ACTH secretion

The adrenal gland lies on the superior surface of each kidney. It is a double organ composed of an outer cortex and an inner medulla In response to ACTH secreted by the anterior pituitary, the adrenal cortex secretes several hormones (the glucocorticoids, the mineralocorticoids, and small amounts of sex hormones). 

Normally, circulating glucocorticoids (of which cortisol is the most prominent in humans) cause feedback inhibition of ACTH release so that cortisol secretion is, to some extent, self-limiting. However, many patients suffering from major depression have an increased concentration of plasma cortisol but reduced ACTH secretion. The latter abnormality seems to be partly due to a reduction in the number of CRF receptors in the pituitary, although it is thought that decreased ACTH secretion could provoke the adrenal hyperplasia which is common in depression. This would result in excessive secretion of cortisol and contribute to the inhibition of ACTH release (Musselman and Nemeroff 1993). 

Braughler, J.M., Chase, R.L., NefF, G.L., Yonkers, P.A., Day, J.S., HaU, E.D., Sethy, V.H. and Lahti, R.A. (1988). A new 21-amino steroid antioxidant lacking glucocorticoid activity stimulates ACTH secretion and blocks arachidonic acid release from mouse pituitary tumor (ArT-20) cells. J. Pharmacol. Exp. Ther, 244, 423-427. 

ACTH-secreting pituitary tumor (Cushing s disease)—70% of cases of endogenous Cushing s syndrome... 

ACTH-secreting non-pituitary tumors (ectopic ACTH syndrome)—15% of cases of endogenous Cushing s syndrome usually from small cell lung carcinoma, bronchial carcinoids, pheochromocytoma, or thymus, pancreatic, ovarian, or thyroid tumor. The tumor is usually disseminated (difficult to localize). 

Pharmacotherapy generally is reserved for patients (1) in whom the ectopic ACTH-secreting tumor cannot be localized ... 

The observed Li+-induced stimulation of corticotropin (ACTH) secretion from cells in culture, requiring extracellular Ca2+, involves a corresponding and apparently associated increase in the concentration of Ins(l)P, indicating some interaction with phosphoinositide metabolism [176], Pretreatment with Li+ desensitizes the cells, reducing this Li+-induced stimulation of ACTH secretion. Li+ initially raises plasma cortisol levels in manic-depressives however the levels are subsequently reduced with chronic Li+ treatment in both patients and controls [177]. This effect is probably secondary to the stimulation and subsequent desensitization of ACTH secretion by Li+, as observed in cultured cells. 

ACTH-dependent Cushing s syndrome is usually caused by overproduction of ACTH by the pituitary gland, causing adrenal hyperplasia (Cushing s disease). Pituitary adenomas account for about 80% of these cases. Ectopic ACTH-secreting tumors and nonneoplastic corticotropin hypersecretion are responsible for the remaining 20% of cases. 

Cyproheptadine can decrease ACTH secretion monitoring should include morning plasma cortisol and 24-hour urinary free cortisol concen-... 

Tretinoin can reduce ACTH secretion through inhibition of transcriptional activities. Its use has been limited to animal models, and efficacy in humans is undetermined. 

Receptors exhibit structural complementarity with their ligand in the same way that enzymes are complementary to their substrate. Often the actual binding of the hormone to its receptor involved just a small portion of both molecules. The peptide ACTH secreted by the pituitary gland contains 39 amino acids, but only about 12 of these near the N-terminal are required to engage the receptor. Furthermore, and as noted in Section 4.4.1, LH, FSH, TSH and hCG all share a common a subunit and their receptors recognize only the [3 unit. 

Hypotension T ACTH secretion T Insulin secretion T Glucagon secretion... 

Giving exogenous corticosteroids suppresses ACTH secretion which results in adrenal gland atrophy. Therefore glucocorticosteroid doses should be tapered off to allow the patient to adjust and prevent symptoms of adrenal insufficiency. For the short acting glucocorticosteroids an alternate day regimen should be considered to lower the risks for adrenal suppression. 

IV.a.1.9. Adrenal suppression. It results from inhibition of pituitary ACTH secretion, and some suppression of the normal adrenal response to stress may persist for years after stopping therapy. Rapid withdrawal of corticosteroid therapy can therefore precipitate dangerous acute adrenal insufficiency ( Addisonian crisis , with hypotension, vomiting, coma and ultimately death), and for this reason steroid treatment should always be reduced gradually, sometimes over many months, according to the dose and duration of therapy. 

Cushing s disease (caused by a pituitary ACTH-secreting adenoma) or Cushing s syndrome from an adrenal tumour is normally treated by surgical removal of the primary lesion where possible. Cases of ectopic ACTH syndrome associated with carcinoma of the bronchus cannot be treated surgically, and often benefit from medical therapy to control adrenal steroid excess. 

Asaba K, Makino S, Hashimoto K (1998) Effect of urocortin on ACTH secretion from rat anterior pituitary in vitro and in vivo comparison with corticotropin-releasing hormone. Brain Res 806 95-103... 

Wotjak CT, Ludwig M, Ebner K, Russell JA, Singewald N, Landgraf R, Engelmann M (2002) Vasopressin from hypothalamic magnocellular neurons has opposite actions at the adenohypophysis and in the supraoptic nucleus on ACTH secretion. Eur J Neurosci 16 477-485... 

Cortisone acetate and hydrocortisone are usually the corticoids of choice for replacement therapy in patients with primary adrenocortical insufficiency (such as Addison s disease), or after adrenalectomy where both glucocorticoid and mineralo-corticoid replacement is needed. In secondary adrenal insufficiency, associated with inadequate corticotrophin (ACTH) secretion, glucocorticoid replacement alone is usually adequate [62]. 

This hormone stimulates the cortex of adrenal gland to produce its hormones. The amount of ACTH secreted depends upon the concentration in the blood of the hormones from the adrenal cortex and on stimulation by hypothalamus. 

Urgent treatment is often begun with an oral dose of 30-60 mg prednisone per day or an intravenous dose of 1 mg/kg methylprednisolone every 6 hours the daily dose is decreased after airway obstruction has improved. In most patients, systemic corticosteroid therapy can be discontinued in a week or 10 days, but in other patients symptoms may worsen as the dose is decreased to lower levels. Because adrenal suppression by corticosteroids is related to dose and because secretion of endogenous corticosteroids has a diurnal variation, it is customary to administer corticosteroids early in the morning after endogenous ACTH secretion has peaked. For prevention of nocturnal asthma, however, oral or inhaled corticosteroids are most effective when given in the late afternoon. 

Corticotropinreleasing hormone (CRH) Used rarely to distinguish Cushing s disease from ectopic ACTH secretion... 

Secretion of adrenocortical steroids is controlled by the pituitary release of corticotropin (ACTH). Secretion of the salt-retaining hormone aldosterone is primarily under the influence of angiotensin. Corticotropin has some actions that do not depend on its effect on adrenocortical secretion. However, its pharmacologic value as an anti-inflammatory agent and its use in testing adrenal function depend on its secretory action. Its pharmacology is discussed in Chapter 37 and is reviewed only briefly here. 

The rate of aldosterone secretion is subject to several influences. ACTH produces a moderate stimulation of its release, but this effect is not sustained for more than a few days in the normal individual. Although aldosterone is no less than one third as effective as cortisol in suppressing ACTH, the quantities of aldosterone produced by the adrenal cortex and its plasma concentrations are insufficient to participate in any significant feedback control of ACTH secretion. 

The action of HA is indirect, mediated primarily via activation of corticotropin-releasing hormone (CRH) originating in parvocellular neurons in the PVN and secondly via vasopressin (AVP) originating in parvo- and magnocellular neurons in the PVN and in the SON [18-24]. The effect of CRH is predominantly mediating in character (i.e. HA releases CRH which subsequently stimulates ACTH secretion) [18] while the effect of AVP seem to be mediating as well as permissive in character (i.e. AVP has to be present in order for HA to exert its effect on ACTH secretion) [25]. Besides these two important mediators, prostaglandins are involved in HA-induced release of the POMC-derived peptides from the anterior lobe [26], whereas catecholamines, oxytocin (OT) and serotonin (5-HT) do not participate [27-28, Willems et al. (unpublished observations)]. 

Similar to the effect on restraint stress, RmHA (10 mg/kg x 2 ip) inhibited the ACTH and P-END response to insulin-induced hypoglycemia, which increases neuronal HA turnover [30-31]. This inhibitory effect was completely or partly reversed by THIOP. Likewise, the responses of the POMC-derived peptides and corticosterone to immune stimulation with the E.coli lipopolysaccharide (LPS) endotoxin, which augmented neuronal HA turnover, were reduced by RmHA pretreatment [39]. The effect of RmHA was equal to that of HA synthesis inhibition by a-FMH [39]. In lactating female rats suckling-induced ACTH secretion was reduced by pretreatment with RmHA (Fig. 6) as well as by a-FMH [32],... 

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