Reproductive Endocrine Related Mood Disorders-Differential Sensitivity

National Institute Of Mental Health

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Abstract

This report includes work arising from the following clinical protocols: NCT00005011, NCT00056901, NCT00059228, NCT00082043, NCT00100360, NCT00001177, NCT00001259, and NCT00001481. The studies conducted within this project are relevant to our understanding of womens behavioral health, sex differences in psychiatric illness and the course of affective disorders in general. The innovation in our work is both conceptual as well as applied. In the past, RMDs were considered to be hormone excess or deficiency states, prompting treatments to correct these inferred hormonal imbalances. We address critical mechanistic questions about the role of reproductive hormones on brain function and behavior in RMDs. We employ steroid receptor modulators to isolate and characterize the effects of specific steroids on behavior in both women with RMDs and well-characterized asymptomatic controls. These clinical studies have demonstrated that a change in steroid hormone secretion induces affective symptoms in most women clinically diagnosed with RMDs, but the identical hormonal intervention has no effect in asymptomatic controls. The alteration in affective state in RMDs represents an abnormal behavioral response to normal physiology. Thus, our work has reframed the understanding of these conditions from hormonal excess or deficiency states to that of ovarian steroid-sensitive behavioral states (i.e., atypical endocrinopathies). We also employ both multimodal neuroimaging studies and cellular models to investigate the physiologic basis of the hormone sensitive phenotype in RMDs. We have characterized neuronal hubs that are differentially regulated by ovarian steroids in women with RMDs, developed a steroid metabolomics platform to examine the steroid metabolome in PMDD, demonstrated an impact of genotypic variation in steroid-regulated genes on the central nervous system (CNS) response to steroids (in a brain region-specific manner), and identified underlying cellular mechanisms for the alterations in steroid signaling in both PMDD and PMD (the mechanisms underlying several of which are being actively pursued). These findings are unique and serve to inform our understanding of the pathophysiology of these conditions and their potential comorbidities, their clinical management and use of hormone therapies. Finally, having developed and tested these methods in women with RMDs, we will employ these techniques in our new studies of postpartum psychosis a condition potentially lethal to both mother and child. Findings to date include: 1) the differential affective and behavioral response to normal physiologic events in women with PMDD compared with control women a behavioral phenotype in which we have explored the underlying biologic risks. We now have replicated these original findings in ten women with PMDD and fifteen controls. We found the identical phenomenon of mood destabilization after exposure to physiologic levels of either estradiol or progesterone in women with PMDD, but no effect of hormonal exposure in asymptomatic control women. 2) We have identified the subgenual anterior cingulate cortex (SGCC) to be differentially regulated by ovarian steroids in women with PMDD compared with control women (i.e., regional cerebral blood flow rCBF during a resting state exam is decreased during estradiol or progesterone exposure when PMDD symptoms recur). The degree of altered rCBF also correlated with gene expression in the ESC/E(Z) pathway of genes a family of genes which we previously identified to be differentially expressed (increased) in cell lines from women with PMDD compared to controls, and members of which are differentially regulated by estradiol and progesterone in cell culture (see below). 3) In collaboration with Dr. David Goldman at NIAAA, we developed lymphoblastoid cell lines (LCLs) and human induced-pluripotent cell lines (h-IPSCs) from women with and without PMDD who had participated in our GnRH agonist-induced ovarian suppression studies. The behavioral outcomes observed during these protocols serve to refine the hormone-sensitive phenotype beyond simply the established clinical diagnoses. Our in vitro experimental strategies attempt to recapitulate the endocrine events that trigger mood symptoms in women with PMDD. In our first study, pathway analyses of the LCL transcriptome revealed, among others, over-expression of ESC/E(Z) complex genes (an ovarian steroid-regulated gene silencing complex) in untreated LCLs from women with PMDD, with more than half of these genes over-expressed as compared to controls. In contrast, protein expression of ESC/E(Z) genes was decreased in untreated PMDD LCLs. Finally, mRNA expression of several ESC/E(Z) complex genes were increased by P in controls only and decreased by E in PMDD LCLs. These findings provided the first evidence of a plausible biological substrate for the differential behavioral response to E/P in women with PMDD. Indeed, these data suggest that women with PMDD have an intrinsic abnormality in their epigenetic capacity that could manifest in an alteration in their ability to translate environmental events into long-term changes in gene expression. Second, we performed transcriptomic analyses of LCLs derived from women with PMDD and asymptomatic controls cultured under untreated (steroid-free), estradiol-treated, and progesterone-treated conditions. Weighted gene correlation network analysis (WGCNA) of transcriptomes identified four gene modules with significant differences in the response patterns in women with PMDD (versus control LCLs) that also differed across hormone exposures, including multiple pathways governing intracellular Ca2+ dynamics and the endoplasmic reticulum (ER) stress response. These data suggest that estradiol-dependent aberrations in cellular Ca2+ dynamics and ER stress may contribute to the pathophysiology of PMDD and could guide treatment development to focus on medications regulating intracellular calcium signaling (known to be involved with affective state regulation) in PMDD. To investigate the cellular basis underlying the differential affective response that we and others have observed in PPD, lymphoblastoid cell lines (LCLs) were derived from women with and without past PPD and compared transcriptomically in hormone conditions (HCs) mimicking pregnancy and parturition. RNA-sequencing identified unique differentially expressed genes (DEGs). DEGs tended to be downregulated in PPD, and significantly independent of HC. Two of these PPD DEGs were evolutionarily conserved cellular stress regulators: IMPACT, an integrative response protein maintaining translational homeostasis, and WWTR1, a transcriptional coactivator in the Hippo pathway mediating cell proliferation and survival. Correspondingly, significant gene network modules were linked to cell cycle progression, estrogen response, and immune dysregulation, suggesting an innate difference in intracellular signaling in PPD. HC-dependent responses were also observed in PPD LCLs, such as increased GATA3 expression (an upstream regulator of IMPACT and WWTR1) and differentially phosphorylated eiF2 (the ultimate downstream target of IMPACT). These data implicate both HC-dependent and -independent genes as potentially influencing mood and/or escalating PPD risk. This intrinsic downregulation of IMPACTs translation and WWTR1s transcription networks may suggest a novel link between PPD and a compromised ability to maintain homeostasis in the context of cellular stress occurring during pregnancy and parturition.