W5 Growth hormone & Corticosteroid responsive conditions (SM) Flashcards
What is the pituitary gland?
What hormones (class) are secreted from this gland?
- A chickpea sized gland located in the skull
- An extension of the hypothalamus
- Separated into the Anterior and Posterior pituitary glands
- Responsible for growth, development, reproduction, metabolism in the body
- Peptide
- Anterior- glandular cells
- Posterior- neural cells
Which cell types are in the anterior pituitary gland?
Somatotrophs- Somatotropin, growth hormone (GH)
Corticotrophs- Corticotropin, adrenocarticotropic hormone (ACTH)
Lactotrophs- Prolactin
Thyrotrophs- Thyrotropin, TSH
Gonadotropins- Gonadotropins, leutinising hormone (LH), follicle stimulating hormone (FSH)
trope/trope: cells
trophic/tropin: hormone
Which hormones are stored/released in the posterior pituitary gland?
Oxytocin
ADH/Vasopressin
Pituitary tumours:
benign or malignant usually?
signs?
mri scan:
Pituitary tumours are mostly benign and slow-growing
not metastatic usually
Over/underproduction of hormones (hyper/hypo)
Local effects: pressure on surrounding structures
- headaches, visual disturbances
MRI images show the normal pituitary gland (solid white arrow) and a pituitary tumour (dashed white arrow)
The optic chiasm (where the optic nerves meet) is shown by the green arrows and is pushed up by the pituitary tumour (see slide)
Hypothalamic-releasing and anterior pituitary tropic hormones
Hypothalamus acts on anterior pituitary which acts on peripheral glands to release hormones
e.g. CRH in Hypothalamus —- ACTH in AP — Cortisol from Adrenal cortex
GHRH in Hyp— GH in AP— IGF-1 from Liver (HPA Axis)
somatostatin and dopamine suppress GH release in AP
Somatotropin, GH
Structure?
main role?
- GH is secreted by acidophilic cells of anterior pituitary glands.
- GH is a peptide hormone, 21.5 K Da single-chain polypeptide (190 AA) with 2
disulphide bridges - GH is stored in the cells as granules, and it is released as pulsatile
- Major role in growth (linear) and metabolism
What are the functions of growth hormone?
Direct? (6)
Indirect?
Direct – on metabolism:
* Increase Blood Glucose
(anti-insulin effect)
* Increase Gluconeogenesis (Liver)
* Increase Protein synthesis (Muscle)
* Decrease Glucoseuptake (Muscle)
* Increase Lipolysis (Adipose)
* Decrease Glucose uptake (Adipose)
Indirect – growth:
* Insulin-like growth factors (somatomedins) from liver
Lean body Mass
* Increase Hypertrophy (cell size)
* Increase protein synthesis
Organ size- IGFs
* Increase Hyperplasia (cell number)
* Cell division
Linear growth
* Increase Skeletal growth
What are the Influencers of GH release? (5)
- Blood glucose, free fatty acids and amino acid levels influence GH release
- Sleep and exercise affect GH release
GH, disorders (Deficiency/Insufficiency)
What is the main example?
symptoms in adults?
symptoms in children
Dwarfism
(stunted growth)
* Congenital (genetic mutations or structural issues in the baby’s brain)
* Acquired (damage to the pituitary gland, injury, infection, radiation)
* Idiopathic (unknown cause)
Children:
Small face, impaired hair and nail growth, delayed tooth development, delayed puberty and low blood sugar
Adults:
* Malaise, excessive tiredness, anxiety and depression
* Osteoporosis and impaired hair growth
* Poor muscular tone, decrease in lean body mass
* Hypoglycaemia
* Increase in adipose tissue (especially around the waist)
GH, disorders (Deficiency/Insufficiency)
Treatment? (2)
- Hormone Replacement
Biological and Biosimilar medicine should be prescribed and dispensed.) - Somatropin (Recombinant Human Growth Hormone)
Used to treat growth failure in children and adults*
Used in Turner syndrome and Prader-Willi syndrome
Used in short bowel syndrome and to prevent weight loss in AIDSis
*Prescribed to adults only if the following criteria are fulfilled (NICE TA64)
* Severe GH deficiency, defined as a peak GH response of less than 9 mU/litre (3 ng/ml) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test.
* Perceived impairment of quality of life (QoL), as demonstrated by a reported score of at least 11 in the disease-specific ‘Quality of life assessment of growth hormone deficiency in adults’ (QoL-AGHDA) questionnaire.
* Under treatment for other pituitary hormone deficiencies as required
GH, disorders (excess/hyper)
What are 2 examples?
Symptoms? (8)
- Gigantism in children
- Acromegaly in adults
Symptoms:
* coarsening of facial features
* enlarged hands and feet (arthritis)
* headaches, vision disturbance
* sleep apnoea, general tiredness
* hypertension, cardiomegaly
* glucose intolerance (diabetes)
* irregular or loss of periods (females); impotence (males)
* bowel polyps
GH, disorders (excess/Hyper)
Treatment:
Goals? (2)
Non-pharmacological? (2)
Drugs? (3)
- Reduce GH levels/block GH action
- Treat the symptoms and conditions (hypertension, diabetes, arthritis…)
- Surgery: Effective and can completely cure acromegaly. But, removing large adenomas is a bit of a challenge.
- Radiation: Stereotactic or conventional radiation methods
(require extreme care and hormonal replacement to maintain other pituitary
hormones)
Drugs:
1. Somatostatin analogues
Octreotide, Lanreotide, Pasireotide
2. Dopamine (D2) receptor agonist
Bromocriptine, Cabergoline
3. GH receptor antagonists
Pegvisomant
GH, disorders (Excess/Hyper)
Pharmacological treatment:
What are the 3 types?
How often are these treatments given?
Drugs
* Somatostatin analogues: A monthly injection of either octreotide, lanreotide or pasireotide –slows down the release of GH and can sometimes also shrink tumours
* GH receptor antagonist: a daily pegvisomant injection –blocks the effects of growth hormone and can significantly improve symptoms
* Dopamine (D2) receptor agonist: bromocriptine or cabergoline tablets –can stop growth hormone being produced, but they only work in a small proportion of people
What are the Hormones of the Adrenal Gland? (4)
3- steroidal
1- catecholamine
Where does the adrenal gland sit?
Steroidal:
* Aldosterone- Mineralocorticoids (Mineral Balance)
* Cortisol- Glucocorticoids (Glucose Metabolism)
* Dehydroepiandosterone- Androgens (Masculinisation)
Catecholamines (Sympathetic activation):
* Adrenaline/Noradrenaline
Adrenal gland sits on top of kidneys
Corticosteroids biosynthesis:
Zone-specific steroidogenesis
What are the 3 zones?
Differential expression of biosynthetic enzymes in the different zones of the adrenal cortex (no need to memorise the various enzymes and steps)
3 zones:
Zona glomerulosa, Zona fasciculata, zona reticularis
Cortisol and Corticosteroids:
What type of hormone?
When is it secreted? regulated by..
What are their functions? (6)
What does cortisol at high physiological levels cause? (3)
- Cortisol and its derivatives are steroid hormones that regulate glucose metabolism.
- Secretion – Regulated by the level of ACTH/CRH (HPA axis)
- Inc gluconeogenesis
- Inc Protein breakdown
- Dec Glucose uptake
- Dec Protein synthesis
- Inc Lipolysis
- Dec glucose uptake, lipogenesis
-Anti-inflammatory/immunosuppressive effects
-Permissive, integrated role for other endocrine hormones (growth, stress, blood glucose)
-Stress response: Conversion of protein to
glucose, with a negative nitrogen balance
What is the Anti-inflammatory effect of Corticosteroids OR glucocorticoids? (MOA)
- The anti-inflammatory effect of CS occurs from the synthesis of lipocortin, which inhibits phospholipase A2, ultimately decreasing the production of prostaglandins and leukotrienes.
- CS represses inducible COX-2, which also inhibits the production of prostaglandins & leukotrienes
(*phospholipids cant be converted into arachidonic acid)
What is the Anti-inflammatory effect of corticosteroids/glucocorticoids? (genomic pathway) at the DNA level:
CS also act directly at the DNA level to increase the expression of anti-inflammatory genes and indirectly inhibit inflammatory transcription factors, such as NFkB, to decrease the expression of
pro-inflammatory genes.
-Upregulates anti-inflammatory genes/proteins
-Lipocortin 1/annexin 1 & others
-Downregulates inflammatory
genes/cytokine proteins
-Interleukins, NFkB, TNF-a &
others
Summary:
Corticosteroids suppress inflammation primarily through genomic mechanisms:
Directly: Enhancing transcription of anti-inflammatory genes like lipocortin 1 and IkB-alpha.
Indirectly: Inhibiting pro-inflammatory transcription factors like NF-κB and AP-1, reducing the expression of cytokines (e.g., TNF-α, IL-6), chemokines, and adhesion molecules
Immunosuppressive effect of
Corticosteroids/Glucocorticoids?
CS inhibits the humoral factors involved
in the inflammatory response and
suppresses all immune cells’ maturation,
differentiation, and proliferation
Corticosteroid analogues and clinical uses
Cortisol (hydrocortisone, Prednisolone, Dexamethasone, Bethamethasone, Aldosterone, Fludrocortisone)…
Anti-inflammatory
* Asthma, COPD
* Ulcerative colitis, Crohn’s disease (IBD)
* Rheumatoid arthritis
* Skin conditions, e.g. eczema, psoriasis
* Others, inc. rhinitis, conjunctivitis, local injections ( joints/ soft
tissue)….
Immunosuppression
* Organ transplantation
Replacement therapy
* Addison’s disease (Adrenal insufficiency)
Others
* Pre-term labour (enhance foetal lung maturation)
What is Cushing’s syndrome? (excess glucocorticoids)
Excess Cortisol
(also excess aldosterone & excess adrenal androgens)
Cushing’s disease:
- ACTH-secreting pituitary tumour
Cushing’s syndrome (signs and symptoms):
- Altered fat deposition
*Truncal obesity
* “Buffalo hump”
* round face - Excess production of adrenal androgens
(in ACTH-dependent CS)
* Acne
* Female frontal balding
* Female hirsutism
* Menstrual irregularities3. Protein breakdown, muscle wasting
* Testicular atrophy
* Thin arms and legs
* Muscle weakness
* Thin skin
* Purple striae - Loss of collagen and immunosuppression
* Poor wound healing
* Easy bruising
* Infections (skin) - Mental changes
* Cognitive difficulties
* Emotional instability
* Depression
* Sleep disturbances - Altered glucose metabolism and utilisation
* Hyperglycaemia, insulin resistance (diabetes) - Excess aldosterone (mineralocorticosteroid activity)
* Sodium (water) retention, hypokalaemia
* hypertension - Altered bone metabolism
* arthritis
Cushing’s syndrome- Diagnosis
- Cortisol measurements (serum, urine, saliva)
Loss of diurnal rhythm of cortisol release in Cushing’s syndrome = Cortisol levels are very high constantly throughout the day
Cushing’s syndrome (excess glucocorticoids)
- Ectopic (10%)- eg: Bronchial tumour
- Secondary cause (80%)- Pituitary tumour
- Primary Cause (10%)- Adrenal carcinoma/adenoma)
