Longitudinal Analysis of Estrogen Receptor Gene Methylation, Estradiol, and Depressive Symptoms During the Perinatal Period

DNA methylation of estrogen receptor genes (ESR1, ESR2, and GPER) may affect the expression of the estrogen receptors (ERs) alpha, beta, and G protein-coupled estrogen receptor (GPER). Altered receptor expression may in turn affect the receptors' sensitivity to estrogen, thereby modulating vulnerability to depression during periods of estrogen fluctuation. The aim of this study was to investigate the association between the methylation of ESR1, ESR2, and GPER, depressive symptoms, and estradiol during the perinatal period using a longitudinal design. A total of 159 women were followed longitudinally from 34 to 36 weeks of gestation to 8-12 weeks postpartum. Depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Salivary estradiol levels were quantified, and DNA methylation was analyzed using dried blood spots. Multivariate linear regressions and paired t-tests were used for analysis. Depressive symptoms were negatively associated with the mean overall ESR1 methylation during pregnancy (β = -0.41, p = 0.002), but not during the postpartum period (p ≥ 0.05). Haplotype CA during pregnancy (p ≤ 0.001) and haplotype TA (p = 0.03) during postpartum modified the relationship between depressive symptoms and overall mean ESR1 DNAm. No associations emerged for ESR2, GPER, or estradiol at either time point (all p ≥ 0.05). The mean overall methylation of ESR1 increased from pregnancy to postpartum (t = -2.59, p = 0.012) and was positively associated with depressive symptom scores during pregnancy (β = 0.418, p = 0.031). This work suggests that lower DNA methylation levels of ESR1, which may reflect higher ER-alpha expression and thus greater sensitivity to estrogen, are associated with increased depressive symptoms during pregnancy. The findings highlight molecular pathways of estrogen sensitivity, particularly via ER-alpha, as a promising target for future biomarker research for perinatal depression.