Metformin improves ovarian follicle dynamics by reducing theca cell proliferation and CYP-17 expression in an androgenized rat model

Roberta Rassi Mahamed,Manuel De Jesus Simões,Gisela Rodrigues Silva Sasso,José Maria Soares-,Edmund Chada Baracat,Maria Candida Pinheiro Baracat,Carla Cristina Maganhin

doi:10.1186/s13048-018-0392-1

Abstract

BackgroundMetformin 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.MethodsThirty-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.ResultsThe 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.ConclusionMetformin improves the carbohydrate metabolism, reduces proliferation, and decreases CYP-17 expression in the follicular structures of androgenized rats.

Highlights

Metformin influences insulin receptor signaling, which might interfere with the proliferation of ovarian follicular structures and steroidogenesis
In Polycystic ovarian syndrome (PCOS), insulin sensitivity is thought to regulate the expression of glucose transporters in granulosa cells by reducing glucose uptake within the oocyte, thereby reducing the resources available for energy metabolism [3].The insulin receptor sensitizer substance acts as an intracellular second messenger, regulating the activities of insulin and glucose metabolism and transport [4] and decreasing hyperandrogenism and insulin resistance in PCOS women [5].the exact mechanisms through which an increase in androgen levels leads to ovulation disorder are not yet fully understood
The Androgenized group (GA) rats presented higher glucose and insulin levels and increased weight compared with the rats in the control group (CG) and Androgenized group with metformin (GAmet) groups (p < 0.05) (Fig. 1a, b, and c)

Summary

Introduction

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. In PCOS, insulin sensitivity is thought to regulate the expression of glucose transporters in granulosa cells by reducing glucose uptake within the oocyte, thereby reducing the resources available for energy metabolism [3].The insulin receptor sensitizer substance acts as an intracellular second messenger, regulating the activities of insulin and glucose metabolism and transport [4] and decreasing hyperandrogenism and insulin resistance in PCOS women [5].the exact mechanisms through which an increase in androgen levels leads to ovulation disorder are not yet fully understood. The use of animal models is important to better understand the actions involved [6]

Objectives

Methods

Results

Discussion

Conclusion