Adrenal Glands Part 2

Control of Adrenal Cortical Hormone Synthesis Control of aldosterone synthesis: The control of aldosterone synthesis is more complex than that of the glucocorticoids Although cells of the zona glomerulosa express ACTH receptors and ACTH is required for optimal secretion, ACTH is not an important regulator of aldosterone production in most species Angiotensin II production is the hormonal signal for increase production of aldosterone Angiotensin II reacts with specific G-protein-coupled membrane receptors, but does not use cyclic AMP as its second messenger

Stimulation of Aldosterone Synthesis by Angiotensin II Angiotensin II (AII) activates G-protein subunits which cause: Activation of PLC to release IP3 & DAG IP3 causes increase in Ca2+ release DAG activates PKC to phosphorylate StAR and to open Ca2+ channels calmodulin-dependent protein kinase (CAM kinase II) increases the activity and synthesis of the StAR protein transfer of cholesterol into the mitochondria and the formation of pregnenolone The increase in cytosolic Ca2+ stimulates the enzymes which catalyzes the critical final reactions in aldosterone synthesis The resulting depolarization of the membrane opens voltage-gated calcium channels and allows calcium to enter. PLC: phospholipase C. , DAG: diacylglycerol; IP3: inositol trisphosphate; PKC: protein kinase C; CAM kinase II calcium: calmodulin-dependent protein kinase II; StAR: steroid acute regulatory protein

Regulation of Aldosterone by Potassium and Atrial Natriuretic Factor Cells of the zona glomerulosa are exquisitely sensitive to changes in concentration of potassium in the extracellular fluid As extracellular potassium increases voltage-sensitive calcium channels are activated This increases intracellular calcium and activates calmodulin kinase II which increases aldosterone as already described Synthesis and secretion of aldosterone are negatively regulated by atrial natriuretic factor (ANF): which activates potassium channels and thereby opposes opening of voltage sensitive calcium channels Additionally, ANF reduces synthesis and phosphorylation of the StAR protein and inhibits transcription of its gene

Adrenal Steroid Hormones in Blood Adrenal cortical hormones are transported in blood bound to a specific plasma protein: Transcortin or corticosteroid binding globulin (CBG), and to a lesser extent to albumin CBG has a single steroid hormone binding site whose affinity for cortisol is nearly 20 times higher than for aldosterone The androgens bind mainly to albumin Other endogenous steroids usually do not significantly affect cortisol binding to CBG; an exception is in late pregnancy, when progesterone may occupy about 25% of the binding sites on CBG

Postsecretory Metabolism of Adrenal Cortical Hormones Metabolic transformations of steroid hormones are not confined to the glands of origin, but may continue after secretion, and may increase, decrease, or otherwise change biological activity Several steroid metabolizing enzymes are expressed in steroid target tissues Under normal circumstances the concentration of free or unbound cortisol in plasma is about 100 times that of aldosterone the mineralocorticoid receptor binds aldosterone and cortisol with nearly equal affinity, it cannot distinguish between the two classes of steroid hormones Among these are two isoforms of the enzyme 11 β hydroxysteroid dehydrogenase (11 β HSD I and 11 β HSD II) HSD: hydroxysteroid dehydrogenase Oxidation of cortisol to cortisone renders the steroid incapable of binding to the mineralocorticoid receptor

Postsecretory Transformations of Androgens Dehydroepiandrosterone sulfate (DHEAS), the major product of the zona reticularis, is the most abundant steroid hormone in the circulation Neither DHEAS nor its close relative androstenedione bind to the androgen receptor, but these 19 carbon steroids are converted to active male and female sex hormones within some peripheral target cells For the most part, these peripherally formed hormones do not enter the circulation, and their biological actions are limited to the cells in which they are formed The term Intracrinology has been used to describe production of hormones by the cells in which they act without escaping into the extracellular fluid

Extra-adrenal Synthesis of Testosterone and Estrogens From DHEAS

Inactivation of Adrenal Cortical Steroids Mammals cannot degrade the ring structure of the steroid nucleus Steroid hormones are inactivated, mainly in the liver, by metabolic changes that make them unrecognizable to their receptors This also makes them more soluble to pass through renal glomerular capillaries and to be excreted in the urine Because recognizable hormonal derivatives are excreted in urine, it is possible to estimate daily secretory rates of steroid hormones by the noninvasive technique of measuring their abundance in urine The major products of adrenal steroid hormone degradation are glucuronide esters of 17-hydroxycorticosteroids (17-OHCS) derived from cortisol, and 17-ketosteroids (17 KS) derived from glucocorticoids and androgens.

Physiology of the Mineralocorticoids Aldosterone is by far the most important mineralocorticoid which can produce mineralocorticoid effects Reabsorption of sodium is diminished in the absence of aldosterone, and with loss of sodium, there is an: accompanying loss of water and a resulting decrease in blood volume Simultaneous with the loss of sodium, the ability to excrete potassium is impaired, and with continued dietary intake, plasma concentrations of potassium may increase Causes cardiac arrhythmia and weakness of muscles including the heart

Proposed Mechanisms of Action of Aldosterone in The Kidney Aldosterone sensitive cells, called principal cells Sodium enters principal cells in the cortical collecting ducts through epithelial sodium channels (ENaC) Na+ is extruded into the interstitial space by the sodium/potassium ATPase pump Potassium exits through ROMK (renal outer medullary K) channels in the luminal surface or through basolateral potassium channels

Proposed Mechanisms of Action of Aldosterone in The Kidney After a delay of ~30 minutes aldosterone increases expression of the serum glucocorticoid-induced kinase 1 (SGK1) SGK1 increases ENaC in luminal membranes by phosphorylating and inactivating the ubiquitin ligase Nedd4-2 that initiates ENaC retrieval SGK1 also phosphorylates and increases the activity of ROMK channels ROMK: renal outer medullary K+ MR: mineralocorticoid receptor; HSD II: 11 β-hydroxysteroid dehydrogenase II

Regulation of Aldosterone Secretion

Physiology of the Glucocorticoids Effects on energy metabolism

Physiology of the Glucocorticoids Effects on lung development Increase maturation and surfactant production during fetal development Glucocorticoids and responses to injury Exert anti-inflammatory effects, modulate synthesis, secretion, and actions of inflammatory mediators Glucocorticoids modulate virtually all aspects of the inflammatory response by multiple tissue-specific actions that modulate synthesis, secretion, and actions of inflammatory mediators

Regulation of Glucocorticoid Secretion In the absence of ACTH the concentration of cortisol in blood decreases to very low values, and the inner zones of the adrenal cortex atrophy Vasopressin (AVP) also exerts an important influence on ACTH secretion by augmenting the response to CRH