SUN-197 Differential Gene Expression in Response to Estradiol Withdrawal in Perimenopausal Depression

Abstract

The risk of depression increases 2-3 fold for women during the menopause transition compared to premenopausal women. Additionally, peri/postmenopausal women with even minor depression are at an increased risk of cardiovascular mortality (Wassertheil-Smoller et al, 2004). Clinical studies show both the therapeutic benefits of estradiol (E2) in perimenopausal depression (PMD) (Schmidt et al, 2000, Soares et al, 2001) and the symptom-provoking effects of E2-withdrawal (E2-WD) in women with past PMD, which are not experienced by those without past PMD (Schmidt et al, 2015). It has been suggested that a heightened sensitivity to changes in ovarian steroids such as E2 may contribute to the onset of PMD. We hypothesized that the differential affective/behavioral responsivity to E2-WD in PMD could be observed on a cellular level. To test this hypothesis, we performed RNA-seq on lymphoblastoid cell lines (LCLs) derived from women with a past PMD (n=8), or asymptomatic controls (AC) (n=9). These LCLs were examined in 3 different experimental conditions: 1) vehicle-treated media, 2) E2-treated media, or 3) E2-treated media which was changed to vehicle-treated media and collected 24 hours later, to mimic E2-WD on a cellular level. Levels of E2 in cell culture media were confirmed using High Performance Liquid Chromatography/Tandem Mass Spectrometry. EDGE-R analysis of differential gene expression revealed significant transcript expression changes between women with PMD and AC in all three treatment conditions. Of particular interest, the gene CXCL10, which has been previously linked to cardiovascular disease, is significantly upregulated (puncor<1.55x10-5) in the cells of women with past PMD, and had the most extreme increase in transcription in the E2WD treatment condition. Additionally, a Gene Set Enrichment Analysis (GSEA) of 498 differentially expressed genes (p-value<0.05) after E2-WD in PMD indicates several “Hallmark” gene sets (which summarize and represent well-defined biological states or processes) may be dysregulated in PMD after E2-withdrawal, including the mTORC pathway, E2-response, and cholesterol homeostasis. Currently, we’re establishing an independent replication cohort (n=10/group) of AC and past PMD cases to verify genes and gene networks found to be significantly changed in the RNA-seq analysis. These preliminary validation efforts using qRT-PCR confirm a significant increase (t(18)=3.121, p<0.006) in CXCL10 after E2-WD in PMD compared to AC. Our results support the hypothesis that the differential responsivity to E2-WD in PMD could be linked to rapid gene expression changes on a cellular level. Further analysis is being done to determine if both intrinsic genetic differences as well as differential sensitivity to E2-WD could underlie PMD.