LAUSR

Polycystic ovary syndrome (PCOS) is a common condition of reproductive aged women. In a well-validated sheep model of PCOS, testosterone (T) treatment of pregnant ewes culminated in placental insufficiency and intrauterine growth restriction of offspring. The purpose of this study was to explore specific mechanisms by which T excess compromises placental function in early, mid-, and late gestation. Pregnant Suffolk sheep received T propionate 100 mg intramuscularly or control vehicle twice weekly from gestational days (GD) 30 to 90 (term = 147 days). Placental harvest occurred at GD 65, 90, and 140. Real time RT-PCR was used to assess transcript levels of pro-inflammatory (TNF, IL1B, IL6, IL8, CCL2, CD68), antioxidant (glutathione reductase, superoxide dismutase -1 and -2), and angiogenic (VEGF and HIF1A) genes. Lipid accumulation was assessed using triglyceride assays and oil red O staining. Placental measures of oxidative and nitrative stress included TBARS assay and high pressure liquid chromatography. Tissue fibrosis was assessed with picrosirius red staining. T-tests and Cohen's effect size analyses were used for statistical analysis. At GD 65, T-treated placentomes showed increased lipid accumulation and collagen deposition. Notable findings at GD 90 were a significant increase in HIF1A expression and a large effect increase in VEGF expression. At GD 140, T-treated placentomes displayed large effect increases in expression of hypoxia and inflammatory markers. In summary, T treatment during early pregnancy induces distinct, gestational age-specific effects on placental milieu, which may underlie the previously observed phenotype of placental insufficiency.