Adrenal Cortex Hormones Flashcards
1
Q
Secretory Products of the Adrenal Glands
A
•corticosteroid hormones
- glucocorticoids (cortisol)
- mineralocorticoids (aldosterone)
- androgens
- The synthesis of these hormones via the steroidogenic pathway begins with cholesterol that is modified by an intricate network of enzymes.
- The steroid product of a cell is determined by its expression of specific enzymes.
- As the sole site of production of glucocorticoids and mineralocorticoids, the adrenal cortex has far-reaching and important effects on intermediary metabolism and electrolyte balance in the body.
2
Q
Glucocorticoids
A
- Glucocorticoids (e.g., cortisol) play a major role in the regulation of carbohydrate, protein, and lipid metabolism.
- They also modulate the effects of other hormones on these same processes.
3
Q
Mineralocorticoids
A
•Aldosterone, the most important mineralocorticoid, participates in the regulation of renal sodium reabsorption and potassium excretion, thereby promoting salt retention and affecting blood pressure homeostasis.
4
Q
Adrenal Steroid Synthesis: Initial Events
A
- The adrenal steroid hormones are synthesized from cholesterol that is mostly derived from the plasma. However, a small portion is synthesized in situ from acetyl-CoA.
- Much of the cholesterol in the adrenal is esterified by acylCoA:cholesterol acyl transferase (ACAT) and stored in cytoplasmic storage vacuoles.
- The first event in these biosynthetic pathways is activation of a cholesterol esterase that catalyzes the production of free cholesterol from cholesterol ester.
-This esterase is activated in the adrenal zona fasciculata (ZF)/zona reticularis (ZR) by ACTH, via cAMP. In the zona glomerulosa (ZG), angiotensin II activates the esterase, via IP3/Ca2+ and DAG.
5
Q
Adrenal Steroid Synthesis: Entering the Mitochondria, Then Leaving the Mitochondria
A
- Steroidogenic Acute Regulatory Protein (StAR) facilitates transport of free (unesterified) cholesterol across the outer mitochondrial membrane.
- The StAR function is increased by ACTH in two ways.
- First, the protein is induced in response to cAMP.
- Second, maximal activity of StAR requires protein kinase A to phosphorylate serine residue(s) on the protein.
- After transport, cholesterol is modified by the mitochondrial enzyme cytochrome P-450 side-chain cleavage enzyme (P-450scc).
- P-450scc when activated by ACTH (zona fasciculate [ZF]/ zona reticularis [ZR]) or angiotensin II (ZG, converts cholesterol to pregnenolone.
- Cleavage of the side chain involves sequential hydroxylations, at carbon-22 and then at carbon-20, followed by side chain cleavage to yield the 21-carbon steroid.
- Therefore, the enzyme is also referred to as 20,22-lyase.
•Pregnenolone leaves the mitochondrion for further processing in the smooth endoplasmic reticulum
6
Q
Adrenal Steroid Synthesis: Up Until Corticosterone
A
- Conversion of cholesterol to pregnenolone is the rate limiting reaction in the biosynthesis of steroid hormones.
- P-450scc is stimulated by tropic hormones from the anterior pituitary (e.g., ACTH, LH, FSH).
- The tropic hormones also stimulate the esterase and inhibit ACAT to boost the pool of free cholesterol.
- All mammalian steroid hormones are formed from cholesterol via pregnenolone through a series of reactions that occur in either the mitochondria or smooth endoplasmic reticulum of the adrenal or gonadal cell.
- Hydroxylases that require molecular oxygen and NADPH are essential, among other steps.
7
Q
Mineralocorticoid Synthesis
A
- Synthesis of aldosterone follows the mineralocorticoid pathway in the zona glomerulosa
- Progesterone is then hydroxylated in the SER by 21-hydroxylase to form 11-deoxycortico-sterone (DOC). DOC is an active (Na+ - retaining) mineralocorticoid that has 1/25 the activity of aldosterone.
- DOC is next transferred to the mitochondrion for hydroxylation by 11beta-hydroxylase to produce corticosterone that is a short-lived intermediate that is produced by the aldosterone synthase complex.
-Corticosterone has glucocorticoid activity but is not important in humans. It also is a very weak mineralocorticoid (0.1% the potency of aldosterone).
- Hydroxylation on carbon-21 is required to confer both mineralocorticoid and glucocorticoid activity.
- Hydroxylation of corticosterone by 18- hydroxylase followed by oxidation on carbon-18 of the hydroxyl group to an aldehyde yields aldosterone.
-The ZG contains a mitochondrial 18- hydroxylase, but lacks the 17alpha-hydroxylase of the SER that is found in the zona fasciculata and zona reticularis.
•The production of aldosterone by the ZG cells is ultimately regulated by the renin angiotensin system. Angiotensin II binds to specific glomerulosa cell receptors to elicit responses.
8
Q
Glucocorticoid Synthesis
A
- As in the formation of aldosterone, the synthesis of cortisol first includes formation of pregnenolone and then progesterone, followed by 3 successive hydroxylations at carbons 17, 21, and 11 by the 17alpha-, 21- and 11beta-hydroxylases, respectively.
- 17alpha-Hydroxylase, an SER enzyme, acts upon either pregnenolone or progesterone.
- In humans, the important intermediate in the zona fasciculate (ZF) is 17alpha-hydroxyprogesterone, because corticosterone is not an important glucocorticoid in humans.
-Therefore, the formation of cortisol as an endproduct is the favored pathway in the ZF.
- The 17alpha-hydroxyprogesterone is hydroxylated in the SER by 21-hydroxylase to form 11-deoxycortisol.
- 11-Deoxycortisol is then hydroxylated in the mitochondria by 11betahydroxylase to form cortisol, the most potent natural glucocorticoid hormone in humans.
- Reactions of the corticosteroid pathway occur primarily in the ZF and secondarily in the ZR.
- The ZF (and ZR), unlike the ZG, lacks 18-hydroxylase activity.
- However, in certain congenital adrenal hyperplasia diseases the pathway towards formation of corticosterone in the ZF (and also ZR) is increased abnormally leading to overproduction of 11-deoxycorticosterone as an alternate mineralocorticoid.
9
Q
Generally, steroids that contain a hydroxyl group on carbon-17 have more […] and less […] strength.
A
Generally, steroids that contain a hydroxyl group on carbon-17 have more glucocorticoid and less mineralocorticoid strength.
10
Q
Control of Cortisol Synthesis - Acute
A
•In reaction to acute emotional or physical stress, the initial CNS input is translated into a neural response at the neurohypothalamus causing activation of the sympathetic nervous system. The SNS triggers release of epinephrine from the adrenal medulla. Epinephrine increases heart rate and stimulates muscle and liver glycogenolysis in just 7 seconds!
11
Q
Control of Cortisol Synthesis - Chronic
A
- Chronic stress is characterized by the secretion of cortisol that depends on ACTH.
- In response to stress, a second translation of the CNS input occurs in the endocrine hypothalamus instigating the release of corticotropin releasing hormone (CRH) that stimulates the corticotrophs of the anterior pituitary.
- CRH operates on corticotroph cells of the anterior pituitary via Gs leading to stimulation of adenylyl cyclase.
- As a consequence of this signal, corticotrophs process and release the products of a complex peptide, proopiomelanocortin (POMC).
- POMC contains, as part of its sequence, a number of hormones including ACTH and beta-lipotropin.
- ACTH signals the ZF to produce and release cortisol.
- By the stimulatory action of cortisol on gluconeogenesis through induction of key enzymes (e.g., phosphoenolpyruvate carboxykinase), and its catabolic effect on muscle protein breakdown to provide glucose precursors, cortisol permits long-term response to the stress over a period of hours.
- Besides these metabolic effects, cortisol induces phenylethanolamine Nmethyltransferase (PNMT) to promote the conversion of norepinephrine to epinephrine in the adrenal medulla thus aiding in the response to stress.
- The POMC peptide undergoes cleavage at different locations depending on the desired product of the cell.
-In the corticotrophic cell of the anterior pituitary, cleavage (at positions 3 and 5) releases ACTH and beta-lipotropin into the general circulation.
- In the case of ACTH, the mechanism of its action on ZF/ZR involves primarily Gs and increased cAMP, but also includes key contributions from IP3-intracellular Ca/DAG second messengers, plus enhanced calcium uptake from outside the cell.
- ACTH stimulates all three of these classes of second messenger events to elicit cortisol synthesis and release.
- However, the bottom line is that cAMP predominates as a second messenger in the case of ACTH. Some beta-lipotropin arising in the corticotroph may be further degraded peripherally, at site 7, to form beta-endorphin.
- Some beta-endorphin can be secreted directly into the CNS by endorphin neurons that are programmed to cut at site 7 during stress.
- beta-endorphin elicits analgesia/ euphoria to help cope with stress and pain, and quiets organs like the gut through its endogenous morphine-like actions, which are mediated by lowering cAMP (Gi).
12
Q
POMC Cleavage
A
- In humans, select neurons process POMC (cleavage at sites 3 and 4) to yield alpha-MSH, a satiety factor.
- In the pars intermedia, POMC is cleaved at sites 4 and 7 to release alpha-MSH/CLIP (corticotropin-like intermediary peptide), and beta-lipotropin/beta-endorphin, respectively, into the circulation.
- Cleavage of beta-lipotropin at site 6 yields alpha-MSH (not shown).
- Thus, a variety of POMC neurons exist in the brain, some process POMC to ACTH (stress), some to beta-endorphin (pain) and some to alpha-MSH (eating behavior).
13
Q
Cortisol Release Determinants
A
- The amount of cortisol secreted by the adrenal is almost entirely determined by the intensity of the ACTH stimulus.
- Increased circulating cortisol provides long loop negative feedback on the hypothalamus and anterior pituitary to decrease CRH and ACTH secretion, respectively.
- Reduced exposure of the cortex to ACTH, results in adrenal atrophy whereas excessive stimulation by ACTH causes adrenal hyperplasia.
- Negative feedback on CRH and ACTH release is the mechanism that is primarily responsible for regulation of cortisol secretion by the adrenal cortex.
- However, superimposed upon this basic control system is a diurnal (circadian) rhythm of release. In humans, the frequency of cortisol secretory bursts is greatest during the early morning hours and at a minimum late at night.
- As a result, cortisol concentration in the blood is far greater in the morning than at night.
- The diurnal rhythm is related primarily to sleep and activity cycles.
14
Q
Cortisol Binding to Serum Proteins
A
•About 80% of blood cortisol is bound with high affinity to the serum binding protein, corticosteroid-binding globulin (CBG), also known as transcortin. Of the remaining, 15% is bound to albumin, and 5% is free. (Note similarity to thyroid hormones in the circulation).
15
Q
Aldosterone Binding to Serum Proteins
A
- aldosterone, the primary mineralocorticoid, is mainly associated (50%) with albumin, an association of relatively low affinity.
- Since aldosterone is poorly bound to plasma proteins, it is readily available for metabolism by the liver.
- Nearly all of the free aldosterone in blood is metabolized in one passage through the liver. This rapid metabolism by the liver explains the short half-life and relatively low concentrations of aldosterone in circulation.
16
Q
What happens after cortcosteroids diffuse into cells?
A
- After diffusing into the cell, corticosteroids bind to intracellular receptors located in either the cytoplasm or the nucleus.
- These receptors contain both a hormone and a DNA binding domain analogous to other lipophilic receptors.
- The hormone-receptor complex forms a homodimer before binding to DNA at the glucocorticoid responsive element.
- Thus specific genes are induced ultimately leading to formation of specific proteins/enzymes that generate metabolic responses.
- Note that the steroid hormone binding to DNA as a homodimer of the hormone-receptor complex contrasts with the mechanisms for nonsteroidal lipophilic hormones (i.e., thyroid hormone, vitamin D, vitamin A) in which the hormone-receptor complex binds as part of a heterodimer coupled with RXR.
18
Q
Effects of Glucocorticoids II
A
- Because it is a steroid hormone, the action of cortisol involves gene expression and responses occur within a relatively long time frame.
- Fasting induces, among other things, an increased release of glucose from the liver, to maintain a relatively consistent concentration of glucose in blood.
- In its metabolic regulating capacity, cortisol maintains the concentration of glucose in blood, in part, by the induction of enzymes involved in gluconeogenesis.
- Approximately 50% of the carbons needed for gluconeogenesis are derived from amino acids. In concert with this need, cortisol enhances the release of amino acids from proteins in muscle.
- The amino acids released (especially alanine) are transported to the liver to be converted to glucose.
- Cortisol further indirectly fosters gluconeogenesis by enhancing lipolysis to release from adipose tissue fatty acids that provide energy in the liver to drive gluconeogenesis.
- Cortisol also initiates mechanisms to conserve glucose because the mobilized fatty acids serve as an alternate energy source in muscle and spare glucose by inhibiting its oxidation.
- Additionally, the glycerol released from the fat cell with the fatty acids also serves as a substrate for gluconeogenesis.
