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Reg Phys and Pharm > The Pituitary-Adrenal Axis > Flashcards

The Pituitary-Adrenal Axis Flashcards

- State the class of hormone to which cortisol belongs and identify where it is synthesised - Describe signalling events associated with steroid-based hormones - Understand how ACTH release is regulated and discuss how it regulates cortisol release - Identify the sites of action of cortisol and explain how cortisol exerts its effects - Describe the cconsequences of cortisol excess and its deficiency and discuss the phenotypes manifested in Cushings syndrome and Addison's disease

1
Q

What is the adrenal gland

A
  • hybrid gland of cortex and a medulla
  • hormones are important eregulators of metabolism and serve an important role in adaptation to stress
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2
Q

Role of cortisol

A
  • glucocorticoid
  • increases plasma glucose levels
  • deficiency = hypoglycaemia
  • synthetic analogs are widely used in treatment of disorders ranging from skin rashed to arthiritis
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3
Q

Role of Aldosterone

A
  • mineralocorticoid
  • promotes salt and water retention by kidney
  • critical for normal salt/water balance
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4
Q

What is synthesised by the adrenal cortex

A
  • androgenic steroids
  • converted by peripheral tissue to testosterone h
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5
Q

Products of the medulla

A

catecholamines e.g. epinephrine and norepinephrine

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6
Q

Role of the adrenal gland in modulating short-term stress

A
  • hypothalamus activates adrenal medulla via nerve impulses
  • adrenal medulla secretes epinephrine and norepinephrine
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7
Q

Role of the adrenal gland in modulating long-term stress

A
  • hypothalamus activates adrenal cortex via hormone signals
  • adrenal cortex secretes mineralocorticoids and glucocorticoids
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8
Q

Effects of epinephrine and norepinephrine

A
  • glycogen breakdown to glucose; increased blood glucose
  • increased blood pressure
  • increased breathing rate
  • increased metabolic rate
  • change in blood flow patterns, leads to increased alertness and decreased digestive, excretory and reproductive system activity
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9
Q

Effects of mineralocorticoids

A
  • retention of sodium ions and water by kidney
  • increased blood volume and blood pressure
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10
Q

Effects of glucocorticoids

A
  • proteins and fats are broken down and converted to flucose, leading to increased blood glucose
  • partial suppression of immune system
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11
Q

What are steroid hormones

A
  • derived from cholesterol and differ in ring structure and side chains
  • lipid soluble -> freely permeable to membranes; not stored in cells, leave shortly after synthesis
  • carried in the blood complexed to specific binding globulins e.g. corticosteroid binding globulin transports cortisol
  • enzymes which produce steroid hormones from cholesterol are located in mitochondria and SmER
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12
Q

Sources of cholesterol for steroid synthesis

A
  • amount of free cholesterol in cell is maintained fairly constant
  • cholesterol precursor comes from cholesterol synthesised within cell from acetate
  • esterified cholesterol level
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13
Q

What is the rate-limiting step in steroid hormone synthesis

A
  • the transport of free cholesterol from cytoplasm into mitochondria
  • this is carried out by the Steroidogenic Acute Regulatory Protein (StAR)
  • cholesterol moves from outer membrane to inner membrane where it is converted to pregnenolone
  • occurs in adrenal, ovary, and testis
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14
Q

What determines which pathway is taken in adrenal steroidogenesis

A
  • each step is regulated by specific enzyme
  • different zones have different relative activities of enzymes, resulting in different chemical reactions taking place
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15
Q

Adrenal Steroidogenesis in the Zona glomerulosa

A

1) pregnenolone -> progesterone by 3beta-hydroxysteroid dehydrogenase
2) progesterone -> aldosterone via 21-hydroxylase, 11beta-hydroxylase, 18 hydroxylase/oxidase

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16
Q

Adrenal steroidogenesis in the Zona fasciculata

A

17alpha-hydroxypregnenolone -> glucocorticoids via 3 beta-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11beta-hydroxylase

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17
Q

Adrenal steroidogenesis in the Zona retuicularis

A

dehydroeepiandrosterone -> androstenedione via 3beta-hydroxysteroid dehydrogenase

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18
Q

Function of zona fasciculata

A
  • largest and most actively steroidogenic zone
  • produces glucocorticoid hormone
  • corticotropin-releasing hormone (CRH) is secreted by paraventricular nuclei
  • CRH comes through hypophyseal portal system and stimualtes corticotropes in anterior pituitary gland, stimulating ACTH secretion
  • ACTH binds to GPCR, activating Gs, binding GTP and activating G protein
  • G protein binds to AC, converting ATP to cAMP and activating PKA
  • PKA is responsible for cholesterol synthesis and secretion
19
Q

Cholesterol synthesis

A

cholesterol -> pregnenolone -> progesterone -> 17-OH progesterone -> 11-deoxycortisol -> cortisol

20
Q

Transport and metabolism of cortisol

A
  • transported in blood predominantly bound to corticosteroid-binding globulin (CBG) and albumin
  • unbound free form of the hormone exerts biologic effects within target cells and feeds back on pituitary and hypothalamus
  • liver is predominant site of steroid inactivation and conjugates 95% of active and inactive steroids with glucuronide or sulfate for excretion by kidney
21
Q

Mechanism of action of cortisol

A
  • only unbound hormones can diffuse into target cell, so most hydrophobic steroids are bound to plasma protein carriers
  • receptors are in cytoplasm or nucleus
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  • receptor-hormone complex bindns to DNA and activates or represses one or more genes
  • activated genes create new mRNA that move back into cytoplasm
  • translation produces new proteins for cell processes
  • some steroid hormones are also used to bind to membrane receptors that use second messenger systems to create rapid cellular responses
22
Q

Role of cortisol in regulating gene transcription

A
  • acts primarily through GR and binds to GRE to regulate gene transcription
  • in absence of hormone, GR resides in cytoplasm in stable complex with several molecular chaperones, including heat-shock protein 90 and cyclophilins
  • cortisol-GR binding promotes dissociation of chaperone proteins
23
Q

Binding of cortisol-GR results in

A
  • rapid translocation of cortisol-GR complex into nucleus
  • dimerisation and binding to GREs near basal promoters of cortisol-regulated genes
  • recruitment of coactivator/co-repressor proteins, followed by covalent modification of chromatin
  • change in assembly of GTFs, leading to changes in transcription rate
  • phosphorylation, followed by nuclear export and/or degradation of the GR, thereby terminating signal
24
Q

Metabolic effects of cortisol in muscle during fasting

A
  • increased protein degradation
  • increased protein synthesis
  • decreased glucose utilization
  • decreased sensitivity to insulin
25
Q

Metabolic effects of cortisol in fat cells during fasting

A
  • decreased glucose utilization
  • decreased sensitivity to insulin
  • increased lipolysis
26
Q

Metabolic effects of cortisol in liver during fasting

A
  • increased glycogen storage
  • increased gluconeogenesis by increased activity and amount of enzymes
27
Q

Actions of glucocorticoids

A
  • gluconeogenesis
  • vascular responsiveness to catecholamines
  • suppression of inflammatory and immune responses
  • modulation of CNS function; catabolic and diabetogenic qualities
28
Q

Effect of cortisol on immune response

A
  • prescribed to suppress inflammation and immune system
  • analogs of glucocorticoid are frequently used pharmacologically
  • when cortisol levels are high, many of body defence mechanisms against infection are inhibited
29
Q

Side effects of a disruption of physiologic homeostasis levels of cortisol

A
  • alterations in water balance
  • weight gain
  • hypertension
  • muscle weakness
  • diabetes
  • osteoporosis
  • mediated through genomic function of GR
30
Q

How to regulate the mineralocorticoid action of cortisol

A
  • can bind to MR with high affinity and activate wrong set of genes
  • transported in inactive form
  • enzyme that converts it to active form is only present in tissues that express the GR including liver, adipose, skin and CNS
  • natural black licorice contains GZA which inhibits 11beta-HSD2 (converts cortisol to active form) and thereby increases mineralocorticoid activity of cortisol
31
Q

Glucocorticoid regulation by HPA axis

A
  • ACTH
  • Suprachiasmatic nucelus and retina impose a circadian rhythm on CRH secretion, ATCH secretion and therefore Cortisol
  • pulsatile release of CRH and ACTH
32
Q

CRH in hypothalamus inhibits

A
  • synthesis
  • transcription of CRH
  • CRH release
33
Q

ACTH in anterior pituitary inhibits synthesis of

A
  • CRH receptor
  • ACTH
  • ACTH release
34
Q

Consequence of CRH/ACTH inhibition on immune system

A

suppressed

35
Q

Consequence of CRH/ACTH inhibition on liver

A

gluconeogenesis

36
Q

Consequence of CRH/ACTH inhibition on muscle

A

protein catabolism

37
Q

Consequence of CRH/ACTH inhibition on adipose tissue

A

lipolysis

38
Q

Effects of pituitary lesion/lack of ACTH

A

Fasciculata and reticularis atrophy
- ACTH acts as trophic factor
- AngII and high K trophic for glomerulosa
No cortisol; dependency on exogenous glucocorticoids

39
Q

Effects of excess ACTH

A
  • enlarged adrenals
  • excess steroids
40
Q

Adrenal hyperplasia

A
  • 21-hydroxylase deficiency
  • varying degree of virilism in females, including hirsutism and clitoral hyperplasia
  • precocious puberty in boys
  • when HPA axis is overstimulated, excess ACTH is shunted into androgen production pathway
41
Q

Cushing Syndrome (elevated cortisol levels)

A
  • salt and water retention with renal loss of K+ results in “moon face”
  • fluid retention leads to cardiac hypertrophy due to prolonged hypertension
  • peripheral oedema due to glucocorticoid-induced diabetes (resistant to even large doses of insulin)
  • catabolism causes muscle wasting, fat accumulation, osteoporosis, buffalo hump, and fractures
  • skin is thin with ulcers and red stirrer and poor wound healing
  • impaired fibrocyte formation and capillary resistance
42
Q

Addison Disease (insufficient steroid hormone)

A
  • overproduction of ACTH due to decreased negative feedback by cortisol
  • skin hyperpigmentation
43
Q

Glucocorticoid deficiency symptoms

A

predisposition to hypoglycaemia, hypotension, changes in mood and personality, muscle weakness, anaemia, decreased GI motility and appatite, decreased water clearance

Reg Phys and Pharm (16 decks)

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