Impacts of selective serotonin reuptake inhibitors on reproductive biology : insights from murine and ovine models

Author / Creator

Reis Domingues, Rafael, author

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Online

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Summary

Maternal use of antidepressants has increased throughout the last decades and selective serotonin reuptake inhibitors (SSRI) are the most prescribed antidepressants. Despite the widespread use of S...

Maternal use of antidepressants has increased throughout the last decades and selective serotonin reuptake inhibitors (SSRI) are the most prescribed antidepressants. Despite the widespread use of SSRI by women during their reproductive period and pregnancy, an increasing number of studies warns of possible detrimental effects of maternal use of SSRI during pregnancy including low birthweight/small for gestational age and preterm birth. The present thesis sought to investigate the pathophysiology of SSRI-related pregnancy outcomes and to propose measures to mitigate the adverse effects of SSRI. We proposed and tested a physiological model for the occurrence of adverse pregnancy outcomes related to SSRI exposure during gestation: maternal use of SSRI increases free circulating maternal serotonin and serotonin signaling leading to vasoconstriction of the uterine and placental vascular beds with consequent decrease of blood perfusion to the uterus, placenta, and fetus resulting in placental hypoxia and dysfunction which ultimately lead to suboptimal embryonic/fetal development. We demonstrated the effects of two common SSRI, fluoxetine and sertraline, on pregnancy and neonatal outcomes in mice. We also reported and validated the use of serotonin transporter-deficient mice (Sert-/-) to enhance our understanding of the effects of modulating the serotonin transporter, the biological target site for SSRI. Overall, Sert-/- mice have similar pregnancy outcomes compared to wild-type mice treated with SSRI: increased embryonic mortality, decreased offspring weight, increased neonatal mortality. Utilizing strategic breeding schemes between WT, Sert-/-, and Sert+/-, we determined that lack of maternal, rather than embryonic/placental SERT expression, is associated with poor pregnancy outcomes. Histopathological and transcriptomic placental changes associated with maternal SSRI exposure and genotype (Sert-/-) are consistent with the observed pregnancy outcomes. In an ovine model, ultrasonography during late pregnancy allowed us to assess placental alterations related to SSRI treatment and its impact on pregnancy length (preterm birth) and neonatal morbidity (decreased birthweight, acidemia, hypocalcemia). We were able to prevent the effects of increased serotonin signaling with prevention of some placental alterations and restoration of the number of pups born in SSRI-treated and Sert-/- mice by implementing a therapy that is an antagonist for the serotonin receptors 2A and 2C. An incidental finding in our studies was the endocrine disruption effects of SSRI, particularly fluoxetine, in nonpregnant mice. Short-term fluoxetine treatment has estrogenic action that appears to be associated with increased estrogen synthesis. Importantly, the endocrine disruption action of fluoxetine is not an off-target drug effect but SERT-dependent and serotonin-mediated as demonstrated in Sert-/- and Tph1-/- (no peripheral synthesis of serotonin) mouse models. Taken together, these studies unraveled multiple actions of SSRI on reproductive function. Importantly, our work developed a possible therapeutic measure to mitigate the effects of SSRI on pregnancy outcomes potentially benefiting women and infant worldwide.

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