TranscortinHandbook of Hormones, Aiwu Zhou, in Methods in Enzymology The hormone-carrying serpins, thyroxine- and corticosteroid-binding globulinsTBG and CBG, provide a corticosteroid-binding example of the way the serpin conformational corticosteroid-binding can be adapted not only to give an irreversible switching-off of corticosteroid-binding but also more significantly to allow a constant dynamic modulation of activity. This is illustrated here with the demonstration that hormone release from both TBG and CBG corticosteroid-binding responsive to changes in ambient temperature and specifically to changes in body temperature. An exception to this adaptation of the serpin mechanism is corticosteroid-binding with corticosteroid-binding family member, corticoateroid-binding, in which hormone release is modulated by a redox anapolon headache and is apparently independent of changes in the serpin framework.
Corticosteroid-binding Globulin - an overview | ScienceDirect Topics
Handbook of Hormones, Aiwu Zhou, in Methods in Enzymology , The hormone-carrying serpins, thyroxine- and corticosteroid-binding globulins , TBG and CBG, provide a clear example of the way the serpin conformational mechanism can be adapted not only to give an irreversible switching-off of function but also more significantly to allow a constant dynamic modulation of activity.
This is illustrated here with the demonstration that hormone release from both TBG and CBG is responsive to changes in ambient temperature and specifically to changes in body temperature.
An exception to this adaptation of the serpin mechanism is seen with another family member, angiotensinogen, in which hormone release is modulated by a redox switch and is apparently independent of changes in the serpin framework.
Cutler, in Principles of Medical Biology , Albumin has a higher capacity but lower affinity for cortisol than CBG. Consequently, cortisol dissociates from albumin rapidly to become available to tissues.
CBG also has high affinity for cortisone, corticosterone, deoxycorticosterone, progesterone, and hydroxyprogesterone. Many factors can alter CBG concentration, which in turn affects the total level of plasma cortisol. Estrogens, thyroid hormone, and diabetes mellitus increase levels of CBG. Liver disease, nephrotic syndrome, hypothyroidism, multiple myeloma, and obesity decrease levels of CBG.
All steroid hormones have a common mechanism of action Figure 7. They bind to specific intracellular receptor s which may be cytoplasmic or nuclear. Many steroids bind to more than one type of receptor and thereby exert more than one effect in a given tissue.
The relative affinity for a receptor determines the relative bioactivity of that steroid. For example, cortisol, which binds tightly to the glucocorticoid receptor and weakly to the mineralocorticoid receptor, has primarily glucocorticoid activity and only modest mineralocorticoid activity. Binding of cortisol to the glucocorticoid receptor causes dissociation of an inhibitory protein heat shock protein. Primary cortisol resistance has been described due to mutations in the glucocorticoid receptor in patients presenting with hypercortisolism without signs of Cushing's syndrome or precocious puberty, due to ACTH-induced stimulation of adrenal androgens.
Glucocorticoids have multiple actions and are essential for survival Table 1. They regulate metabolism, immune, renal, cardiovascular, and central nervous system function, as well as growth and development. During stress, glucocorticoid levels can increase fold.
This increase enhances cardiac output and contractility; increases vascular resistance; mobilizes energy via lipolysis, gluconeogenesis, and proteolysis; and increases skeletal muscle contractility.
Cortisol exerts negative-feedback effects on the hypothalamus and pituitary, and may also inhibit higher cortical centers that lead to corticotropin-releasing hormone CRH stimulation. The amplitude and frequency of each ACTH pulse determines the daily cortisol production rate. The diurnal rise in cortisol secretion, as well as increased levels during stress, result from CNS stimulation of the HPA axis that transiently overrides the negative-feedback effects of cortisol.
It is secreted into the hypophyseal portal vessels in a pulsatile fashion and regulates the episodic secretion of ACTH and cortisol. Stress and other metabolic factors increase hypothalamic secretion of CRH and vasopressin. Adrenocorticotropic hormone ACTH is produced by corticotroph cells in the anterior pituitary and stimulates the adrenal cortex. ACTH regulates cortisol production by binding to G protein-coupled membrane receptors on adrenocortical cells.
Ultimately, this results in the conversion of cholesterol to pregnenolone by mechanisms that are still not well understood. ACTH also maintains adrenal size, enhances later steps in steroidogenesis, and increases cholesterol uptake from lipoproteins. Lloyd Axelrod, in Endocrinology: Adult and Pediatric Seventh Edition , In normal individuals, circadian fluctuations occur in the capacity of corticosteroid-binding globulin transcortin to bind cortisol and prednisolone. Patients who have received prednisone for a prolonged period have no diurnal variation in the binding capacity of corticosteroid-binding globulin for cortisol or prednisolone, and both capacities are reduced in comparison with normal persons.
Thus, long-term glucocorticoid therapy not only changes the endogenous secretion of steroids but also affects the transport of some glucocorticoids in the circulation. This may explain why the disappearance of prednisolone from the circulation is more rapid in those individuals who have previously received glucocorticoids. The pituitary—adrenal axis is altered minimally in cirrhosis. However, serum concentrations of corticosteroid-binding globulin are often decreased, and the serum halflives of both cortisol and dexamethasone are prolonged in cirrhotics, apparently as a consequence of hepatic parenchymal damage.
Thyroid hormone measurements are altered in patients with most chronic liver diseases, primarily as a consequence of changes in peripheral thyroid hormone metabolism. Thus, serum T3 is usually reduced and serum reverse T3 elevated in cirrhosis, while serum T4 is generally normal and serum TSH is normal or mildly elevated. In contrast to advanced alcoholic cirrhosis, patients with infectious hepatitis, chronic active hepatitis, and primary biliary cirrhosis may have elevated serum levels of thyroxine-binding globulin, thereby raising total serum T4 and T3, although free hormone levels and serum TSH are usually normal [,].
In patients with cirrhosis, basal serum GH is increased, and paradoxical increases in GH are observed following glucose ingestion or TRH administration [,]. These features appear to be independent of the etiology or structural changes of liver disease, and are observed with cirrhosis of any cause.
Serum levels of IGF-1 are depressed in patients with chronic liver disease and reduced negative feedback effects of IGF-1 on GH secretion may contribute to disordered GH regulation, as may changes in brain neurotransmitters that occur as a result of altered amino acid metabolism.
Abnormalities of GH secretion appear to return toward normal after successful liver transplantation, although effects of immunosuppressive drugs and residual encephalopathy complicate interpretation of the results. Serum PRL is sometimes mildly elevated in cirrhotic patients; this may reflect potentiating effects of estrogens on PRL release and a disordered hypothalamic neurotransmitter function.
Gonadal function and gonadotrophin secretion are altered in patients with cirrhosis; many of the changes appear to correlate with the degree of liver dysfunction, although some may be specifically due to toxic effects of ethanol on the testis. Men with advanced cirrhosis usually have decreased serum concentrations of total and free testosterone; estradiol is normal or mildly increased, and estrone considerably increased. Increased estrogen concentrations are primarily a consequence of increased peripheral aromatization of androgens especially androstenedione rather than decreased hepatic removal.
Serum LH is normal or moderately elevated. It has been argued that the failure of LH to rise substantially in the face of low free testosterone concentrations suggests concurrent hypothalamic—pituitary dysfunction; however, these findings may be due to gonadotrophin-suppressing effects of elevated serum estradiol, estrone, and other estrogen metabolites e.
Seminiferous tubule damage may occur in cirrhotics and alcoholics, with a rise in serum FSH concentrations. Gonadotrophin responses to GnRH are intact or blunted. Premenopausal women with alcoholic liver disease have lower serum estradiol but higher serum estrone levels than healthy women, again presumably due to altered peripheral steroid metabolism. Gonadotrophin concentrations are normal or low, and respond normally to GnRH. In summary, gonadal function is depressed in cirrhotics and further worsened by chronic alcohol intake.
There is partial reversal of these abnormalities following liver transplantation [,]. The half-life is relatively short at 15 to 20 minutes. The classic functions of aldosterone are regulation of extracellular volume and control of potassium homeostasis. These effects are mediated by the binding of free aldosterone to the mineralocorticoid receptor in the cytosol of epithelial cells, principally in the kidney. Mineralocorticoid receptors have tissue-specific expression.
For example, the tissues with the highest concentrations of these receptors are the distal nephron, colon, and hippocampus. Lower levels of mineralocorticoid receptors are found in the rest of the gastrointestinal tract and heart. Transport to the nucleus and binding to specific binding domains on targeted genes leads to their increased expression.
Aldosterone-regulated kinase appears to be a key intermediary, and its increased expression leads to modification of the apical sodium channel, resulting in increased sodium ion transport across the cell membrane see Chapter The increased luminal negativity augments tubular secretion of potassium by the tubular cells and of hydrogen ion by the interstitial cells.
Glucocorticoids and mineralocorticoids bind equally to the mineralocorticoid receptor. Mineralocorticoid escape refers to the counterregulatory mechanisms that are manifested after 3 to 5 days of excessive mineralocorticoid administration. Several mechanisms contribute to this escape, including renal hemodynamic factors and increased levels of atrial natriuretic peptide. In addition to the classic genomic actions mediated by aldosterone binding to cytosolic receptors, mineralocorticoids have acute, nongenomic actions resulting from activation of an unidentified cell surface receptor.
This action involves a G protein signaling pathway and probably a modification of the sodium-hydrogen exchange activity. This effect has been demonstrated in both epithelial and nonepithelial cells. Aldosterone has additional, nonclassic effects primarily on nonepithelial cells. Aldosterone-mediated actions include the expression of several collagen genes; genes controlling tissue growth factors e. The action of angiotensin II on aldosterone involves a negative feedback loop that also includes extracellular fluid volume Fig.
Sodium restriction activates the RAA axis. The effects of angiotensin II on both the adrenal cortex and the renal vasculature promote renal sodium conservation.
On the other hand, with suppression of renin release and suppression of the level of circulating angiotensin, aldosterone secretion is reduced and renal blood flow is increased, promoting sodium loss. The RAA loop is very sensitive to dietary sodium intake. Sodium excess enhances the responsiveness of the renal and peripheral vasculature and reduces the adrenal responsiveness to angiotensin II. Sodium restriction has the opposite effect. Therefore, sodium intake modifies target tissue responsiveness to angiotensin II, a fine-tuning mechanism that appears to be critical to maintaining normal sodium homeostasis without a chronic effect on blood pressure.
Excess aldosterone secretion causes hypertension through two main mechanisms: It has a single steroid hormone binding site whose affinity for cortisol is nearly 20 times higher than for aldosterone. Under normal circumstances the concentration of free or unbound cortisol in plasma is about times that of aldosterone.
Probably because they circulate bound to plasma proteins, adrenal steroids have a relatively long half-life in blood: Some of the circulating glucocorticoid also binds nonspecifically to albumin, as described for thyroid hormones see Chapter 6. Although there is a bias for assuming that free hormone is most important for entering target cells and producing effects, there also is evidence to support a role for interaction of occupied CBG with target cell membranes that facilitates dissociation of glucocorticoids from CBG and their entrance into the target cell.
Aldosterone does not bind significantly to CBG or other plasma proteins; consequently, aldosterone is present primarily in the free state at much lower total concentrations in the blood than are the glucocorticoids. Aldosterone is cleared from the blood much more rapidly because of the lack of binding proteins.
Both natural and synthetic steroids are highly lipophilic and largely bound to one of two plasma proteins: Free steroid molecules diffuse across the cell membrane where they interact with glucocorticoid receptors GR in the cytoplasm Fig. Interaction with a glucocorticoid molecule leads to shedding of the heat-shock protein to expose the active site. The resultant activated receptor GRa then diffuses into the nucleus where it interacts with a specific glucocorticoid response element GRE on the chromatin of the DNA to influence transcription and, consequently, de novo synthesis of steroid-susceptible proteins.
Glucocorticoids may also down-regulate transcription. An example of this is the inhibition of transcription of activating protein-1 AP-1 , a factor responsible for the synthesis of many proinflammatory cytokines and growth factors. The complexities of these processes account for the considerable time delay of 6—12 hours, even after intravenous administration, before the beneficial effects of corticosteroids begin to be observed.