Endocrinology - Week 3 Flashcards Preview

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Flashcards in Endocrinology - Week 3 Deck (87)
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describe cholesterol

• Polar head group
• Steroid body
• Hydrophobic side chain

Component of cell membrane as its attracted to polar heads and hydrophobic tails in the membrane


what are the three types of corticosteroids

(made in the cortex)

• Mineralocorticoids
o Salt and water retention

• Glucocorticoids
o Glucose synthesis
o Protein and lipid metabolism
o Inflammation and immune response

• Adrenal androgens
o Fetal steroids and growth


what are the three types of sex steroids

(made in the gonads)

• Androgens
o Growth and function of the male reproductive system

• Oestrogens
o Growth and function of the female reproductive system

• Progesterones
o Female menstrual cycle and maintenance of pregnancy


what steroid is often forgotten?

vitamin D


how do steroid hormones work

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

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


how are steroids made

• first step : hydrophobic 6 carbon side chain removed
o steroid hormones more water soluble than cholesterol

• most steroids have a varied substituent at C-17
o Enzyme nomenclature indicates the site of action …
o e.g. ‘17α-hydroxylase’ introduces a hydroxyl group at C- 17

• extra specificity from side chain modification e.g. C-11
o Enzyme nomenclature indicates the site of action …
o e.g. ‘11β-hydroxylase’ introduces a hydroxyl group at C- 11


what types of enzyme are involved in steroid synthesis

• cytochrome P450s (over 1000 of these)
o Highly expressed in
 Liver (drug detoxification)
 Organs that synthesise steroids
• adrenal cortex,
• testis, ovary, placenta
o Cleave or modify cholesterol side groups
o Example: (clue in the name)
 cholesterol side chain cleavage enzyme (SSC; CYP 11A1)
 Converts cholesterol to pregnenolone
 C27 → C21 = First step in steroid synthesis

• steroid dehydrogenases
o Steroid dehydrogenases/reductases: (usually paired)
o Key concept:
 Interconvert active & inactive forms of steroid
o Example: 11β-HSD1 and 11β-HSD2 - liver & peripheral tissues
 Turn cortisone into cortisol (active form) and vice versa


describe cortisol metabolism and transport

• Made and released from the adrenal gland
• Much binds to transport proteins
• Cortisol converted to cortisone by the liver
• Then reactivated at the site of action


describe adrenal gland blood supply

• From renal arteries or aorta
• Short arteries penetrate capsule and form a subcapsular plexus of arterioles
• These then give off sinusoidal capillaries which separate chords of cells
• The medulla gets its blood from long arteries and capillaries from cortex
• Medulla and cortex drain via the central medullary vein


describe adrenal glands

• Around the 12th thoracic vertebra
• Positioned anteriorly on superior poles of kidneys

• 80-90% of normal gland
• Makes steroid hormones
• 10-20%
• Makes catecholamines (adrenaline and noradrenaline)


describe the adrenal cortex

• Zona glomerulosa
o Synthesizes aldosterone (SALT)

• Zona fasciculata
o Synthesizes cortisol (SUGAR)

• Zona reticularis
o Synthesizes “C19” adrenal androgens (SEX)
 Under the control of the HPA axis
 Also regulated by ACTH from pituitary
o Prenatal DHEA production
 Role in maintaining oestrogenic environment
 role in foetal development??
o Postnatal DHEA production:
 role in initiation of puberty (adrenarche)??
 main source of androgens & post-menopausal oestrogen in females
 role in longevity; elixir of life??


what determines which steroid is synthesised in each zone

determined by zone-specific P450 gene expression

• zona glomerulosa produces mineralocorticoid (aldosterone) due to expressing a gene for aldosterone synthase but not 17α-Hydroxylase and 11β-Hydroxylase

• zona fasciculata produces glucocorticoid (cortisol) due to having 17α-Hydroxylase and 11β-Hydroxylase but not aldosterone synthase

• zona reticularis produces adrenal androgen (“C19”) due to having 17α-Hydroxylase but not aldosterone synthase and only a little 11β-Hydroxylase


what determines Corticotrophin-Releasing Hormone (CRH) secretion from PVN of the hypothalamus

• diurnal circadian rhythm from the suprachiasmic nucleus stimulates the hypothalamus to release CRH at the median eminence
• there are a number of things which inhibit or promote this release
o ADH/AVP (potentiates CRH)
o cortisol negative feedback


why do cortisol levels have a diurnal rhythm

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


how does CRH stimulate ACTH release

Hypothalamic CRH stimulates AdrenoCorticoTrophic Hormone (ACTH) secretion
from anterior pituitary corticotrophs
• CRH stimulates production of pro-opiomelanocortin (POMC) …
• POMC cleaved to ACTH and other peptides


how does ACTH stimulate cortisol synthesis

ACTH stimulates cortisol synthesis & secretion from adrenal zona fasciculata (&ZR) cells
• cortisol & adrenal androgen synthesis and release (1-2 mins)
• cholesterol ester hydrolase increased which increases free cholesterol
• activates StAR protein (steroid acute regulatory protein) which increases cholesterol transport to mitochondria
o this is the rate limiting step which is shown by mutations to this protein

Cortisol feeds back on production of CRH from hypothalamus & ACTH from the anterior pituitary


describe cortisol

• Essential for survival and to resist physiological and environmental stress
• Part of the ‘counter-regulatory’ hormone defence against hypoglycaemia
• Levels rise as plasma glucose falls:
o glucagon (from α cells of the pancreas)
o adrenaline (epinephrine)
o noradrenaline (norepinephrine)
o growth hormone
o cortisol
• Dual action of cortisol:
o Anabolic in the liver to promote gluconeogenesis
o Catabolic in peripheral muscle & fat to promote protein and lipid breakdown


what are the normal physiological actions of cortisol

maintains plasma glucose levels for the brain

• Increased gluconeogenesis & liver glucose output

• 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


what are the pathophysiological actions of cortisol

elevated plasma glucose & peripheral tissue wasting

• Elevated plasma glucose = secondary diabetes mellitus

• 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


describe cortisol excess phenotype

• Phenotype: Hypertension; low plasma K+, elevated plasma cortisol, low plasma aldosterone & renin activity
• Hypertension due to multiple effects of elevated plasma cortisol


what would you see with a ACTH-secreting pituitary tumour


HIGH Plasma Cortisol


what would you see with a Cortisol-secreting adrenal tumour


HIGH Plasma Cortisol


what is important if a patient presents with excess adrenal androgens (DHEA)

also need to think about excess cortisol as they are intimately linked (both produced in zona reticularis)


what are the 3 main physiological factors that regulate blood pressure

• Cardiac output
– volume of blood pumped out by the heart
– stroke volume x heart rate (beats/min)

• Vascular tone
– ‘stiffness’ or resistance of blood vessels
– balance between vasoconstrictor & vasodilator influences

• Extracellular fluid (ECF) volume
– Interstitial fluid in tissues
– intravascular fluid in the plasma
– increased by kidney water resorption

• these are all regulated by hormones


how do the three adrenal hormone systems regulate blood pressure

Cardiac output:
increased by:
catecholamines (SNS)
cortisol potentiation (HPA)

Vascular tone (vasoconstriction):
increased by:
angiotensin II (AII; RAS)
aldosterone (RAS)
catecholamines (SNS)
cortisol potentiation (HPA)

Extracellular fluid (ECF) volume:
increased by:
aldosterone (RAS)
cortisol (HPA)


what causes endocrine hyper(hypo)tension:

caused by excess (lack):
aldosterone from ZG
cortisol or precursors from ZF
catecholamines from medulla


what is the role of the kidney in blood pressure

mechanisms regulating renin release from kidney juxtaglomerular (JG) cells
Renin release in response to:
JG cell baroreceptors
• reduced ECF & renal perfusion pressure
• directly activates renin release
Macula densa cell Na+ sensing
• decreased Na+ load to distal tubule (↓ECF/plasma Na+)
• activates sympathetic innervation of JG apparatus
Carotid arch baroreceptors
• Low systemic arterial pressure (reduced ECF, cardiac output, vascular tone)
• activates sympathetic innervation of JG apparatus


what are the rapid and long term effects of RAS and aldosterone

Rapid (secs)
 vasoconstriction
Postural regulation of BP

Rapid (mins)
 aldosterone synthesis
Catecholamine synthesis

6-48 hr
 Na+ & water reabsorption via RAAS

Long term
smooth muscle
 cell hyperplasia
 cell hypertrophy
Long-lasting change
in vascular tone

Long term
 aldosterone synthase
enzyme expression
 glomerulosa cell

Long term
 thirst
 salt appetite
 ADH release


what is the link between aldosterone and heart failure

• Plasma aldosterone elevated in patients with heart failure
• Standard HF therapy: ACE inhibitor + loop diuretic + digoxin
• Clinical & experimental studies show benefits of
mineralocorticoid receptor antagonists e.g. spironolactone
• Spironolactone (MR antagonist) blocks aldosterone action in kidney AND other tissues (e.g. heart)
• Which otherwise leads to:
- myocardial remodelling,
- Na+ retention & vascular dysfunction
• Decreases all-cause mortality in heart failure patients


describe hypertension epidemiology and classification

• risk factor - high blood pressure … 1.2 billion people worldwide!
- ~30% lifestyle/environmental (poor diet, lack of exercise)
- ~70% major familial/genetic mono- or polygenic component

• 85-90% classified as ‘Primary’ or ‘Essential’ hypertension
- all cases without any identifiable cause
• 10-15% classified as ‘secondary’ hypertension
- neoplasia, vascular damage & endocrine causes