Hypothalamus-pituitary-adrenocortical

Figure 18.3. Endocrine-immune inter-relationship in depression. In depression, the hypothalamic-pituitary-adrenal (HPA) axis is up-regulated with a down-regulation of its negative feedback controls. Corticotrophin releasing factor (CRF) is hypersecreted from the hypothalamus and induces the release of adrenocortico-trophic hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. The negative feedback of cortisol to the hypothalamus, pituitary and immune system is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.

The common association of sympathoadrenal and pituitary adrenocortical activity in stress has suggested that catecholamines play a special role in regulating ACTH secretion. Several theories have been proposed through the years to explain this relationship. These included (a) Long s concept (l952) that emotional stimuli activate the hypothalamus which in turn stimulates the adrenal medulla via the spinal cord and splanchnic nerves, and the subsequently released epinephrine stimulates the release of ACTH ... 

Replacement therapy for secondary or tertiary adrenocortical insufficiency These deficiencies are caused by a defect either in CRF production by the hypothalamus or corticotropin production by the pituitary (see p. 247). [Note Under these conditions, the adrenal cortex synthesis of mineralocorticoids is less impaired than that of glucocorticoids.] The adrenal cortex responds to corticotropin administration by synthesizing and releasing the adrenal corticosteroids. Hydrocortisone is also used for these deficiencies. 

Experiments in dogs showed that emotional stimulation could evoke an adrenocortical response. Impulses from the higher centers reaching the pituitary by way of the hypothalamus (El, Gl). 

Isolation of the pituitary in dogs by section of the stalk and removal of the hind brain does not inhibit a brisk adrenocortical response to injury (W5) this indicates that a humoral mechanism must be involved in stimulating the pituitary (HIO). A corticotropic stimulating or releasing hormone has been isolated from the hypothalamus which appears to be epinephrine in some animals (Gl), but not in man. 

The simple experiment of removing the pituitary and from the sella turcica to another site of the body also demonstrated the role of the hypothalamus in the control of anterior pituitary function. When the transplanted tissue is placed in a site remote from the sella turcica, for example, the anterior chamber of the eye, the kidney capsule or temporal lobe of the brain, partial or complete atrophy of the ovaries, testes, reproductive tracts, thyroid gland and adrenal cortices is observed together with a reduction in the rate of body growth. When, however, the transplanted tissue is placed in the vicinity of the hypothalamus and pituitary stalk, regeneration of the hypophysial portal vessels occurs and anterior pituitary function is restored as shown by the maintenance of reproductive, thyroid and adrenocortical activity [5]. 

The adenohypophysis, the hypothalmus and higher centres in the brain have all been proposed as possible sites of action of the corticosteroids. Evidence for inhibition at the pituitary level has been obtained from studies both in vivo and in vitro and it appears that the corticoids act directly on the adenohypophysis to inhibit the release but not the synthesis of ACTH induced by CRF [269,345— 348]. Recent studies indicate that the hypothalamus is more sensitive to the inhibitory influences of corticosteroids [349]. Certainly corticosteroids inhibit adrenocortical activity when implanted into the hypothalamus [350,351]. Moreover, very small doses of corticosteroid inhibit the secretion of CRF by isolated hypothalami in vitro [301,349]. Corticosteroid treatment reduces the hypothalamic CRF content [352,353] and prevents the release of CRF from already increased stores in the median eminence of adrenalectomized rats [354] and depresses hypothalamic unit activity [355]. However, in these experiments, the corticosteroids were given either orally or systemically and thus the results may be the consequence of the steroid s action either on the hypothalamus or on higher centres in the brain. Substantial evidence exists that corticosteroids may exert feedback effects at extrahypothalamic sites in the central nervous system [356—359]. The possible involvement of the amygdala... 

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