Evaluation of estrus suppression in the mare through the use of an altrenogest delivering intravaginal device, An

Abstract

The ability to avoid adverse behavior in mares through manipulation of their reproductive cyclicity has been a desired technique for many years. The mare's sour reputation when in heat, is known by competitive professionals and hobby riders alike. As the breeding season approaches during long daylight days in the northern hemisphere, the mare will begin to transition into her regular twenty-one day interovulatory cycle. The estrus or "standing heat" phase of a mare's cycle occurs for approximately 5-7 days within a given estrous cycle. During this phase, the mare is primarily under the influence of estrogen, produced by the dominant follicle, driving signs of the sexual receptivity. Outward signs of estrus for the mare include: overt interest in other horses (especially stallions), leaning their hind end toward another horse (teasing), lifting their tail, posturing and urinating frequently. Dangerous behaviors associated with estrus such as biting, kicking, irritability, and distraction commonly persuade owners to look into estrus suppression options. Following ovulation, a corpus luteum (CL) is formed and the luteal cells begin to produce progesterone. Progesterone levels increase once again, overcoming the effects of decreasing estrogen levels for twelve to fourteen days, and often alleviating the undesirable behavior. Altrenogest, an oral and injectable synthetic progestin, is the most effective supplement for providing estrus suppression in the mare. The equine industry is in need of a reliable pharmaceutical device to suppress adverse behavior commonly associated with the estrus phase of the mare's cycle, yet allow the mare to resume normal cyclicity upon removal of the device for pursuant of reproductive procedures. A custom intravaginal ring specifically designed for the unique anatomy of the mare will provide a novel and effective method for sustained release of altrenogest administration while being safer to handle and administer. The first experiment focuses on the unique anatomy of the mare's caudal reproductive tract compared to intravaginal ring sizes in order to obtain a pilot device for experimentation. An unmedicated toroidal silicone intravaginal ring measuring 14.2 cm in diameter was selected during experiment one. The second experiment was to evaluate the vaginal ring delivering altrenogest in a trial along with a placebo intravaginal ring and control group to evaluate several parameters associated with estrus behavior suppression. Both oil-based and solid suspension-based intravaginal rings for drug administration was evaluated during experiment two. Finally, the third experiment examined the in vivo evaluation of solid suspension altrenogest IVR as well as the marketability of this product and what the future holds for novel medical devices in equine reproduction. Twelve total mares were used over the course of this study to determine the pharmacokinetics (PKs) and pharmacodynamics (PDs) of intravaginally administered altrenogest. Variables such as: teasing behavior when presented with a stallion, ultrasonographic examination of reproductive changes throughout several cycles, uterine and vaginal cultures, and blood collections for drug hormone bioanalysis were collected and monitored to evaluate the PK and PD of this novel drug delivery device. Throughout experiment three, each mare went through three cycles in a crossover design. An oral form of the drug was administered to serve as a control group, a placebo vaginal ring control group, and therapeutic vaginal ring treatment group were used for this study. This study aims to provide horse owners and trainers an alternative method for delivering behavior modulating hormones, through an effective, therapeutic, steady-state release from a vaginal ring, and importantly enable normal reproductive cyclicity to resume upon removal.