As previously outlined, cardinal symptoms of endometriosis are chronic pain and infertility, which may severely interfere with the patient’s quality of life and be perceived as a persistent stressor. To date, it is well established that high perception of stress may trigger or aggravate the incidence or exacerbation of diseases such as inflammatory bowel disease [128
], immune dermatoses [130
], or pregnancy complications such as spontaneous abortion and pre-eclampsia [132
]. Further, high levels of perceived stress have been proposed to contribute to the progression of endometriosis [133
Nowadays, it is well established that high levels of perceived stress activate the release of neurohormones such as corticotropin-releasing hormone (CRH) as well as adrenocorticotropic hormone (ACTH) and glucocorticoids (GCs) largely via the hypothalamus–pituitary–adrenal (HPA) axis [134
]. Via these stress-related hormones, accompanied by additional stress response mediators like neuropeptides or neurotrophins [137
], immune responses are profoundly altered [135
]. For example, GCs dampen the release of IL-12, IFN-γ, and TNF-α by antigen-presenting cells and Th1 cells, but up-regulate the production of IL-4, IL-10, and IL-13 by Th2 cells [139
]. Thus, it has been proposed that the release of CRH, ACTH, and subsequently GCs induces the selective suppression of the Th1-mediated cellular immunity and elicits a skew in the direction of Th2-dominated immunity. Indeed, it has also been postulated that such Th2 shift may actually protect the organism from systemic surpassing of pro-inflammatory cytokines, which could have severe tissue-injuring features [141
However, besides such well-described immunosuppressive effects of GCs, relevant examples of pro-inflammatory actions of peripheral CRH have recently been introduced, e.g., in the synovia of rheumatoid arthritis patients [142
]. This peripheral CRH leads to proliferation of immunocytes [143
] and production of IL-1, IL-2, and IL-6 [145
]. Moreover, CRH antagonizes some of the immunoregulatory effects of serotonin (5-HT), e.g., the suppression of TNF-α production [147
]. Inflammation can be dampened by blocking CRH at the periphery [148
], as CRH receptors occur on immune cells, e.g., on T cells, monocytes [149
], and mast cells [150
]. Peripheral CRH may, thus, be referred to as “immune” CRH. Immune cells such as T cells, B cells [151
], and mast cells [152
] may be the source of peripheral CRH. Besides, CRH-like immunoreactivity was demonstrated in splenic nerve fibers [153
], in the dorsal horn of the spinal cord, and dorsal root ganglia as well as sympathetic nerve fibers [154
] pointing at a neuronal source of “immune” CRH in descending nerve fibers.
Intriguingly, CRH is highly expressed in endometriotic lesions [44
] and has been proposed to stimulate mast cells to secrete VEGF [150
] (Fig. ). This would facilitate angiogenesis in endometriotic lesions and perpetuate the dissemination of the disease. Thus, it may be proposed that high levels of perceived stress promote the dissemination of endometriosis via CRH-dependent pathways, as peripheral CRH is found increased in response to psychological stress [155
]. It remains to be elucidated whether and how CRH can be made attributable for the peritoneal inflammation present in the peritoneal cavity of patients suffering from endometriosis. In contrast to endometriotic tissue, CRH levels in peritoneal fluid of endometriosis patients were not different from controls; however, CRH-binding protein (CRH-BP) is increased in advanced stages of endometriosis, compared to early stages or healthy controls [156
], which may be interpreted as an attempt of the body to down-regulate high CRH levels.
Neurohormonal responses to stress also include an activation of the sympathetic nervous system with the subsequent increase in catecholamines [137
], and published evidence strongly supports that the immune response can be regulated via the sympathetic nervous system/catecholamines at regional, local, and systemic levels [134
]. For example, lymphocytes express adrenergic receptors and respond to catecholamine stimulation with the development of stress-induced lymphocytosis, inflammation, and distinct changes in lymphocyte trafficking, circulation, proliferation, and cytokine production [139
]. Because sympathetic nerve fibers are present in endometriotic tissue, it appears likely that—besides CRH—catecholamines contribute to the peritoneal inflammation in endometriosis, and an increased release of catecholamines in response to high levels of stress could additionally perpetuate local inflammation.
Besides the classical stress-related neurohormones—the players of the HPA axis and catecholamines—NGF and the neuropeptide SP are now recognized as pivotal mediators of the stress responses [131
]. SP co-functions as neurotransmitter in the central and peripheral nervous system in pain, anxiety, and emotional centers besides stress [131
]. Additionally, SP is a potent pro-inflammatory mediator, as it induces the production and release of cytokines such as IL-1, IL-6, and TNF-α and NGF [162
] and promotes angiogenesis during inflammation [164
]. NGF also enhances pro-inflammation and has been proposed to increase the release of SP [161
]. SP and NGF derived from nerve endings induce leukocyte recruitment and release of pro-inflammatory cytokines, which is generally referred to as neurogenic inflammation. Vice versa, pro-inflammatory cytokines may induce the expression of neuropeptides such as SP and NGF and their cognate receptors [167
], which might provide an explanation for the up-regulation of NGF expression in inflamed areas, e.g., in peritoneal endometriosis [121
]. Interestingly, the activation of PAR-2 on afferent neurons, e.g., by proteases such as mast cell tryptase, leads to subsequent release of pro-inflammatory CGRP and SP [169
], which might provide explanation for pain during inflammation. To date, published evidence on the expression of SP in endometriosis is very limited; some authors report no changes of SP in endometriosis, which could be due to the difficulties in detecting SP because it is a rather small peptide of no more than 11 amino acids [170
]. Hence, future studies employing novel technologies such as gene or protein arrays may allow to investigate the expression of pain-related neurotransmitters as well as their receptors, e.g., SP high affinity receptor neurokinin (NK)-1R [112
] on endometrial tissue. However, as outlined earlier, Tokushige et al. [121
] recently identified an increased number of nerve fibers in peritoneal endometriotic lesions using immunohistochemistry; in fact, these nerve fibers were immunoreactive for SP, CGRP, Ach, NGF, and TH (Fig. ).
In conclusion, a hypothetical scenario on how high stress perception might be related to endometriosis is depicted in Fig. . It may be postulated, in terms of a “brain-body cross talk”, that psychologically stressful conditions promote the aggravation of inflammatory processes, angiogenesis, pain, and infertility via pathways that most likely involve catecholamines, “immune” CRH, NGF, SP, and CGRP (Fig. right), whereby the dependancy between NGF/SP and CRH should be addressed in future experimental settings.
Fig. 3 Hypothetical scenario for endometriosis: the ‘brain–body–brain cross talk’. BBB blood–brain barrier, CGRP calcitonin-gene-related peptide, CRH corticotropin-releasing hormone, NGF nerve growth factor, SP substance (more ...)
Peripheral immunological events in turn signal certain brain regions to induce the so-called sickness response including (neuro)hormonal and behavioral changes [171
]. These profound behavioral alterations are referred to as sickness behavior, which comprises depressive-like behavior and is characterized by reduced locomotor activity, fatigue, hypophagia or anorexia, diminished social interactions, and female sexual behavior [171
]. Interestingly, such sickness behavior can be experimentally provoked by peripheral administration of IL-1 or TNF-α [172
]. In healthy humans, levels of anxiety, depressed mood, and memory function correlate with levels of TNF-α, its soluble receptors, and IL-6 [174
]. Brain regions identified to date comprise structures associated with the central stress system, namely, the hypothalamus, hippocampus, frontal/prefrontal structures, and the limbic system including the amygdala [175
Intravenous as well as intraperitoneal applications of IL-1 result in an increased CRH production in the hypothalamus [176
]. Because elevated levels of central CRH have been associated to the abovementioned behavioral changes during sickness [178
], non-cognitive ‘inflammatory stress’ can induce behavioral and emotional alterations via increase in central CRH. As mentioned earlier in this review, IL-1, IL-6, and TNF-α are elevated in peritoneal fluid of endometriosis patients. Evidently, due to the up-regulation of pro-inflammatory cytokines not only in the peritoneal fluid but also in the peripheral blood of patients with endometriosis [179
], this ‘inflammatory stress’ may increase stress perception in affected patients due to the onset of the sickness response, which includes an increase in central CRH as well as behavioral changes and which would aggravate the strain generated by symptoms such as pain and infertility in terms of a ‘body–brain cross talk’ (Fig. , left).
Undoubtedly, the question that arises is how peripheral ‘inflammatory stress’ can reach the central nervous system. Here, it has been proposed that peripheral blood cytokines bypass the blood–brain barrier (BBB) entering in the circumventricular organs [180
]. Secondly, these cytokines might cross the BBB, especially when its permeability is enhanced, e.g., in stressful conditions [181
]. Thus, perceived stress might predispose certain individuals to develop sickness behavior during illness. Finally, vagal nervous afferents might be involved, as suggested by experiments in rats where behavior has been investigated before and after vagotomy and upon intraperitoneal application of IL-1β [182
], and IL-1β-induced inhibition of social exploration was attenuated in vagotomized rats. Because Ach+
nerve fibers were found in endometriotic tissue, as illustrated above, behavioral changes mediated by vagal afferents might play a relevant role in endometriosis (Fig. , left).
In conclusion, dissemination of endometriosis may be sustained and advanced by high levels of perceived stress accompanying neuroendocrine-immune disequilibrium in affected patients. This, in turn, fosters additional stressors such as pain and infertility and induces sickness response. As a result, stress perception is even higher, which induces a vicious cycle of ‘brain–body–brain cross talk’ in affected women (Fig. ).