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Enhanced sensitivity to oestrogen signalling may drive increased risk for depressive symptoms when exposed to peripartum sex-steroid hormone fluctuations.
Testing if 116 pre-identified sex steroid-responsive transcripts that predicted perinatal depression (PND) translates to a pharmacological model of hormone-induced mood changes.
We generated longitudinal, genome-wide gene-expression and DNA-methylation data from 60 women exposed to a gonadotrophin-releasing hormone agonist (GnRHa) or placebo. We used linear mixed-effect models to assess differences between baseline and follow-up for gene expression and DNA methylation in the biphasic ovarian response to GnRHa.
Of the 116 PND-predictive transcripts, a significant (19%) overlap was observed with those differentially expressed post-GnRHa at both early and later follow-up, indicating sustained effects. Similarly, 49% of tested genes were differentially methylated post-GnRHa at the late follow-up. Within the GnRHa group, a large proportion of PND genes were significantly associated (gene expression; DNA methylation) with changes in depressive symptoms (28%; 66%), oestradiol levels (49%; 66%) and neocortex serotonin transporter binding (8%; 45%) between baseline and follow-up.
Our data bridge clinical PND biomarkers with a pharmacological model of sex hormone-induced mood changes and directly relate oestrogen-induced biological changes with depressive symptoms and associated serotonin-signalling changes. Our data highlight that individual variations in molecular sensitivity to oestrogen associate with susceptibility to hormone-induced mood changes and hold promise for candidate biomarkers.
Declaration of interest
V.G.F. received honorarium for being a speaker for H. Lundbeck A/S. E.B.B. receives research funding from Böhringer Ingelheim to investigate FKBP5 as a potential drug target for depression.
This chapter describes the biological processes and some of the molecular mediators required during early implantation events and illustrates the clinical consequences when these processes are perturbed. Implantation occurs at approximately 6-7 days after fertilization. Initial adhesion of the blastocyst to the uterine wall, termed apposition, is unstable. The temporal and spatial expression of several growth factors, cytokines and adhesion molecules within the uterus and pre-implantation blastocyst suggests that they may play important roles. Reproductive pathologies resulting from implantation defects span a spectrum of clinical presentations ranging from infertility to recurrent pregnancy loss to pre-eclampsia. Infertility may result from failure of fertilization or from loss of the fertilized blastocyst prior to implantation. Pre-eclampsia, a clinical syndrome characterized by hypertension and proteinuria that develops after 20 weeks' gestation, is the leading cause of maternal mortality in the industrialized world and increases perinatal mortality five-fold.