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

Rafael R Domingues1,2, Jessica Fox3, Emma Day3

  • 1Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, WI, USA. domingues.2@osu.edu.

Scientific Reports
|December 10, 2025
PubMed

Insights

Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine can affect uterine dynamics. Fluoxetine

Area of Science:

  • Endocrinology
  • Pharmacology
  • Reproductive Biology

Background:

  • Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed antidepressants.
  • SSRIs may act as endocrine disruptors, potentially interfering with estrogen signaling pathways.

Purpose of the Study:

  • To investigate the in vivo effects of fluoxetine on uterine dynamics using uterotropic bioassays.
  • To determine if fluoxetine directly binds the estrogen receptor or modulates estrogen signaling.

Main Methods:

  • Uterotropic bioassays were performed in prepubertal, virgin mature, and pseudopregnant mice.
  • Gene expression analysis (Alkp, Igfbp3) was conducted in uterine tissues.
  • Experiments utilized mice with genetic ablation of the serotonin transporter (Slc6a4-/-) and peripheral serotonin synthesis (Tph1-/-).

Main Results:

  • Fluoxetine did not elicit estrogenic effects in prepubertal mice, indicating no direct estrogen receptor binding.
  • In mature and pseudopregnant mice, fluoxetine (2 mg/kg/d) induced a uterotropic response, increasing uterine weight, thickness, and epithelial height.
  • Uterine gene expression was altered (Alkp upregulated, Igfbp3 downregulated), suggesting estrogen signaling modulation.
  • The uterotropic response was absent in Slc6a4-/- and Tph1-/- mice.

Conclusions:

  • The uterotropic response to fluoxetine is dependent on serotonin transporter inhibition.
  • Fluoxetine's effects on the uterus are mediated by circulating serotonin and involve modulation of estrogen signaling pathways.
Keywords:
Endocrine disruptionEstrogen signalingSelective serotonin reuptake inhibitorSerotonin transporterUterotrophic assay

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