Estrogens generally have stimulatory effects on lymphocyte presence, concentration, and function (Lee et al., 2010; Oertelt-Prigione, 2012; Pennell et al., 2012; Rodriguez-Garcia et al., 2013; Moulton, 2018) though cell type and tissue-specific effects of estrogen stimulation have also been suggested (Pung et al., 1985; Chen et al., 2015). levels on the immune system within the female, interrogating how the endocrine, nervous, and immune systems converge to impact womens mental health is warranted. Here, we review the impacts of endogenous estrogens as well as exogenously administered estrogen-containing therapies on affect and immunity and discuss these observations in the context of distinct reproductive milestones across the female lifespan. A theoretical framework Gamma-glutamylcysteine (TFA) and important considerations for additional study in regards to mental health and major depression are provided. Keywords: estrogen, sex differences, major depressive disorder, peripheral immune system, mood Introduction Mood disorders, including major depressive disorder (MDD), are a significant global health issue (Krishnan and Nestler, 2008). Worldwide lifetime prevalence of mood disorders has been reported to be nearly 10% (Steel et al., 2014), and in 2010 2010, the nearly 300 million global cases of MDD accounted for 8.2% of all disease-induced years lived with disability (Ferrari et al., 2013a). In the US alone, one in six adults will receive an MDD diagnosis in their lifetime and more than 13 million Americans experience a major depressive episode with severe impairment each year (Kessler et al., 2005; Ferrari et al., 2013b; Brody et al., 2018). Annual costs associated with this condition are estimated at $210 billion (Greenberg et al., 2015). MDD is generally considered a brain-targeted disease associated with persistent sadness, guilt, anhedonia (reduced interest in rewarding stimuli), despair, and in some cases, suicide (Krishnan and Nestler, 2008). Due to a happenstance discovery of psychiatric patients showing improved mood when treated with monoamine oxidase inhibitors (Schildkraut, 1965), MDD has historically been associated with deficiencies in serotonergic (5-HT), dopaminergic, and noradrenergic signaling within limbic, reward, and brainstem structures (Krishnan and Nestler, 2008). Problematically, available pharmacologic treatments targeting these presumed dysregulated monoamine systems are associated with delayed and inadequate symptom alleviation in a large proportion of patients (Trivedi et al., 2006; Al-Harbi, 2012; Akil et al., 2018). This led the field to conclude that the pathology of MDD is more complex than previously appreciated, that the neurotransmitters thought to underlie MDD-associated brain Rabbit Polyclonal to EHHADH pathology may not be the sole contributors to its Gamma-glutamylcysteine (TFA) presentation, that the therapeutic interventions targeting these systems will likely remain insufficient at imparting symptomatic relief. Emerging data strongly implicate Gamma-glutamylcysteine (TFA) additional mechanisms in the manifestation of mood disorders. As a result, many researchers have begun considering biological factors that could significantly contribute to the development and persistence of MDD. One of these factors is that of genetic sex and the accompanying differences in sex hormone secretion across the lifespan. A substantial amount of research attention has been paid to Gamma-glutamylcysteine (TFA) the role of sex hormones, especially the steroid hormone estrogen, in driving development of MDD in women (Wharton et al., 2012; Eid et al., 2019). In addition to sex hormones, converging data amassed over the past few decades also support significant immune contributions to brain function and mood (Leonard, 2010; Dantzer, 2018). Indeed, it is now accepted that inflammatory cascades mediated by innate and adaptive arms of the immune system significantly contribute to MDD, at least in some patient subsets (Maes, 2011; Wohleb et al., 2016; Herkenham and Kigar, 2017). Sex differences in the susceptibility to certain infections, the presence of sex hormone receptors on immune cells, and shifts in the function of the immune system during distinct periods of the reproductive lifespan all point to a critical role of sex hormones in modulating immunity (Pennell et al., 2012; Klein and Flanagan, 2016). Given the known sex differences in the prevalence of mood disorders, emerging support for the immune systems role Gamma-glutamylcysteine (TFA) in mediating susceptibility or resilience to psychosocial stress, and the potentially profound impacts of sex hormones (especially estrogens) on impacting immunity, the consideration of neuro-immuno-endocrine interactions in the context of mood and MDD across the female lifespan, is warranted. Here, we will review evidence regarding the mood impacts of these factors individually, describe shifts in immune responses during key reproductive milestones, highlight a few examples of potential autoimmune consequences of estrogenic stimulation in females, and summarize the small but growing collection of findings exploring the convergence of sex, sex hormones and immune function in the context of mood and.
