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Biol 432 > Steroid Synthesis > Flashcards

Steroid Synthesis Flashcards

1
Q

Hans Selye

A

A Slovakian-Canadian endocrinologist – investigated the non-specific response of an organism to different stressors and was one of the first to recognize the importance of glucocorticoids in the stress response

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2
Q

where are glucocortioicds and mineralocorticoids produced

A

in the cortex

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3
Q

The adrenal gland

A

two distinct endocrine organs (cortex and medulla) organized into a single gland (not true for some species like amphibians and fish)

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4
Q

what can be considered a catecholamine factory

A

the adrenal medulla

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5
Q

where is aldosterone produced

A

in the outer areas of the cortex (zona glomerulosa - layer 1)

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6
Q

where are cortisol and androgens produced

A

in the zona fasiculata (layer 2) & is an area very rich in lipids

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7
Q

where are epinepherine and norepinepherine produced

A

in the zona reticularis (layer 3)

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8
Q

Zona glomerulosa (activity of 17a hydroxylase and p450)

A

no 17alpha-hydroxylase activity but has P450 aldosterone

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9
Q

Zona fasiculata (activity of 17a hydroxylase and p450)

A

no P450 aldosterone has large mitochondria, lipid droplet and SER – this is the area that will respond when you’re under stress

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10
Q

Zona reticularis (activity of 17a hydroxylase and p450)

A

have other enzymes that will help you make other androgens including 17alpha hydroxylase (produce basal level of cortisol but also a lot of androgen)

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11
Q

Adrenal Medulla

A
  • Sympathetic ganglion innervated by sympathetic preganglionic fibers – very important part of the autonomic nervous system
  • Stimulated causes release of epinephrine
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12
Q

Mineralocorticoids - what zone are they in and what do they do

A

in the zona glomerulosa and control electrolyte balance aldosterone promotes Na+ retention and K+ excretion

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13
Q

glucocorticoids - what zone are they in and what do they do

A

in the zona fasiculata & reticularis - response to ACTH
• Especially cortisol, stimulates fat and protein catabolism, gluconeogenesis (from AA’s and fatty acids) and release of fatty acids and glucose into blood to repair damaged tissues

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14
Q

sex steroids - what zone and they in and what are they/do they do

A

Zona reticularis - androgens and DHEA
Dehydroepiandrosterone – other tissues convert to testosterone, androstenedione, and estrogen (important after menopause)

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15
Q

what receptor does cortisol bind to

A

the glucocorticoid receptor (which are found on ALL cells)

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16
Q

Corticosteroid-binding globulin (CBG) - what does it do / what is it (3)

A
  • Decreases metabolic clearance rate of glucocorticoids
  • Bound steroid is not biologically activity so reduces wild fluctuations in cortisol secretion
  • Synthetic steroids don’t bind significantly to CBG
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17
Q

why can stress be measured in saliva

A

there are no binding proteins in saliva so there is free cortisol

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18
Q

what type of steroids bind to albumin

A

synthetic steroids

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19
Q

Process of glucose regulation (5 steps)

A
  • To maintain blood glucose is a very dynamic process: in the faster state, cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in blood
  • Stimulation of gluconeogenesis – liver: synthesis of glucose from amino acids and lipids which enhances the expression of enzymes involved
  • Mobilization of amino acids – substrates for gluconeogenesis
  • Inhibition of glucose uptake in muscle and adipose tissue – mechanism to conserve glucose
  • Stimulation of fat breakdown in adipose tissue – fatty acids release by lipolysis are used for production of energy in tissues like muscle and the release glycerol provides another substrate for gluconeogenesis
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20
Q

what are widely used as drugs to treat anti inflamatory conditions such as arthritis, asthma or dermatitis

A

Glucocorticoids - because they have potent anti-inflammatory and immunosuppressive properties

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21
Q

Glucocorticoid role in fetal development

A

•Maturation of the lung and production of the surfactant = extrauterine lung function
–>Mice with homozygous disruptions in the corticotrophin-releasing hormone gene die at birth due to pulmonary immaturity
•Unique to fetal –chronic high GC levels inhibits growth in children

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22
Q

Steroid Action (cholesterol first converted to____then..)

A

cholesterol is first converted to pregnenelone in mitochondria then to progesterone then from there branches off to cortisol, corticosterone and testosterone

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23
Q

most important glucocorticoid in humans and rodents

A

humans: cortisol
rodents: corticosterone

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24
Q

function of aldosterone

A

aldosterone will regulate amount of sodium, sodium chloride, bicarbonate and amount of potassium (extremely important for cardiac function) - potassium being regulated is important - regulation of blood pressure and water being regulated through renin-angiotensin system

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25
Q

How is cholesterol processed?

A

Receptor mediated endocytosis - needs in all layers of the adrenal cortex

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26
Q

Receptor mediated endocytosis steps (w/ cholesterol)

A
  1. receptors cluster in clathrin coated pits
  2. vesicles shed clathrin and fuse with other vesicles to form endosomes
  3. proton pumps in endosome make acidic and cause dissociation of LDL and receptor
  4. enzymes in lysozome breakdoen ApoB to aa and cleave ester bonds to free FA and cholesterol
  5. cholesterol used for membrane synthesis, steroid and vitamin D and regulation of enzymes and LDL receptor levels
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27
Q

what is the rate limiting step in the mitochondria during steroid synthesis

A

conversion of cholesterol to pregnenalone by cytochrome p450SCC (side chain convertase)

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28
Q

What has compartment and tissue specific expression in steroid synthesis

A

Cytp450s (6 enzymes in family)

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29
Q

Where are steroids mainly produced

A

in adrenals gonads and placenta (some in nervous system)

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30
Q

where is 17a hydroxylase expressed (steroid synthesis)

A

in layers 2 and 3 but NOT in layer 1 - therefore no cortisol or androgens are expressed in layer 1

31
Q

where is p450 aldo expressed (steroid synthesis)

A

in layer 1 but NOT in layers 2 and 3 so no aldosterone is expressed in layers 2 and 3

32
Q

basic steroid structure

A

four rings (a-d) with different side chains for different hormones

33
Q

ACTH stimulating cortisol synthesis via GPCR - Adenylyl cyclase path

A
  • LDL binding to its receptor getting into lipid droplet (via endocytosis)
  • ACTH to GPCR will be increase in GAS that will activate AC and will increase CAMP which gives rise to PKA and would then cause an upregulation in cholesterol esters and liberation of cholesterol itself and transport to mitochondria through the protein StAR
  • Cytochrome P450 side chain convertase (SCC) will convert cholesterol into pregnenolone
34
Q

Steroid family receptor signalling (3 steps)

A
  • Hormone diffuses across the membrane
  • Inactive R bound to HSP in cytosol – Hormone binding release HSP dimerization and nuclear localization
  • Hormone-receptor complex binds to HRE and activates transcription e.g. up-regulating enzymes involved in glucose synthesis
35
Q

what are the 3 main ways cortisol is regulated

A

circadian rhythm, stress and feedback

36
Q

“short” regulation of cortisol

A

ACTH inhibits own secretion

37
Q

“long” regulation of cortisol

A

•cortisol paths can be fast or slow – cortisol can act on pituitary or hypothalamus and can be fast and depend on the rate of change of cortisol levels (nonnuclear) or can be slow and depends on the absolute levels of cortisol to decrease ACTH synthesis (nuclear)

38
Q

what axis allows for hypothalamus to communicate to the corticotrophs

A

portal axis

39
Q

pulsatile secretion of cortisol (morning vs. night)

A

amplitude and frequency are highest in the morning and lowest at night

40
Q

what are the three mechanisms of neuroendocrine control

A
  • episodic / circadian rhythm of ACTH release
  • stress responsiveness of HPA axis
  • feedback inhibition by cortisol of ACTH release
41
Q

what is happening during sleep vs spikes (cortisol)

A

just before rising from sleep there is an increase in ACTH production leading to increased production of cortisol

42
Q

what time of day do CRH and ACTH peak

A

CRH and ACTH peak before awakening and decline during the day – stress may stimulate ACTH (mediated by VP and CRH; if high doses of exogenous corticosteroids used then they can supress ACTH)

43
Q

what is an easily regulated and suitable measure of circadian rhythm

A

Core body temperature is easily measured and a suitable marker of CR
-HR and work level are non-invasive but are dominated by external influences

44
Q

some cues of circadian rhythm

A

Sleep pattern, light and dark, feeing time, physical work and stress

45
Q

circadian rhythm dysregulation can cause what

A

CNS/pituitary, cushings syndrome, liver diseases, renal failure and drug addiction

46
Q

relationship between the HPA and CRH (corticotropin releasing hormone) (5 things)

A
  • The hypothalamic-pituitary adrenal (HPA) axis plays important roles in maintaining alertness and modulating sleep
  • Besides its role in the stress response CRH plays a role in circadian dependant alerting and perhaps in cueing
  • CRH is found in the hypothalamic paraventricular nucleus (PVN)
  • The circadian rhythm of cortisol secretion derives from connections between the PVN and the primary endogenous pacemaker – the suprachiasmatic nucleus (SCN)
  • CRH is released in a circadian-dependant pulsatile fashion from the parvocellular cells of the PVN
47
Q

what is the so called endogenous cellular clock

A

The suprachiasmatic nucleus (SCN)

-situated above the optic chiasm on each side of the 3rd ventricle

48
Q

what observations (2) establish the SCN as a master clock

A
  • Lesions of the SCN in rodents abolish locomotor activity rhythms as well as other rhythms and grafting SCN tissue to a lesioned animal restores its circadian rhythmicity
  • Restored rhythms have the characteristics of the donor – not those of the acceptor
49
Q

where does the SCN receive photic input from

A
  • The ‘core’ of the SCN receives photic input from the retina through the retino-hypothalamic tract
  • Response to this photic input involves the induction of various genes as well as chromatin remodelling within SCN neurons
  • In the retina photoreceptive cells that are involved in entrainment of the SCN clock are distinct from those involved in vision and rather constitute a subset of retinal ganglion cells
50
Q

where does the SCN receive non-photic input from?

A

The SCN also receives non-photic input from different parts of the brain in particular through neuropeptide Y (NPY) projections from the median raphe nucleus

51
Q

output from the SCN (2)

A

The suprachiasmatic nucleus controls various rhythms including body temperature, activity and hormone levels through nervous projections to other nuclei of the hypothalamus and other brain regions
• In particular sleep wake cycles are regulated through projections form the SCN to the dorsomedial hypothalamus and the posterior hypothalamic area

52
Q

the central clock of the SCN can be adjusted by what

A

by light or day night cycles of the environment

53
Q

Peripheral oscillators - can be entrained by what

A

Peripheral oscillators can be entrained by neuronal pathways, hormones and maybe most importantly by feeding rhythms (which depend on sleep and activity rhythm). 3V, third ventricle of the brain

54
Q

summary of stress stimulators of ACTH release (8)

A
  • Physical Exercise and work
  • Emotional – emotion as a stimulus to the SCN either happy or unhappy (happy emotions can decrease cortisol levels)
  • Pain and trauma increase ACTH release
  • Hypoxia – important to consider more than a stimulus for RBC production but is a type of stress and body will try to decrease amount of hypoxia a given tissue is experiencing
  • Surgery
  • Depression – places big demands on what is going on in adrenal cortex (low levels of serotonin, blood sugar levels)
  • Infection – glucocorticoids play a really big role – at first increase in ACTH release then there will be an immune response and a demand for a certain level of blood sugar
  • Vasopressin may also be release with CRH during stress
55
Q

Cushings Syndrome (Hyperadrenocorticism) - what is it

A

excess cortisol caused by adrenal tumor or excess ACTH

56
Q

Cushings Syndrome symptoms

A
  1. Protein depletion – muscle wasting, poor muscle development and wound healing
  2. Fat redistribution – increase abdominal weight
  3. Mental problems – depression and some mania
  4. Inhibition of bone formation – suppression of calcium absorption and impair vitamin D metabolism
57
Q

what is the most prevalent disorder involving glucocorticoids in man and animals

A

Cushings Syndrome

58
Q

with cushings syndrome excessive levels of glucocorticoids are seen in what 2 situations

A
  1. Excessive endogenous production of cortisol
    - Primary adrenal defect (ACTH-independent)
    - Excessive secretion of ACTH (ACTH-dependent) – problem in pituitary or hypothalamus
  2. Administration of glucocorticoids for therapeutic purposes
    - Common side-effect of these widely used drugs – synthetic versions of cortisol commonly used in therapy for people who have arthritis
59
Q

Addisons disease (hypoadrenocorticism) - what is it

A

insufficient production of cortisol often accompanied by an aldosterone deficiency

60
Q

common causes of Addisons Disease

*rare 100/1 million people

A
  • infectious disease (e.g. tuberculosis, CMV, HIV and fungi in humans
  • autoimmune destruction of the adrenal cortex (JFK hyperpigmentation)
61
Q

symptoms of Addisons disease

A
  • opposite to what you see with cushings
  • Hypoglycemia, Na+ and K+ imbalances, dehydration, hypotension, weight loss and weakness
  • Increase in ACTH and an increase in POMC also increase MSH production so therefore is an increase in melanin in the skin
62
Q

Can you get cushings / addisons from treatment with steroids

A

Yes - excess glucocorticoid therapy
If you chronically take dexamethasone or pregnazone this leads to problems (if longer then 3 weeks) you will start to have negative feedback on synthetic steroids - first see cushings syndrome type symptoms then will lead to Addison’s

63
Q

physiological effects of mineralocorticoids (3)

A
  • critical role in regulating concentrations of minerals (especially Na+ and K+) in extracellular fluids
  • imbalance and / or loss of these minerals leads rapidly to life-threatening abnormalities in electrolyte and fluid balance (heart attack)
  • major target is distal tubule of the kidney – stimulates exchange of Na+ and K+
64
Q

three primary physiological effects of mineralocorticoids results:

A
  1. Increased active reabsorption of sodium
  2. Increased passive reabsorption of water with consequent expansion of extracellular fluid volume – this is an osmotic effect directly related to increased reabsorption of sodium
  3. Increased renal excretion of potassium
    - These effects in turn result in an increased of blood pressure and blood volume
65
Q

mineralocorticoid action (3)

A
  • Aldosterone acts in the lumen of the kidney tubule causing Na+ pumped across cells into extracellular fluid (conserved) while K+ and H+ pumped into lumen (will be lost via urine). Water follows sodium so also reabsorbed
  • In response to sodium moving in there will be increased movement of potassium out and that will be moved into the lumen and increase potassium in the urine
  • Will maintain pH here as well to maintain extracellular fluid
66
Q

Two main regulators of aldosterone secretion

A
  1. Concentration of potassium ion in the extracellular fluid:
    - Increase in plasma K+ strongly increases aldosterone secretion (pumping out K+ and taking up Na+) Low K+ suppresses aldosterone
  2. Angiotensin II
67
Q

Angiotensin 2 positive vs. negative regulation effects on aldosterone

A
  • Positive regulation: decreased renal blood flow stimulates and increase in angiotensin II (regulates vasoconstriction to increase blood pressure) increase in aldosterone secretion
  • Negative regulation: if blood pressure is too high there is a release of atrial natriuretic peptide (ANP) which decreases blood pressure by vasodilation and acts to decrease water and Na+ - decrease in aldosterone secretion
68
Q

The renin-angiotensin system -what does it regulate

A
  • The juxtaglomerular cells are a source of renin

* This system regulates blood pressure

69
Q

The renin-angiotensen aldosterone axis (3)

A
  • is a protein that is synthesized I the liver and is acted on by renin (a protease) and will convert to angiotensin I and ACE converts to angiotensin II
  • Will bind to GPCR and will cause release of aldosterone in the zona glomerulosa and will cause sodium and water retention which will increase blood pressure
  • So direct action of angiotensin II is to cause vasoconstriction
70
Q

Chronic licorice intoxication (2)

A

•Syndrome of water and sodium retention coupled with low plasma K+, hypertension and low renin activity
•Licorice inhibits 11B-HSD so there is no inactivation of cortisol (to cortisone) in the kidney – if cortisol is not inactive the net effect is similar to aldosterone excess
-Pseudohyperaldosertonsism – endogenous mineralocorticoid secretion is normal

71
Q

where are steroids synthesized

A

in the SER and mitochondria & produced in the adrenal cortex

72
Q

Aldosterone competes with cortisol for mineralocorticoid receptor (2)

A
  • MR binds aldosterone and cortisol with equal affinity

- however cortisol serum concentrations are much higher then aldosterone - although not a problem because of 11B-HSD

73
Q

11 B-HSD

  • what is it
  • what are its effects
  • role with aldosterone
A

B-hydroxysteroid dehydrogenase (11B-HSD):
•Aldosterone responsive cells express the enzyme 11B-HSD)
-Converts cortisol into cortisone (biologically inactive – very weak affinity for MR)
-Allows aldosterone to bind its receptor without competition
•If you don’t remove all the cortisol you will have a hyper effect – hyperaldosteronism even though you don’t have high levels of aldosterone circulating

Biol 432 (11 decks)

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