RESUMEN
BACKGROUND: Metformin influences insulin receptor signaling, which might interfere with the proliferation of ovarian follicular structures and steroidogenesis. We hypothesize that reductions in glucose and insulin levels might interfere with CYP-17 expression and histomorphological changes in an androgenized rat model. The aim of this study was to analyze the effect of metformin on CYP-17 expression, follicular dynamics, and proliferative parameters in neonatally androgenized female rats. METHODS: Thirty-six newborn rats were randomly allocated to the following three groups on the third day of life: control (CG, n = 12), androgenized (GA, n = 12), and androgenized + metformin (GAmet, n = 12). The GA and GAmet animals were administered 0.1 mL of testosterone propionate (1.25 mg/animal) diluted in castor oil (vehicle) in a single dose; the CG rats received a subcutaneous injection of the vehicle in the dorsum. After 90 days, gavage treatment was initiated, distilled water was administered to the CG and GA rats, and metformin (150 mg/kg) was administered to the GAmet animals. The treatment was administered daily for six weeks. Following anesthesia, blood was drawn for biochemical measurements, and the ovaries were removed for histological and immunohistochemical analyses of Ki67, VEGFA and CYP17 expression. The glucose and insulin levels were also measured. RESULTS: The comparison of the GA and GAmet animals revealed that metformin decreased the weight as well as the glucose and insulin levels, slowed the proliferation of the theca interna and interstitial cells, as evidenced by Ki-67 and VEGF-A expression, and diminished CYP17 expression in the analyzed ovarian structures. In addition, metformin reduced the number of degenerating follicles and interstitial cells and improved angiogenesis. CONCLUSION: Metformin improves the carbohydrate metabolism, reduces proliferation, and decreases CYP-17 expression in the follicular structures of androgenized rats.
Asunto(s)
Familia 17 del Citocromo P450/genética , Regulación de la Expresión Génica/efectos de los fármacos , Metformina/farmacología , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/metabolismo , Células Tecales/efectos de los fármacos , Células Tecales/metabolismo , Animales , Biomarcadores , Proliferación Celular/efectos de los fármacos , Familia 17 del Citocromo P450/metabolismo , Modelos Animales de Enfermedad , Femenino , Glucosa/metabolismo , Inmunohistoquímica , Insulina/metabolismo , Síndrome del Ovario Poliquístico/etiología , Síndrome del Ovario Poliquístico/metabolismo , RatasRESUMEN
Metformin improved the glucose rate and the homeostasis model assessment-insulin resistance (HOMA-IR) index and caused partial reversion of ovaries and uterine morphology in female rats androgenized with testosterone.