Pituitary-adrenal axis, cortisol release

Figure 33-2. Hypothalamic-pituitary-adrenal axis. Corticotropin-releasing hormone (CRH) acts to increase pituitary ACTH secretion, which enhances steroid hormone synthesis by the adrenal, including production of cortisol (hydrocortisone), which controls CRH/ACTH secretion via negative feedback.

Patients with PTSD have a hypersecretion of corticotropin-releasing factor but demonstrate subnormal levels of cortisol at the time of trauma and chronically. Dysregulation of the hypothalamic-pituitary-adrenal axis may be a risk factor for eventual development of PTSD. 

Corticotropin-releasing factor and arginine vasopressin, which are released predominantly by the paraventricular nucleus of the hypothalamus, are important regulators of corticotropin (ACTH) release, which in turn triggers the release of cortisol and other steroids by the adrenal gland. Both the administration of certain psychoactive agents and emotional arousal originating from the limbic system are able to modify the functions of the pituitary-adrenal axis and stimulate the synthesis of cortisol. 

Secondary adrenal insufficiency most commonly results from exogenous corticosteroid use, leading to suppression of the hypothalamic-pituitary-adrenal axis and decreased release of ACTH, resulting in impaired androgen and cortisol production. Mirtazapine and progestins (e.g., medroxyprogesterone acetate, megestrol acetate) have also been reported to induce secondary adrenal insufficiency. Secondary disease typically presents with normal mineralocorticoid concentrations. 

Use in diagnosis dexamethasone suppression test. Dexamethasone acts on the h5q othalamus (like hydrocortisone), to reduce output of corticotropin releasing hormone (CRH), but it does not interfere with measurement of corticosteroids in blood or urine. Normal suppression of cortisol production after administering dexamethasone indicates that the hypothalamic/pituitary/adrenal axis is intact. Failure of suppression implies pathological hypersecretion of ACTH by the pituitary or of cortisol by the adrenal. Dexamethasone is used because its action is prolonged (24 h). There are several ways of carrying out the test. 

In a double-blind, randomized pilot study of the efficacy and adverse effects of inhaled fluticasone in 25 newborn preterm infants who required mechanical ventilation for treatment of respiratory distress syndrome, the infants were randomized to receive inhaled fluticasone 1000 micrograms/day or placebo (47). The hypothalamic-pituitary-adrenal axis was assessed by the response to corticotropin-releasing factor. AU basal and post-stimulation plasma corticotropin and serum cortisol concentrations were significantly less with inhaled fluticasone than placebo. Cumulative high-dose inhaled glucocorticoids caused moderately severe suppression of both the pituitary and the adrenal glands. This systemic activity is probably associated with pulmonary vascular absorption that avoids hepatic first-pass metabolism. 

Figure 50-8 The regulatory feedback loop of the hypothalamic-pituitary-adrenal axis. CRH under the influence of neural factors and other modifiable factors that control its pulsatile and circadian secretion acts on the pituitary to produce hormone (ACTH). ACTH in turn stimulates the adrenal gland to form cortisol, aldosterone, dehydroepiandrosterone (DHEA), and androstenedione. Corticosteroids and gamma amino butyric acid (GABA) are inhibitory to CRH and ACTH release, and AVP stimulates ACTH release.

Also, since the hypothalamic-pituitary-adrenal axis (HPA) of the fetus in E+ mares appears to be compromised and results in prolonged gestation lengths in mares, and the associated problems thereof, domperidone may be having some effect on the HPA system since mares receiving domperidone while grazing E+ fescue foal at or near their expected foaling date with normal, healthy foals. And, since ACTH levels in foals from E+ mares are low, and ACTH is the stimulus for adrenal cortisol release and since normal fetal adrenal cortisol levels appear to be... 

Hypothalamic-Pituitary-Adrenal (HPA) axis An integrated neuroendocrine system linking the hypothalamus (noradrenaline and corticotropin-releasing factor CRF) with the anterior pituitary (corticotropin or ACTH) and the adrenal cortex (cortisol). 

Figure 18.2. Endocrine-immune inter-relationship in normal subject. The hypothalamic-pituitary-adrenal (HPA) axis is a feedback loop that includes the hypothalamus, the pituitary and the adrenal glands. The main hormones that activate the HPA axis are corticotrophin releasing factor (CRF), arginine vasopressin (AVP) and adrenocorticotrophic hormone (ACTH). The loop is completed by the negative feedback of cortisol on the hypothalamus and pituitary. The simultaneous release of cortisol into the circulation has a number of effects, including elevation of blood glucose for increased metabolic demand. Cortisol also negatively affects the immune system and prevents the release of immunotransmitters. Interference from other brain regions (e.g. hippocampus and amygdala) can also modify the HPA axis, as can neuropeptides and neurotransmitters.

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.

ACTH adrenocorticoh ophic hormone is a peptide hormone released by anterior pituitary cells in response to shessful stimuli that causes the synthesis and release of cortisol (corticosteroid) from the adrenal cortex. It is an important component of the hypothalamic-pituitary-adrenal (HPA) axis. ACTH is released from pro-opiomelanocortin and secreted from corticotropes in response to corticotropin-releasing hormone (CRH) released by the hypothalamus. 

Cortisol is produced in the zona fasciculata and zona reticularis of the adrenal cortex, the end prixluct of a cascade of hormones which make up the hypothalamic-pituitary-adreniKortical axis (Fig. 2). Corticotrophin releasing hormone (CRH) is secreted by the hypothalamus under the influence of cerebral factors. Adrenocorticotrophic hormone (corticotrophin. orsimply ACTH) is secreted by the anterior pituitary under the control of CRH to maintain the fa.scicular and reticular zones of the adrenal cortex and to stimulate the secretion of cortisol. Ilypolhalamie secretion of CRH and pituitary secretion of ACTH are modulated by cortisol in negative feedback liwps. 

Many steroid hormones are regulated by this type of axis—e.g., thyroxin, cortisol, estradiol, progesterone, and testosterone. In the case of the glucocorticoids, the hypothalamus releases corticotropin-releasing hormone (CRH or corticoliberin, a peptide consisting of 41 amino acids), which in turn releases corticotropin (ACTFl, 39 AAs) in the pituitary gland. Corticotropin stimulates synthesis and release of the glandular steroid hormone cortisol in the adrenal cortex. 

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