Selective P2Y2 Receptor Agonists Stimulate Vaginal Moisture in Ovariectomized Rabbits

Abstract

As many as 10 million American women 50 to 74 years of age describe reduced vaginal lubrication, uncomfortable or frankly painful intercourse, decreased arousal, and difficulty reaching orgasm. These symptoms have been associated with the postmenopausal drop in estrogen levels. The P2Y 2 receptor agonists are purinergic receptor ligands currently under study for their prosecretory effects in numerous clinical settings. Stimulation of P2Y 2 receptors activates phospholipase C, prompting intracellular release of calcium that increases surface liquid and hydrates secretions. This study examined the potential role for P2Y 2 receptor agonists in treating vaginal dryness. Two weeks after ovariectomy, rabbits received daily instillations of one of two agonists, 0.9% INS45973 or 8.1% INS365, for 16 days, while control animals received vehicle only. Swabs were used as moisture probes. In situ hybridization studies were carried out to estimate receptor mRNA in vaginal and cervical tissues from female cynomolgus monkeys. Vaginal moisture was significantly reduced after ovariectomy in vehicle-exposed rabbits. Both P2Y 2 receptor agonists increased moisture in ovariectomized animals. Moisture levels were comparable to those in control animals when INS365 was administered and significantly higher than in controls with INS45973. Ovariectomy resulted in minimal inflammation, which was not observed when animals were given either agonist. The cytoplasm of cells in both cervical gland and endocervical epithelium, but not the stroma, exhibited positive staining for receptor mRNA. Examination of vaginal tissue samples showed positive staining in the cytoplasm of stratified squamous epithelial cells, but not in the submucosa or muscularis. Synthetic P2Y 2 receptor agonists are able to increase vaginal moisture in estrogen-deprived animals, and they could relieve postmenopausal vaginal dryness by increasing mucin production as well as augmenting pelvic blood flow. This approach might be safer than systemic or topical estrogen replacement in high-risk women.