Adrenal Glands Flashcards
Steroid Hormone Synthesis
Cholesterol is transported to the inner mitochondrial membrane via StAR and converted to pregnenolone by P450cc (found on membrane); synthesis of the steroid then proceeds in an unregulated fashion inside the mitochondria
*Transport across the mitochondrial membrane= rate-limiting
Cholesterol Esters
Storage form of the substrate (cholesterol) for steroid hormones that are formed by cholesterol acyltransferase
*Necessary because steroid hormones cannot be stored
3 types of steroid binding proteins
- Corticosteroid binding globulin
- Sex-steroid binding globulin
- Vitamin D binding globulin
Steroid Hormone Metabolism
Are broken down to glucuronic acid and sulfate by the liver and further excreted by the kidneys
*Conjugation increases the steroid’s water solubility and decreases its affinity for binding protein
Steroid Hormone Receptors
When bound to a steroid, it releases its complex of HSPs and activates its NLS to travel to the nucleus and activate transcription
=>Binds to HRE as two homodimers and recruits CoAs and HAT to induce action
Aldosterone Synthase
Expressed in the zona glomerulosa; converts DOC to aldosterone
17a-hydroxylase
Leads to the formation of 11-dehydroxy cortisol and w/ the fnxn of 11B-hydroxlase it forms cortisol
*Absent in the zona glomerulosa
P450c17
Assists the fnxn of 17a-hydroxylase and 17,20-lyase in the zona fasciculata and reticularis
17,20-lyase
Fnxns to produce androgens; found in high concentration in the zona reticularis
Transcription of StAR
Zona glomerulosa: Induced by A-II (Gq)
*Hyperkalemia will also induce
Zona fasciculata and reticularis: Induced by ACTH (Gs)
Aldosterone
Mostly found unbound; therefore, it has a very short half-life
11B-hyrdoxysteroid dehydrogenase II
Converts cortisol to the physiologically inactive cortisone; present in mineralcorticoid tissues
- DOC and Aldosterone react similarly w/ receptors. This prevents cortisol from influencing
- 11B-hydroxysteroid dehydrogenase I is found in corticoid tissues and converts cortisone back to cortisol
DHEA
Secreted bound to sulfate, is slowly metabolized due to strong binding to albumin, and good indicator of adrenal fnxn
Fetal zone
Secretes large amounts or DHEA sulfate that is converted to estrogen by the placenta
Adrenarche
Rise in DHEA secretion during puberty; is not involved in initiating puberty
*Females use DHEA to grow axillary and pubic hair; males dont really need it
Most accurate measurement of cortisol production
24 hour urine cortisol excretion
Synthetic glucocorticoids
Have enhanced stimulation due to their increased affinity for the glucocorticoid receptor and decreased plasma clearance
*Dexamethasone
Effects of ACTH
Acute: Increased transcription of StAR, increased activity of cholesterol esterase
Chronic: Proliferation of the zona fasciculata and reticularis, increased steroidogenic enzymes, increased LDL receptors
AVP
Secrete into the hypothalamophyseal system during times of stress; induces ACTH secretion via a Gq pathway
Regulation of cortisol release
Regulated by the SCN sending neurons to the PVN; induces a diurnal rhythm w/ increased levels in the morning
Stress and glucocorticoid release
Can override the SCN and cause release of cortisol
Glucocorticoid Actions
Permissive Effects: Helps glucagon by increasing glycogen synthase activity
*More glycogen to be broken down when needed
Synergistic: Inhibits fasting hypoglycemia by promoting gluconeogenesis and antagonizing the action of insulin =>Increased FFAs
-Promotes protein catabolism in muscle, decreases GLUT-4, inhibits Ca2+ uptake,
*When present in excess, actually PROMOTES fat deposition in adipocytes
Alveolar Maturation
Stimulated by cortisol; also promotes surfactant production
*Glucocorticoids are used to accelerate fetal lung maturation in premies
Anti-inflammatory actions of glucocorticoids
- Inhibits production of TNF-a and IL-1
- Produces lipocortin => inhibitor of Phospholipase A2 => Decreased prostaglandin synthesis
- Inhibits NO synthase
- Glucocorticoids also suppress immune fnxn
Cholesterol source
LDLs are compartmentalized and undergo lysosomal degradation to generate free cholesterol
*Cholesterol esterase also produces some new cholesterol from stored lipids
Addison’s Disease
Adrenocortical insufficiency usually caused by an AI disorder
Aldosterone deficiency => Hyponatremia, polyuria, hypotension, hyperkalemia
Cortisol deficiency => Hypoglycemia, weakness, hyperpigmentation (ACTH accumulation)
*Kennedy had this
Secondary Adrenocortical Insufficiency
Decreased ACTH from pituitary; common to see w/ superphysiological concentrations of synthetic glucocorticoids used as anti-inflammatories
-Inhibits prod. of ACTH => Adrenal atrophy
Pseudohypoaldosteronism
Loss of the mineralcorticoid receptor leading to hyperkalemia, salt wasting, and metabolic acidosis (decreased H+ secretion)
Cushing’s Syndrome
Mostly caused by abuse of glucocorticoids; also can be ectopic ACTH secreting tumor
*Assoc. w/ obesity, hypertension, hirsutism, purple stria on abdomen, moon face, acne, and decreased healing capability (anti-Wolverine)
Cushing’s Disease
Disease of excess production of ACTH by the pituitary; same symptoms as Cushing’s Syndrome
Conn’s Syndrome
Usually due to an adenoma of the zona glomerulosa
=>Mild hypertension, metabolic alkalosis, hypokalemia
Congenital Adrenal Hyperplasia
Genetically inherited deficiency for the synthetic enzymes of the steroid pathway
*Most commonly block of the 21a-hydroxylase enzyme
Symptoms include: build-up of steroid intermediates, adrenal hypertrophy, excess ACTH
(M)Early maturation of genitalia and appearance of secondary sexual characteristics, early closure of the epiphyseal plate
(F)Fusion of labia [if prior to 12 weeks] and clitoral hypertrophy; absence of breast development and period
Chromaffin Cells
Cells of the adrenal medulla that secrete catecholamines directly into the bloodstream; only source of epinephrine in the body
Catecholamine Synthesis
TH converts tyrosine to DOPA which then becomes dopamine
=> Dopamine transported into a chromaffin (secretory) granule via VMAT and converted to NER
=>NER diffuses out and is converted to ER by PNMT; transported back into granule via VMAT
Catecholamine release
Stored in chromaffin granules w/ Ca2+, ATP, and chromogranin; released after Ach (sympathetic depolarization) or Cortisol stimulation (increases PMNT fnxn and prevents chromafffin cells from becoming post-ganglionic fibers)
Catecholamine Degrading Enzymes
MAO and COMT; work rapidly in the liver, heart, and kidney
*Rapid degradation => no good serum assay
Catecholamine metabolites
Metanephrines (formed by COMT) and Vanillylmandelic acid (formed by MAO)
Adrenergic Receptor Actions
a1- Increased IP3, intracellular Ca2+
a2- Decreased cAMP
B1,2,3- Increased cAMP
Pheochromocytoma
Tumor of the chromaffin cells causing tachycardia, tremors, sweating, increased BMR
21B-hydroxylase
Forms DOC from progesterone
11B-hydroxylase
Converts DOC to corticosterone or cortisol
