Temporal Development of Cardiometabolic Complications in A Hyperandrogenemic Model of Polycystic Ovary Syndrome

INTRODUCTION: Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in young women, being characterized by androgen excess and irregular ovulation. Insulin resistance (IR), dyslipidemia, obesity, and hypertension are highly prevalent in this population. The etiology of PCOS is unknown. Most patients begin developing symptoms around puberty. However, there is a delay in the diagnosis of PCOS, so the metabolic characteristics of PCOS early on are unclear. We have demonstrated in a hyperandrogenemic PCOS rat model that obesity, increases in blood pressure, and IR are present after 3 months of androgen excess. Using this model, we tested the hypothesis that androgen-induced IR, obesity, and dyslipidemia would develop in a time-dependent manner. METHODS: Four-week-old Sprague Dawley female rats were randomly selected for sham or dihydrotestosterone pellet (DHT, 7.5mg/90 days) implantation (n=13-17/group). Body composition was measured by EchoMRI; 24-hour urine was collected with metabolic cages; and fasting plasma glucose, insulin, and lipid panel were collected at 1 (early), 2 (intermediate), and 3 (late) months of DHT treatment. IR was assessed by homeostatic model assessment for IR (HOMA-IR). RESULTS: After 1 month of DHT, PCOS rats had decreased fasting glycemia (122.0 ± 2.8 vs 133.6 ± 3.1 mg/dL, P<0.01) and insulinemia, leading to decreased HOMA-IR (4.3 ± 0.4 vs 7.4 ± 0.5, P<0.001). However, there were no differences between the groups in IR at 2 months of DHT, while at 3 months both fasting insulin (21.0 ± 1.6 vs 14.2 ± 1.4 µU/mL, P<0.01) and HOMA-IR (6.3 ± 0.5 vs 4.3 ± 0.5, P<0.05) increased in PCOS compared to controls. Low-density lipoprotein cholesterol (LDL) was increased in PCOS compared to controls at all time points, while triglycerides were only elevated at 2 months (84.9 ± 5.4 vs 65.1 ± 2.9 mg/dL, P<0.01) and 3 months (70.7 ± 5.3 vs 54.5 ± 4.5 mg/dL, P<0.05) of DHT. Meanwhile, there were no differences in high-density lipoprotein cholesterol throughout the study. Lean mass was elevated at all time points in PCOS compared to controls, though fat mass was only elevated after 2 and 3 months (21.6 ± 1.9 vs 16.7 ± 0.8 g, P<0.05) of DHT. Proteinuria, a marker of renal injury, was elevated in PCOS at all time points. CONCLUSIONS: In this PCOS model, early cardiometabolic complications include increases in LDL and renal injury. Intermediate cardiometabolic complications include increases in fat mass and triglyceridemia. However, DHT had a differential effect on fasting insulin and HOMA-IR by lowering them initially at 1 month of treatment and then gradually increasing them above control levels by 3 months of DHT. These data indicate that androgen excess has a differential effect in cardiometabolic complications with time in female rats. In women with PCOS, these data may lead to a better characterization, and more effective treatments, for the evolving metabolic profile in women with PCOS. © FASEB.