Insulin Resistance Directly Contributes to Androgenic Potential Within Ovarian Theca Cells

Objective: To investigate whether insulin resistance (IR) within theca cells may directly contribute to their hyperandrogenism, a heritable trait of polycystic ovary syndrome (PCOS). Design: In vitro cell model. Setting: University-affiliated laboratory. Animal(s): Porcine ovaries. Intervention(s): Ovarian theca cells from porcine follicles were isolated and cultured. Insulin resistance was induced in theca cells without (Con) or with dexamethasone (Dex); cells were further treated by troglitazone (Tro) and metformin (Met) in IR cells or by vehicle only in IR and Con cells. Main Outcome Measure(s): Medium glucose and T levels; reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot for insulin signal molecules and androgenic enzyme. Result(s): As compared with Con cells, Dex-treated cells had significantly lower [³H]-glucose uptake (565 ± 58 cpm/10⁶ vs. 1077 ± 78 cpm/10⁶) but higher medium glucose levels (16.31 ± 0.39 nmol/L vs. 10.62 ± 1.02 nmol/L) and had approximately twofold T levels (0.82 ± 0.20 μg/L vs. 0.38±0.08μg/L). Troglitazone and Met significantly reduced the medium glucose and testosterone concentrations to levels comparable to those in Con cells. The RT-PCR and Western blot showed that the two sensitizers in different ways reversed the altered messenger RNA and protein expression of insulin receptor substrate-1, glucose transporter-4, peroxisome proliferator-activated receptor-γ, and 17α-hydroxylase in Dex-induced IR cells. Conclusion(s): Insulin resistance induced by Dex could directly exaggerate androgenic potential within theca cells, suggesting the possible involvement of this ovarian metabolic phenotype in PCOS hyperandrogenism.