Fluoxetine and its active metabolite norfluoxetine disrupt estrogen synthesis in a co-culture model of the feto-placental unit

- Fluoxetine induces aromatase (CYP19) activity in a feto-placental co-culture model.
- Norfluoxetine is a competitive inhibitor of CYP19 in human placental BeWo cells.
- In the feto-placental model, norfluoxetine decreases estrogen secretion.
- In the feto-placental model, fluoxetine is without effect on estrogen secretion.
- Fluoxetine and 17β-estradiol inhibit serotonin transporter activity in BeWo cells.

The effects of fluoxetine, one of the most prescribed selective serotonin-reuptake inhibitors (SSRIs) during pregnancy, and its active metabolite norfluoxetine were studied on placental aromatase (CYP19) and feto-placental steroidogenesis. Fluoxetine did not alter estrogen secretion in co-culture of fetal-like adrenocortical (H295R) and trophoblast-like (BeWo) cells used as a model of the feto-placental unit, although it induced CYP19 activity, apparently mediated by the serotonin (5-HT)2A receptor/PKC signaling pathway. Norfluoxetine decreased estrogen secretion in the feto-placental co-culture and competitively inhibited catalytic CYP19 activity in BeWo cells. Decreased serotonin transporter (SERT) activity in the co-culture was comparable to 17β-estradiol treatment of BeWo cells. This work shows that the complex interaction of fluoxetine and norfluoxetine with placental estrogen production, involves 5-HT-dependent and -independent mechanisms. Considering the crucial role of estrogens during pregnancy, our results raise concern about the impact of SSRI treatment on placental function and fetal health.

Proposed mode of action of the antidepressant fluoxetine on estrogen synthesis in human placental BeWo cells. Fluoxetine stimulates serotonin 5-HT2A receptor either by inhibiting serotonin transporter (SERT) and increasing serotonin (5-HT) extracellular levels or by stimulating directly 5-HT2A and then phospholipase C/protein kinase C (PLC/PKC) pathway to induce CYP19 activity. In turn, estrogens inhibit SERT activity. Norfluoxetine inhibits CYP19 catalytic activity, decreasing estrogen secretion.199