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BIOL432: Molecular Endocrinology > Steroid Glucocorticoids > Flashcards

Steroid Glucocorticoids Flashcards

1
Q

What is the adrenal cortex derived from?

A

Mesodermal tissue

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2
Q

Why is the adrenal cortex highly vascularized and innervated?

A

You need to be able to get hormones into the bloodstream quickly, and be able to sense hormone levels

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3
Q

What are the three layers of the adrenal cortex?

A

The zona reticularis (inner), the zona fasciculata (middle), and the zona glomerulosa (outer), they are surrounded by a connective tissue capsule

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4
Q

Where is the adrenal gland?

A

It sits on top of the kidneys, it is composed of a cortex and medulla

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5
Q

What is produced by the zonal glomerulosa?

A

aldosterone (mineralocorticoid), it is deficient in the enzyme required for synthesis of cortisol and androgen precursors

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6
Q

What is the zonal glomerulosa regulated by?

A

It is regulated by the renin-angiotensin system and ACTH

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7
Q

What is produced by the zona fasciculata and reticularis?

A

Cortisol and androgens. These layers are deficient in the enzyme required to make aldosterone, they are regulated by ACTH

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8
Q

What is the zona fasciculata rich in?

A

Lipid droplets (store cholesterol), mitochondria, and SER –> allows for rapid synthesis of steroid hormones

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9
Q

Does the fasciculata produce acute or basal levels of cortisol/steroid hormones?

A

Fasciculata is responsible for acute production of cortisol, the reticularis is responsible for basal levels

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10
Q

What does the adrenal medulla produce?

A

Epinephrine and norepinephrine

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11
Q

Which layer is the thickest layer?

A

The zona fasciculata (middle)

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12
Q

Which enzyme is present in the zona glomerulosa that is not present in the other two layers?

A

P450 aldosterone

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13
Q

Which enzyme is present in the fasciculata and reticularis that is not present in the glomerulosa?

A

17-alpha hydroxylase

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14
Q

What causes release of catecholamines from the adrenal medulla?

A

the adrenal medulla acts as a sympathetic ganglion innervated by sympathetic preganglionic fibers, stimulation causes the release of nor or epi. 80-90% of circulating catecholamines are epi in primates

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15
Q

What are the functions of mineralocorticoids, and where are they produced?

A

Produced by the zona glomerulosa, involved in controlling electrolyte balance

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16
Q

What does aldosterone do?

A

Promotes Na+ retention and K+ excretion, thereby controlling levels of water

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17
Q

What are glucocorticoids and where are they produced?

A

They are produced by the zona fasciculata/reticularis, respond to ACTH stimulation. Produce cortisol, which stimulates fat and protein catabolism, gluconeogenesis and release of fatty acids and glucose into blood to repair damaged tissues

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18
Q

What is produced by the zona reticularis?

A

sex steroids: androgens –> DHEA (dihydroepiandrosterone, which tissues convert to test), androstenedione (maintains estrogen production), and estrogen (important after menopause)

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19
Q

Where does cortisol bind?

A

To the glucocorticoid receptor, as well as plama-binding proteins

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20
Q

Where are glucocorticoid receptors found?

A

They are found in all cells. The receptor responses to GC can vary widely due to expression of specific genes in different cell types/

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21
Q

Can GCs also bind to mineralocorticoid receptor?

A

Yes, with same affinity as aldosterone. Specificity is in the activity of GC metabolic enzyme, which removes GC

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22
Q

What is the corticosteroid-binding globulin?

A

transcortin. It decreases metabolic clearance rate of glucocorticoids, reduces fluctuations in cortisol concentrations. Transcortin doesnt bind syntehtic steroids.

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23
Q

Which type of binding protein binds to synthetic steroids?

A

albumin (binds 15% of total cortisol)

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24
Q

How much cortisol is circulating freely?

A

only 10%

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25
Q

What are the effects of prolonged fasting/stress on glucose regulation?

A

Cortisol stimulates several processes that collectively serve to increase and maintain normal levels of glucose in the blood:
1. Stimulation of gluconeogenesis in the liver: synthesis of glucose from amino acids and lipids, enhancing expression of enzymes involved
2. Mobilization of amino acids through breakdown of proteins to act as substrates for gluconeogenesis and enzyme synthesis
3. Inhibition of glucose uptake by skeletal muscle and adipose tissue to conserve glucose
4. Stimulation of fat breakdown in adipose tissue to release fatty acids through lipolysis. This provides a substrate for gluconeogenesis
5. Breakdown of lymphoid tissues –> cortisol breaks down lymphoid tissue to produce amino acids for gluconeogenesis, which leads to immune suppression

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26
Q

How do glucocorticoids regulate the immune system?

A

They have potent anti-inflammatory and immunosuppressive properties resulting in decreased migration of inflammatory cells to site of injury, decreased enzymes involved in prostaglandins, impair antigen processing and antibody production, induce apoptosis in lymphocytes, especially T cells.

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27
Q

What are the roles of glucocorticoids in fetal development?

A

Promote development of many systems through other growth factors. Involved in maturation of the lung and production of surfactant that is critical for extrauterine lung function. Chronic high GC levels in fetus inhibits growth in children

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28
Q

What is the general outline of steroid biosynthesis?

A

cholesterol –> prenenolone –> progesterone –> cortisol (glucocorticoid) / corticosterone (mineralocorticoid –> aldosterone) / testosterone (converted by aromatase to estradiol)

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29
Q

How is cholesterol processed in the cell?

A

Cholesterol in food - 75% of LDL packaged by liver, 25% is made from acetate by acetylCoA in cells. LDL from food enters the blood stream, then binds to and LDL receptor on the surface of the cells. The receptors then cluster in clathrin-coated pits, and then intake the receptor+LDL through endocytosis. The vesicles shed clathrin and fuse with other vesicles to form endosomes. There is recycling of the receptor and then a lysosome joins with the endosome, which results in breakdown of ApoB to aa and cleavage of ester bonds in the cholesteryl ester to form free FA and cholesterol. The cholesteryl ester droplet is stored in lipid droplets, then used for membrane synthesis, steroid and vit D, and regulation of enzymes and LDL receptor levels

30
Q

What is an apolipoproteinB100?

A

It is an LDL particle that carries cholesteryl esters, it also contains ApoB-100

31
Q

What is the rate limiting step of steroid synthesis?

A

Conversion of cholesterol to pregnenolone by P450SCC, this occurs in the mitochondria

32
Q

What is P450SCC?

A

side chain convertase, converts the hydrophobic side chain to an amphipathic one

33
Q

Where are the main locations of steroid synthesis?

A

adrenals, gonads, and placenta, some nervous system

34
Q

What are the steps of aldosterone synthesis?

A
  1. Cholesterol –> pregnenolone by P450SCC
  2. Pregnenolone to progesterone through delta 4 pathway
  3. Progesterone to deoxycorticosterone by 21-a-hydroxylase
  4. Deoxycorticosterone to corticosterone by P450aldo
  5. Corticosterone to aldosterone
35
Q

What are the steps of cortisol production?

A
  1. Pregnenolone converted either to 17-a-OH-pregnenolone by 17-a-hydroxylase, or pregnenolone converted to progesterone
  2. 17-a-OH-pregnenolone –> 17a-OH-progesterone, or progesterone –> 17a-OH-progesterone by 17-a-hydroxylase
  3. 17a-OH-progesterone –> 11-deoxycortisol by 21 alpha hydroxylase
  4. 11-deoxycortisol –> cortisol

**17a-hydroxylase is only present in layers 2 and 3

36
Q

How is estradiol produced?

A
  1. Pregnenolone to 17a-OH-pregnenolone by 17a-hydroxylase
  2. 17a-OH-pregnenolone –> DHEA
  3. DHEA –> androstenedione
  4. androstenedione –> estrone through aromatase
  5. estrone to estradiol
37
Q

How is dihydrotestosterone produced?

A
  1. Pregnenolone to 17a-OH-pregnenolone by 17a-hydroxylase
  2. 17a-OH-pregnenolone –> DHEA
  3. DHEA –> androstanediol
  4. androstanediol –> testosterone
  5. testosterone –> dihydrotestosterone
38
Q

How is cortisol synthesis stimulated?

A

ACTH binds to a GPCR (Gs) –> this activates AC –> production of cAMP –> PKA –> activation of cholesteryl ester hydrolase (CEH) –> converts cholesteryl esters to cholesterol in lipid droplet, liberating it so that it can be transported to mitochondria –> StAR (steroidigenic acute regulatory protein) transports cholesterol from outer to inner mitochondrial membrane –> P450SCC in mito converts cholesterol to pregnenolone ——> cortisol

39
Q

What type of receptor do glucocorticoids bind to?

A

Steroid family nuclear receptors. Inactive receptor bound to HSP in cytosol, hormone binding releases HSP. This leads to dimerization and exposure of nuclear localization signal. Hormone binds, then the dimer enters the nucleus and binds to the HRE in the DNA.

40
Q

How are levels of cortisol regulated?

A

Stress (physical, emotional, chemical) can cause release of CRH –> release of ACTH from anterior pituitary –> ACTH acts on adrenal cortex to inc release of cortisol

Circadian rhythm –> combination of positive and negative control on CRH secretion results in pulsatile secretion of cortisol (amplitude and frequency are highest in the morning and lowest at night)

ACTH can also inhibit secretion of CRH (short feedback), and cortisol can inhibit release of ACTH and CRH (long feedback) by decreasing their synthesis

41
Q

How do levels of cortisol and ACTH change throughout the day?

A

CRH and ACTH peak before awakeninh, and decline during the day. Stress may stimulate ACTH (VP and CTH), or high doses of corticosteroids can suppress ACTH

42
Q

Why is body temperature used as a marker for circadian rhythm?

A

In humans, the hypothalamus is not easily studied non-invasively. HR and work level are dominated by external influence. Core body temperature is easily measured and a suitable marker for CR

43
Q

What causes dysregulation of CR?

A

Dysregulation of communication between the CNS and pituitary, Cushing’s syndrome, Liver disease, renal failure, drug addiction

44
Q

How does the HPA maintain circadian rhythm?

A

CRH is produced in the hypothalamic paraventricular nucleus (PVN) and secreted in a pulsatile fashion from the parvocellular cells of the PVN, highest in the morning. There are connections between the PVN and the suprachiasmatic nucleus (SCN). Core of SCN receives photic input from the retina through the retino-hypothalamic tract. CRH and arginine vasopressin (AVP) receptors on the anterior pituitary control release of ACTH to the bloodstream.

45
Q

What are the inputs to the SCN?

A

The circadian clock can function autonomously without any cues, but can be reset by environmental cues. The core SCN receives photic input from the retina through the retino-hypothalamic tract. The SCN also receives non-photic input from different parts of the brain, through NPY projections from the intergeniculate leaflet and serotinergic projections from the median raphe nucleus

46
Q

What is the response to photic input in the SCN?

A

There is induction of various genes as well as chromatin remodelling in the SCN neurons. In the retina, there are photoreceptive cells that constitute a subset of RGC (express melanopsin, and two cryptochromes).

47
Q

What is the output from the SCN?

A

There SCN controls various rhythms, including body temp, activity and hormone levels, through various nervous projections to other nuclei of the hypothalamus and other brain regions. Sleep-wake cycles are regulated through projections from the SCN to the dorsomedial hypothalamus and posterior hypothalamic area. SCN also extends signals to the periphery through the autonomic NS, via the paraventricular nucleus.

48
Q

What is Cushing syndrome?

A

When you have excess cortisol, may be caused by an adrenal tumor, or excess ACTH

49
Q

What does Cushing syndrome cause?

A

Hyperglycemia, hypertension (ACTH-dependent tumor will cause changes in aldosterone as well), weakness, edema, muscle, bone loss with fat deposition in shoulders and face (breaking down muscle because you are producing excess cortisol)

50
Q

What are the 4 main symptoms of Cushing syndrome?

A
  1. protein depletion (muscle wasting, poor muscle development and wound healing) –> deterioration of skeletal muscle and lymphoid tissue
  2. Fat redistribution (increase abdominal weight –> releasing free FAs)
  3. Mental problems (depression, some mania)
  4. Inhibition of bone formation (suppression of calcium absorption and impaired vitamin D metabolism) –> high levels of cortisol suppress Ca absorption and Vit D production
51
Q

What are the two situations in which excess levels of glucocorticoids are observed?

A
  1. Excessive endogenous production of cortisol
  2. Administration of glucocorticoid for therapeutic purposes
52
Q

What causes excessive endogenous production of cortisol?

A

A primary adrenal defect (ACTH-independent) or excessive secretion of ACTH (ACTH-dependent)

53
Q

What is addison’s disease?

A

Insufficient production of cortisol, often accompanied by an aldosterone deficiency

54
Q

What is the cause of addison’s disease?

A

Infectious diseases (infection roots in the adrenal cortex and dec aldosterone and cortisol), and autoimmune diseases of the adrenal cortex (JFK hyperpigmentation –> a lot of POMC –> lost cortisol leads to loss of negative regulation –> hyperpigmentation)

55
Q

What are the effects of addison’s disease?

A

Hyposecretion of glucocorticoids and mineralocorticoids, hypoglycemia, Na and K imbalances, dehydration, hypotension, weight loss, weakness. Underproduction of cortisol by adrenal cortex –> lack negative regulation on pituitary –> increase in ACTH secretion –> melanin synthesis and bronzing of the skin

56
Q

What are the long term effects of glucocorticoid therapy?

A

First get Cushing syndrome, after a few weeks, may lead to decreased ACTH due to -ve regulation from high levels of cortisol –> adrenal atrophy –> addison’s disease

57
Q

What are the three main physiological effects of mineralocorticoids?

A
  1. critical role in regulating concentrations of minerals (Na and K) in extracellular fluids
  2. Imbalance and/or loss of these minerals leads to rapidly life threatening abnormalities in electrolyte and fluid balance (heart attack)
  3. Major target is distal tubule of the kidney
58
Q

Where is the major target of mineralocorticoids?

A

Main target is distal tubule of the kidney, stimulating exchange of NA and K

59
Q

What is the effect of mineralocorticoids on Na?

A

Get increased active resorption of sodium

60
Q

What is the effect of mineralocorticoids on water?

A

Increased passive water resorption due to resorption of Na, leads to expansion of extracellular fluid volume

61
Q

What is the effect of mineralocorticoids on K?

A

Increased renal excretion of potassium?

62
Q

What is the overall effect of mineralocorticoids on blood pressure?

A

Increase in blood pressure and blood volume

63
Q

What does high K in extracellular fluid do?

A

It stimulates aldosterone

64
Q

What are the actions of aldosterone?

A

activation of Na channel through kinases –> increased uptake of Na through tubular lumen

Stimulation of transcription of Na-K ATPase –> inc Na pumps in tubular epithelial cells

Has these effects on sweat glands, salivary glands, and colon

Major net effect is conservation of sodium, which causes concservation of water

65
Q

What are the regulators of aldosterone?

A
  1. concentrations of K in extracellular fluid (high K = more aldosterone secretion, low K suppresses aldosterone)
  2. Decreased renal blood flow stimulates angiotensin II, which increases aldosterone, high blood pressure –> ANP release –> dec blood pressure –> dec aldosterone
  3. Na deficiency stimulates aldosterone, high Na suppresses
66
Q

What produces renin?

A

juxtaglomerular cells

67
Q

What is the renin-angiotensin-aldosterone axis?

A

Renin is released when there is low BP or low Na, and converts angiotensinogen to angiotensin I –> angiotensin 2 by angiotensin converting enzyme –> binds to angiotensin receptors –> aldosterone secretion, vasoconstriction, sympathetic activation –> blood pressure regulation

68
Q

What produces angiotensinogen?

A

Liver

69
Q

What causes hyperaldosteronism?

A

Adrenal adenoma or hyperplasia, also arises from increase in mineralocorticoid-like activity, when other steroids cause increased renal Na reabsorption. Causes hypokalemia, hypertension, and edema

70
Q

What enzyme is expressed in aldosterone-responsive cells?

A

11-B-hydroxysteroid dehydrogenase, which converts cortisol to cortisone (biologically inactive) in aldosterone responsive cells, allowing aldosterone to bind to its receptor, even though aldosterone and cortisol have the same affinity to the receptor

BIOL432: Molecular Endocrinology (12 decks)

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