Corticosteroids, Mineralocorticoids, and ADH - Witt

Define hormone.

Any signaling molecules produced by glands that are transported by the circulatory system to the target distant organs to regulate physiology and behavior

Define exocrine gland.

An organ that synthesizes substances for release into cavities inside the body or its outer surface

Define endocrine gland.

An organ that synthesizes substances for release into the blood stream or into cavities inside the body or its outer surface

What is a steroid?

A lipid-soluble compound consisting of a primary set of 17-carbon atoms arranged in four interconnected rings situated in a 6-6-6-5 configuration.

Where are steroid hormones produced?

Adrenal cortex, testis, ovary, and some peripheral tissues (i.e. adipose tissue and brain)

What are all steroid hormones derived from?

Cholesterol

How are steroids and hormones related?q

Not all hormones are steroids and not all steroids are hormones

Describe the characteristics of steroid hormones.

- immediately released from cell after synthesis

- lipid soluble allowing them to interact with cytoplasmic or nuclear receptors

- slower acting and longer half-life than peptide hormones

What are the physiological effects of Mineralocorticoids?

Na+, K+, and water homeostasis

What are the physiological effects of Glucocorticoids?

Glucose homeostasis, anti-inflammatory, and various others

What is the major representative of Mineralocorticoids?

Aldosterone

What is the major representative of Glucocorticoids?

Cortisol

What is the first and rate-limiting step in the synthesis of steroids?

Conversion of cholesterol to pregnenolone via a side-chain cleavage carried out by CYP11A1

What is steroidogenic acute regulatory protein (STARD1)?

A transport protein that regulates cholesterol transfer within the mitochondria, which is critical in the production of steroid hormones

What stimulates steroidogenic acute regulatory protein (STARD1)?

Adrenocorticotropic hormone (ACTH)

Where are the enzymes responsible for producing steroids from cholesterol located?

In the mitochondria and smooth ER

Where are the adrenal cortexes located?

Directly above the kidneys and below the peritoneum

What is the function of the inner medulla?

Produces catecholamines (epinephrine and norepinephrine)

What does the inner medulla consist of?

It is made up of chromaffin cells. It is innervated by preganglionic sympathetic fibers.

What is the effect of norepinephrine and epinephrine released by the adrenal medulla?

It has the same effects on target organs as direct stimulation by sympathetic nerves

What are the 3 zones of cells of the outer cortex of the adrenal gland?

1. Zona glomerulosa

2. Zona fasciculata

3. Zona reticularis

What class of steroid does the zona glomerulosa produce?

Mineralocorticoids (aldosterone)

What class of steroid does the zona fasciculata produce?

Glucocorticoids (cortisol)

How does ACTH stimulate the release of cortisol?

It binds to a cell surface receptor causing an increase in intracellular cAMP. This results in increased cortisol release.

What class of steroid does the zona reticularis produce?

Androgens (DHEA)

What are the functions of neurosteroids?

- modulation of neural plasticity

- learning and memory processes

- behavior

- seizure susceptibility

- response to stress, anxiety, and depression

How are steroid hormones carried throughout the bloodstream?

Due to their low water solubility, steroids must be carried in the blood by forming a complex with corticosteroid-binding globulin or serum albumin

What is the function of aromatase?

Aromatase (CYP19A1) is responsible for the key step in the biosynthesis of estrogens

What are the functions of aldosterone?

- increases reabsorption of Na+

- increases reabsorption of water (expanding extracellular fluid volume)

- increase renal excretion of potassium and hydrogen ions

What is the major target of Aldosterone? What is its physiological effect?

Target: distal tubule of kidneys

Effect: Increased blood pressure

What are the two most significant regulators of aldosterone secretion?

1. Concentration of K+ ions in extracellular fluid

2. Angiotensin II

How does the concentration of potassium in extracellular fluid affect aldosterone secretion?

A small increase in K+ levels stimulates aldosterone secretion

How does Angiotensin II increase the secretion of aldosterone?

It increases the frequency of membrane potential oscillations in zona glomerulosa cells resulting in enhanced Ca2 entry, which promotes aldosterone production

What is the function of aldosterone synthase?

A steroid hydroxylase that is encoded by the CYP 11B2 gene. It catalyzes the hydroxylation of the steroid group.

How does Aldosterone increase the reabsorption of Na+ and excretion of K+?

Aldosterone induces serum and glucocorticoid-inducible kinase (Sgk), corticosteroid hormone-induced factor (CHIF), and Kirsten Ras, which increase the activity and number of transport proteins

What is the sequence of events that leads to cortisol release?

Stressors -> CRH release -> ACTH release -> Cortisol release

What is the implication of long-term glucocorticoids therapy?

Adrenal atrophy

Where is the ACTH receptor (MCR2) located? What is its function?

Located: zona fasciculata

Function: stimulates production of cortisol via increased cAMP

What occurs in the acute phase following MCR2 activation?

StAR stimulates an increase in the supply of cholesterol substrate to steroigenic enzymes in the mitochondria

What occurs in the chronic phase following MCR2 activation?

Increased transcription of enzyme production

What are the metabolic effects of glucocorticoids?

- stimulation of gluconeogenesis

- mobilization of amino acids in extrahepatic tissues

- inhibition of glucose uptake

- stimulation of fat breakdown

Overall: Increase and maintain normal concentrations of glucose in blood

What are the CNS effects of glucocorticoids?

- memory/cognition

- sleep-wake cycles/arousal

- emotional status/behavior

What is the effect of Steroids on the lungs?

Stimulate the production of surfactant phospholipids, enhance the expression of surfactant-associated proteins, and structural maturation

What are the anti-inflammatory and immunosuppressive effects of glucocorticoids?

- inhibit tissue recruitment of WBCs

- upregulate the expression of anti-inflammatory proteins

- down-regulate the expression of pro-inflammatory proteins

What is the "dawn phenomenon"?

A natural early morning spike of cortisol to aid in arousal

What receptor does Cortisol interact with?

Glucocorticoid receptor (GR) or nuclear receptor subfamily 3

Describe the process of transactivation by glucocorticoids.

Cortisol binds to its receptor resulting in homodimerization of the receptor. The receptor is then translocated into the nucleus, where it activates gene transcription.

Describe the process of transrepression by glucocorticoids.

The activation of the glucocorticoid receptor allows for it to form a complex with other transcription factors (such as AP-1 and NfkB) preventing them from binding to their target thus repressing gene expression

What is the result of histone acetylation?

Following acetylation by coactivators, DNA unwinds from the histone allowing it to be transcribed by RNA polymerase II

What is the result of histone deacetylation?

DNA will be tightly rewound around the core histones making it inaccessible to RNA polymerase II

Describe the anti-inflammatory process of glucocorticoids at LOW doses.

Glucocorticoids will bind to the GR receptor causing it to translocate into the nucleus where it recruits histone deacetylase-2 preventing transcription of inflammatory genes

Describe the anti-inflammatory process of glucocorticoids at HIGH doses.

Glucocorticoids bind to GR which then binds to glucocorticoid response elements. These GRE then recruit coactivators that acetylate histones leading to the transcription of anti-inflammatory genes, such as Lipocortin

What is the function of Lipocortin?

Inhibits the activity of phospholipase-A2 (PLA2)

What is the function of phospholipase-A2?

Releases arachidonic acid from the plasma membrane to allow for eicosanoid synthesis (pro-inflammatory compounds)

What is the potency of a drug's glucocorticoid vs mineralocorticoid affinity dependent on?

- receptor affinity

- targeted objective of use

- pharmacokinetics

What endogenous molecule does Fludrocortisone mimic?

Aldosterone

What are the 4 routes of administration of corticosteroids?

1. Topical

2. Inhaled

3. Oral

4. Systemic

What are the clinical features of Cushing's Syndrome?

- moon face

- buffalo hump

- obesity

- thin skin

- slow wound healing/easy bruising

- increased hair

- bronze skin

- acne

- red cheeks

What is Cushing's syndrome (aka hyperadrenocorticism)?

An endocrine disorder caused by high levels of cortisol in the blood

What is Cushing's disease?

A benign tumor in the pituitary gland that produces large amount of ACTH and thus cortisol

What are the 2 causes of Cushing's syndrome?

- excessive endogenous production of cortisol

- administration of glucocorticoids for therapeutic purposes

What is the first-line treatment for Cushing's syndrome?

Surgery

What is the mechanism of action of Metyrapone?

- inhibits 11-hydroxylase activity thus inhibiting cortisol synthesis

- suppresses biosynthesis of aldosterone

What is the role of Metyrapone in Cushing's syndrome?

Used as a diagnostic test

What is the mechanism of action of Aminoglutethimide?

Inhibits the conversion of cholesterol to pregnenolone by inhibiting CYP11A1 resulting in decreased production of glucocorticoids, mineralocorticoids, and estrogens/androgens

What is the mechanism of action of Ketoconazole?

Inhibits 11-hydroxylase and 17-hydroxylase (takes several weeks to effect)

What is the mechanism of action of Etomidate?

Reversibly inhbits 11 beta-hydroxylase in addition to anesthetic properties

What is the mechanism of action of Mitotane?

- inhibits hydroxylation of 11-desoxycortisol and 11-desoxycorticosterone

- inhibits adrenocortical function

What is the indication of Mitotane?

Treatment of inoperable adrenal cortical carcinomas

What drug is Mitotane structurally related to?

DDT (an insecticide)

What is the mechanism of action of Cyproheptadine?

- H1 antagonist

- nonselective-serotonin receptor antagonist

- decreases ACTH hormone

What is the mechanism of action of Pasireotide?

Binds somatostatin receptors 1, 2, 3, and 5 in the corticotropic cells of ACTH producing adenomas resulting in inhibition of ACTH secretion

What is the mechanism of action of Mifepristone?

Progesterone and glucocorticoid receptor antagonist (will result in higher cortisol and ACTH levels)

What are the causes of Addison's disease?

- destruction of adrenal glands by infection or an autoimmune attack

- inherited mutation in the ACTH receptor on adrenal cells

What is secondary adrenal insufficiency?

Insufficient ACTH produced by the pituitary gland to stimulate the adrenal glands

Where is ADH produced?

Produced in the hypothalamus then transported by axons to the posterior pituitary gland where it enters the blood stream

What are the physiological effects of ADH?

- decreased serum osmolality

- decreased urine volume

- increased urine osmolality

What is the function of osmoreceptors? Where are they located?

Osmoreceptors located in the anterolateral hypothalamus sense small changes in osmotic pressure and in response increase or decrease ADH secretion

What is the function of barorecpetors? Where are they located?

Baroreceptors located in the carotid sinus and aortic arch measure blood pressure. If suppressed due to large changes in BP, ADH will be released

Where is the primary action of the V2 receptor?

Distal convoluted tubule and collecting duct

What is the function of the V2 receptor?

When ADH binds to V2 (Gs-coupled receptor), it results in the phosphorylation of AQP2 allowing for water to be reabsorbed from the urine

What is the function of the V1 receptor?

Vasoconstriction

Describe Diabetes insipidus.

A disease characterized by excretion of large amounts of severely diluted urine that cannot be reduced by reduced fluid intake (urine is bitter)

What are the causes of diabetes insipidus?

- ADH deficiency

- kidney insensitivity to ADH

What is central diabetes insipidus caused by?

Damage to the hypothalamus or pituitary gland as a result of surgery, infection, tumor, or head injury

What is dipsogenic diabetes insipidus caused by?

A defect of damage to the thirst mechanism, which is located in the hypothalamus resulting in increased thirst

(not treatable with desmopressin)

What is nephrogenic diabetes insipidus caused by?

An inability of the kidney to respond normally to ADH caused by a defect in the kidney, genetics, kidney disease, drugs.

Vasopressin (ADH)-resistant

What is the treatment for central diabetes insipidus?

Desmopressin

What is the mechanism of action of Desmopressin?

- binds to V2 receptors in the renal collecting duct to increase water absorption

- stimulates release of factor VIII due to stimulation of V1 receptors

What drugs enhance the antidiuretic response to vasopressin (ADH)?

- NSAIDs

- carbamazepine

- chlorpropamide

What drugs inhibit the antidiuretic response to vasopressin (ADH)?

- lithium

- colchicine

- vinca alkaloids

How does Lithium inhibit the antidiuretic response to vasopressin (ADH)?

- reduces the V2- mediated stimulate of adenylyl cyclase

- increase plasma levels of parathyroid hormone

What is the mechanism of action of Conivaptan?

Antagonist of V1A and V2 resulting in increased free water excretion, increased net fluid loss, increased urine output, and decreased urine osmolality

What is the mechanism of action of Tolvaptan?

Selective V2 receptor antagonist used to treat hyponatremia

What is the mechanism of action of demeclocycline?

Blocks the action of vasopressin (ADH) in the kidney in hyponatremia due to SIADH

What condition can Demeclocycline therapy lead to?

Nephrogenic diabetes insipidus (reversible)