Formulation and testing of a non-steroidal aromatase inhibitor intravaginal device for the control of ovarian function in cattle

Abstract

The study was designed to formulate intravaginal devices that provide biologically active circulating concentrations of an aromatase inhibitor for a minimum of 4 days, and to determine their physiologic effects in cattle. Three compounds with estradiol inhibitory capability (letrozole, anastrozole and fenbendazole) were tested in vitro using bovine granulosa cell culture. Letrozole was found to be the most efficient and potent inhibitor. A wax-based vehicle was selected for further development of a letrozole intravaginal device based on its steady release rate. Cycling heifers were assigned randomly to be given an intravaginal device containing wax plus gel coat (n=4), wax formulation (n=4), no formulation (blank device, control, n=4). Intravaginal devices were inserted on Day 3 (Day 0=ovulation) and kept in place for 8 days. The addition of a letrozole-containing gel coating hastened the initial increase on plasma concentrations, while the letrozole-containing wax-based vehicle maintained prolonged delivery from the intravaginal device. The dominant follicle diameter profile was larger in heifers treated with the wax plus gel coat device (P<0.04), and the interwave interval was prolonged in heifers in the letrozole-treated groups compared to controls (P<0.001). Plasma estradiol concentrations were reduced significantly in the letrozole-treated groups. Plasma progesterone concentrations were lower in the wax letrozole-treated group (P<0.02). We concluded that wax base plus gel coat intravaginal devices are suitable for the development of a letrozole-based protocol for the synchronization of ovulation in cattle. It effectively reduced estradiol production resulting in prolonged dominant follicle growth and lifespan, without adversely affecting progesterone production.