Lecture 11 - Synthetic Glucocorticoids - anti-inflammatory agents with side effects Flashcards
Steroid hormones: what are the types, what do they do, and what are the examples of each type?
- Glucocorticoid - regulate metabolism and communicate ‘stress’ - cortisol
- Mineralocorticoid - regulate water balance - aldosterone
- Androgens - regulate reproductive health - testosterone and DHT
- Progestins - regulate reproductive health - progesterone
- Estrogens - regulate reproductive health - oestrogen
Glucocorticoids: what are they, what do they bind to, what do they do, and what are some examples?
Cholesterol-derived steroid hormones that are synthesised and secreted by the adrenal gland
Glucocorticoid receptors - intracellular nuclear transcription factors
Affect metabolism, inflammation, and the immune system
Cortisol
Glucocorticoid receptors: what are they, what is their activation pathway, what are some examples, and what do they do?
Intracellular nuclear receptors that act as transcription factors once activated
Glucocorticoid binds leading to activation - dimerisation occurs, they then move to the nucleus and act as TFs
Liver:
* Phosphoenolpyruvate carboxykinase (PEPCK) - transactivation of a gene producing an enzyme that controls the rate of gluconeogenesis
* Tyrosine aminotransferase (TAT) - transactivation of a gene producing an enzyme involved in gluconeogenesis
Adipose Tissue:
* CCAAT/enhancer binding protein (C/EBP) delta (CEBPD) - transactivation of a gene producing a (TF - ER) protein that activates adipogenesis
Glucocorticoid receptor structure
AF-1 at its N-terminal - binds co-factors involved in the transcription of the genes it binds to
AF-2 and LBD at its C-terminal - AF-2 also binds cofactors for transcription and LBD is the ligand binding domain
The receptor forms a horseshoe shape such that the N- and C- terminals are near each other
Between the N- and C- terminals, roughly in the middle of the receptor is the DBD (DNA binding domain)
Glucocorticoid receptors: do they only activate genes?
No, GRs also inhibit genes
Genes producing the following molecules may be repressed by GRs:
* IL-1β
* IL-8
* IL-4
* IL-5
* TNFα – Tumour necrosis factor α
* GM-CSF – Granulocyte-macrophage colony-stimulating factor
* Osteocalcin
Osteocalcin: what is it, what does it do, what can it clinically be used for, and how do glucocorticoids affect their transcription?
Protein involved in bone mineralisation
Marker of bone formation
Glucocorticoids inhibit osteocalcin transcription in osteoblasts by
suppressing Egr2/Krox20-binding enhancer
Glucocorticoid receptor action: how may it affect transcription?
- Binding to GREs - either positively or negatively influencing transcription
- Binding to cofactors required for transcription - represses TFs that require those cofactors
GRE: what is it, what does it do, and how may glucocorticoids affect it?
Glucocorticoid response element
Specific DNA sequence that binds to the glucocorticoid receptor (GR)
GR-GRE binding can either activate or repress transcription
NFκB: what is it, what does it do, and how may glucocorticoids affect it?
Nuclear factor kappa B
Group of proteins that control many functions in a cell, including:
* Cell growth and survival
* Immune response
* Inflammatory resoinse
* Cytokine production
* DNA transcription
GR can bind to Jun and Fos, two cofactors required for NFκB action, and prevent TNF gene transcription
NRE: what is it, what does it do, and how may glucocorticoids affect it?
Nuclear response element
Involved in transcriptional induction by stimuli that activate NF-κB, such as IL-1, MEKK1, and TAK1
Inhibition of NF-κB action results in reduced NRE action
Glucocorticoid feedback inhibition: what is the process?
- Anterior pituitary gland produces ACTH
- ACTH promotes glucocorticoid production from the adrenal gland
- Glucocorticoids cause physiological effects as well as interacting with the pituitary gland
- Glucocorticoids enter the nucleus of cells, dimerising and binding to and repressing the POMC gene, reducing ACTH production
POMC gene: what is it, what does it code for, and what does it do?
Proopiomelanocortin gene
Proopiomelanocortin (POMC)
Produces ACTH after POMC is cleaved
Steroid treatments: how may they be used and what examples are there?
Anti-inflammatory agents:
* Arthritis - 56 – 68% of patients treated with GCs (Diurnal Ltd 2015)
* Asthma - 5.4 million people in the UK receiving treatment for asthma (may
not all be steroids)
* Skin disorders
Anti-proliferative agents
* cancer - ie lymphoblastic leukaemia
Steroid treatments: what are some stats?
Estimated that 0.5% of population is treated with glucocorticoids (Diurnal Ltd 2015)
In 2018 in UK 41 million prescriptions for GCs in community ie not hospitals
Sales of Steroids:
* European Union - 15 million people take systemic glucocorticoids on an annual basis (Meijer & Periera 2019)
* Globally the corticosteroid market is $4.56 billion in 2021 (ResearchandMarkets.com)
* Use increased in the last 3 years because they have been shown to be beneficial in the treatment of Covid and other corona-viruses due to their ability to modulate the inflammatory response
Steroid treatments: how similar are steroids?
Most are extremely similar, with some (such as cortisol and prednisolone) differing solely by the presence of a double bond in one of the rings in the molecule
Mifepristone: what is it and what does it do?
It is the morning after pill
Antagonises progesterone at the glucocorticoid receptor
Steroid treatments: what are the observable side effects?
Excess glucocorticoids resulting in:
* Truncal obesity
* Glucose intolerance - diabetes
* Hypertension
* Striae, bruising, poor wound healing
* Myopathy
* Osteoporosis
* Buffalo hump on the neck - fat distribution
* Fullness of face
* Acne
* Mental disturbance
* Receding hair
* Hirsuitism (excess body hair), amenorrhea, acne (Women)
Steroid treatments: what are the internal side effects?
- Metabolism
- Growth effects
- Eye
- Bone
- Cardiovascular effects
- Hypertension
- Infections
- Neuropsychiatric disorders
- Decreased wound healing
Metabolic side effects of steroid treatment
- Hyperglycaemia, glycosuria and diabetes
(Type II-like) - Inhibition of protein synthesis, enhanced
catabolism - Calcium absorption is decreased in the intestine, probably due to antagonism of vitamin D
- Re-distribution of fat
Growth side effects of steroid treatment
Stunting can occur in children
Ocular side effects of steroid treatment
Topical steroids can increase intraocular pressure (occurs in 1/3 of the population) which can lead to glaucoma
Osteo side effects of steroid treatment
Glucocorticoids increase Ca²⁺ resorption
Increased Ca²⁺ resorption from bone leads to osteoporosis - this occurs in 60% of patients with natural Cushing’s syndrome
Cardiovascular side effects of steroid treatment
Increased cardiac output and decreased total peripheral resistance in normal subjects
Blood pressure side effects of steroid treatment
Excess glucocorticoids can lead to hypertension
Hypertension - glucocorticoids affect sodium retention and potassium excretion, resulting in increased blood pressure
Immune system side effects of steroid treatment
Immune suppression - patients on glucocorticoids vulnerable to infections
Neuropsychiatric side effects of steroid treatment
- Alterations in EEG (electroencephalogram)
- Seizures
- Minor sleep disorders
- Psychosis
Disturbances are present in about 1/3 of patients
Skin side effects of steroid treatment
Decreased wound healing
Zones of the adrenal gland: what are they and what do they produce?
zona glomerulosa - aldosterone
zona fasciculata - cortisol
zona reticularis - testosterone
zona glomerulosa: what part of the adrenal gland is it, what does it produce, and what are the stages of production?
Outer zone
aldosterone
Cholesterol - pregnenolone - preogesterone - 11-deoxy corticosterone - corticosterone - aldosterone
zona fasciculata: what part of the adrenal gland is it, what does it produce, and what are the stages of production?
Middle zone
cortisol
Cholesterol - pregnenolone - progesterone - 17aOH progesterone - II-deoxycortisol - cortisol
zona reticularis: what part of the adrenal gland is it, what does it produce, and what are the stages of production? - testosterone
Inner zone
Testosterone
Low blood pressure due to low fluid: what senses this and what is the process that counteracts this?
Kidneys sense low fluid/Na⁺
- Renin converts angiotensinogen into angiotensin I, promoting fluid retention
- ACE converts angiotensin I into angiotensin II which acts on the lungs
- Angiotensin II also promotes fluid retention as well as aldosterone production
- Aldosterone results in Na⁺ retention
- Pituitary senses increased Na⁺ levels and releases arginine vasopressin (AVP/ADH)
- Anti-diuretic hormone (AVP/ADH) increases fluid retention and blood pressure
Angiotensin I: what is its precursor, what is the enzyme that causes it to be produced, and what does it do?
Angiotensinogen
Renin
- Constricts blood vessels, which helps maintain blood pressure
- Triggers the body to intake water and salt (Na⁺)
Angiotensin II: what is its precursor, what is the enzyme that causes it to be produced, and what does it do?
Angiotensin I
Angiotensin convertin enzyme (ACE)
- Constricts blood vessels, which helps maintain blood pressure
- Triggers ADH production - promoting the retention of water and salt (Na⁺)
- Triggers aldosterone production
Aldosterone: what is it produced by, what is its main precursor, what is its receptor, what factors cause its production, and what does it do?
Zona glomerulosa - the outer part of the adrenal gland
Cholesterol
Mineralocorticoid receptor
Angiotensin II mainly but also ACTH and hyperkalemia (high K⁺) may
Increases sodium retention in the kidney - important for osmotic balance
Angiotensin I: what is its precursor, what is the enzyme that causes it to be produced, and what does it do?
Angiotensinogen
Renin
- Constricts blood vessels, which helps maintain blood pressure
- Triggers the body to intake water and salt (Na⁺)
Adrenal gland: what are the types of disorders?
Hyperactivity:
* Cushing’s syndrome - hypercortisolemia
* Sex steroid excess
Hypoactivity:
* Addison’s disease - hypoadrenalism
* Adrenal enzyme defects - CAH
Addison’s disease: what is it and what are the clinical features?
Loss of adrenal cortex activity - low cortisol, low aldosterone (mineralocorticoid deficiency)
- Sodium loss - water loss
- Hypotension/faintness
- Addisonian crisis with collapse due to fainting from hypotension
- Weakness
- Weight loss
- Lassitude
- Skin pigmentation - high ACTH levels
Addison’s disease: how is it diagnosed, what are the causes, and what are the treatments?
- High ACTH
- Low cortisol
- Low aldosterone
- Low sodium, high potassium, and low blood pressure/fluid volume
- Can test by seeing if synthetic ACTH causes a rise in cortisol levels - if it doesn’t fix, the adrenal gland is the issue
Bilateral adrenalectomy - removed
Adrenal infarction - closes down
Autoimmune
Idiopathic - unknown cause
Tuberculosis in rare cases
Intravenous saline administered followed by hydrocortisone 2-3 times daily and may need to give glucocorticoids which mimic aldosterone action
Why are there high ACTH levels in Addison’s disease?
No negative feedback from cortisol - continual ACTH production
Why do high ACTH levels cause pigmentation?
ACTH has the same sequence as MSH which stimulates melanocytes - ACTH can start stimulating skin cells to produce pigments if ACTH is in too large amounts
Adrenal sex steroid excess: how frequent is it, what is it caused by, what types are there, and do they affect different people differently?
Rare to get tumour without cortisol causing Cushing’s Syndrome but if the tumour derives from the inner zone then it may happen
Congenital adrenal hyperplasia - defects in enzymes producing aldosterone/cortisol result in increased sex steroid production which eventually causes hyperplasia
Androgens (more common):
* In men - no effect
* in women- virilisation, hirsutism ie frontal baldness, acne, and menstrual disturbance
Oestrogens:
* Men- feminisation-breast development, fat distribution is different, lower muscle mass
* In women - no effect
Adrenal enzyme defects: what are the conditions called, what are the types, and how frequent are the defects?
Congenital adrenal hyperplasia
Most common is 21-hydroxylase (90%) but 3βHSD and 11β-hydroxylase may also occur
CAH: what is it, what is it caused by, what does it do, and what is the process?
Congenital adrenal hyperplasia
Adrenal enzyme defects - reducing aldosterone/cortisol production
- Cause excess sex steroid production and its effects
- Cause water/salt loss (aldosterone)
- Hypoglycaemia and other effects (cortisol)
Lack of feedback inhibition from cortisol - increased ACTH production - ACTH promotes adrenal growth, causing adrenal hyperplasia
Can you live with no cortisol?
no
CAH: what are the general clinical features?
General features:
* Severely affected neonates can present with salt wasting crisis
* Failure to gain weight, vomiting, dehydration, shock
* Death due to adrenal crisis occurs without
treatment.
CAH: what are the clinical features in girls?
Clinical features in Girls:
* May be virilised at birth, with clitoral
hypertrophy and varying degrees of
ambiguous genitalia, making assignment of
sex difficult on clinical grounds
* In milder forms, the child may appear
normal at birth, but early growth is rapid so
taller and stronger at age 5-6 years
* Epiphyses fuse early causing short final
height
* Breasts may develop, but menstruation is
absent or infrequent
* Hirsutism may occur
CAH: what are the clinical features in boys?
Clinical features in Boys:
* Normal genitalia at birth
* High initial growth rate, taller and stronger
than classmates (but short final height)
* Precocious puberty – premature growth of
pubic and axillary hair, large penis
* Small testes, no spermatogenesis
CAH: how is it treated?
Treatment:
* Hydrocortisone to replace cortisol.
* Fludrocortisone (synthetic mineralocorticoid) to replace aldosterone
* Treatment suppresses androgen hypersecretion and prevents further virilisation
* Boys develop normally, girls may need
corrective surgery
* Genetic counselling is available
