Stress, sex hormones, inflammation, and major depressive disorder: Extending Social Signal Transduction Theory of Depression to account for sex differences in mood disorders

Abstract

Social Signal Transduction Theory of Depression is a biologically plausible, multi-level theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental adversity with internal biological processes that drive depression pathogenesis, maintenance, and recurrence. Central to this theory is the hypothesis that interpersonal stressors involving social threat (e.g., social conflict, evaluation, rejection, isolation, and exclusion) upregulate inflammatory processes that can induce several depressive symptoms, including sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. The original article describing this formulation (Psychol Bull 140:774-815, 2014) addressed critical questions involving depression onset and recurrence, as well as why depression is strongly predicted by early life stress and comorbid with anxiety disorders and certain physical disease conditions, such as asthma, rheumatoid arthritis, chronic pain, and cardiovascular disease. Here, we extend the theory to help explain sex differences in depression prevalence, which is a defining feature of this disorder. Central to this extension is research demonstrating that ovarian hormone fluctuations modulate women's susceptibility to stress, brain structure and function, and inflammatory activity and reactivity. These effects are evident at multiple levels and are highly context-dependent, varying as a function of several factors including sex, age, reproductive state, endogenous versus exogenous hormones, and hormone administration mode and dose. Together, these effects help explain why women are at greater risk for developing inflammation-related depressed mood and other neuropsychiatric, neurodevelopmental, and neurodegenerative disorders during the reproductive years, especially for those already at heightened risk for depression or in the midst of a hormonal transition period.

Keywords: Cytokines; Depression; Disease; Inflammation; Life stress; Neuroinflammation; Risk; Sex differences; Sex hormones; Social threat.

Fig. 1

The role of sex hormones in Social Signal Transduction Theory of Depression. Social Signal Transduction Theory of Depression describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental adversity with internal biological processes that drive depression pathogenesis, maintenance, and recurrence, as well as the co-occurrence of depression with other inflammation-related neuropsychiatric, neurodevelopmental, and neurodegenerative disorders. a Briefly, social-environmental circumstances that are neurocognitively appraised as threats are represented in the brain, which in turn influences the activity of the SNS, HPA axis, and vagus nerve. Neuroeffector molecules from these systems engage specific, highly conserved gene transcription programs in differing target cells. In leukocytes, for example, SNS and HPA signaling generally suppress innate antiviral genes (e.g., IFNA, IFNB), whereas SNS signaling activates—and HPA signaling generally inhibits—pro-inflammatory cytokine genes (e.g., IL1B, IL6, IL8, TNF). These changes represent a systematic shifting of immune system resources toward an increased pro-inflammatory and reduced anti-viral (i.e., type I interferon response) state, with corresponding effects for several immune-mediated health outcomes including depression. b These pathways can also be depicted conceptually, highlighting the fact that experiences of social-environmental adversity can become self-promoting via both external social recursion and internal physiologic recursion. Sex hormones can modulate these processes on several levels. For example, sex hormones can affect external social recursion by altering social behavior patterns including the tendency to socially isolate or respond defensively or aggressively to perceived threat. Such behaviors can in turn alter the actions of conspecifics in the surrounding environment and give rise to social stressors (e.g., social conflict, evaluation, rejection, isolation, exclusion) that further heighten the actual level of adversity in the environment and, therefore, an individual’s perception of such threat. Sex hormones can also affect internal physiologic recursion at several levels, including: (i) by influencing the perception, processing, and regulation of threat and fear via brain regions rich in neurosteroid receptors, such as the amygdala, prefrontal cortex, and hippocampus, and the direct and indirect interaction with key targets in monoaminergic systems (e.g., MAO-A, 5-HTT) and the interplay of sex hormone metabolites with inhibitory neurotransmission, such as ALLO-facilitated GABA-ergic inhibition of pro-inflammatory mediators (e.g., TNF-α via TLR4 signal inhibition); (ii) via modulation of SNS and HPA axis reactivity, as sex hormones can influence parasympathetic/sympathetic activity in addition to cortisol responses to psychosocial stress given that estrogen can enhance the activity of choline uptake and acetycholine synthesis, affect vascular endothelial properties, and may blunt cortisol responsivity, whereas progesterone may increase HPA axis reactivity to stress; and (iii) by influencing the activity of several cellular signal transduction processes that directly modulate innate and adaptive immune system dynamics, including (a) genomic signaling: for example, estrogen can bind directly to estrogen response elements in gene promoters or serve as cofactors with other transcription factors (i.e., NF-ĸB, AP-1), thus modulating IFN-γ expression; (b) non-genomic signaling: sex hormones can exert rapid effects via neurosteroid receptors on immune cells (e.g., by affecting dendritic and B cell development and function via membrane-bound non-genomic signaling mechanisms and membrane-associated specific kinase signaling pathways); (c) post-translational modification of neurosteroid receptors by acetylation, lipophilic moieteism, and ubiquitination; and (d) possible epigenetic mechanisms (e.g., microRNAs, histone modifications, and acetylation). Importantly, the effects of sex hormones on all of these levels are highly context-dependent. Therefore, factors like sex, age, reproductive state, endogenous versus exogenous hormones, and hormone administration mode and dose need to be carefully considered to fully understand the effects that sex hormones have on risk for depression and other inflammation-related neuropsychiatric, neurodevelopmental, and neurodegenerative diseases (e.g., asthma, rheumatoid arthritis, chronic pain, metabolic syndrome, cardiovascular disease, Alzheimer’s disease, etc.). ACTH, adrenocorticotropin hormone; ADRB2, β₂-adrenergic receptor; CRH, corticotrophin releasing hormone; PRR, pattern recognition receptor; SNS, sympathetic nervous system; HPA axis, hypothalamic-pituitary-adrenal axis; MAO-A, monoamine oxidase-A; 5-HTT, serotonin transporter; ALLO, allopregnanolone; GABA, gamma-aminobutyric acid; TLR4, toll-like receptor 4; ER, estrogen receptor; NF-ĸB, nuclear factor-ĸB; AP-1, activator protein 1; IFN-γ, interferon-γ; MDD, major depressive disorder. Adapted from Slavich and Cole 2013 and Slavich and Irwin 2014