Uterotropic response to the antidepressant fluoxetine (Prozac) is dependent on a functional serotonin transporter and circulating serotonin.

Selective serotonin reuptake inhibitors (SSRI) are the most used antidepressants. However, they appear to pose a role as endocrine disrupting agents, particularly related to estrogen signaling. We sought to investigate the in vivo effects of fluoxetine, the most well-known SSRI, on uterine dynamic using uterotropic bioassays. In prepubertal mice, lack of increase in uterine weight in a three-day uterotrophic assay indicated fluoxetine does not directly bind estrogen receptor to elicit estrogenic effects. Conversely, in virgin, sexually mature mice and pseudopregnant mice, fluoxetine (2 mg/kg/d) elicited uterotropic response with increased uterine weight. Further, we observed increased uterine thickness, increased epithelial height, increased endometrial grands, and altered uterine gene expression (upregulated Alkp and downregulated Igfbp3) consistent with the uterotropic response and suggestive with modulation of estrogen signaling. In mice with genetic ablation of the serotonin transporter (Slc6a4-/-, target site for SSRI) and depleted peripheral (nonneuronal) synthesis of serotonin (Tph1-/-), fluoxetine did not elicited uterotropic response. Therefore, the uterotropic response to fluoxetine is dependent on inhibition of serotonin transporter function and mediated by circulating serotonin.