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The adrenal gland- physio
Terms in this set (16)
Overview of the Adrenal Gland:
The adrenal glands produce three classes of ? hormones (mineralocorticoids, glucocorticoids and adrenal androgens), and two ? hormones (epinephrine and norepinephrine).
Although it is difficult to assign a single specific physiological function to the adrenal gland, many of the adrenal hormones are involved in some aspect of the body's response to ?.
The glucocorticoids, primarily cortisol, play important roles in the regulation of ? metabolism and have a multitude of additional effects on many physiological systems and organs in the body.
The mineralocorticoid, aldosterone, is vital in maintaining ?.
Although the adrenal androgens DHEA and androstenedione are quite weak androgens compared to testosterone, they may have effects on the establishment and maintenance of ?
The main catecholamine produced in by the adrenal gland is? (adrenaline), which mediates the primary physiological responses to 'flight-or-fight' situations and other physiological stresses.
The adrenal gland is composed of essentially two functionally and developmentally distinct endocrine organs: ? and the ?.
Embryologically, the cortex is derived from mesoderm while the medulla is derived from neural crest cells that migrate into the developing cortex. The cortex and medulla synthesize different chemical classes of hormones. The cortex produces ?, while the medulla produces ?.
The cortex is composed of three discreet layers, each of which makes a distinct set of cortical hormones. The specific set of hormones produced from each layer is determined by ?
carbohydrate and protein
salt and water balance
secondary sex characteristics.
the cortex (outer layer), and the medulla (inner core)
cholesterol- derived, lipid soluble steroid hormones, water soluble amine hormones derived from tyrosine
the set of enzymes present in the cells in that layer.
Biosynthesis of Adrenal Cortical Hormones:
Biosynthesis of all of the cortical steroids is initiated by the enzymatic removal of the cholesterol side-chain, by the ? .
The product (?) is converted, in multiple enzymatic steps, to either ?.
Loss-of-function mutation in any of these enzymes reduces the amount of the downstream products and may cause overproduction of other hormones.
For example, reduced activity of ? diminishes production of both cortisol and aldosterone and increases production of the ?
What enzyme is not present in the glomerulosa ?
watch lecture to see how much you need to know from this figure
side chain cleavage (SSC) enzyme
pregnenolone,- cortisol, aldosterone, or an androgen
21α-hydroxylase, sex steroids.
SER 17 alpha hydroxylase
Regulation of Corticosteroid Production:
The secretion of cortisol is directly controlled by the pituitary hormone ?. In the absence of ACTH cortisol secretion is greatly reduced. Additionallyt, factors that increase ACTH production increases cortisol's production.
Production of ACTH is under ? control, and there are a number of factors that feed into the hypothalamus that ultimately result in an increase in ACTH production.
When stimulated, small-bodied neurons in the hypothalamus secrete ?, which is transported in the portal vessels to the anterior pituitary where it stimulates
? to release ACTH into the blood stream. ACTH binds to receptors on cells of the ? and stimulates the production of cortisol.
The production of cortisol is regulated by multiple negative feedback loops. ? negatively affect their own synthesis primarily by suppression ACTH production via a direct effect on pituitary ?. In addition, cortisol acts at the hypothalamic level to inhibit ?. ? also exerts a short-term negative feedback on hypothalamic CRF release.
Cortisol is secreted into the circulation in an episodic fashion that follows a 24 hour, or circadian, cycle. This cycle is entrained, to circadian rhythms of ACTH secretion. ACTH is secreted by the hypothalamus in a highly pulsatile manner throughout the day, but with a higher overall rate of secretion in the ?
ACTH (Adrenocorticotropic hormone)
corticotrophin releasing hormone (CRH), corticotrophs, zona fasciculata
Glucocorticoids, corticotrophs, CRH secretion, ACTH
early morning hours.
ACTH is generated from proteolytic digestion of the ?
In the adult, POMC (proopiomelanocortin) produced in ? is processed to yield several peptides and ACTH.
In the fetus, some corticotrophs produce a different set of peptides, including the ?. When ACTH is pathologically overproduced (as in Addison's), some POMC is processed in the fetal pattern, producing the MSHs and causing a ?
POMC precursor peptide
corticotrophs, melanocyte stimulating hormones γ-MSH and α-MSH, hyperpigmentation of skin.
ACTH action in the adrenal cortex:
ACTH exerts its action on adrenal cortex cells through a specific ? on the cell membrane that activates the ? signaling pathway. Activation of this pathway in cortical cells stimulates hormone production by multiple mechanisms.
1) Stimulation of the rate-limiting step catalyzed by ?
2) Stimulation of?
3) Stimulation of ?
4) Stimulation of ?
If ACTH levels are chronically elevated (as opposed to the normal periodic elevations)?
While the production of cortisol is very strongly stimulated by ACTH, this is not the case for the other cortical hormones. Although ACTH does influence aldosterone production, the primary stimuli for aldosterone biosynthesis are ?
GPCR (the ACTH receptor), PKA (protein kinase A)
the side-chain cleavage enzyme (also known as SSC, CYP11A1 and 20,22-desmolase)
11β-Hydroxylase and the other enzymes required for corticosteroid synthesis
cholesterol uptake from plasma (by increasing Low density lipoprotein (LDL) receptor levels)
cholesterol ester hydrolysis, which acts to generate free cholesterol for steroid biosynthesis
hyperplasia of adrenal cortex can occurs.
increased blood potassium levels, low blood pressure, and angiotensin II.
Like all steroid hormones, the physiologic action of cortisol is exerted through a ?
The cortisol receptor, known as the ?, is found in virtually all cells in the body. As with many steroid hormone receptors, In the absence of hormone, the receptor is located in the ?. Binding of hormone indices the receptor to ?
In the case of cortisol, its target genes are different in each tissue, so that the ? The wide range of tissue-specific responses to cortisol, combined with the widespread distribution of GR, generates an enormous complexity in how the body responds to cortisol.
specific intracellular receptor within target cells
glucocorticoid receptor (or GR), cytoplasm, translocate to the nucleus where it binds to hormone response elements (HREs) in the regulatory regions (promoters) of target genes, and stimulates (or suppress) transcription of these genes.
set of genes activated by the hormone in the liver is not identical to the cortisol-responsive genes in the brain.,
Physiological effects of cortisol:
Carbohydrate metabolism: One of the primary effects of cortisol, and the basis of its classification as a glucocorticoid, is to ?. This is accomplished by stimulating?
Protein metabolism: Cortisol inhibits ? and increases ? especially in ?. The liberated amino acids are used by the liver for ?, a process that is strongly stimulated by glucocorticoids. These negative effects on protein metabolism, may contribute to the ?
Lipid metabolism: Cortisol increases ? and raises ?. A large portion of the fat liberated from adipose is ?
Importantly, the lipid-releasing activity of cortisol does not occur equally in all adipose tissue depots. In conditions of chronically elevated cortisol, ?
Inflammation and the immunity: The effects of cortisol on inflammation are complex and not fully understood. Although cortisol plays a role in all stages of a normal inflammatory response, from initiation to resolution, it is most commonly associated with ? The anti-inflammatory effect of cortisol is due, in part, to ? Among many other effects, cortisol can also suppress ?
The immunosuppressive and anti-inflammatory actions of the glucocorticoids are exploited clinically for the inhibition of transplant rejection and for the treatment of allergic and autoimmune syndromes. The risks associated with this therapy are increased susceptibility to infection and the induction of Cushing's syndrome, similar to Cushing's disease, which is caused by ACTH-secreting pituitary adenoma.
increase blood glucose levels, hepatic gluconeogenesis and glucose production and inhibiting peripheral glucose utilization (via antagonism of insulin action).
protein synthesis , protein breakdown, muscle and liver, gluconeogenesis, reduction of connective tissue integrity that is seen in syndromes of chronically elevated glucocorticoids (Cushing's).
lipolysis in peripheral adipose beds, circulating fatty acid levels, absorbed and stored in the liver producing fatty liver., many peripheral adipose beds are reduced in size while others, mainly in the face and trunk, actually expand.
immune suppression. , suppression of prostaglandin production, mainly via inhibition of phospholipase-A2., lymphoid tissues, to suppress the conversion of T-cells to antibody forming cells.
Effects of cortisol on insulin signaling:
The metabolic effects of cortisol conspire to increase ?Cortisol inhibits insulin action in both the ?). This effect of cortisol is evident in conditions of chronic hypercortisolemia, as in Cushing's, which are often accompanied by ?
check diagram for any missed functions of cortisol
insulin resistance and promote a 'pro-diabetic' state., liver and muscle, diabetes
The primary action of aldosterone is to ? Aldosterone acts on its own nuclear receptor termed the >?.
The mineralocorticoid receptor is present in the ?, it upregulates a ? that pumps three sodium ions out of the cell, into the interstitial fluid and two potassium ions into the cell from the interstitial fluid. This results in reabsorption of sodium (Na+) ions and water (which follows sodium) into the blood, and a net loss of plasma K+ ions into the urine.
increase blood pressure by promoting Na+ and water retention, and lowering plasma K+ concentrations. , mineralocorticoid receptor
principal cells of the distal tubule and the collecting duct of the kidney nephron, Na+/K+ exchanger
Corticosteroid 'Cross-Talk' at the molecular level:
A peculiarity of the corticosteroid family of hormones is the molecular similarity of the ?. This chemical similarity leads to the possibility of cortisol interacting with, and activating, the mineralocorticoid receptor. The fact that cortisol frequently circulates at much higher concentrations than aldosterone presents the possibility of this receptor 'cross-talk' in many tissues.
This potential problem is managed by the expression of ? in tissues where the mineralocorticoid receptor is present, such as the kidney. 11βHSD2 converts ?
What enzyme converts cortisone back to cortisol in tissues that need cortisol?
cortisol vs cortisone just depends on if there is a mineralcorticoid receptor or a glucocorticoid receptor
glucocorticoid cortisol and mineralocorticoid aldosterone, 11-beta-dehydogenase-2 (11βHSD2), the active cortisol into the inactive cortisone.
11,B-HSD-1= 11 ketoreductase
Biosynthesis and regulation of catecholamine production:
The adrenal medulla comprises approximately 25% of the adrenal gland mass and produces catecholamine hormones: ?. While most of the ? found in circulation is from sympathetic nerve endings rather than from the adrenals, nearly all the ? found in circulation is derived from the adrenal gland.
Because the autonomic nervous system exerts direct control over the hormone producing ?, hormone release occurs quickly in response to stressors such as imminent danger, and is the main mediator of the 'flight-fight' response.
In many ways, the adrenal medulla is analogous to post ganglionic sympathetic neurons. Both cell types are derived from ?. In addition, both release ?. They differ in that the adrenal medulla makes the ? hormone epinephrine, while post ganglionic sympathetic neurons secrete norepinephrine which acts specifically on ?
norepinephrine, epinephrine (and a small amount of dopamine), norepinephrine, epinephrine
chromaffin cells in the medulla
neural precursors during development. , catecholamines in response to sympathetic signals (acetylcholine), distant acting , target cells at the point of release.
Synthesis of catecholamines:
The catecholamines are synthesized in the ?.
? is the rate limiting enzyme in the pathway and is stimulated by ? and is subject to auto-regulatory negative feedback inhibition by ?.
Norepinephrine is converted to epinephrine by, ?. This enzyme is stimulated by ?, which occurs since the medulla is directly downstream from the circulation draining the adrenal cortex.
L-tyrosine to .... to .... to ..
check lecture for what we need to know from the figures
chromaffin cells of the adrenal medulla, Tyrosine hydroxylase, sympathetic nerve action, norepinephrine
phenylethanolamine N-methyltransferase (PNMT)., cortisol
L-dopa, dopamine, norepi, epi
Factors that stimulate catecholamine release:
Catecholamine release from the adrenal medulla is mediated by the ? that transmits signals from the ? ot the ? when certain stress situations are present. Among these stresses are:
1. Fight/Flight stimuli
4. Increased sympathetic nervous system tone
5. Trauma, hypovolemia, anoxia
8. Extreme temperatures
The effects of norepinephrine and epinephrine are mediated by the actions of two classes of adrenergic receptors: ?
Both alpha and beta receptors have multiple family members - e.g. α1, α2, β1 and β2. Although many hormones have their biological effects by interacting with a single highly specific receptor (e.g. insulin), the situation with the catecholamines is more complex.
Both hormones can bind to and activate all of the adrenergic receptors - albeit with different affinities.
Depending on the amount of each receptor on a given cell type, and the relative concentration of the two hormones, the biological effects of the catecholamines can vary substantially from one tissue to the next.
General actions of catecholamines
1. Cardiovascular/Circulatory System: ?
2. Nervous System: ?
3. Metabolism: ?
4. Digestive System: ?
sympathetic nervous system, CNS to the adrenal gland
alpha (α) and beta (β).
Increased rate and force of cardiac contraction. Constriction or dilation of arterioles causing a shift in blood flow patterns.
Increased alertness, and nerve activity in general.
Increased blood glucose, FA, ketone bodies. Increased metabolic
Decreases GI motility and secretion.
Metabolic effects of adrenergic receptor activation:
In effects of epinephrine on carbohydrate metabolism are mediated mainly by the ?. The primary direct effect of epinephrine is the ?. This is brought about by the combined effects of increased of ?.
Both effects are mediated by the ? which signals via ?
Additional epinephrine-mediated effects in ?, ? , and ? contribute to the overall metabolic outcome of rapidly increasing energy availability.
Degradation of catecholamines:
The biological actions of catecholamines are very brief, lasting only ∼10 seconds in the case of epinephrine. Circulating catecholamines are degraded first by the enzyme ?, which is present in high concentrations in ?. COMT converts epinephrine to?>.
A second enzyme, ?, converts these metabolites to ?. Direct measurement of epinephrine is difficult, but the concentration of ? in the urine is a useful indicator of the total adrenal catecholamine production.
norepinephrine and epinephrine can be converted to ?, then to ?
norepinephrine via COMT can be converted to ? What about epinephrine? then what are both converted to ?
liver, stimulation of hepatic glucose production and release, glycogenolysis and gluconeogenesis, beta-adrenergic receptor, which signals through cAMP/PKA pathways., muscle, adipose and the pancreas
catecholamine-O-methyltransferase (COMT), endothelial cells and the heart, liver, and kidneys, metanephrine, monoamine oxidase, vanillylmandelic acid (VMA), metanephrines and VMA
dihydroxymandelic acid, VMA, normetanephrine, metanephrine, VMA
Adrenal Gland Pathologies:
Glucocorticoid excess is most commonly seen in individuals receiving ?. Less commonly, individuals overproduce cortisol either because of a primary cortisol-producing adrenal tumor or secondary to a pituitary adenoma that produces ACTH.
In either case, the cortisol excess causes a constellation of symptoms including truncal adiposity (abdomen, neck, face), hypertension, loss of subcutaneous adipose and connective tissue in the extremities, reduced bone density & mineralization, muscle weakness and wasting, and hyperglycemia. This constellation is referred to as ?. The term Cushing's disease is used for the subset of cases caused by ?
corticosteroids for treatment of chronic inflammatory
Cushing's syndrome, an ACTH-secreting pituitary tumor.
Glucocorticoid deficiency - or more accurately ? (which includes both glucocorticoid and mineralocorticoid) - also produces a wide array of symptoms. Conditions leading to glucocorticoid insufficiency, no matter the origin, are referred to as ?. Although tuberculosis was once a common cause of primary adrenal insufficiency, today ?.
Failure of adrenal cortical hormone secretion
leads to increases in circulating concentrations of
? as well as ? which cause ?
The combined absence of glucocorticoid and
mineralocorticoid leads to ?
Addison's is classified as either: primary, secondary or tertiary depending on where the defect resides;?
,? , or ? respectively.
adrenal insufficiency, Addison's disease, autoimmune adrenal disease is the most common cause, ACTH as well as other products of POMC including α-MSH and γ-MSH, skin hyperpigmentation.
hypoglycemia and hyperkalemia..
the adrenals, the pituitary or the hypothalamus
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