Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress

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Abstract

The stress system coordinates the adaptive responses of the organism to stressors of any kind.1 The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus–norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary–adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic β-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic–pituitary–adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and β-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5′ deiodinase, which converts the relatively inactive tetraiodothyronine (T4) to triiodothyronine (T3), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing “low turnover” osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.

Section snippets

Physiology of the stress response

Life exists by maintaining a complex dynamic equilibrium or homeostasis that is constantly challenged by intrinsic or extrinsic adverse forces, the stressors [1]. Under favorable conditions, individuals can be invested in vegetative and pleasurable functions that enhance their emotional and intellectual growth and development and the survival of their species, such as food intake and sex. In contrast, activation of the stress response during threatening situations that are beyond the control of

Regulation of the stress response

The orchestrated interplay of several neurotransmitter systems in the brain underlies the characteristic phenomenology of behavioral, endocrine, autonomic and immune responses to stress [28]. These transmitters include CRH, AVP, opioid peptides, dopamine and norepinephrine.

HPA axis–immune system interactions

It has been known for several decades that stress, whether inflammatory, traumatic or psychological, is associated with concurrent activation of the HPA axis. In the early 1990s, it also became apparent that cytokines and other humoral mediators of inflammation are potent activators of the central stress response, constituting the afferent limb of a feedback loop through which the immune/inflammatory system and the CNS communicate [34].

All three inflammatory cytokines, tumor necrosis factor-α

HPA axis: pathophysiology

Generally, the stress response with the resultant activation of the HPA axis is meant to be acute or at least of a limited duration. The time-limited nature of this process renders its accompanying antireproductive, antigrowth, catabolic and immunosuppressive effects temporarily beneficial rather than damaging. In contrast, chronicity of stress system activation would lead to the syndromal state that Selye described in 1936 [4]. Because CRH coordinates behavioral, neuroendocrine and autonomic

Future directions

There has been a long search for small molecular weight CRH antagonists that could be absorbed orally and cross the blood brain barrier to treat disorders characterized by a hyperactive CRH neuron as in melancholic depression. Antalarmin, a prototype CRH receptor type 1 antagonist, shows that this concept bears merit [5], [28]. This small pyrrolopyrimidine compound, binds with high affinity to the CRH receptor type 1, decreases the activity of the HPA axis and LC/NE, blocks the development and

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    1

    “Stress” is defined as a state of disharmony or threatened homeostasis. The concepts of stress and homeostasis can be traced back to ancient Greek history, however, the integration of these notions with related physiologic and pathophysiologic mechanisms and their association with specific illnesses are much more recent.

    In the present overview, we focus on the cellular and molecular infrastructure of the physiologic and behavioral adaptive responses to stress and we define the pathophysiologic effects of the dysregulation of the stress response, which may result in vulnerability to several disease entities, such as anxiety or depression and chronic inflammatory processes.

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