Synthesis, secretion and metabolism of adrenal cortical hormones

The differences between the chemical structure of the main steroid compounds synthesized in the adrenal glands come down to the unequal saturation of carbon atoms and the presence of additional groups. To designate steroid hormones, not only systematic chemical nomenclature (often quite cumbersome) is used, but also trivial names.

The initial structure for the synthesis of steroid hormones is cholesterol. The amount of steroids produced depends on the activity of enzymes catalyzing individual stages of the corresponding transformations. These enzymes are localized in various fractions of the cell - mitochondria, microsomes and cytosol. Cholesterol used for the synthesis of steroid hormones is formed in the adrenal glands themselves from acetate and partially enters the gland with molecules of low-density lipoproteins (LDL) or high-density lipoproteins (HDL), synthesized in the liver. Different sources of cholesterol in these cells are mobilized differently under different conditions. Thus, an increase in the production of steroid hormones under conditions of acute stimulation of ACTH is ensured by the conversion of a small amount of free cholesterol formed as a result of the hydrolysis of these esters. At the same time, the synthesis of cholesterol from acetate also increases. With prolonged stimulation of the adrenal cortex, cholesterol synthesis, on the contrary, decreases, and its main source becomes plasma lipoproteins (against the background of an increase in the number of LDL receptors). With abetalipoproteinemia (absence of LDL), the adrenal glands respond to ACTH with a smaller than normal release of cortisol.

In the mitochondria, cholesterol is converted into pregnenolone, which is the precursor of all vertebrate steroid hormones. Its synthesis is a multi-stage process. It limits the rate of biosynthesis of adrenal steroids and is subject to regulation (by ACTH, angiotensin II, and potassium, see below). In different zones of the adrenal cortex, pregnenolone undergoes various transformations. In the zona glomerulosa, it is converted mainly into progesterone and then into 11-deoxycorticosterone (DOC), and in the zona fasciculata, into 17a-oxypregnenolone, which serves as a precursor of cortisol, androgens, and estrogens. In the pathway of cortisol synthesis, 17a-hydroxyprogesterone is formed from 17a-hydroxypregnenolone, which is sequentially hydroxylated by 21- and 11 beta-hydroxylases into 11-deoxycortisol (cortexolone, or compound S), and then (in the mitochondria) into cortisol (hydrocortisone, or compound F).

The main product of the zona glomerulosa of the adrenal cortex is aldosterone, the synthesis pathway of which includes intermediate stages of the formation of progesterone, DOC, corticosterone (compound B) and 18-hydroxycorticosterone. The latter, under the action of mitochondrial 18-hydroxysteroid dehydrogenase, acquires an aldehyde group. This enzyme is present only in the zona glomerulosa. On the other hand, it lacks 17a-hydroxylase, which prevents the formation of cortisol in this zone. DOC can be synthesized in all three zones of the cortex, but the greatest amount is produced in the zona fasciculata.

Among the secretory products of the fasciculate and reticular zones there are also C-19 steroids with androgenic activity: dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), androstenedione (and its 11beta-analog) and testosterone. All of them are formed from 17a-oxypregnenolone. In quantitative terms, the main androgens of the adrenal glands are DHEA and DHEA-S, which can be converted into each other in the gland. DHEA is synthesized with the participation of 17a-hydroxylase, which is absent in the glomerular zone. The androgenic activity of adrenal steroids is mainly due to their ability to be converted into testosterone. The adrenal glands themselves produce very little of this substance, as well as estrogens (estrone and estradiol). However, adrenal androgens can serve as a source of estrogens formed in subcutaneous fat, hair follicles, and the mammary gland. In the fetal zone of the adrenal cortex, 3beta-hydroxysteroid dehydrogenase activity is absent, and therefore the main products are DHEA and DHEA-S, which are converted in the placenta into estrogens, providing 90% of estriol production and 50% of estradiol and estrone in the mother's body.

The steroid hormones of the adrenal cortex are bound to plasma proteins in different ways. As for cortisol, 90-93% of the hormone present in plasma is bound. About 80% of this binding is due to specific corticosteroid-binding globulin (transcortin), which has a high affinity for cortisol. A smaller amount of the hormone is bound to albumin and a very small amount to other plasma proteins.

Transcortin is synthesized in the liver. It is a glycosylated protein with a relative molecular weight of about 50,000, binding up to 25 μg% of cortisol in a healthy person. Therefore, at high concentrations of the hormone, the level of free cortisol will no longer be proportional to its total content in the plasma. Thus, at a total concentration of cortisol in the plasma of 40 μg%, the concentration of free hormone (about 10 μg%) will be 10 times higher than at a total cortisol level of 10 μg%. As a rule, transcortin, due to its greatest affinity for cortisol, binds only to this steroid, but at the end of pregnancy, as much as 25% of the steroid bound by transcortin is represented by progesterone. The nature of the steroid in combination with transcortin may also change in congenital adrenal hyperplasia, when the latter produce large amounts of corticosterone, progesterone, 11-deoxycortisol, DOC, and 21-deoxycortisol. Most synthetic glucocorticoids are weakly bound to transcortin. Its level in plasma is regulated by various factors (including hormonal ones). Thus, estrogens increase the content of this protein. Thyroid hormones have a similar property. An increase in the level of transcortin is noted in diabetes mellitus and a number of other diseases. For example, liver and kidney (nephrosis) changes are accompanied by a decrease in the content of transcortin in plasma. Transcortin synthesis may also be inhibited by glucocorticoids. Genetically determined fluctuations in the level of this protein are usually not accompanied by clinical manifestations of hyper- or hypocorticism.

Unlike cortisol and a number of other steroids, aldosterone does not interact specifically with plasma proteins. It is only very weakly bound to albumin and transcortin, as well as to erythrocytes. Under physiological conditions, only about 50% of the total amount of the hormone is bound to plasma proteins, with 10% of it associated with transcortin. Therefore, with an increase in the level of cortisol and complete saturation of transcortin, the level of free aldosterone may change insignificantly. The bond of aldosterone with transcortin is stronger than with other plasma proteins.

Adrenal androgens, with the exception of testosterone, bind predominantly to albumin, and rather weakly. Testosterone, on the other hand, almost completely (98%) specifically interacts with testosterone-estradiol-binding globulin. The concentration of the latter in plasma increases under the influence of estrogens and thyroid hormones and decreases under the influence of testosterone and STH.

Hydrophobic steroids are filtered by the kidneys, but are almost entirely (95% of cortisol and 86% of aldosterone) reabsorbed in the tubules. Their excretion with urine requires enzymatic transformations that increase their solubility. They are mainly reduced to the transition of ketone groups to carboxyl and C-21 groups to acidic forms. Hydroxyl groups are able to interact with glucuronic and sulfuric acids, which further increases the water solubility of steroids. Among the many tissues in which their metabolism occurs, the most important place is occupied by the liver, and during pregnancy - the placenta. Some of the metabolized steroids enter the contents of the intestine, from where they can be reabsorbed unchanged or modified.

Cortisol disappears from the blood with a half-life of 70-120 minutes (depending on the administered dose). About 70% of the labeled hormone enters the urine per day; 90% of this hormone is excreted with urine in 3 days. About 3% is found in feces. Unchanged cortisol makes up less than 1% of excreted labeled compounds. The first important stage of hormone degradation is the irreversible restoration of the double bond between the 4th and 5th carbon atoms. This reaction produces 5 times more 5a-dihydrocortisol than its 5beta form. Under the action of 3-hydroxysteroid cehydrogenase, these compounds are quickly converted into tetrahydrocortisol. Oxidation of the 11beta-hydroxyl group of cortisol leads to the formation of cortisone. In principle, this transformation is reversible, but due to the smaller amount of cortisone produced by the adrenal glands, it is shifted towards the formation of this particular compound. The subsequent metabolism of cortisone occurs like that of cortisol and goes through the stages of dihydro- and tetrahydroforms. Therefore, the ratio between these two substances in the urine is also preserved for their metabolites. Cortisol, cortisone and their tetrahydro derivatives can undergo other transformations, including the formation of cortols and cortolones, cortolic and cortolic acids (oxidation in the 21st position) and oxidation of the side chain in the 17th position. β-hydroxylated metabolites of cortisol and other steroids can also be formed. In children, as well as in a number of pathological conditions, this pathway of cortisol metabolism acquires primary importance. 5-10% of cortisol metabolites are C-19, 11-hydroxy and 17-ketosteroids.

The half-life of aldosterone in plasma does not exceed 15 minutes. It is almost completely extracted by the liver in one blood passage, and less than 0.5% of the native hormone is found in the urine. About 35% of aldosterone is excreted as tetrahydroaldosterone glucuronide, and 20% as aldosterone glucuronide. This metabolite is called acid-labile, or 3-oxo-conjugate. Part of the hormone is found in the urine as 21-deoxytetrahydroaldosterone, which is formed from tetrahydroaldosterone excreted with bile under the influence of intestinal flora and is reabsorbed into the blood.

More than 80% of androstenedione and only about 40% of testosterone are eliminated in one blood passage through the liver. Mostly androgen conjugates enter the urine. A small proportion of them is excreted through the intestine. DHEA-S can be excreted unchanged. DHEA and DHEA-S are capable of further metabolism through hydroxylation at the 7- and 16-positions or conversion of the 17-keto group into a 17-hydroxy group. DHEA is also irreversibly transformed into androstenedione. The latter can be converted into testosterone (mainly outside the liver), as well as into androsterone and etiocholanolone. Further reduction of these steroids leads to the formation of androstanediol and etiocholandiol. Testosterone in target tissues is converted to 5a-dihydrotestosterone, which is irreversibly inactivated, turning into 3a-androstanediol, or reversibly into 5a-androstenedione. Both of these substances can be transformed into androsterone. Each of the listed metabolites is capable of forming glucuronides and sulfates. In men, testosterone and androstenedione disappear from plasma 2-3 times faster than in women, which is probably explained by the effect of sex steroids on the level of testosterone-estradiol-binding protein in plasma.

Physiological effects of adrenal cortex hormones and their mechanism of action

The compounds produced by the adrenal glands influence many metabolic processes and body functions. The very names - gluco- and mineralocorticoids - indicate that they perform important functions in regulating various aspects of metabolism.

Excess glucocorticoids increase glycogen formation and glucose production by the liver and decrease glucose uptake and utilization by peripheral tissues. This results in hyperglycemia and decreased glucose tolerance. In contrast, glucocorticoid deficiency decreases hepatic glucose production and increases insulin sensitivity, which can lead to hypoglycemia. The effects of glucocorticoids are opposite to those of insulin, whose secretion increases under conditions of steroid hyperglycemia. This leads to normalization of fasting blood glucose levels, although impaired carbohydrate tolerance may persist. In diabetes mellitus, excess glucocorticoids worsen impaired glucose tolerance and increase the body's need for insulin. In Addison's disease, less insulin is released in response to glucose intake (due to the small increase in blood sugar levels), so the tendency toward hypoglycemia is mitigated and fasting sugar levels usually remain normal.

Stimulation of hepatic glucose production under the influence of glucocorticoids is explained by their action on the processes of gluconeogenesis in the liver, the release of gluconeogenesis substrates from peripheral tissues and the gluconeogenic effect of other hormones. Thus, in well-fed adrenalectomized animals, basal gluconeogenesis is preserved, but its ability to increase under the influence of glucagon or catecholamines is lost. In hungry animals or animals with diabetes mellitus, adrenalectomy leads to a decrease in the intensity of gluconeogenesis, which is restored by the introduction of cortisol.

Under the influence of glucocorticoids, virtually all stages of gluconeogenesis are activated. These steroids increase the overall synthesis of protein in the liver with an increase in the formation of a number of transaminases. However, the most important stages of gluconeogenesis for the action of glucocorticoids apparently occur after transamination reactions, at the level of functioning of phosphoenolpyruvate carboxykinase and glucose-6-phosphate dehydrogenase, the activity of which increases in the presence of cortisol.

In muscles, adipose and lymphoid tissues, steroids not only inhibit protein synthesis, but also accelerate its breakdown, which leads to the release of amino acids into the blood. In humans, the acute effect of glucocorticoids is manifested by a selective and pronounced increase in the content of branched-chain amino acids in plasma. With prolonged action of steroids, only the level of alanine increases. Against the background of starvation, the level of amino acids increases only briefly. The rapid effect of glucocorticoids is probably explained by their anti-insulin action, and the selective release of alanine (the main substrate of gluconeogenesis) is due to direct stimulation of transamination processes in tissues. Under the influence of glucocorticoids, the release of glycerol from adipose tissue (due to stimulation of lipolysis) and lactate from muscles also increases. Acceleration of lipolysis leads to an increased flow of free fatty acids into the blood, which, although they do not serve as direct substrates for gluconeogenesis, by providing this process with energy, save other substrates that can be converted into glucose.

An important effect of glucocorticoids in the sphere of carbohydrate metabolism is also the inhibition of glucose absorption and utilization by peripheral tissues (mainly adipose and lymphoid). This effect can manifest itself even earlier than the stimulation of gluconeogenesis, due to which, after the introduction of cortisol, glycemia increases even without an increase in glucose production by the liver. There is also data on the stimulation of glucagon secretion and inhibition of insulin secretion by glucocorticoids.

The redistribution of body fat observed in Itsenko-Cushing syndrome (deposits on the neck, face and trunk and disappearance on the limbs) may be associated with the unequal sensitivity of various fat depots to steroids and insulin. Glucocorticoids facilitate the lipolytic action of other hormones (somatotropic hormone, catecholamines). The effect of glucocorticoids on lipolysis is mediated by inhibition of glucose absorption and metabolism in adipose tissue. As a result, the amount of glycerol required for re-esterification of fatty acids decreases, and more free fatty acids enter the blood. The latter causes a tendency to ketosis. In addition, glucocorticoids can directly stimulate ketogenesis in the liver, which is especially pronounced under conditions of insulin deficiency.

The effect of glucocorticoids on the synthesis of specific RNA and proteins has been studied in detail for individual tissues. However, they also have a more general effect in the body, which comes down to stimulating the synthesis of RNA and protein in the liver, inhibiting it, and stimulating its breakdown in peripheral tissues such as muscle, skin, adipose and lymphoid tissue, fibroblasts, but not the brain or heart.

Glucocorticoids, like other steroid compounds, exert their direct effects on the cells of the body by initially interacting with cytoplasmic receptors. They have a molecular weight of about 90,000 daltons and are asymmetric and possibly phosphorylated proteins. Each target cell contains from 5,000 to 100,000 cytoplasmic glucocorticoid receptors. The binding affinity of these proteins to the hormone is almost identical to the concentration of free cortisol in the plasma. This means that receptor saturation normally ranges from 10 to 70%. There is a direct correlation between the binding of steroids to cytoplasmic receptors and the glucocorticoid activity of hormones.

Interaction with the hormone causes a conformational change (activation) of the receptors, as a result of which 50-70% of the hormone-receptor complexes bind to certain regions of nuclear chromatin (acceptors) containing DNA and, possibly, some nuclear proteins. Acceptor regions are present in the cell in such large quantities that they are never completely saturated with hormone-receptor complexes. Some of the acceptors interacting with these complexes generate a signal that leads to acceleration of transcription of specific genes with a subsequent increase in the level of mRNA in the cytoplasm and increased synthesis of the proteins encoded by them. Such proteins may be enzymes (for example, those involved in gluconeogenesis), which will determine specific reactions to the hormone. In some cases, glucocorticoids reduce the level of specific mRNA (for example, those encoding the synthesis of ACTH and beta-endorphin). The presence of glucocorticoid receptors in most tissues distinguishes these hormones from steroids of other classes, the tissue representation of receptors for which is much more limited. The concentration of glucocorticoid receptors in a cell limits the magnitude of the response to these steroids, which distinguishes them from hormones of other classes (polypeptide, catecholamines), for which there is an "excess" of surface receptors on the cell membrane. Since glucocorticoid receptors in different cells are apparently the same, and the responses to cortisol depend on the cell type, the expression of a particular gene under the influence of the hormone is determined by other factors.

Recently, data have been accumulating on the possible action of glucocorticoids not only through gene transcription mechanisms but also, for example, by modifying membrane processes; however, the biological significance of such effects remains unclear. There are also reports of heterogeneity of glucocorticoid-binding cellular proteins, but it is unknown whether all of them are true receptors. Although steroids belonging to other classes can also interact with glucocorticoid receptors, their affinity for these receptors is usually lower than for specific cellular proteins that mediate other effects, in particular mineralocorticoid ones.

Mineralocorticoids (aldosterone, cortisol, and sometimes DOC) regulate ion homeostasis by influencing the kidneys, intestines, salivary and sweat glands. Their direct effect on the vascular endothelium, heart, and brain cannot be ruled out. However, in any case, the number of tissues in the body that are sensitive to mineralocorticoids is much smaller than the number of tissues that respond to glucocorticoids.

The most important of the currently known target organs of mineralocorticoids are the kidneys. Most of the effects of these steroids are localized in the collecting ducts of the cortex, where they promote increased sodium reabsorption, as well as the secretion of potassium and hydrogen (ammonium). These actions of mineralocorticoids occur 0.5-2 hours after their administration, are accompanied by activation of RNA and protein synthesis, and persist for 4-8 hours. With a mineralocorticoid deficiency, sodium loss, potassium retention, and metabolic acidosis develop in the body. Excess hormones cause opposite shifts. Under the influence of aldosterone, only a portion of the sodium filtered by the kidneys is reabsorbed, so under conditions of salt load, this effect of the hormone is weaker. Moreover, even with normal sodium intake, in conditions of excess aldosterone, the phenomenon of escape from its action occurs: sodium reabsorption in the proximal renal tubules decreases and eventually its excretion comes into line with intake. The presence of this phenomenon can explain the absence of edema in chronic aldosterone excess. However, in edema of cardiac, hepatic or renal origin, the body's ability to "escape" from the action of mineralocorticoids is lost, and secondary hyperaldosteronism developing in such conditions aggravates fluid retention.

With respect to the secretion of potassium by the renal tubules, the escape phenomenon is absent. This effect of aldosterone depends to a large extent on sodium intake and becomes evident only under conditions of sufficient sodium intake in the distal renal tubules, where the effect of mineralocorticoids on its reabsorption is manifested. Thus, in patients with a reduced glomerular filtration rate and increased sodium reabsorption in the proximal renal tubules (heart failure, nephrosis, liver cirrhosis), the kaliuretic effect of aldosterone is practically absent.

Mineralocorticoids also increase urinary excretion of magnesium and calcium. These effects, in turn, are related to the action of hormones on renal sodium dynamics.

The important hemodynamic effects of mineralocorticoids (in particular, changes in blood pressure) are largely mediated by their renal action.

The mechanism of aldosterone's cellular effects is generally the same as that of other steroid hormones. Cytosolic mineralocorticoid receptors are present in target cells. Their affinity for aldosterone and DOC is much greater than their affinity for cortisol. After interaction with the steroid that has penetrated the cell, hormone-receptor complexes bind to nuclear chromatin, increasing the transcription of certain genes with the formation of specific mRNA. Subsequent reactions, caused by the synthesis of specific proteins, probably consist of an increase in the number of sodium channels on the apical surface of the cell. In addition, under the influence of aldosterone, the ratio of NAD-H/NAD and the activity of a number of mitochondrial enzymes (citrate synthetase, glutamate dehydrogenase, malate dehydrogenase, and glutamate oxalacetate transaminase) that participate in the generation of biological energy necessary for the functioning of sodium pumps (on the serous surface of the distal renal tubules) increase in the kidneys. The effect of aldosterone on phospholipase and acyltransferase activity cannot be ruled out, as a result of which the phospholipid composition of the cell membrane and ion transport change. The mechanism of action of mineralocorticoids on the secretion of potassium and hydrogen ion in the kidneys is less studied.

The effects and mechanism of action of adrenal androgens and estrogens are discussed in the chapters on sex steroids.

Regulation of hormone secretion by the adrenal cortex

The production of adrenal glucocorticoids and androgens is controlled by the hypothalamic-pituitary system, whereas the production of aldosterone is controlled primarily by the renin-angiotensin system and potassium ions.

The hypothalamus produces corticoliberin, which enters the anterior pituitary gland through the portal vessels, where it stimulates the production of ACTH. Vasopressin has similar activity. ACTH secretion is regulated by three mechanisms: the endogenous rhythm of corticoliberin release, its stress-induced release, and the mechanism of negative feedback, realized mainly by cortisol.

ACTH causes rapid and sharp shifts in the adrenal cortex. Blood flow in the gland and cortisol synthesis increase within 2-3 minutes after ACTH administration. In a few hours, the mass of the adrenal glands can double. Lipids disappear from the cells of the fascicular and reticular zones. Gradually, the boundary between these zones is smoothed out. The cells of the fascicular zone resemble the cells of the reticular zone, which creates the impression of a sharp expansion of the latter. Long-term stimulation of ACTH causes both hypertrophy and hyperplasia of the adrenal cortex.

Increased synthesis of glucocorticoids (cortisol) is due to the acceleration of the conversion of cholesterol into pregnenolone in the fascicular and reticular zones. Other stages of cortisol biosynthesis are probably also activated, as well as its excretion into the blood. At the same time, small amounts of intermediate products of cortisol biosynthesis enter the blood. With longer stimulation of the cortex, the formation of total protein and RNA increases, which leads to hypertrophy of the gland. Already after 2 days, an increase in the amount of DNA in it can be recorded, which continues to grow. In the case of adrenal atrophy (as with a decrease in the ACTH level), the latter react to endogenous ACTH much more slowly: stimulation of steroidogenesis occurs almost a day later and reaches a maximum only by the 3rd day after the start of replacement therapy, and the absolute value of the reaction is reduced.

On the membranes of adrenal cells, sites have been found that bind ACTH with varying affinity. The number of these sites (receptors) decreases at high and increases at low ACTH concentrations ("downregulation"). Nevertheless, the overall sensitivity of the adrenal glands to ACTH under conditions of its high content not only does not decrease, but, on the contrary, increases. It is possible that ACTH under such conditions stimulates the appearance of some other factors, the effect of which on the adrenal gland "overcomes" the effect of downregulation. Like other peptide hormones, ACTH activates adenylate cyclase in target cells, which is accompanied by phosphorylation of a number of proteins. However, the sterogenic effect of ACTH may be mediated by other mechanisms, for example, by potassium-dependent activation of adrenal phospholipase A ₂. Be that as it may, under the influence of ACTH, the activity of esterase, releasing cholesterol from its esters, increases, and cholesterol ester synthetase is inhibited. The capture of lipoproteins by adrenal cells also increases. Then, free cholesterol on the carrier protein enters the mitochondria, where it is converted into pregnenolone. The effect of ACTH on cholesterol metabolism enzymes does not require activation of protein synthesis. Under the influence of ACTH, the conversion of cholesterol into pregnenolone itself is apparently accelerated. This effect is no longer manifested under conditions of inhibition of protein synthesis. The mechanism of the trophic effect of ACTH is unclear. Although hypertrophy of one of the adrenal glands after removal of the second is certainly associated with the activity of the pituitary gland, specific antiserum to ACTH does not prevent such hypertrophy. Moreover, the introduction of ACTH itself during this period even reduces the DNA content in the hypertrophic gland. In vitro, ACTH also inhibits the growth of adrenal cells.

There is a circadian rhythm of steroid secretion. The plasma cortisol level begins to rise several hours after the onset of night sleep, reaches its maximum soon after awakening, and falls in the morning. In the afternoon and until evening, the cortisol content remains very low. These fluctuations are superimposed by episodic "bursts" of the cortisol level, occurring with varying periodicity - from 40 minutes to 8 hours or more. Such emissions account for about 80% of all cortisol secreted by the adrenal glands. They are synchronized with ACTH peaks in plasma and, apparently, with hypothalamic corticoliberin emissions. Diet and sleep patterns play a significant role in determining the periodic activity of the hypothalamic-pituitary-adrenal system. Under the influence of various pharmacological agents, as well as in pathological conditions, the circadian rhythm of ACTH and cortisol secretion is disrupted.

A significant place in the regulation of the activity of the system as a whole is occupied by the mechanism of negative feedback between glucocorticoids and the formation of ACTH. The former inhibit the secretion of corticoliberin and ACTH. Under stress, the release of ACTH in adrenalectomized individuals is much greater than in intact ones, while exogenous administration of glucocorticoids significantly limits the increase in the concentration of ACTH in the plasma. Even in the absence of stress, adrenal insufficiency is accompanied by a 10-20-fold increase in the ACTH level. A decrease in the latter in humans is observed as early as 15 minutes after the administration of glucocorticoids. This early inhibitory effect depends on the rate of increase in the concentration of the latter and is probably mediated by their effect on the membrane of pituicytes. Later inhibition of pituitary activity depends mainly on the dose (and not the rate) of the administered steroids and is manifested only under conditions of intact RNA and protein synthesis in corticotrophs. There are data indicating the possibility of mediation of early and late inhibitory effects of glucocorticoids by different receptors. The relative role of inhibition of corticoliberin secretion and directly ACTH in the feedback mechanism requires further clarification.

Adrenal production of mineralocorticoids is regulated by other factors, the most important of which is the renin-angiotensin system. Renin secretion by the kidneys is controlled primarily by the concentration of chloride ion in the fluid surrounding the juxtaglomerular cells, as well as by renal vascular pressure and beta-adrenergic substances. Renin catalyzes the conversion of angiotensinogen to the decapeptide angiotensin I, which is cleaved to form the octapeptide angiotensin II. In some species, the latter undergoes further transformations to yield the heptapeptide angiotensin III, which is also capable of stimulating the production of aldosterone and other mineralocorticoids (DOC, 18-hydroxycorticosterone, and 18-oxydeoxycorticosterone). In human plasma, the level of angiotensin III is no more than 20% of the level of angiotensin II. Both stimulate not only the conversion of cholesterol into pregnenolone, but also corticosterone into 18-hydroxycorticosterone and aldosterone. It is believed that the early effects of angiotensin are due mainly to the stimulation of the initial stage of aldosterone synthesis, whereas in the mechanism of long-term effects of angiotensin, its influence on subsequent stages of the synthesis of this steroid plays a large role. There are angiotensin receptors on the surface of the cells of the glomerular zone. Interestingly, in the presence of excess angiotensin II, the number of these receptors does not decrease, but on the contrary, increases. Potassium ions have a similar effect. Unlike ACTH, angiotensin II does not activate adrenal adenylate cyclase. Its action depends on the concentration of calcium and is probably mediated by the redistribution of this ion between the extra- and intracellular environment. Prostaglandin synthesis may play a certain role in mediating the effect of angiotensin on the adrenal glands. Thus, prostaglandins of the E series (their level in the serum increases after the introduction of angiotensin II), unlike P1T, are capable of stimulating the secretion of aldosterone, and inhibitors of prostaglandin synthesis (indomethacin) reduce the secretion of aldosterone and its response to angiotensin II. The latter also has a trophic effect on the glomerular zone of the adrenal cortex.

An increase in plasma potassium also stimulates aldosterone production, and the adrenal glands are highly sensitive to potassium. Thus, a change in its concentration by only 0.1 mEq/l, even within physiological fluctuations, affects the rate of aldosterone secretion. The effect of potassium does not depend on sodium or angiotensin II. In the absence of kidneys, potassium probably plays a major role in regulating aldosterone production. Its ions do not affect the function of the zona fasciculata of the adrenal cortex. Directly acting on aldosterone production, potassium at the same time reduces renin production by the kidneys (and, accordingly, the concentration of angiotensin II). However, the direct effect of its ions is usually stronger than the counterregulatory effect mediated by a decrease in renin. Potassium stimulates both the early (conversion of cholesterol to pregnenolone) and late (change of corticosterone or DOC to aldosterone) stages of mineralocorticoid biosynthesis. Under conditions of hyperkalemia, the plasma 18-hydroxycorticosterone/aldosterone concentration ratio increases. The effects of potassium on the adrenal cortex, like those of angiotensin II, are highly dependent on the presence of potassium ions.

Aldosterone secretion is also controlled by the serum sodium level. Salt load reduces the production of this steroid. To a large extent, this effect is mediated by the effect of sodium chloride on the release of renin. However, a direct effect of sodium ions on the processes of aldosterone synthesis is also possible, but it requires very sharp changes in the concentration of the cation and has less physiological significance.

Neither hypophysectomy nor suppression of ACTH secretion with dexamethasone affect aldosterone production. However, in conditions of prolonged hypopituitarism or isolated ACTH deficiency, the aldosterone response to dietary sodium restriction may be reduced or even completely eliminated. In humans, ACTH administration transiently increases aldosterone secretion. Interestingly, a decrease in its level in patients with isolated ACTH deficiency is not observed under glucocorticoid therapy, although glucocorticoids themselves can inhibit steroidogenesis in the glomerular zone. Dopamine apparently plays a certain role in the regulation of aldosterone production, since its agonists (bromocriptine) inhibit the steroid response to angiotensin II and ACTH, and antagonists (metoclopramide) increase the aldosterone level in plasma.

As with cortisol secretion, plasma aldosterone levels exhibit circadian and episodic oscillations, although to a much lesser degree. Aldosterone concentrations are highest after midnight - up to 8-9 a.m. and lowest from 4 to 11 p.m. The periodicity of cortisol secretion does not affect the rhythm of aldosterone release.

In contrast to the latter, the production of androgens by the adrenal glands is regulated mainly by ACTH, although other factors may also participate in the regulation. Thus, in the prepubertal period, there is a disproportionately high secretion of adrenal androgens (in relation to cortisol), which is called adrenarche. However, it is possible that this is associated not so much with different regulation of glucocorticoid and androgen production, but with spontaneous restructuring of the steroid biosynthesis pathways in the adrenal glands during this period. In women, the level of androgens in the plasma depends on the phase of the menstrual cycle and is largely determined by the activity of the ovaries. However, in the follicular phase, the share of adrenal steroids in the total concentration of androgens in the plasma is almost 70% testosterone, 50% dihydrotestosterone, 55% androstenedione, 80% DHEA and 96% DHEA-S. Mid-cycle, the adrenal contribution to total androgen concentrations drops to 40% for testosterone and 30% for androstenedione. In men, the adrenal glands play a very minor role in creating total plasma androgen concentrations.

Adrenal production of mineralocorticoids is regulated by other factors, the most important of which is the renin-angiotensin system. Renin secretion by the kidneys is controlled primarily by the concentration of chloride ion in the fluid surrounding the juxtaglomerular cells, as well as by renal vascular pressure and beta-adrenergic substances. Renin catalyzes the conversion of angiotensinogen to the decapeptide angiotensin I, which is cleaved to form the octapeptide angiotensin II. In some species, the latter undergoes further transformations to yield the heptapeptide angiotensin III, which is also capable of stimulating the production of aldosterone and other mineralocorticoids (DOC, 18-hydroxycorticosterone, and 18-oxydeoxycorticosterone). In human plasma, the level of angiotensin III is no more than 20% of the level of angiotensin II. Both stimulate not only the conversion of cholesterol into pregnenolone, but also corticosterone into 18-hydroxycorticosterone and aldosterone. It is believed that the early effects of angiotensin are due mainly to the stimulation of the initial stage of aldosterone synthesis, whereas in the mechanism of long-term effects of angiotensin, its influence on subsequent stages of the synthesis of this steroid plays a large role. There are angiotensin receptors on the surface of the cells of the glomerular zone. Interestingly, in the presence of excess angiotensin II, the number of these receptors does not decrease, but on the contrary, increases. Potassium ions have a similar effect. Unlike ACTH, angiotensin II does not activate adrenal adenylate cyclase. Its action depends on the concentration of calcium and is probably mediated by the redistribution of this ion between the extra- and intracellular environment. Prostaglandin synthesis may play a certain role in mediating the effect of angiotensin on the adrenal glands. Thus, prostaglandins of the E series (their level in the serum increases after the introduction of angiotensin II), unlike P1T, are capable of stimulating the secretion of aldosterone, and inhibitors of prostaglandin synthesis (indomethacin) reduce the secretion of aldosterone and its response to angiotensin II. The latter also has a trophic effect on the glomerular zone of the adrenal cortex.

An increase in plasma potassium also stimulates aldosterone production, and the adrenal glands are highly sensitive to potassium. Thus, a change in its concentration by only 0.1 mEq/l, even within physiological fluctuations, affects the rate of aldosterone secretion. The effect of potassium does not depend on sodium or angiotensin II. In the absence of kidneys, potassium probably plays a major role in regulating aldosterone production. Its ions do not affect the function of the zona fasciculata of the adrenal cortex. Directly acting on aldosterone production, potassium at the same time reduces renin production by the kidneys (and, accordingly, the concentration of angiotensin II). However, the direct effect of its ions is usually stronger than the counterregulatory effect mediated by a decrease in renin. Potassium stimulates both the early (conversion of cholesterol to pregnenolone) and late (change of corticosterone or DOC to aldosterone) stages of mineralocorticoid biosynthesis. Under conditions of hyperkalemia, the plasma 18-hydroxycorticosterone/aldosterone concentration ratio increases. The effects of potassium on the adrenal cortex, like those of angiotensin II, are highly dependent on the presence of potassium ions.

Aldosterone secretion is also controlled by the serum sodium level. Salt load reduces the production of this steroid. To a large extent, this effect is mediated by the effect of sodium chloride on the release of renin. However, a direct effect of sodium ions on the processes of aldosterone synthesis is also possible, but it requires very sharp changes in the concentration of the cation and has less physiological significance.

Neither hypophysectomy nor suppression of ACTH secretion with dexamethasone affect aldosterone production. However, in conditions of prolonged hypopituitarism or isolated ACTH deficiency, the aldosterone response to dietary sodium restriction may be reduced or even completely eliminated. In humans, ACTH administration transiently increases aldosterone secretion. Interestingly, a decrease in its level in patients with isolated ACTH deficiency is not observed under glucocorticoid therapy, although glucocorticoids themselves can inhibit steroidogenesis in the glomerular zone. Dopamine apparently plays a certain role in the regulation of aldosterone production, since its agonists (bromocriptine) inhibit the steroid response to angiotensin II and ACTH, and antagonists (metoclopramide) increase the aldosterone level in plasma.

As with cortisol secretion, plasma aldosterone levels exhibit circadian and episodic oscillations, although to a much lesser degree. Aldosterone concentrations are highest after midnight - up to 8-9 a.m. and lowest from 4 to 11 p.m. The periodicity of cortisol secretion does not affect the rhythm of aldosterone release.

In contrast to the latter, the production of androgens by the adrenal glands is regulated mainly by ACTH, although other factors may also participate in the regulation. Thus, in the prepubertal period, there is a disproportionately high secretion of adrenal androgens (in relation to cortisol), which is called adrenarche. However, it is possible that this is associated not so much with different regulation of glucocorticoid and androgen production, but with spontaneous restructuring of the steroid biosynthesis pathways in the adrenal glands during this period. In women, the level of androgens in the plasma depends on the phase of the menstrual cycle and is largely determined by the activity of the ovaries. However, in the follicular phase, the share of adrenal steroids in the total concentration of androgens in the plasma is almost 70% testosterone, 50% dihydrotestosterone, 55% androstenedione, 80% DHEA and 96% DHEA-S. Mid-cycle, the adrenal contribution to total androgen concentrations drops to 40% for testosterone and 30% for androstenedione. In men, the adrenal glands play a very minor role in creating total plasma androgen concentrations.