Peripartal treatment with low-dose sertraline accelerates mammary gland involution and has minimal effects on maternal and offspring bone.

Women mobilize up to 10% of their bone mass during lactation to provide milk calcium. About 8%-13% of mothers use selective serotonin reuptake inhibitors (SSRI) to treat peripartum depression, but SSRIs independently decrease bone mass. Previously, peripartal use of the SSRI fluoxetine reduced maternal bone mass sustained post-weaning and reduced offspring bone length. To determine whether these effects were fluoxetine-specific or consistent across SSRI compounds, we examined maternal and offspring bone health using the most prescribed SSRI, sertraline. C57BL/6 mice were given 10 mg/kg/day sertraline, from the beginning of pregnancy through the end of lactation. Simultaneously, we treated nulliparous females on the same days as the primiparous groups, resulting in age-matched nulliparous groups. Dams were euthanized at lactation day 10 (peak lactation, n = 7 vehicle; n = 9 sertraline), lactation day 21 (weaning, n = 9 vehicle; n = 9 sertraline), or 3m post-weaning (n = 10 vehicle; n = 10 sertraline) for analysis. Offspring were euthanized at peak lactation or weaning for analysis. We determined that peripartum sertraline treatment decreased maternal circulating calcium concentrations across the treatment period, which was also seen in nulliparous treated females. Sertraline reduced the bone formation marker, procollagen 1 intact N-terminal propeptide, and tended to reduce maternal BV/TV at 3m post-weaning but did not impact maternal or offspring bone health otherwise. Similarly, sertraline did not reduce nulliparous female bone mass. However, sertraline reduced immunofluorescence staining of the tight junction protein, zona occludens in the mammary gland, and altered alveoli morphology, suggesting sertraline may accelerate mammary gland involution. These findings indicate that peripartum sertraline treatment may be a safer SSRI for maternal and offspring bone rather than fluoxetine.

Effect of Low and High Doses of Two Selective Serotonin Reuptake Inhibitors on Pregnancy Outcomes and Neonatal Mortality.

Selective serotonin reuptake inhibitors (SSRI) are the most common antidepressant used by pregnant women; however, they have been associated with adverse pregnancy outcomes and perinatal morbidity in pregnant women and animal models. We investigated the effects of two SSRI, fluoxetine and sertraline, on pregnancy and neonatal outcomes in mice. Wild-type mice were treated daily with low and high doses of fluoxetine (2 and 20 mg/kg) and sertraline (10 and 20 mg/kg) from the day of detection of a vaginal plug until the end of lactation (21 days postpartum). Pregnancy rate was decreased only in the high dose of fluoxetine group. Maternal weight gain was reduced in the groups receiving the high dose of each drug. Number of pups born was decreased in the high dose of fluoxetine and low and high doses of sertraline while the number of pups weaned was decreased in all SSRI-treated groups corresponding to increased neonatal mortality in all SSRI-treated groups. In conclusion, there was a dose-dependent effect of SSRI on pregnancy and neonatal outcomes in a non-depressed mouse model. However, the distinct placental transfer of each drug suggests that the effects of SSRI on pup mortality may be mediated by SSRI-induced placental insufficiency rather than a direct toxic effect on neonatal development and mortality.

Sexual dimorphism in immunometabolism and autoimmunity: Impact on personalized medicine.

Immune cells play essential roles in metabolic homeostasis and thus, undergo analogous changes in normal physiology (e.g., puberty and pregnancy) and in various metabolic and immune diseases. An essential component of this close relationship between the two is sex differences. Many autoimmune diseases, such as systemic lupus erythematous and multiple sclerosis, feature strikingly increased prevalence in females, whereas in contrast, infectious diseases, such as Ebola and Middle East Respiratory Syndrome, affect more men than women. Therefore, there are fundamental aspects of metabolic homeostasis and immune functions that are regulated differently in males and females. This can be observed in sex hormone-immune interaction where androgens, such as testosterone, have shown immunosuppressive effects whilst estrogen is on the opposite side of the spectrum with immunoenhancing facilitation of mechanisms. In addition, the two sexes exhibit significant differences in metabolic regulation, with estrous cycles in females known to induce variability in traits and more pronounced metabolic disease phenotype exhibited by males. It is likely that these differences underlie both the development of metabolic and autoimmune diseases and the response to current treatment options. Sexual dimorphism in immunometabolism has emerged to become an area of intense research, aiming to uncover sex-biased effector molecules in the various metabolic tissues and immune cell types, identify sex-biased cell-type-specific functions of common effector molecules, and understand whether the sex differences in metabolic and immune functions influence each other during autoimmune pathogenesis. In this review, we will summarize recent findings that address these critical questions of sexual dimorphism in immunometabolism as well as their translational implications for the clinical management of autoimmune diseases.