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Introduction
The steroid hormones are all derived from cholesterol. Moreover, with the exception of vitamin D, they all contain the same cyclopentanophenanthrene ring and atomic numbering system as cholesterol. The conversion of C27 cholesterol to the 18-, 19-, and 21-carbon steroid hormones (designated by the nomenclature C with a subscript number indicating the number of carbon atoms, e.g. C19 for androstanes) involves the rate-limiting, irreversible cleavage of a 6-carbon residue from cholesterol, producing pregnenolone (C21) plus isocaproaldehyde. Common names of the steroid hormones are widely recognized, but systematic nomenclature is gaining acceptance and familiarity with both nomenclatures is increasingly important. Steroids with 21 carbon atoms are known systematically as pregnanes, whereas those containing 19 and 18 carbon atoms are known as androstanes and estranes, respectively. The important mammalian steroid hormones are shown below along with the structure of the precursor, pregneolone. Retinoic acid and vitamin D are not derived from pregnenolone, but from vitamin A and cholesterol respectively.
Pregnenolone: produced directly from cholesterol, the precursor molecule for all C18, C19 and C21 steroids
Progesterone: a progestagen, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteal phase of the menstrual cycle, differentiation factor for mammary glands
Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake
Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone
Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics
Cortisol: dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and Na+ uptake, numerous effects on the immune system
All the steroid hormones exert their action by passing through the plasma membrane and binding to intracellular receptors. The mechanism of action of the thyroid hormones is similar; they interact with intracellular receptors. Both the steroid and thyroid hormone-receptor complexes exert their action by binding to specific nucleotide sequences in the DNA of responsive genes. These DNA sequences are identified as hormone response elements, HREs. The interaction of steroid-receptor complexes with DNA leads to altered rates of transcription of the associated genes.
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Steroid Hormone Biosynthesis Reactions
The particular steroid hormone class synthesized by a given cell type depends upon its complement of peptide hormone receptors, its response to peptide hormone stimulation and its genetically expressed complement of enzymes. The following indicates which peptide hormone is responsible for stimulating the synthesis of which steroid hormone:
Luteinizing Hormone (LH): progesterone and testosterone
Adrenocorticotropic hormone (ACTH): cortisol
Follicle Stimulating Hormone (FSH): estradiol
Angiotensin II/III: aldosterone
The first reaction in converting cholesterol to C18, C19 and C21 steroids involves the cleavage of a 6-carbon group from cholesterol and is the principal committing, regulated, and rate-limiting step in steroid biosynthesis. The enzyme system that catalyzes the cleavage reaction is known as P450-linked side chain cleaving enzyme (P450ssc)or 20,22-desmolase, or cholesterol desmolase, and is found in the mitochondria of steroid-producing cells, but not in significant quantities in other cells.
Mitochondrial desmolase is a complex enzyme system consisting of cytochrome P450, and adrenadoxin (a P450 reductant). The activity of each of these components is increased by 2 principal cAMP- and PKA-dependent processes. First, cAMP stimulates PKA, leading to the phosphorylation of a cholesteryl-ester esterase and generating increased concentrations of cholesterol, the substrate for desmolase. Second, long-term regulation is effected at the level the gene for desmolase. This gene contains a cAMP regulatory element (CRE) that binds cAMP and increases the level of desmolase RNA transcription, thereby leading to increased levels of the enzyme. Finally, cholesterol is a negative feedback regulator of HMG CoA reductase activity (see regulation of cholesterol synthesis). Thus, when cytosolic cholesterol is depleted, de novo cholesterol synthesis is stimulated by freeing HMG CoA reductase of its feedback constraints. Subsequent to desmolase activity, pregnenolone moves to the cytosol, where further processing depends on the cell (tissue) under consideration.
The various hydroxylases involved in the synthesis of the steroid hormones have a nomenclature that indicates the site of hydroxylation (e.g. 17***945;-hydroxylase introduces a hydroxyl group to carbon 17). These hydroxylase enzymes are members of the cytochrome P450 class of enzymes and as such also have a nomenclature indicative of the site of hydroxylation in addition to being identified as P450 class enzymes (e.g. the 17***945;-hydroxylase is also identified as P450c17). The officially preferred nomenclature for the cytochrome P450 class of enzymes is to use the prefix CYP. Thus, 17***945;-hydroxylase should be identified as CYP17A1. There are currently 57 identified CYP genes in the human genome.
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Steroids of the Adrenal Cortex
The adrenal cortex is responsible for production of 3 major classes of steroid hormones: glucocorticoids, which regulate carbohydrate metabolism; mineralocorticoids, which regulate the body levels of sodium and potassium; and androgens, whose actions are similar to that of steroids produced by the male gonads. Adrenal insufficiency is known as Addison disease, and in the absence of steroid hormone replacement therapy can rapidly cause death (in 1 - 2 weeks).
The adrenal cortex is composed of 3 main tissue regions: zona glomerulosa, zona fasciculata, and zona reticularis. Although the pathway to pregnenolone synthesis is the same in all zones of the cortex, the zones are histologically and enzymatically distinct, with the exact steroid hormone product dependent on the enzymes present in the cells of each zone. Many of the enzymes of adrenal steroid hormone synthesis are of the class called cytochrome P450 enzymes. These enzymes all have a common nomenclature and a standardized nomenclature. The standardized nomenclature for the P450 class of enzymes is to use the abbreviation CYP. For example the P450ssc enzyme (also called 20,22-desmolase or cholesterol desmolase) is identified as CYP11A1. In order for cholesterol to be converted to pregnenolone in the adrenal cortex it must be transported into the mitochondria where CYP11A1 resides. This transport process is mediated by steroidogenic acute regulatory protein (StAR). This transport process is the rate-limiting step in steroidogenesis.
Synthesis of the various adrenal steroid hormones from cholesterol. Only the terminal hormone structures are included. 3***946;-DH and ***916;4,5-isomerase are the two activities of 3***946;-hydroxysteroid dehydrogenase type 1 (gene symbol HSD3B2), P450c11 is 11***946;-hydroxylase (CYP11B1), P450c17 is CYP17A1. CYP17A1 is a single microsomal enzyme that has two steroid biosynthetic activities: 17***945;-hydroxylase which converts pregnenolone to 17-hydroxypregnenolone (17-OH pregnenolone) and 17,20-lyase which converts 17-OH pregnenolone to DHEA. P450c21 is 21-hydroxylase (CYP21A2, also identified as CYP21 or CYP21B). Aldosterone synthase is also known as 18***945;-hydroxylase (CYP11B2). The gene symbol for sulfotransferase is SULT2A1. Place your mouse over structure names to see chemical structures. Click here for a larger format picture.
Conversion of prenenolone to progesterone requires the two enzyme activities of HSD3B2: the 3***946;-hydroxysteroid dehydrogenase and ***916;4,5-isomerase activities. Zona glomerulosa cells lack the P450c17 that converts pregnenolone and progesterone to their C17 hydroxylated analogs. Thus, the pathways to the glucocorticoids (deoxycortisol and cortisol) and the androgens [dehydroepiandosterone (DHEA) and androstenedione] are blocked in these cells. Zona glomerulosa cells are unique in the adrenal cortex in containing the enzyme responsible for converting corticosterone to aldosterone, the principal and most potent mineralocorticoid. This enzyme is P450c18 (or 18***945;-hydroxylase, CYP11B2), also called aldosterone synthase. The result is that the zona glomerulosa is mainly responsible for the conversion of cholesterol to the weak mineralocorticoid, corticosterone and the principal mineralocorticoid, aldosterone.
Cells of the zona fasciculata and zona reticularis lack aldosterone synthase (P450c18) that converts corticosterone to aldosterone, and thus these tissues produce only the weak mineralocorticoid corticosterone. However, both these zones do contain the P450c17 missing in zona glomerulosa and thus produce the major glucocorticoid, cortisol. Zona fasciculata and zona reticularis cells also contain P450c17, whose 17,20-lyase activity is responsible for producing the androgens, dehydroepiandosterone (DHEA) and androstenedione. Thus, fasciculata and reticularis cells can make corticosteroids and the adrenal androgens, but not aldosterone.
As noted earlier, P450ssc is a mitochondrial activity. Its product, pregnenolone, moves to the cytosol, where it is converted either to androgens or to 11-deoxycortisol and 11-deoxycorticosterone by enzymes of the endoplasmic reticulum. The latter 2 compounds then re-enter the mitochondrion, where the enzymes are located for tissue-specific conversion to glucocorticoids or mineralocorticoids, respectively.
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Regulation of Adrenal Steroid Synthesis
Adrenocorticotropic hormone (ACTH), of the hypothalamus, regulates the hormone production of the zona fasciculata and zona reticularis. ACTH receptors in the plasma membrane of the cells of these tissues activate adenylate cyclase with production of the second messenger, cAMP. The effect of ACTH on the production of cortisol is particularly important, with the result that a classic feedback loop is prominent in regulating the circulating levels of corticotropin releasing hormone (CRH), ACTH, and cortisol.
Mineralocorticoid secretion from the zona glomerulosa is stimulated by an entirely different mechanism. Angiotensins II and III, derived from the action of the kidney protease renin on liver-derived angiotensinogen, stimulate zona glomerulosa cells by binding a plasma membrane receptor coupled to phospholipase C. Thus, angiotensin II and III binding to their receptor leads to the activation of PKC and elevated intracellular Ca2+ levels. These events lead to increased P450ssc activity and increased production of aldosterone. In the kidney, aldosterone regulates sodium retention by stimulating gene expression of mRNA for the Na+/K+?ATPase responsible for the reaccumulation of sodium from the urine.
The interplay between renin from the kidney and plasma angiotensinogen is important in regulating plasma aldosterone levels, sodium and potassium levels, and ultimately blood pressure. Among the drugs most widely employed used to lower blood pressure are the angiotensin converting enzyme (ACE) inhibitors. These compounds are potent competitive inhibitors of the enzyme that converts angiotensin I to the physiologically active angiotensins II and III. This feedback loop is closed by potassium, which is a potent stimulator of aldosterone secretion. Changes in plasma potassium of as little as 0.1 millimolar can cause wide fluctuations (?50%) in plasma levels of aldosterone. Potassium increases aldosterone secretion by depolarizing the plasma membrane of zona glomerulosa cells and opening a voltage-gated calcium channel, with a resultant increase in cytoplasmic calcium and the stimulation of calcium-dependent processes.
Although fasciculata and reticularis cells each have the capability of synthesizing androgens and glucocorticoids, the main pathway normally followed is that leading to glucocorticoid production. However, when genetic defects occur in the 3 enzyme complexes leading to glucocorticoid production, large amounts of the most important androgen, dehydroepiandrosterone (DHEA), are produced. These lead to hirsutism and other masculinizing changes in secondary sex characteristics.
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Functions of the Adrenal Steroid Hormones
Glucocorticoids: The glucocorticoids are a class of hormones so called because they are primarily responsible for modulating the metabolism of carbohydrates. Cortisol is the most important naturally occurring glucocorticoid. As indicated in the Figure above, cortisol is synthesized in the zona fasciculata of the adrenal cortex. When released to the circulation, cortisol is almost entirely bound to protein. A small portion is bound to albumin with more than 70% being bound by a specific glycosylated ***945;-globulin called transcortin or corticosteroid-binding globulin (CBG). Between 5% and 10% of circulating cortisol is free and biologically active. Glucocorticoid function is exerted following cellular uptake and interaction with intracellular receptors as discussed below. Cortisol inhibits uptake and utilization of glucose resulting in elevations in blood glucose levels. The effect of cortisol on blood glucose levels is further enhanced through the increased breakdown of skeletal muscle protein and adipose tissue triglycerides which provides enegry and substrates for gluconeogenesis. Glucocorticoids also increase the synthesis of gluconeogenic enzymes. The increased rate of protein metabolism leads to increased urinary nitrogen excretion and the induction of urea cycle enzymes.
In addition to the metabolic effects of the glucocorticoids, these hormones are immunosuppressive and anti-inflammatory. Hence, the use of related drugs such as prednisone, in the acute treatment of inflammatory disorders. The anti-inflammatory activity of the glucocorticoids is exerted, in part, through inhibition of phospholipase A2 (PLA2) activity with a consequent reduction in the release of arachidonic acid from membrane phospholipids. Arachidonic acid serves as the precursor for the synthesis of various eicosanoids. Glucocorticoids also inhibit vitamin D-mediated intestinal calcium uptake, retard the rate of wound healing, and interfere with the rate of linear growth.
Mineralocorticoids: The major circulating mineralocorticoid is aldosterone. Deoxycorticosterone (DOC) exhibits some mineralocorticoid action but only about 3% of that of aldosterone. As the name of this class of hormones implies, the mineralocorticoids control the excretion of electrolytes. This occurs primarily through actions on the kidneys but also in the colon and sweat glands. The principle effect of aldosterone is to enhance sodium reabsorption in the cortical collecting duct of the kidneys. However, the action of aldosterone is exerted on sweat glands, stomach, and salivary glands to the same effect, i.e. sodium reabsorption. This action is accompanied by the retention of chloride and water resulting in the expansion of extracellular volume. Aldosterone also enhances the excretion of potassium and hydrogen ions from the medullary collecting duct of the kidneys.
Androgens: The androgens, androstenedione and DHEA, circulate bound primarily to sex hormone-binding globulin (SHBG). Although some of the circulating androgen is metabolized in the liver, the majority of interconversion occurs in the gonads (as described below), skin, and adipose tissue. DHEA is rapidly converted to the sulfated form, DHEA-S, in the liver and adrenal cortex. The primary biologically active metabolites of the androgens are testosterone and dihydrotestosterone which function by binding intracellular receptors, thereby effecting changes in gene expression and thereby, resulting in the manifestation of the secondary sex characteristics.
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Clinical Significance of Adrenal Steroidogenesis
Introduction
The steroid hormones are all derived from cholesterol. Moreover, with the exception of vitamin D, they all contain the same cyclopentanophenanthrene ring and atomic numbering system as cholesterol. The conversion of C27 cholesterol to the 18-, 19-, and 21-carbon steroid hormones (designated by the nomenclature C with a subscript number indicating the number of carbon atoms, e.g. C19 for androstanes) involves the rate-limiting, irreversible cleavage of a 6-carbon residue from cholesterol, producing pregnenolone (C21) plus isocaproaldehyde. Common names of the steroid hormones are widely recognized, but systematic nomenclature is gaining acceptance and familiarity with both nomenclatures is increasingly important. Steroids with 21 carbon atoms are known systematically as pregnanes, whereas those containing 19 and 18 carbon atoms are known as androstanes and estranes, respectively. The important mammalian steroid hormones are shown below along with the structure of the precursor, pregneolone. Retinoic acid and vitamin D are not derived from pregnenolone, but from vitamin A and cholesterol respectively.
All the steroid hormones exert their action by passing through the plasma membrane and binding to intracellular receptors. The mechanism of action of the thyroid hormones is similar; they interact with intracellular receptors. Both the steroid and thyroid hormone-receptor complexes exert their action by binding to specific nucleotide sequences in the DNA of responsive genes. These DNA sequences are identified as hormone response elements, HREs. The interaction of steroid-receptor complexes with DNA leads to altered rates of transcription of the associated genes.
back to the top
Steroid Hormone Biosynthesis Reactions
The particular steroid hormone class synthesized by a given cell type depends upon its complement of peptide hormone receptors, its response to peptide hormone stimulation and its genetically expressed complement of enzymes. The following indicates which peptide hormone is responsible for stimulating the synthesis of which steroid hormone:
Luteinizing Hormone (LH): progesterone and testosterone
Adrenocorticotropic hormone (ACTH): cortisol
Follicle Stimulating Hormone (FSH): estradiol
Angiotensin II/III: aldosterone
The first reaction in converting cholesterol to C18, C19 and C21 steroids involves the cleavage of a 6-carbon group from cholesterol and is the principal committing, regulated, and rate-limiting step in steroid biosynthesis. The enzyme system that catalyzes the cleavage reaction is known as P450-linked side chain cleaving enzyme (P450ssc)or 20,22-desmolase, or cholesterol desmolase, and is found in the mitochondria of steroid-producing cells, but not in significant quantities in other cells.
Mitochondrial desmolase is a complex enzyme system consisting of cytochrome P450, and adrenadoxin (a P450 reductant). The activity of each of these components is increased by 2 principal cAMP- and PKA-dependent processes. First, cAMP stimulates PKA, leading to the phosphorylation of a cholesteryl-ester esterase and generating increased concentrations of cholesterol, the substrate for desmolase. Second, long-term regulation is effected at the level the gene for desmolase. This gene contains a cAMP regulatory element (CRE) that binds cAMP and increases the level of desmolase RNA transcription, thereby leading to increased levels of the enzyme. Finally, cholesterol is a negative feedback regulator of HMG CoA reductase activity (see regulation of cholesterol synthesis). Thus, when cytosolic cholesterol is depleted, de novo cholesterol synthesis is stimulated by freeing HMG CoA reductase of its feedback constraints. Subsequent to desmolase activity, pregnenolone moves to the cytosol, where further processing depends on the cell (tissue) under consideration.
The various hydroxylases involved in the synthesis of the steroid hormones have a nomenclature that indicates the site of hydroxylation (e.g. 17***945;-hydroxylase introduces a hydroxyl group to carbon 17). These hydroxylase enzymes are members of the cytochrome P450 class of enzymes and as such also have a nomenclature indicative of the site of hydroxylation in addition to being identified as P450 class enzymes (e.g. the 17***945;-hydroxylase is also identified as P450c17). The officially preferred nomenclature for the cytochrome P450 class of enzymes is to use the prefix CYP. Thus, 17***945;-hydroxylase should be identified as CYP17A1. There are currently 57 identified CYP genes in the human genome.
back to the top
Steroids of the Adrenal Cortex
The adrenal cortex is responsible for production of 3 major classes of steroid hormones: glucocorticoids, which regulate carbohydrate metabolism; mineralocorticoids, which regulate the body levels of sodium and potassium; and androgens, whose actions are similar to that of steroids produced by the male gonads. Adrenal insufficiency is known as Addison disease, and in the absence of steroid hormone replacement therapy can rapidly cause death (in 1 - 2 weeks).
The adrenal cortex is composed of 3 main tissue regions: zona glomerulosa, zona fasciculata, and zona reticularis. Although the pathway to pregnenolone synthesis is the same in all zones of the cortex, the zones are histologically and enzymatically distinct, with the exact steroid hormone product dependent on the enzymes present in the cells of each zone. Many of the enzymes of adrenal steroid hormone synthesis are of the class called cytochrome P450 enzymes. These enzymes all have a common nomenclature and a standardized nomenclature. The standardized nomenclature for the P450 class of enzymes is to use the abbreviation CYP. For example the P450ssc enzyme (also called 20,22-desmolase or cholesterol desmolase) is identified as CYP11A1. In order for cholesterol to be converted to pregnenolone in the adrenal cortex it must be transported into the mitochondria where CYP11A1 resides. This transport process is mediated by steroidogenic acute regulatory protein (StAR). This transport process is the rate-limiting step in steroidogenesis.
Synthesis of the various adrenal steroid hormones from cholesterol. Only the terminal hormone structures are included. 3***946;-DH and ***916;4,5-isomerase are the two activities of 3***946;-hydroxysteroid dehydrogenase type 1 (gene symbol HSD3B2), P450c11 is 11***946;-hydroxylase (CYP11B1), P450c17 is CYP17A1. CYP17A1 is a single microsomal enzyme that has two steroid biosynthetic activities: 17***945;-hydroxylase which converts pregnenolone to 17-hydroxypregnenolone (17-OH pregnenolone) and 17,20-lyase which converts 17-OH pregnenolone to DHEA. P450c21 is 21-hydroxylase (CYP21A2, also identified as CYP21 or CYP21B). Aldosterone synthase is also known as 18***945;-hydroxylase (CYP11B2). The gene symbol for sulfotransferase is SULT2A1. Place your mouse over structure names to see chemical structures. Click here for a larger format picture.
Conversion of prenenolone to progesterone requires the two enzyme activities of HSD3B2: the 3***946;-hydroxysteroid dehydrogenase and ***916;4,5-isomerase activities. Zona glomerulosa cells lack the P450c17 that converts pregnenolone and progesterone to their C17 hydroxylated analogs. Thus, the pathways to the glucocorticoids (deoxycortisol and cortisol) and the androgens [dehydroepiandosterone (DHEA) and androstenedione] are blocked in these cells. Zona glomerulosa cells are unique in the adrenal cortex in containing the enzyme responsible for converting corticosterone to aldosterone, the principal and most potent mineralocorticoid. This enzyme is P450c18 (or 18***945;-hydroxylase, CYP11B2), also called aldosterone synthase. The result is that the zona glomerulosa is mainly responsible for the conversion of cholesterol to the weak mineralocorticoid, corticosterone and the principal mineralocorticoid, aldosterone.
Cells of the zona fasciculata and zona reticularis lack aldosterone synthase (P450c18) that converts corticosterone to aldosterone, and thus these tissues produce only the weak mineralocorticoid corticosterone. However, both these zones do contain the P450c17 missing in zona glomerulosa and thus produce the major glucocorticoid, cortisol. Zona fasciculata and zona reticularis cells also contain P450c17, whose 17,20-lyase activity is responsible for producing the androgens, dehydroepiandosterone (DHEA) and androstenedione. Thus, fasciculata and reticularis cells can make corticosteroids and the adrenal androgens, but not aldosterone.
As noted earlier, P450ssc is a mitochondrial activity. Its product, pregnenolone, moves to the cytosol, where it is converted either to androgens or to 11-deoxycortisol and 11-deoxycorticosterone by enzymes of the endoplasmic reticulum. The latter 2 compounds then re-enter the mitochondrion, where the enzymes are located for tissue-specific conversion to glucocorticoids or mineralocorticoids, respectively.
back to the top
Regulation of Adrenal Steroid Synthesis
Adrenocorticotropic hormone (ACTH), of the hypothalamus, regulates the hormone production of the zona fasciculata and zona reticularis. ACTH receptors in the plasma membrane of the cells of these tissues activate adenylate cyclase with production of the second messenger, cAMP. The effect of ACTH on the production of cortisol is particularly important, with the result that a classic feedback loop is prominent in regulating the circulating levels of corticotropin releasing hormone (CRH), ACTH, and cortisol.
Mineralocorticoid secretion from the zona glomerulosa is stimulated by an entirely different mechanism. Angiotensins II and III, derived from the action of the kidney protease renin on liver-derived angiotensinogen, stimulate zona glomerulosa cells by binding a plasma membrane receptor coupled to phospholipase C. Thus, angiotensin II and III binding to their receptor leads to the activation of PKC and elevated intracellular Ca2+ levels. These events lead to increased P450ssc activity and increased production of aldosterone. In the kidney, aldosterone regulates sodium retention by stimulating gene expression of mRNA for the Na+/K+?ATPase responsible for the reaccumulation of sodium from the urine.
The interplay between renin from the kidney and plasma angiotensinogen is important in regulating plasma aldosterone levels, sodium and potassium levels, and ultimately blood pressure. Among the drugs most widely employed used to lower blood pressure are the angiotensin converting enzyme (ACE) inhibitors. These compounds are potent competitive inhibitors of the enzyme that converts angiotensin I to the physiologically active angiotensins II and III. This feedback loop is closed by potassium, which is a potent stimulator of aldosterone secretion. Changes in plasma potassium of as little as 0.1 millimolar can cause wide fluctuations (?50%) in plasma levels of aldosterone. Potassium increases aldosterone secretion by depolarizing the plasma membrane of zona glomerulosa cells and opening a voltage-gated calcium channel, with a resultant increase in cytoplasmic calcium and the stimulation of calcium-dependent processes.
Although fasciculata and reticularis cells each have the capability of synthesizing androgens and glucocorticoids, the main pathway normally followed is that leading to glucocorticoid production. However, when genetic defects occur in the 3 enzyme complexes leading to glucocorticoid production, large amounts of the most important androgen, dehydroepiandrosterone (DHEA), are produced. These lead to hirsutism and other masculinizing changes in secondary sex characteristics.
back to the top
Functions of the Adrenal Steroid Hormones
Glucocorticoids: The glucocorticoids are a class of hormones so called because they are primarily responsible for modulating the metabolism of carbohydrates. Cortisol is the most important naturally occurring glucocorticoid. As indicated in the Figure above, cortisol is synthesized in the zona fasciculata of the adrenal cortex. When released to the circulation, cortisol is almost entirely bound to protein. A small portion is bound to albumin with more than 70% being bound by a specific glycosylated ***945;-globulin called transcortin or corticosteroid-binding globulin (CBG). Between 5% and 10% of circulating cortisol is free and biologically active. Glucocorticoid function is exerted following cellular uptake and interaction with intracellular receptors as discussed below. Cortisol inhibits uptake and utilization of glucose resulting in elevations in blood glucose levels. The effect of cortisol on blood glucose levels is further enhanced through the increased breakdown of skeletal muscle protein and adipose tissue triglycerides which provides enegry and substrates for gluconeogenesis. Glucocorticoids also increase the synthesis of gluconeogenic enzymes. The increased rate of protein metabolism leads to increased urinary nitrogen excretion and the induction of urea cycle enzymes.
In addition to the metabolic effects of the glucocorticoids, these hormones are immunosuppressive and anti-inflammatory. Hence, the use of related drugs such as prednisone, in the acute treatment of inflammatory disorders. The anti-inflammatory activity of the glucocorticoids is exerted, in part, through inhibition of phospholipase A2 (PLA2) activity with a consequent reduction in the release of arachidonic acid from membrane phospholipids. Arachidonic acid serves as the precursor for the synthesis of various eicosanoids. Glucocorticoids also inhibit vitamin D-mediated intestinal calcium uptake, retard the rate of wound healing, and interfere with the rate of linear growth.
Mineralocorticoids: The major circulating mineralocorticoid is aldosterone. Deoxycorticosterone (DOC) exhibits some mineralocorticoid action but only about 3% of that of aldosterone. As the name of this class of hormones implies, the mineralocorticoids control the excretion of electrolytes. This occurs primarily through actions on the kidneys but also in the colon and sweat glands. The principle effect of aldosterone is to enhance sodium reabsorption in the cortical collecting duct of the kidneys. However, the action of aldosterone is exerted on sweat glands, stomach, and salivary glands to the same effect, i.e. sodium reabsorption. This action is accompanied by the retention of chloride and water resulting in the expansion of extracellular volume. Aldosterone also enhances the excretion of potassium and hydrogen ions from the medullary collecting duct of the kidneys.
Androgens: The androgens, androstenedione and DHEA, circulate bound primarily to sex hormone-binding globulin (SHBG). Although some of the circulating androgen is metabolized in the liver, the majority of interconversion occurs in the gonads (as described below), skin, and adipose tissue. DHEA is rapidly converted to the sulfated form, DHEA-S, in the liver and adrenal cortex. The primary biologically active metabolites of the androgens are testosterone and dihydrotestosterone which function by binding intracellular receptors, thereby effecting changes in gene expression and thereby, resulting in the manifestation of the secondary sex characteristics.
back to the top
Clinical Significance of Adrenal Steroidogenesis
, the retinoid-related orphan receptor (ROR***945
