Gonadotropin-releasing hormone targeting for gonadotroph ablation: an approach to non-surgical sterilization

Surgical sterilization is the mainstay of dog and cat population control, but its use is still often limited by the costs and effort involved, especially in developing countries. An ideal non-surgical sterilant that is safe, effective, permanent, administered as a single injection and capable of being manufactured inexpensively could have a significant impact on the world-wide dog and cat overpopulation problem. One approach towards developing such an agent is the targeting of pituitary gonadotrophic cells with cytotoxic agents using gonadotropin-releasing hormone (GnRH). GnRH is a peptide that binds to high-affinity receptors selectively expressed on gonadotrophs and some types of cancers. Both small molecules and proteins have been conjugated to GnRH analogues to generate targeted cytotoxic and imaging agents. Although most of these efforts have focused on development of human cancer therapeutics, available reproductive studies in rats and dogs suggest that current compounds do not have sufficient therapeutic windows for complete gonadotroph ablation, in part owing to poor stability of peptide targeting sequences. The only reported longer-term study of gonadotroph ablation in dogs reported suppression of serum testosterone for 8 months, but endocrine function then recovered, raising important questions about the mechanism of reproductive suppression and its recovery. Although studies to date suggest that this is a potentially attractive approach to non-surgical sterilization, ideal agents are yet to be developed, and important mechanistic questions remain to be answered.