Effects of dopamine agonists on the estradiol-induced prolactin surge in ovariectomized female Wistar Han rats

Abstract

Dopamine agonists (DAs) are approved for the treatment of hypodopaminergic pathologies, including Parkinson's disease, restless legs syndrome, and periodic limb movement disorder. During drug development, drugs acting on dopaminergic receptors are often associated with a rat-specific endocrine tumor response, including changes in fertility, which are ascribed to DA-induced suppression of pituitary prolactin release. Although these effects are not observed in or relevant to humans, given species differences in the effects of prolactin on reproductive organs, modeling DA-mediated changes in prolactin and the reproductive system remains important for preclinical drug development. We investigated the effects of 2 D2/D3 DAs, pergolide and rotigotine, on the estradiol (E2)-induced prolactin surge in ovariectomized (OVX) female Wistar Han rats. Daily treatment with DAs over 7 days led to a reduction in the prolactin surge in E2-implanted OVX rats. Specifically, pergolide induced a significant decrease in prolactin levels at all time points compared with the OVX-E2 control group. Similarly, rotigotine dose-dependently suppressed plasma prolactin levels compared with the OVX-E2 control group. This study demonstrates the utility of the OVX rat model in evaluating the effects of DAs on the E2-induced prolactin surge. These results support the use of rotigotine, a DA with a long history of safe human use without significant endocrine-related adverse events, as a positive control at a dose level of 5.0 mg/kg/day for future nonclinical toxicity studies investigating the effects of novel DAs on reproductive hormones in rats.

Keywords: dopamine agonists; fertility; pergolide; prolactin surge; reproductive tumors; rotigotine.