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
What is the adrenal gland
- hybrid gland of cortex and a medulla
- hormones are important eregulators of metabolism and serve an important role in adaptation to stress
Role of cortisol
- glucocorticoid
- increases plasma glucose levels
- deficiency = hypoglycaemia
- synthetic analogs are widely used in treatment of disorders ranging from skin rashed to arthiritis
Role of Aldosterone
- mineralocorticoid
- promotes salt and water retention by kidney
- critical for normal salt/water balance
What is synthesised by the adrenal cortex
- androgenic steroids
- converted by peripheral tissue to testosterone h
Products of the medulla
catecholamines e.g. epinephrine and norepinephrine
Role of the adrenal gland in modulating short-term stress
- hypothalamus activates adrenal medulla via nerve impulses
- adrenal medulla secretes epinephrine and norepinephrine
Role of the adrenal gland in modulating long-term stress
- hypothalamus activates adrenal cortex via hormone signals
- adrenal cortex secretes mineralocorticoids and glucocorticoids
Effects of epinephrine and norepinephrine
- 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
Effects of mineralocorticoids
- retention of sodium ions and water by kidney
- increased blood volume and blood pressure
Effects of glucocorticoids
- proteins and fats are broken down and converted to flucose, leading to increased blood glucose
- partial suppression of immune system
What are steroid hormones
- 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
Sources of cholesterol for steroid synthesis
- amount of free cholesterol in cell is maintained fairly constant
- cholesterol precursor comes from cholesterol synthesised within cell from acetate
- esterified cholesterol level
What is the rate-limiting step in steroid hormone synthesis
- 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
What determines which pathway is taken in adrenal steroidogenesis
- each step is regulated by specific enzyme
- different zones have different relative activities of enzymes, resulting in different chemical reactions taking place
Adrenal Steroidogenesis in the Zona glomerulosa
1) pregnenolone -> progesterone by 3beta-hydroxysteroid dehydrogenase
2) progesterone -> aldosterone via 21-hydroxylase, 11beta-hydroxylase, 18 hydroxylase/oxidase
Adrenal steroidogenesis in the Zona fasciculata
17alpha-hydroxypregnenolone -> glucocorticoids via 3 beta-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11beta-hydroxylase
Adrenal steroidogenesis in the Zona retuicularis
dehydroeepiandrosterone -> androstenedione via 3beta-hydroxysteroid dehydrogenase
Function of zona fasciculata
- 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
Cholesterol synthesis
cholesterol -> pregnenolone -> progesterone -> 17-OH progesterone -> 11-deoxycortisol -> cortisol
Transport and metabolism of cortisol
- 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
Mechanism of action of cortisol
- only unbound hormones can diffuse into target cell, so most hydrophobic steroids are bound to plasma protein carriers
- receptors are in cytoplasm or nucleus
love u x - 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
Role of cortisol in regulating gene transcription
- 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
Binding of cortisol-GR results in
- 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
Metabolic effects of cortisol in muscle during fasting
- increased protein degradation
- increased protein synthesis
- decreased glucose utilization
- decreased sensitivity to insulin
Metabolic effects of cortisol in fat cells during fasting
- decreased glucose utilization
- decreased sensitivity to insulin
- increased lipolysis
Metabolic effects of cortisol in liver during fasting
- increased glycogen storage
- increased gluconeogenesis by increased activity and amount of enzymes
Actions of glucocorticoids
- gluconeogenesis
- vascular responsiveness to catecholamines
- suppression of inflammatory and immune responses
- modulation of CNS function; catabolic and diabetogenic qualities
Effect of cortisol on immune response
- 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
Side effects of a disruption of physiologic homeostasis levels of cortisol
- alterations in water balance
- weight gain
- hypertension
- muscle weakness
- diabetes
- osteoporosis
- mediated through genomic function of GR
How to regulate the mineralocorticoid action of cortisol
- 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
Glucocorticoid regulation by HPA axis
- ACTH
- Suprachiasmatic nucelus and retina impose a circadian rhythm on CRH secretion, ATCH secretion and therefore Cortisol
- pulsatile release of CRH and ACTH
CRH in hypothalamus inhibits
- synthesis
- transcription of CRH
- CRH release
ACTH in anterior pituitary inhibits synthesis of
- CRH receptor
- ACTH
- ACTH release
Consequence of CRH/ACTH inhibition on immune system
suppressed
Consequence of CRH/ACTH inhibition on liver
gluconeogenesis
Consequence of CRH/ACTH inhibition on muscle
protein catabolism
Consequence of CRH/ACTH inhibition on adipose tissue
lipolysis
Effects of pituitary lesion/lack of ACTH
Fasciculata and reticularis atrophy
- ACTH acts as trophic factor
- AngII and high K trophic for glomerulosa
No cortisol; dependency on exogenous glucocorticoids
Effects of excess ACTH
- enlarged adrenals
- excess steroids
Adrenal hyperplasia
- 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
Cushing Syndrome (elevated cortisol levels)
- 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
Addison Disease (insufficient steroid hormone)
- overproduction of ACTH due to decreased negative feedback by cortisol
- skin hyperpigmentation
Glucocorticoid deficiency symptoms
predisposition to hypoglycaemia, hypotension, changes in mood and personality, muscle weakness, anaemia, decreased GI motility and appatite, decreased water clearance
