Stress and the Endocrine System

In nonstressful conditions, cortisol secretion is regulated within the hypothalamic-pituitary-adreno-cortical (HPAC) axis by classic negative feedback to the pituitary gland via the systemic circulation and to the hypothalamus and hippocampus by way of cerebrospinal fluid. During states of stress, regulation differs from the classic HPAC pattern in that the feedback mechanism is inhibited and the feedforward processes are enhanced (Fig. 2-6).

Hypothalamus

(pvnJ

CRH neurons

AVP neurons

Anterior pituitary

Adrenal cortex

(pvnJ

AVP neurons

Hypothalamus

Anterior pituitary

Adrenal cortex

Glucocorticoids

Target cells

CRH 41 amino acids:

SQEPPISLDLTFHLLREVLEMTK ADQLAQQAHSNRKLLDIA

POMC

-MSH ACTH

a-LPH ACTH (human) 39 amino acids:

SYSMEHFRWGKPVGKKRRPV KVYPNGAEDESAEAFPLEF

Cortisol

ß-endorphin

COOH

Figure 2-6 Left, Schematic representation of the hypothalamic-pituitary-adrenocortical axis (HPAC). Right, The amino acid sequences of CRH and ACTH are shown. The precursor molecular form from which ACTH is cleaved is also shown, with many of its hormone products, including ACTH, P-endorphin, P-LPH, y-LPH, a-MSH, and y-MSH. ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; LPH, lipotropic hormone; MSH, melanocyte-stimulating hormone; POMC: proopiomelanocortin.

A central feedback subsystem, the corticotropin-releasing factor (CRF) system, contains specialized neurons that synthesize CRF and act together to integrate the CNS's response to stress. CRF, functioning also as a peptide transmitter, integrates sensory information from the cortex with emotional states and behaviors that are regulated by the amygdala and hippocampus to shape auto-nomic, hormonal, and behavioral responses to the stress. Some features of the central CRF system are summarized in Figure 2-7. The central CRF system binds the functions of the cortex, hypothalamus, and brainstem to integrate the outflow to the peripheral organs.

Cortisol acts upon two types of receptors: min-eralocorticoid (type I) and glucocorticoid (type II). Type I receptors respond to low levels of cortisol,

Hypothalamus Hippocampus Crf

Figure 2-7 An oversimplified model of corticotropin-release factor (CRF) system. Open lines Part of the model indicates the classic feedback pathways of cortisol regulation in hypothalamus-pituitary-adrenocortical (HPAC) axis. CRF neurons found in different areas of the central nervous system and their communication with other parts of the central nervous system (CNS) manifest their extensive function during response to stress, regulating autonomic nervous system, endocrine system, and stress-related posture and locomotion. Cortisol acts on all cell types in the CNS and peripheral tissues, including the immune system. ACTH, Adrenocorticotropic hormone; BNST, bed nuclei of the stria terminalis.

Figure 2-7 An oversimplified model of corticotropin-release factor (CRF) system. Open lines Part of the model indicates the classic feedback pathways of cortisol regulation in hypothalamus-pituitary-adrenocortical (HPAC) axis. CRF neurons found in different areas of the central nervous system and their communication with other parts of the central nervous system (CNS) manifest their extensive function during response to stress, regulating autonomic nervous system, endocrine system, and stress-related posture and locomotion. Cortisol acts on all cell types in the CNS and peripheral tissues, including the immune system. ACTH, Adrenocorticotropic hormone; BNST, bed nuclei of the stria terminalis.

whereas type II receptors respond to high levels. During periods of stress, cortisol secretion increases and activates type II receptors. Insufficient cortisol secretion causes alterations in sensory thresholds and impairments in learning and memory ability. Excessive cortisol secretion is related to severe depression and to cognitive and mood disturbances. Repeatedly elevated or prolonged high levels of cortisol sensitize the amygdala and increase the CRF-gene expression. As a result, high levels of stress increase stress reactivity with far-reaching physiologic consequences. Gastrointestinal disorder is one of the consequences of amygdala sensitization, as is irritable bowel syndrome.7

Prolonged or repeated exposure to severe, life-threatening stress is followed, in some cases, by posttraumatic stress disorder (PTSD). Affected people may manifest psychologic distress, sleep disturbance, enhanced startle reactions, and alcohol or drug abuse. The research suggests that after prolonged and high levels of cortisol exposure at the amygdala, the central CRF system is sensitized and causes PTSD symptoms.8 The central sensiti-zation of the CRF system would have the effect of shifting the balance from a negative feedback process to a permanent feedforward process, which would result in a more reactive HPAC axis, accompanied by frontal-limbic alterations associated with anxiety. Patients with PTSD show reduced hippocampus volumes.9 The hippocampus is the only area in the CNS that is known to spontaneously produce new nerve cells throughout life. High levels of cortisol exposure inhibit the growth of new cells and make existing cells more vulnerable to cell death.10

Another stress hormone, epinephrine, is regulated by the hypothalamic-sympathetic-adrenom-edullary (HSAM) axis. During periods of stress, the hypothalamus and the brainstem send activating signals via sympathetic nerve fibers to the adrenal medulla, where the cells release stored epinephrine into circulation. The circulating epinephrine activates a stress response by increasing cardiac output and respiration rate, dilating peripheral blood vessels, releasing fuel from adipose tissue and the liver, and enhancing skeletal muscle contraction. The secretion of epinephrine and that of cortisol are linked together. The central CRF system activates both HPAC and HSAM pathways. Simultaneously, the pituitary secretion of ACTH results in cortisol secretion from the adrenal cortex via the HPAC axis and adrenal medullary secretion of epinephrine, which is activated by autonomic signals, via the HSAM axis. Both hormones work in concert to initiate and maintain stress responses and to establish memories of stress events. During stressful experiences, cortisol acts on the amygdala and hippocampus to consolidate the formation of declarative memories (the factual memory of events). These two stress hormones have different regulatory strategies. Cortisol is directed by negative feedback or positive feedforward processes between peripheral circulation and the brain neurons. Epinephrine, which does not pass the blood-brain barrier, is regulated by autonomic reflexes that are under the control of the hypothalamus, acted upon by cortisol.

Under the influence of long-term stress, the combination of sensitization of the amygdala and loss of hippocampus volume can permanently alter not only the cognitive process but also homeosta-sis, affecting energy balance and adaptive behavior, which results in health problems.

The brain organizes physiologic responses to meet homeostatic demands during stress. Homeostasis is regulated at different levels during stress responses. The cortex and limbic system exert the highest control over the entire system through cognitive processes to alter behavior with the goal of maintaining homeostasis. To reduce emotional agitation, coping behavior can be problem focused or emotion focused. The hypothalamus is responsible for the integration of most autonomic, endocrine, and motor system adaptations, according to commands from the cor-tex-limbic interaction. Departure from homeostasis can be regulated by reflex organization at the hypo-thalamic level. The brainstem receives signals from higher levels and also feeds back signals to higher and lower levels to coordinate the responses. At the lowest level, local organs use intrinsic reflex mechanisms to adjust local physiologic processes. If the stressors last too long, the entire system will adjust to the stress at the expense of homeostasis, resulting in both health problems and a decline in physical and psychologic performance.

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