title: Hyperandrogenism and Insulin Resistance, Not Changes in Body Weight, Mediate the Development of Endothelial Dysfunction in a Female Rat Model of Polycystic Ovary Syndrome (PCOS).
abstract: This study was designed to differentiate the contributions of hyperandrogenism, insulin resistance (IR), and body weight to the development of endothelial dysfunction in polycystic ovary syndrome and determine the effectiveness of insulin sensitization and antiandrogenic therapy after the establishment of vascular and metabolic dysfunction using a rat model of polycystic ovary syndrome. We hypothesized that the observed endothelial dysfunction was a direct steroidal effect, as opposed to changes in insulin sensitivity or body weight. Prepubertal female rats were randomized to the implantation of a pellet containing DHT or sham procedure. In phase 1, DHT-exposed animals were randomized to pair feeding to prevent weight gain or metformin, an insulin-sensitizing agent, from 5 to 14 weeks. In phase 2, DHT-exposed animals were randomized to treatment with metformin or flutamide, a nonsteroidal androgen receptor blocker from 12 to 16 weeks. Endothelial function was assessed by the vasodilatory response of preconstricted arteries to acetylcholine. Serum steroid levels were analyzed in phase 1 animals. Fasting blood glucose and plasma insulin were analyzed and homeostasis model assessment index calculated in all animals. Our data confirm the presence of endothelial dysfunction as well as increased body weight, hypertension, hyperinsulinemia, and greater IR among DHT-treated animals. Even when normal weight was maintained through pair feeding, endothelial dysfunction, hyperinsulinemia, and IR still developed. Furthermore, despite weight gain, treatment with metformin and flutamide improved insulin sensitivity and blood pressure and restored normal endothelial function. Therefore, the observed endothelial dysfunction is most likely a direct result of hyperandrogenism-induced reductions in insulin sensitivity, as opposed to weight gain.
authors: Division of Reproductive Endocrinology and Infertility (A.H., J.K.B., P.C.) and Department of Obstetrics/Gynecology and Reproductive Sciences (N.M., M.M., G.O.), University of Vermont, Burlington, Vermont 05405; Department of Cell Biology (M.M.), University of Calabria, Arcavacata di Rende (Cosenza) 87030, Italy; Northeastern Reproductive Medicine (J.K.B., P.C.), Colchester, Vermont 05446; and Oregon Reproductive Medicine (A.H.), Portland, Oregon 97210.
authors: Amanda
authors: A
authors: Hurliman
authors: Division of Reproductive Endocrinology and Infertility (A.H., J.K.B., P.C.) and Department of Obstetrics/Gynecology and Reproductive Sciences (N.M., M.M., G.O.), University of Vermont, Burlington, Vermont 05405; Department of Cell Biology (M.M.), University of Calabria, Arcavacata di Rende (Cosenza) 87030, Italy; Northeastern Reproductive Medicine (J.K.B., P.C.), Colchester, Vermont 05446; and Oregon Reproductive Medicine (A.H.), Portland, Oregon 97210.
authors: Jennifer
authors: J
authors: Keller Brown
authors: Division of Reproductive Endocrinology and Infertility (A.H., J.K.B., P.C.) and Department of Obstetrics/Gynecology and Reproductive Sciences (N.M., M.M., G.O.), University of Vermont, Burlington, Vermont 05405; Department of Cell Biology (M.M.), University of Calabria, Arcavacata di Rende (Cosenza) 87030, Italy; Northeastern Reproductive Medicine (J.K.B., P.C.), Colchester, Vermont 05446; and Oregon Reproductive Medicine (A.H.), Portland, Oregon 97210.
authors: Nicole
authors: N
authors: Maille
authors: Division of Reproductive Endocrinology and Infertility (A.H., J.K.B., P.C.) and Department of Obstetrics/Gynecology and Reproductive Sciences (N.M., M.M., G.O.), University of Vermont, Burlington, Vermont 05405; Department of Cell Biology (M.M.), University of Calabria, Arcavacata di Rende (Cosenza) 87030, Italy; Northeastern Reproductive Medicine (J.K.B., P.C.), Colchester, Vermont 05446; and Oregon Reproductive Medicine (A.H.), Portland, Oregon 97210.
authors: Maurizio
authors: M
authors: Mandala
authors: Division of Reproductive Endocrinology and Infertility (A.H., J.K.B., P.C.) and Department of Obstetrics/Gynecology and Reproductive Sciences (N.M., M.M., G.O.), University of Vermont, Burlington, Vermont 05405; Department of Cell Biology (M.M.), University of Calabria, Arcavacata di Rende (Cosenza) 87030, Italy; Northeastern Reproductive Medicine (J.K.B., P.C.), Colchester, Vermont 05446; and Oregon Reproductive Medicine (A.H.), Portland, Oregon 97210.
authors: Peter
authors: P
authors: Casson
authors: Division of Reproductive Endocrinology and Infertility (A.H., J.K.B., P.C.) and Department of Obstetrics/Gynecology and Reproductive Sciences (N.M., M.M., G.O.), University of Vermont, Burlington, Vermont 05405; Department of Cell Biology (M.M.), University of Calabria, Arcavacata di Rende (Cosenza) 87030, Italy; Northeastern Reproductive Medicine (J.K.B., P.C.), Colchester, Vermont 05446; and Oregon Reproductive Medicine (A.H.), Portland, Oregon 97210.
authors: George
authors: G
authors: Osol
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D017588:Hyperandrogenism / Q000503:physiopathology* / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008687:Metformin / Q000494:pharmacology; D011085:Polycystic Ovary Syndrome / Q000503:physiopathology*; D011897:Random Allocation; D017208:Rats, Wistar; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D007004:Hypoglycemic Agents; D013196:Dihydrotestosterone; D005485:Flutamide; D008687:Metformin