Adrenocorticotropic hormone synthesis

Pregnenolone is transported from the mitochondria to the ER, where a hydroxyl oxidation and migration of the double bond yield progesterone. Pregnenolone synthesis in the adrenal cortex is activated by adrenocorticotropic hormone (ACTH), a peptide of 39 amino acid residues secreted by the anterior pituitary gland. 

Adrenal hormone production is controlled by the hypothalamus and pituitary gland. Corticotropin-releasing hormone (CRH) is secreted by the hypothalamus and stimulates secretion of adrenocorticotropic hormone (ACTH), also known as corticotropin from the anterior pituitary. ACTH, in turn, stimulates the adrenal cortex to produce cortisol. When sufficient or excessive cortisol levels are reached, a negative feedback is exerted on the secretion of CRH and ACTH, thereby decreasing overall cortisol production. The control of adrenal androgen synthesis also follows a similar negative-feedback mechanism. 

Schimmer, B.P. and Parker, K.L., Adrenocorticotropic hormone adrenocortical steroids and their synthetic analogs inhibitors of the synthesis and actions of adrenocortical hormones, in Goodman and Gilman s The Pharmacological Basis of Therapeutics, 9th ed., Hardman, J.G. and Limbird, L.E., Eds., McGraw-Hill, New York, 1996, chap. 59. 

Amri H, Drieu K, Papadopoulos V. (1997). Ex vivo regulation of adrenal cortical cell steroid and protein synthesis, in response to adrenocorticotropic hormone stimulation, by the Ginkgo biloba extract EGb 761 and isolated ginkgolide B. Endocrinology. 138(12) 5415-26. 

Adrenocorticotropic hormone (ACTH] t adrenal steroid synthesis (e.g., cortisol]... 

Schimmer BP, Parker KL. Adrenocorticotropic hormone adrenocortical steroids and their synthetic analogs inhibitors of the synthesis and actions of adrenocortical hormones. In Brunton LL, et al, eds. 

The primary glucocorticoid released in humans is cortisol (also known as hydrocortisone). Cortisol synthesis and secretion are under the control of specific hypothalamic and pituitary hormones.7,24 31 Corticotropinreleasing hormone (CRH) from the hypothalamus stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH travels in the systemic circulation to reach the adrenal cortex, where it stimulates cortisol synthesis. Cortisol then travels in the bloodstream to various target tissues to exert a number of physiologic effects (see Physiologic Effects of Glucocorticoids, later). 

FIGURE 29-2 Negative feedback control of glucocorticoid synthesis. Cortisol limits its own synthesis by inhibiting the release of corticotropin-releasing hormone [CRH] from the hypothalamus and adrenocorticotropic hormone [ACTH] from the anterior pituitary. 

The adrenal glands are located anatomically above the kidneys. They comprise a three-layer cortex and a medulla. The medulla is the source of catecholamines such as epinephrine, the fight-or-flight hormone. The cortex is the source of aldosterone, the primary mineralocorticoid that is involved in the regulation of sodium reabsorption in the kidneys. In addition, the cortex is also the source of steroids known as glucocorticoids, of which cortisol is the principal endogenous representative. Synthesis and release of cortisol is under the control of adrenocorticotropic hormone (ACTH). 

Schimmer BP, Parker KL (1995) Adrenocorticotropic Hormone Adrenocortical Steroids and Their Synthetic Analogs Inhibitors of the Synthesis and Actions of Adrenocortical Hormones. In Hardman JG, Limbird LE (eds) Goodman Gilman s The Pharmacological Basis of Therapeutics, 9th Edition. McGraw-Hill, New York, pp 1459-1485 Sullivan AT, Kinter LB (1995) Status of safety pharmacology in the pharmaceutical industry 1995. Drug Dev Res 35 166-172... 

The glucocorticoid cortisol is secreted from the adrenal cortex as a stress response under the control of adrenocorticotropic hormone (ACTH, corticotropin) produced by the anterior pituitary. Cortisol promotes catabolism by inducing synthesis of specific proteins. Cortisol binds to a cytosolic cortisol receptor which then translocates to the nucleus and switches on the expression of specific genes, notably that for PEP carboxykinase (PEPCK). Cortisol-induced expression of the key gluconeogenesis enzyme PEPCK increases levels of the enzyme and hence increases gluconeogenesis and available blood glucose. The cAMP-and cortisol-mediated pathways for induction of PEPCK expression are further linked by CREB-dependent expression of a coactivator protein PGC-1 that promotes cortisol-dependent expression of PEPCK. 

IL-6 acts on the pituitary to induce adrenocorticotropic hormone (ACTH) release and directly on the adrenal glands to produce glucocorticoids. It is known that different cytoldnes that share gpl30 as a receptor subunit induce serum amyloid A, and potentiate the induction of IL-6 and the activation of the hypothalamic-pituitary-adrenal axis by IL-1. In particular, LIF, OSM, IL-11, and cardiotrophin-1 potentiate the elevation of serum corticosterone and IL-6 levels induced by IL-1. Furthermore, the potentiation of IL-1-induced serum corticosterone levels is not a consequence of the increased serum IL-6 observed after IL-1 administration. Thus either endogenous IL-6 does not mediate IL-l-induced corticosterone increase, or its role may be fulfilled by other cytokines. This is very important in the understanding of the activation of the hypothalamic-pituitary-adrenal axis and that potentiation of acute phase protein synthesis may represent an important feedback regulatory mechanism of inflammation. ... 

Fig. 3. Summary of key mechanisms of action through which a model adrenotoxicant (indicated by a black star) could disrupt the synthesis of corticosteroids. References presenting data in support of this model are given in the text. ACTH, adrenocorticotropic hormone Rc, receptor G, G-protein AC, adenylyl cyclase Ca, calcium ATP, adenosine triphosphate cAMP, cyclic adenosine monophosphate PKA, protein kinase A StAR, Steroid acute regulatory protein SCC, P450SCO, cholesterol side chain cleaving enzyme 11/3, 11/3-hydroxylase 17a, 17a-hydroxylase 3/3-HSD, 3/3-hydroxysteroid-5A-steroid dehydrogenase C21, 21-hydroxylase ER, endoplasmic reticulum.

ACTH Adrenocorticotropin, adrenocorticotropic hormone a polypeptide hormone released from the anterior pituitary into the bloodstream in response to the binding of CRH. ACTH binds to receptors in the adrenal cortex, causing the synthesis and release of cortisol. 

A study (Amri et al., 1996) of GB extract 761 in rats demonstrated that high doses (10-100 mg/kg) of the extract, as well as isolated ginkgolides A and B at doses of 2 mg/kg, decreased corticosteroid synthesis by up to 50% and 60%, respectively. An associated increase in adrenocorticotropic hormone (ACTH) levels was also seen. 

Corticotropin (ACTH) (adrenocorticotropic hormone) Stimulates steroid synthesis in adrenal cortex... 

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