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Endocrine & Diabetes > Regulation of Adrenal Steroidogenesis > Flashcards

Regulation of Adrenal Steroidogenesis Flashcards

1
Q

Describe an archetypal HP axis feedback circuit

A
  • External neural inputs stimulate hypothalamic-releasing hormone production
  • Hypothalamic releasing-hormone stimulates specific anterior hormone production
  • Anterior pituitary hormone acts on target gland
  • Target gland hormone feeds back on release of pituitary & Hypothalamic hormones
  • Target gland hormone feeds forward on tissue target/metabolism
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2
Q

Describe how the hypothalamus coordinates central neural inputs

A

-Stimuli from somatic & visceral sense organs
-Transmitted via sensory & motor neurons from the forebrain and mid brain
-Produce ‘stimulatory’ or ‘inhibitory’ neurotransmitters
=(dopamine, adrenaline, noradrenaline, serotonin, acetylcholine & various neuropeptides)
-Act on distinct hypothalamic ‘nuclei’
=stimulate production of hypothalamic-releasing hormones

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3
Q

Where do motor and sensory neurons travel through?

A

Motor and sensory neurons from the midbrain and forebrain travel through the medulla oblongata

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4
Q

What is the median eminence and where is it?

A

The median eminence is the functional link between the hypothalamus and the anterior pituitary gland. It lies in the centre of the tuber cinereum and is composed of an extensive array of blood vessels and nerve endings.

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5
Q

Describe the blood supply and the median eminence

A
  • Its extremely rich blood supply arises from the superior hypophyseal artery (a branch of the internal carotid artery), which sends off many small branches that form capillary loops.
  • The small capillary loops extend into the internal and external zones of the median eminence, form anastomoses, and drain into sinusoids that become the pituitary portal veins that enter the vascular pool of the pituitary gland.
  • The flow of blood in these short loops is predominantly in a hypothalamic-to-pituitary direction.
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6
Q

What are the adaptions of the median eminence?

A
  • This well-developed plexus results in a tremendous increase in the vascular surface area.
  • In addition, the vessels are fenestrated, allowing diffusion of the peptide-releasing factors to their site of action in the anterior pituitary gland.
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7
Q

Why is the median eminence involved in the hypophyseal-portal circulation?

A

Because this vascular complex in the base of the hypothalamus and its “arteriolized” venous drainage to the pituitary compose a circulatory system analogous to the portal vein system of the liver, it has been termed the hypophyseal-portal circulation.

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8
Q

What hormone regulates adrenal gland steroid hormone production?

A

ACTH from corticotrophs in anterior pituitary

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9
Q

Describe cholesterol structure

A

C27 sterol (modified steroid)

  1. polar head group (OH)
  2. steroid body (4 ring structure)
  3. hydrophobic side-chain (fatty)
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10
Q

What are the features of cholesterol that relate to its function?

A

-Cholesterol as a component of cell membranes:
-attracted to:
=polar head
=hydrophobic tail
of membrane phospholipids

so steroid hormones are fat-soluble

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11
Q

What are the steroid hormones?

A 
-Corticosteroids
=Mineralocorticoids
=Glucocorticoids
=Adrenal androgens
-Sex steroids
=Androgens
=Oestrogens
=Progesterone
-Vitamin D
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12
Q

Where are corticosteroids made?

A

Cortex of adrenal gland

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13
Q

What are the functions of mineralocorticoids?

A
  • salt & water retention

- (electrolyte & fluid balance)

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14
Q

What are the functions of glucocorticoids?

A
  • glucose synthesis
  • protein & lipid metabolism
  • inflammation, immune response (cortisol suppresses immune system)
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15
Q

What are the functions of adrenal androgens?

A

-Foetal steroids and growth

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16
Q

Where are the sex steroids made?

A

Gonads

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17
Q

What are the functions of androgens?

A

growth & function of the male reproductive system

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18
Q

What are the functions of oestrogens?

A

growth & function of the female reproductive system

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19
Q

What are the functions of progesterone?

A

female menstrual cycle & maintenance of pregnancy

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20
Q

What is the function of vitamin D?

A

Maintain calcium balance (sunlight breaks one of the carbon rings)

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21
Q

What are the specialist modifications of the steroid hormones?

A
  • Glucocorticoids have hydroxyl group at carbon 11

- Sex steroids smaller chains

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22
Q

Describe the classical genomic mechanism for how steroid hormones work

A
  • ‘Classical’ receptors in the cytoplasm activated by steroid binding - translocate to nucleus
  • Gene transcription & protein synthesis in cytoplasm
  • Slow action (>30 mins-48hr)
  • e.g. aldosterone-regulated synthesis of kidney epithelial sodium channel (ENaC) subunits
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23
Q

Describe the non-genomic mechanism for how steroid hormones work

A
  • ‘Non-classical’ receptors, activated by steroid binding, e.g. modifying action of ion channels in the plasma membrane
  • Intra-cellular signalling pathways, e.g. calcium/inositol
  • Rapid signalling (< 1 min)
  • e.g. aldosterone-mediated vasoconstriction of vascular smooth muscle & endothelial cells
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24
Q

How are steroid hormones made?

A

-first step : hydrophobic 6 carbon side chain of cholesterol removed
=steroid hormones more water soluble than cholesterol
-most steroids have a varied substituent at C-17
=Enzyme nomenclature indicates the site of action
=e.g. ‘17α-hydroxylase’ introduces a hydroxyl group at C- 17
-extra specificity from side chain modification e.g. C-11
=Enzyme nomenclature indicates the site of action …
=e.g. ‘11β-hydroxylase’ introduces a hydroxyl group at C- 11

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25
Q

What are the two types of enzymes involved in steroid synthesis?

A
  • Cytochrome P450s

- Steroid dehydrogenases

26
Q

Describe cytochrome P450s

A

-Highly expressed in
=Liver (drug detoxification)
=Organs that synthesise steroids
- adrenal cortex,
- testis, ovary, placenta
-Cleave or modify cholesterol side groups
EG
-cholesterol side chain cleavage enzyme (SSC; CYP 11A1)
Converts cholesterol to pregnenolone
C27 → C21 = First step in steroid synthesis

27
Q

Describe steroid dehydrogenases/ reductases

A

-Usually paired
-Interconvert active and inactive forms of steroid
=11β-HSD1 = 11β-hydroxysteroid dehydrogenase type 1
-Liver and peripheral tissues
-Active cortisol to inactive cortisone
11β-HSD2 = 11β-hydroxysteroid dehydrogenase type 2

28
Q

Describe cortisol metabolism and transport

A
  • Made in adrenal glands,
  • Cortisol recycled through liver, converted into inactive cortisone, which circulates vasculature where it is reactivated at target organ
  • Plasma cortisone & bound cortisol are inactive but are reactivated in target tissues
  • Plasma ratio of cortisol to cortisone is approx 1 : 2
  • Plasma ratio of free to bound cortisol is approximately 4 : 96
  • Transcortin is the usual binding globulin to which cortisol binds in the plasma, with some cortisol also bound to albumin.
  • Unbound cortisol is rapidly excreted in the urine.
  • If there is a pathophysiological excess of cortisol then the binding globulin becomes fully saturated and the unbound cortisol is excreted in the urine - therefore urine can be tested for cortisol excess.
29
Q

What do the adrenal glands do?

A
  • Coordinate the body’s response to:
    (i) internal physiology
    (ii) environmental stimuli
  • First ‘responder’ to physiological ‘stress’
30
Q

Where are the adrenal glands?

A
  • Located around 12th thoracic vertebra
  • Positioned bilaterally & anteriorly on superior poles of the kidneys
  • Triangular in shape; each weighs ~4g
  • Anatomists call them ‘suprarenal’ glands
31
Q

What are the adrenal glands a key component of?

A
  • hypothalamic-pituitary-adrenal (HPA) axis (adrenal cortex)

- neuroendocrine sympathetic nervous system (adrenal medulla)

32
Q

Describe the 2 endocrine glands within the a single anatomical structure (adrenal glands)

A

-Cortex: 80-90% of normal gland= Make steroid hormones:
=Mineralocorticoids
=Glucocorticoids
=adrenal androgens

-Medulla: 10-20% of normal gland, sympathetic NS= Make catecholamines:
=adrenaline (epinephrine)
=noradrenaline (norepinephrine)

33
Q

Describe the blood supply to the adrenal cortex

A

-receives blood from 30-50 short arteries penetrating the capsule
-arteries supply a subcapsular plexus of arterioles
-capillary sinusoids extend through the cortex separating chords of cells
=rapid transmission of stimuli to cells & products to targets

34
Q

Describe the blood supply to the adrenal medulla

A
  • receives long cortical arteries & capillaries from cortex
  • medulla and cortex drain via the central medullary vein (medulla sees the output of the cortex, important in flight or fight to sustain)
35
Q

Describe the functional zones of the adrenal cortex

A

-The outer cortex is 80-90% of the gland
=The outer cortex is yellow due to its high lipid content, the medulla is reddish brown
=The outer zone, the zona glomerulosa lies under a fibrous capsule & comprises 5-10% of the cortex.
=The middle zone, the zona fasciculata, is about 75% of the cortex
=Inner zone= zona reticularis

36
Q

Describe aldosterone

A

-The principal mineralocorticoid
-Made in the zona glomerulosa (ZG)
-Under the control of the RAS
=Regulated by A2 & plasma K+
-Regulates salt & water retention in kidney distal tubule

37
Q

Describe Cortisol

A

-The principal glucocorticoid
-Made in the zona fasciculata (ZF)
-Under the control of the HPA axis
=Regulated by ACTH from pituitary gland
-Regulates glucose homeostasis (gluconeogenesis)
-Stress response
-inflammation, immune response

38
Q

Describe the C19 adrenal androgens

A

-Made in the zona reticularis (ZR)
-Also under the control of the HPA axis
=Also regulated by ACTH from pituitary gland

-Intracrine conversion to testosterone & oestradiol (provide all oestrogens in post-menopausal) in peripheral tissues
=inactive hormone circulate responsible for secondary sexual characteristics
=Excess glucocorticoids= excess adrenal androgens= alterations in hair patterns

39
Q

What are the roles of DHEA production prenatally?

A
  • role in maintaining oestrogenic environment

- role in foetal development= peaks during foetal birth and 20 years

40
Q

What are the roles of DHEA production postnatally?

A
  • role in initiation of puberty (adrenarche)??
  • main source of androgens & post-menopausal oestrogen in females
  • role in longevity; elixir of life??
  • Cancer kill switch
41
Q

How are steroid hormone types determined in each adrenocortical zone?

A

-Zone-specific P450 gene expression determines the steroids synthesised in each adrenocortical zone:

=ZG has aldosterone synthase but lacks 11ß-hydroxylase and 17α-hydroxylase
=ZF has 11ß-hydroxylase and 17α-hydroxylase, but lacks aldosterone synthase
=ZR has 17α-hydroxylase/17, 20 lyase, but lower levels of 11ß-hydroxylase and lacks aldosterone synthase

42
Q

How are mineralocorticoids and glucocorticoids determined?

A

Zone-specific expression of aldosterone synthase & 11ß-hydroxylase give rise to zone-specific mineralocorticoid and glucocorticoid synthesis

43
Q

What enzymes are exclusively expressed in each zone?

A
  • The 11CYPB2 gene encoding aldosterone synthase (AS) is expressed exclusively in the adrenocortical zona glomerulosa (ZG) under the control of AII
  • while the The 11CYPB1 gene encoding 11ß-hydroxylase (11ß-OHase) is expressed exclusively in the adrenocortical zona fasciculata (ZF), under the control of ACTH.
44
Q

Describe the homeostatic feedback regulation of cortisol synthesis by the HPA axis

A
  • Circadian rhythm & stress inputs stimulate CRH release from hypothalamus
  • CRH stimulates ACTH production from pituitary corticotrophs
  • ACTH stimulates cortisol production from adrenal zona fasciculata
  • Cortisol feeds back on production of CRH from hypothalamus & ACTH from the anterior pituitary
45
Q

How is CRH secretion regulated?

A

-Corticotrophin-Releasing Hormone, PVN of hypothalamus

  • Diurnal SCN circadian rhythm
  • Neurotransmitter-mediated ‘stress’ inputs via nerve fibres in the medulla oblongata ‘fight or flight’
  • Stimulatory & inhibitory factors from somatic & visceral sense organs
46
Q

What are the neurotransmitters stimulatory factors?

A
  • serotonin (5HT)
  • acetylcholine
  • encephalin
47
Q

What are the neurotransmitters inhibitory factors?

A

-alpha-adrenergic agonists
-GABA, endorphin
dopamine

48
Q

How do plasma cortisol levels show diurnal rhythm?

A

-Diurnal CRH release regulates ACTH release:
=high in the early morning (04.00-08.00)
=lower later in the day

-ACTH regulates cortisol synthesis:
=High on waking (06.00-10.00)
=lower later in the day (with ‘stress’ activity spikes)
=lowest in the middle of the night

49
Q

How does CRH stimulate ACTH secretion?

A

-CRH binding at G protein coupled surface receptor
-cAMP second messenger (adenyl cyclase)
-Increased POMC peptide synthesis (pro-opiomelanocortin, a polyprotein)
-POMC cleaved to ATCH and other peptides
=ATCH release into peripheral blood from anterior pituitary
=Corticotrophs 15-20% anterior pituitary cells

50
Q

How does ACTH stimulate cortisol synthesis and secretion from ZF and ZR cells?

A

-ACTH binds to G protein-coupled ACTH receptor
-cAMP second messenger (adenyl cyclase)
-Cholesterol ester hydrolase increased and mobilised
=Increased cholesterol transport to mitochondria
=Side chain cleavage enzyme cleaves cholesterol into pregnenolone= cortisol= released into blood

51
Q

How is cholesterol passage cross the mitochondrial lipid membrane regulated?

A

-Steroid acute regulatory (StAR) protein ‘chaperones’ cholesterol across the mitochondrial membrane, promotes cholesterol transport
-StAR protein activity rapidly increased (mins):
=in response to AII (ZG) or ACTH (ZF & ZR) stimulation
=the rate-limiting step in the production of steroid hormones
-Essential nature of StAR shown by:
=Human gene mutations (Lipoid Congenital Adrenal Hyperplasia)
=StAR gene ‘knockout’ experiments in mouse

52
Q

Why is cortisol important?

A
  • Essential for survival and to resist physiological and environmental stress
  • Part of the ‘counter-regulatory’ hormone defence against hypoglycaemia
53
Q

What is the dual action of cortisol?

A
  • Anabolic in the liver to promote gluconeogenesis

- Catabolic in peripheral muscle & fat to promote protein and lipid breakdown

54
Q

What rises as plasma glucose falls?

A
  • glucagon (from α cells of the pancreas)
  • adrenaline (epinephrine)
  • noradrenaline (norepinephrine)
  • growth hormone
  • cortisol
55
Q

What are the anabolic actions of cortisol?

A

Increased gluconeogenesis and liver glucose output

56
Q

What are the catabolic actions of cortisol?

A
  • Inhibition of glucose uptake by peripheral muscle & fat tissue
  • Immune system suppression
  • Increased muscle protein breakdown
  • Increased fat breakdown
  • Increased bone resorption
  • Increased appetite & central fat deposition
57
Q

What are the pathological anabolic actions of cortisol?

A

Elevated plasma glucose = secondary diabetes mellitus

58
Q

What are the pathological catabolic actions of cortisol?

A
  • Muscle and connective tissue wasting and weakness
  • Poor wound healing & skin ulcers
  • Uncontrolled muscle protein breakdown
  • Increased fat redistribution
  • Osteoporosis
  • Uncontrolled appetite & central fat deposition
  • Excess mineralocorticoid action = Na+ & fluid retention & hypertension
59
Q

What is cortisol excess and the phenotype?

A 
Cushing's
=Hypertension
=low plasma K+
=elevated plasma cortisol
=low plasma aldosterone & renin activity
=Hypertension due to multiple effects of elevated plasma cortisol
60
Q

Describe Cushing’s Disease

A
  • ACTH-secreting pituitary tumour
  • HIGH= Plasma ACTH
  • HIGH= Plasma Cortisol
61
Q

Describe Cushing’s Syndrome

A
  • Adrenal or ectopic cortisol-secreting tumour
  • LOW= plasma ACTH
  • HIGH= plasma cortisol

Endocrine & Diabetes (45 decks)

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