stimulated luteinized granulosa cells (LGC) were cultured in the presence/absence and the Drd2 agonist cabergoline. MAIN OUTCOME MEASURE(S): Drd2 and vascularized stained area in the theca layer of antral (< 8 mm) and luteinized follicles was quantified. VEGF, D2, and its related metabolites were measured in the supernatant of cultured LGC by ELISA and HPLC, respectively. VEGFR-2 and Drd2 expressed by LGC was quantified through an In-Cell ELISA. RESULTS: Decreased Drd2 expression and increased vascularization in the theca layer of antral and luteinized follicles of PCOS ovaries was observed. A lower dopamine production and reduced efficacy of cabergoline in inhibiting VEGF secretion was uncovered in LGC from PCOS. CONCLUSIONS: Decreased dopaminergic tone as well as deregulated Drd2 signaling might explain higher VEGF and vascularization leading to increased ovarian hyperstimulation syndrome risk in PCOS.