Steroid Hormones and Adrenal Glands

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Cortisol

An increase in circulating levels of this exerts a negative feedback effect on both the hypothalamus and the anterior pituitary. This leads to a decrease in CRH and ACTH release. In the absence of ACTH stimulation synthesis of this declines.

Hypoglycemia

By inducing the expression of enzymes that support glucose production, cortisol plays an essential role in preventing this during a fast.

Androgen Receptor

DHEA and androstenedione have little androgen activity because of their low affinity for this, however, they are converted to more potent androgens such as testosterone and dihydrotestosterone peripherally.

DHEA Sulfate

During pregnancy, the fetal adrenal gland produces large amounts of this which is converted to estrogens by the placenta.

Alveolar Maturation and Surfactant Production

Glucocorticoids play a role in promoting the development of some organ systems in utero. Most notable is the stimulatory effect that cortisol has on these two things. Because of this effect, glucocorticoids are used clinically to accelerate fetal lung maturation if a premature delivery is anticipated.

Inflammatory Response; Phospholipase A2

Glucocorticoids suppress this by blocking the expression of genes that code for pro-inflammatory cytokines such as TNFα and interleukin-1. They also inhibit the synthesis of key enzymes like this one that catalyze the synthesis of inflammatory agents such as prostaglandins, thromboxanes, and leukotrienes from arachidonic acid.

Hormone Response Elements (HREs)

Hormone-occupied receptors recognize and bind to target genes by means of specific DNA sequences called these that are located in the promoter region of target genes.

Vesicular Monamine Transporter (VMAT)

In catecholamine biosynthesis, dopamine is transported into a secretory granule (chromaffin granule) via a catecholamine-H+ exchanger called this and is converted to norepinephrine.

Androstenedione

Small amounts of this are also released from the zona reticularis along with DHEA.

DNA

Steroid hormone receptors do NOT bind to this unless the hormone is bound to its appropriate binding site on the receptor.

Nuclear Localization Signal (NLS)

Steroid hormone receptors have this that enable them to reside in the nucleus or to be translocated to the nucleus when it is activated.

Low Density Lipoprotein (LDL)

Steroid hormone synthesis involves the enzymatic modification of cholesterol and cholesterol derivatives. The principal source of cholesterol for steroidogenesis is this.

1. Corticosteroid-Binding Globulin (CBG) 2. Sex Steroid-Binding Globulin (SHBG) 3. Vitamin D-Binding Globulin Albumin

These are the three main specific steroid hormone binding proteins. A fraction of the steroid hormone pool also binds non-specifically and with low affinity to this.

Cortisol

This induces PNMT, the enzyme that promotes the conversion of norepinephrine to epinephrine. It also prevents chromaffin cells from developing into postganglionic neurons.

Secondary Adrenocortical Insufficiency

This is associated with insufficient production of ACTH. This often due the prolonged clinical administration of supraphysiological doses of synthetic glucocorticoids that suppress the HPA axis or to a lesion of the pituitary. You can also see this with insufficient production of renin in the kidneys.

Aldosteronism

This is characterized by excessive aldosterone secretion.

Cushing Syndrome

This is characterized by excessive secretion of cortisol. This often due to ingestion of pharmacological doses of glucocorticoids, excessive secretion of ACTH by pituitary, ectopic, non-endocrine ACTH-secreting tumors, and tumors of the adrenal cortex. Patients with this will exhibit clinical features like obesity with a redistribution of fat to trunk and face, hypertension, glucose intolerance, hirsutism, amenorrhea, purple striae and easy bruisability, osteoporosis, mental effects, acne, weakness, and poor wound healing.

Adrenocortical Insufficiency

This is characterized by failure to produce adrenocortical hormones.

Dehydroepiandrosterone (DHEA)

This is the principal adrenal androgen released by the zona reticularis. It is slowly metabolized because of its high affinity for albumin.

Corticotropin Releasing Hormone (CRH)

This is the principal regulator of ACTH secretion. Hypothalamic neurons release this in secretory pulses into the capillary bed of the median eminence. This binds receptors in anterior pituitary corticotropes and stimulates ACTH synthesis and release by a cAMP-dependent mechanism. It is the pulsatile release of this which determines the pulsatile release of ACTH.

DHEA-Sulfate (DHEAS)

DHEA is secreted primarily as this. Plasma levels of this along with DHEA serve as indicators of adrenal androgen production.

11β-Hydroxylase

DOC that is formed in the zona fasciculata is converted to corticosterone by this enzyme in the mitochondria.

Hormone-Sensitive Lipase

During a fast, the principal action of cortisol involves inducing the synthesis of this and other proteins necessary to support fat mobilization and enhance epinephrine and GH-stimulated lipolysis.

Acetylcholine (Ach)

During activation of the adrenal medulla through the sympathetic nervous system, this is released from preganglionic fibers and promotes the release of catecholamines that are stored in chromaffin granules. The binding of this to nicotinic receptors promotes Na+ influx, thereby causing membrane depolarization and opening of voltage-gated calcium channels. This resultant rise in Ca2+ triggers exocytosis. This also promotes the transcription of tyrosine hydroxylase which is the enzyme that catalyzes the rate limiting step in the biosynthetic pathway of catecholamines.

Lipocortin (annexin)

Glucocorticoids also induce the synthesis of anti-inflammatory proteins such as interleukin-10 and this. This acts by inhibiting phospholipase A2.

21-Hydroxylase

In CAH the most frequently blocked enzyme is this. This block is characterized by a virilizing syndrome due to excess androgen production in the adrenal and by non-adrenal tissues from pre-block intermediates. In females this causes fusion of labia and clitoral hypertrophy if exposure to androgens occurs before 12 weeks. Exposure after 12 weeks leads to clitoral hypertrophy alone. Breast development and menstruation will not occur at puberty. In males this causes early increase in somatic growth; premature closure of the epiphyseal plate; early maturation of genitalia and development of secondary sex characteristics.

Phenylethanolamine-N-Methyltransferase (PNMT)

In epinephrine-secreting chromaffin cells, norepinephrine exits the secretory granule by facilitated diffusion and is converted to epinephrine in the cytoplasm by the action of this enzyme. Epinephrine is then transported back into a chromaffin granule via a VMAT where it is stored until released by exocytosis.

Adrenal Glands

In females, these are a major source of androgen hormones whereas in males, most of their androgen hormones are produced by the testis.

Tropic Hormones

In general these hormones mobilize the stored cholesterol by stimulating cholesterol esterase activity and inhibiting cholesterol acyltransferase activity.

Corepressor Proteins

In hormone-dependent negative regulation of gene transcription, steroid hormone-bound receptor dimers recruit these to the hormone binding site.

11-Deoxycorticosterone (DOC)

In humans, the conversion of cholesterol to this occurs via the same biosynthetic pathway in both the zona glomerulosa and the zona fasciculata.

Receptor-Mediated Endocytosis

LDLs bind to plasma membrane receptors and enter steroidogenic cells via this mechanism.

11β-Hydroxysteroid Dehydrogenase II (11β-HSD2)

Normally, cortisol does not contribute to mineralocorticoid activity because it is converted to cortisone by this enzyme that is expressed in mineralocorticoid target tissues such as the kidney. Cortisone is an inactive compound. Cortisol can cause mineralocorticoid hypertension if this enzyme is deficient or inhibited.

Cholesterol Esterase

Steroidogenic ells are able to mobilize cholesterol esters stored in lipid droplets by activating this enzyme.

1. Zona Glomerulosa 2. Zona Fasciculata 3. Zona Reticularis

The adrenal cortex is derived from mesodermal cells and constitutes 80-90% of the gland. It is organized into three distinct layers which from outer to inner are this.

Epinephrine

The adrenal gland is the only source of circulating levels of this. By contrast, most norepinephrine in the blood is released from nerve terminals.

Catecholamines (epinephrine and norepinephrine)

The adrenal medulla is located in the center of the adrenal gland. It is derived from the neuroectodermal cells and is essentially a modified sympathetic ganglion that secretes these.

Receptor Antagonist

The binding of this to the steroid receptor induces a conformational change in the receptor that may prevent coactivators from binding and/or favor corepressor binding to the steroid hormone receptor.

Stress

The effects of this on cortisol release are particularly strong and can override diurnal effects and negative feedback control. Pretty much any type of mental or physical form of this will stimulate cortisol release. Examples of this that provoke ACTH release include hypoglycemia, trauma, infection and surgery.

1. Increased affinity for glucocorticoid receptor 2. Delayed plasma clearance

The enhanced activity of synthetic glucocorticoids like prednisone and dexamethasone is due to these two factors.

Neocortex; Fetal Zone

The fetal adrenal cortex is composed of this outer layer that contains cells that will differentiate into the three morphologically distinct zones of the adult adrenal and this larger zone that is the source of DHEA sulfate. After birth, this outer zone differentiates into the zona glomerulosa and zona fasciculata.

Pregnenolone

The first step in the biosynthesis of steroid hormones is the conversion of cholesterol into this. This reaction is catalyzed by the side chain cleavage enzyme P450scc located in the inner mitochondrial membrane.

Mineralocorticoids

The primary action of these is to maintain extracellular fluid volume by regulating Na+ reabsorption. These also promote K+ and H+ excretion.

Cortisol; 11β-Hydroxylase

The principal glucocorticoid in humans is this. This enzyme is what converts 11-deoxycortisol to this in the synthetic pathway.

ACTH; Angiotensin II (AII)

The transcription of the StAR protein is induced by this via a cAMP-dependent mechanism in cells of the zona fasciculata and reticularis. Its transcription is also induced by this via a Ca2+-calmodulin-dependent mechanism in the zona glomerulosa.

Albumin

There is not a specific aldosterone-binding globulin. Aldosterone does bind to corticosteroid-binding globulin (CBG) but only has a weak affinity for it. Thus, most of the bound aldosterone is associated with this. However a high percentage of aldosterone is free (40-50%).

Pheochromocytomas

These are catecholamine-producing tumors of chromaffin cells of the adrenal medulla or extra-adrenal ganglia. Hypertension is the most common clinical feature. Other symptoms which may occur include tachycardia, tremors, sweating, anxiety and headache. Symptoms are often intermittent. Patients with this condition may also experience weight loss, an increased metabolic rate, and glucose intolerance.

Monoamine Oxidase (MAO) and Catecholamine-O-Methyltransferase (COMT)

These are the two enzymes that are responsible for degrading catecholamines in tissues.

Metanephrines and Vanillylmandelic Acid

These are the two major classes of metabolites that result from the inactivation of catecholamines. Determinations of urinary levels of these metabolites can provide a useful measure of total catecholamine production.

Epinephrine and Norepinephrine

These are the two principal catecholamines released by the adrenal medulla. In humans, approximately 80% of the chromaffin cells secrete this first catecholamine while the other 20% secrete this catecholamine.

Steroid Hormone Receptors

These belong to a superfamily of nuclear receptors that function as ligand-activated transcription factors.

Chromaffin Cells

These cells of the adrenal medulla are modified postganglionic cells that secrete catecholamines directly into the bloodstream. These cells are innervated by cholinergic preganglionic fibers.

K+

This also induces aldosterone synthesis in the zona glomerulosa by a mechanism that is initiated by the activation of voltage-gated Ca2+ channels.

DOC

This and aldosterone have similar affinities for the mineralocorticoid receptor and both steroids are secreted at approximately the same rate; however, this has a high affinity for CBG and less than 5% is free while aldosterone has a very large free fraction (40-50%). Because of this, aldosterone is quantitatively more important than this.

Cholesterol Acyltransferase

This enzyme converts a portion of the cholesterol entering the steroidogenic cell to cholesterol esters which accumulate to form lipid droplets. This provides a reservoir of precursors for steroid hormone synthesis.

ACTH

This hormone, a cleavage product of proopiomelanocortin, is the principal physiological regulator of cortisol release. Corticotropes release this in secretory pulses throughout the day and consequently the adrenal cortex releases cortisol in pulsatile fashion that corresponds to the pulsatile pattern of this hormone's release.

Arginine Vasopressin (AVP)

This is also secreted into the capillaries of the median eminence in response to stress. Most of this is released by CRH-secreting neurons. This also potentiates the action of CRH on ACTH secretion.

11β-ΗSD1

This is an enzyme that converts cortisone to cortisol. It is expressed in tissues that have glucocorticoid receptors such as the liver, skin, adipose tissue and the CNS.

NO Synthase

This is another protein whose expression is inhibited by glucocorticoids. This catalyzes the synthesis of nitric oxide which is a potent vasodilator.

Primary Adrenocortical Insufficiency (Addison Disease)

This is caused by a defect within the adrenal gland. It is an autoimmune disorder. The clinical features of this are due to deficient production of cortisol, aldosterone, and adrenal androgens. People with this often experience, hyponatremia, polyuria, hypotension, dehydration, inability to handle stress, hypoglycemia when stressed or fasting, weakness and fatigue, decreased appetite/weight loss, anemia, hyperpigmentation from excess ACTH secretion, and loss of pubic and axillary hair in females.

Pseudohypoaldosteronism

This is caused by a loss of function mutation in the mineralocorticoid receptor. It is characterized by severe salt wasting in the neonate, hyperkalemia, metabolic acidosis, and a failure to respond to treatment with mineralocorticoids.

Secondary Aldosteronism

This is caused by an inappropriate activation of the renin-angiotensin system.

Primary Aldosteronism (Conn Syndrome)

This is caused by the autonomous secretion of aldosterone, usually by an adenoma arising from the zona glomerulosa. Symptoms include mild hypertension from Na+ and H2O retention, hypokalemia, and metabolic alkalosis due to H+ secretion. Plasma levels of renin are depressed as a result of the expanded ECF volume.

Pregnenolone

This is the precursor used to synthesize all adrenal, gonadal, and placental steroids. The specific synthetic products produced by a given steroidogenic tissue depends on which steroidogenic enzymes are expressed by that tissue. The synthesis of some steroid hormones involves more than one cell type.

Cortisol

This is the principal glucocorticoid in humans.

Aldosterone

This is the principal mineralocorticoid in humans.

Adrenarche

This is the time in early childhood in which circulating levels of adrenal androgens being to rise. It occurs around 6-7 years for girls and 7-8 years for boys. This does not appear to be involved in the initiation of puberty.

ACTH

This plays a role in regulating adrenal androgen secretion, however, because there is no increase in circulating levels of this during adrenarche, other factors are obviously involved in regulating androgen production by the adrenal gland. Adrenal androgens do not exert a negative feedback on the secretion of this.

Free Fraction (Unbound)

This portion of steroid hormone in the blood is in equilibrium with the fraction that is bound to binding proteins. This fraction can readily bind to receptors in target tissues and induce a physiological response.

Conjugation

This process facilitates the clearance of inactivated steroid hormones by increasing their solubility in water and decreasing their affinity for binding proteins. The metabolites of a steroid hormone that has undergone this process are excreted principally by the kidneys.

Steroidogenic Acute Regulatory Protein (StAR); cAMP-dependent

This protein facilitates the movement of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane. It has a very short half-life and its synthesis is rapidly induced by this type of mechanism.

Congenital Adrenal Hyperplasia (CAH)

This refers to a group of genetically transmitted enzymatic deficiencies in the biosynthetic pathway for adrenal steroids. The decrease in negative feedback inhibition from cortisol deficiency leads to a rise in ACTH secretion. The tropic effect of ACTH induces hyperplasia of the adrenal gland. Steroid intermediates directly behind the enzymatic block build up and enter the circulation where they can.

Zona Reticularis

This zone is mainly responsible for synthesizing androgens because it produces cofactors that enhance the 17,20-lyase activity associated with P450c17. Only small amounts of glucocorticoids are formed in this zone.

Zona Glomerulosa

This zone lacks 17α-hydroxylase activity. Hence, it is unable to synthesize cortisol and androgens.

Cholesterol Esters

Upon entering steroidogenic cells, LDLs undergo hydrolysis in the lysosomal compartment and a free cholesterol is released into the cell. This free cholesterol either enters the steroidogenic pathway or undergoes esterification to form these which coalesce into lipid droplets.

Chaperone Proteins (HSP)

When the hormone-binding site is unoccupied, steroid hormone receptors form large molecular weight complexes with these. When the steroid hormone binds to the receptor, the receptor dissociates from these.

Diurnal Rhythm

When the sleep-wake cycle and light-dark cycles are synchronized, cortisol release is characterized by this type of rhythm in which circulating levels of cortisol are highest in the morning upon wakening.

Aldosterone Synthase

Because the zona glomerulosa expresses this enzyme, DOC is converted to aldosterone in this zone. This enzyme catalyzes the 3 steps involved in this conversion. Because the zona glomerulosa is the only zone that expresses this enzyme, it is the only zone that can synthesize aldosterone.

Steroidogenic Cells

Because there are no special mechanisms for the storage of newly synthesized steroid hormones, these cells release steroid hormones as soon as they are synthesized.

Tyrosine Hydroxylase

Catecholamine biosynthesis involves the stepwise modification of tyrosine to dopamine in the cytoplasm of the secretory cell. The conversion of tyrosine to dihydroxyphenylalanine (DOPA) by this enzyme is the first and rate limiting step in catecholamine biosynthesis.

Stress

Catecholamine release by the adrenal medulla is an important part of the acute response to this. Catecholamines are able to rapidly induce an array of adaptive responses by binding to and activating an assortment of adrenergic receptor subtypes.

ATP, Ca2+ and Chromogranin

Catecholamines are stored in chromaffin granules in a complex with these three things.

Glycogen Synthase; Permissive Effect

Cortisol induces the expression of this. Because of this, more glycogen can be formed in response to insulin stimulation following a meal than would be formed in the absence of cortisol. Since epinephrine and glucagon mobilize stored glycogen, then we can say that cortisol has this type of effect on glucagon and epinephrine-induced glycogenolysis. Cortisol has this effect because it ensures that there is more substrate (glycogen) for glucagon and epinephrine to mobilize. Cortisol itself however, does not induce glycogenolysis.

Glucose Uptake

Cortisol inhibits this by skeletal muscle and adipose tissue.

Vasoconstrictors

Cortisol is required for the normal responsiveness of blood vessels to these such as catecholamines and angiotensin II.

Gluconeogenesis

Cortisol promotes this. It does this by inducing the expression of hepatic gluconeogenic enzymes and by promoting protein catabolism and inhibiting protein synthesis.

P450c17

17a-hydroxylase and 17,20-lyase activities are required for the synthesis of cortisol and androgens. These activities are associated with a single enzyme known as this which is expressed in both the zona fasciculata and zona reticularis but NOT the zona glomerulosa.

Rate-Limiting Step

Because cholesterol availability limits the activity of the P450scc enzyme, the transfer of cholesterol to the inner mitochondrial membrane is considered to be this kind of step in the biosynthesis of steroids.

Liver; Glucuronic Acid and Sulfate

Because humans cannot break down the steroid nucleus, steroid hormones are degraded by being converted to inactive metabolites. The principal site of inactivation is here. Following inactivation at this site, steroid hormone metabolites are conjugated to either of these two things.

Coactivator Proteins

Activation of gene transcription occurs when the steroid hormone-bound receptor dimers recruit a complex of these.

Pregnenolone and Progesterone

All 3 zones of the adrenal cortex can synthesize these two things from cholesterol.

Fat Deposition

Although cortisol promotes fat mobilization during a fast, the overall effect of this hormone on fat metabolism is very complex. When present in excess, cortisol promotes this, especially in the trunk and face. This is thought to be due in part, to a cortisol-induced increase in appetite and a resultant increase in caloric intake.

Unmetabolized Cortisol

Although more than 99% of cortisol in the urine is metabolized, a measurement of 24-hour urinary excretion of this is considered to be the most accurate estimate of daily cortisol output.

Osteoporosis

Although the exact role of cortisol in bone formation and calcium homeostasis is unclear, it is apparent that exposure to excess levels of glucocorticoids puts a person at risk for developing this. High concentrations of glucocorticoids antagonize the effect of vitamin D3 on calcium uptake by the small intestine and inhibit renal Ca2+ reabsorption. Moreover, glucocorticoids act directly on bone to inhibit bone formation and, to a lesser extent, to promote bone resorption.


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