Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.

Vamvakopoulos, Nicholas C.; Chrousos, George P.

doi:10.1172/jci116782

Cited by 407 publications

(222 citation statements)

References 58 publications

(32 reference statements)

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“…Evidence suggests that, within the central nervous system, estrogen alters the expression of specific genes related to pain signaling to increase perception of peripheral nociceptive stimuli. [101][102][103] These estrogen-dependent alterations in gene expression increase neuronal excitability by promoting synaptic plasticity leading to increased visceral sensitivity in females, especially during periods of high cycling estrogen. 104 Another estrogenmediated mechanism that could drive visceral hypersensitivity is via the induction of µ-opioid receptor internalization within the medial preoptic nucleus and the posterodorsal medial amygdala.…”

Section: Sex Linked Differences In Visceral Sensitivitymentioning

confidence: 99%

Mechanisms of Stress-induced Visceral Pain

Meerveld

Johnson

2018

J Neurogastroenterol Motil

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Evidence suggests that long-term stress facilitates visceral pain through sensitization of pain pathways and promotes chronic visceral pain disorders such as the irritable bowel syndrome (IBS). This review will describe the importance of stress in exacerbating IBS-induced abdominal pain. Additionally, we will briefly review our understanding of the activation of the hypothalamic-pituitary-adrenal axis by both chronic adult stress and following early life stress in the pathogenesis of IBS. The review will focus on the glucocorticoid receptor and corticotropin-releasing hormone-mediated mechanisms in the amygdala involved in stress-induced visceral hypersensitivity. One potential mechanism underlying persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in stress-induced visceral nociception, alterations in DNA methylation and histone acetylation patterns within the brain, have been linked to alterations in nociceptive signaling via increased expression of pro-nociceptive neurotransmitters. This review will discuss the latest studies investigating the long-term effects of stress on visceral sensitivity. Additionally, we will critically review the importance of experimental models of adult stress and early life stress in enhancing our understanding of the basic molecular mechanisms of nociceptive processing. Taken together, the complex clinical phenotype makes recapitulating IBS in rodent models extremely challenging. However, an aim of this review will be to describe how the use of rodent models of adult stress, early life stress (ELS), and a dysregulated HPA axis has improved our understanding of stress in the pathophysiology of IBS. Pathophysiology of Irritable Bowel Syndrome: Activation of the Brain-Gut AxisEvidence from clinical and basic research points to dysregulation of the bidirectional communication between the brain-gut axis in IBS. 21 The brain-gut axis represents a dynamic interplay between central circuits and peripheral mechanisms. The messengers of this complex circuit include neural, endocrine, metabolic, and immune mediators that are activated by central factors such as stress (Fig. 1). Although IBS is not an inflammatory disorder, the immune system plays a role in the pathogenesis of IBS in at least a subset of patients and likely contributes to the etiology of IBS symptoms. 22,23 A subset of IBS patients display a low grade chronic inflammation, and there is also evidence that following an enteric infection and combined with stressful life events, there is an increased risk of developed post-infectious IBS. [24][25][26][27] Clearly, the immune system and inflammatory processes are modulated by the HPA and autonomic nervous systems. In support, IBS patients also show increased number and reactivity of mast cells. 28,29 Data from peripheral blood mononuclear cells, as well as in mucosal biopsies, from IBS patients show that cytokines levels including TNF-α...

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Section: Sex Linked Differences In Visceral Sensitivitymentioning

confidence: 99%

Mechanisms of Stress-induced Visceral Pain

Meerveld

Johnson

2018

J Neurogastroenterol Motil

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“…In general, estrogen increases the immune response (Grossman, 1984) and androgens inhibit it (Spinedi et al, 1992) such that females have more pronounced responses than males to immune activation. Sex steroids also influence HPA axis activity, since estrogen positively (Vamvakopoulos and Chrousos, 1993) and androgen negatively (Bingaman et al, 1994) modulate corticotrophin releasing hormone (CRH) production such that females exhibit higher plasma corticosterone (CORT) levels compared to males. Studies examining adrenal function following endotoxin (LPS) administration in mice, have found that female plasma CORT levels are significantly higher than male levels regardless of the post-administration time point examined (Spinedi et al, 2004).…”

Section: Cytokine-sex Steroid-immune System Interactionsmentioning

confidence: 99%

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Rana

Aavani

Pittman

2012

Hormones and Behavior

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Humans are exposed to potentially harmful agents (bacteria, viruses, toxins) throughout our lifespan; the consequences of such exposure can alter central nervous system development. Exposure to immunogens during pregnancy increases the risk of developing neurological disorders such as schizophrenia and autism. Further, sex hormones, such as estrogen, have strong modulatory effects on immune function and have also been implicated in the development of neuropathologies (e.g., schizophrenia and depression). Similarly, animal studies have demonstrated that immunogen exposure in utero or during the neonatal period, at a time when the brain is undergoing maturation, can induce changes in learning and memory, as well as dopaminemediated behaviors in a sex-specific manner. Literature that covers the effects of immunogens on innate immune activation and ultimately the development of the adult brain and behavior is riddled with contradictory findings, and the addition of sex as a factor only adds to the complexity. This review provides evidence that innate immune activation during critical periods of development may have effects on the adult brain in a sex-specific manner. Issues regarding sex bias in research as well as variability in animal models of immune function are discussed.

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“…28,29 There are five perfect half-palindromic estrogenresponsive elements in the human CRF-promoter region, which may confer direct estrogenic stimulation on CRF gene expression. 28,65 Differential effects have been described in vitro on gene expression by the two receptor subtypes ESR1 and 2. 66 ESR1 mRNA expression dominates in the human hypothalamus while ESR2 mRNA and protein were lower in this brain area.…”

Section: Sex Hormones Receptor Imbalancementioning

confidence: 99%

Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances

et al. 2008

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Hyperactivity of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus is a prominent feature in depression and may be important in the etiology of this disease. The activity of the CRF neurons in the stress response is modulated by a number of factors that stimulate or inhibit CRF expression, including (1) corticosteroid receptors and their chaperones, heat shock proteins 70 and 90, (2) sex hormone receptors, (3) CRF receptors 1 (CRFR1) and 2, (4) cytokines interleukin 1-b and tumor necrosis factor-a, (5) neuropeptides and receptors, vasopressin (AVP), AVP receptor 1a (AVPR1A) and oxytocin and (6) transcription factor cAMP-response element-binding protein. We hypothesized that, in depression, the transcript levels of those genes that are involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis are upregulated, whereas the transcript levels of the genes involved in the inhibition of the HPA axis are downregulated. We performed laser microdissection and real-time PCR in the PVN and as a control in the supraoptic nucleus. Snap-frozen post-mortem hypothalami of seven depressed and seven matched controls were used. We found significantly increased CRF mRNA levels in the PVN of the depressed patients. This was accompanied by a significantly increased expression of four genes that are involved in the activation of CRF neurons, that is, CRFR1, estrogen receptor-a, AVPR1A and mineralocorticoid receptor, while the expression of the androgen receptor mRNA involved in the inhibition of CRF neurons was decreased significantly. These findings raise the possibility that a disturbed balance in the production of receptors may contribute to the activation of the HPA axis in depression.

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Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.

Cited by 407 publications

References 58 publications

Mechanisms of Stress-induced Visceral Pain

Mechanisms of Stress-induced Visceral Pain

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances

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