W5 Growth hormone & Corticosteroid responsive conditions (SM) Flashcards

1
Q

What is the pituitary gland?
What hormones (class) are secreted from this gland?

A
  • 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
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2
Q

Which cell types are in the anterior pituitary gland?

A

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

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3
Q

Which hormones are stored/released in the posterior pituitary gland?

A

Oxytocin
ADH/Vasopressin

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4
Q

Pituitary tumours:
benign or malignant usually?
signs?
mri scan:

A

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)

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5
Q

Hypothalamic-releasing and anterior pituitary tropic hormones

A

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

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6
Q

Somatotropin, GH
Structure?
main role?

A
  • 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
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7
Q

GH, Functions
Direct?
Indirect?

A

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

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8
Q

Influencers of GH release:

A
  • Blood glucose, free fatty acids and amino acid levels influence GH release
  • Sleep and exercise affect GH release
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9
Q

GH, disorders (Deficiency/Insufficiency)
What is the main example?
symptoms in adults?
symptoms in children

A

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)

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10
Q

GH, disorders (Deficiency/Insufficiency)
Treatment? (2)

A
  1. Hormone Replacement
    Biological and Biosimilar medicine should be prescribed and dispensed.)
  2. 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

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11
Q

GH, disorders (excess/hyper)
What are 2 examples?
Symptoms? (8)

A
  1. Gigantism in children
  2. 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

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12
Q

GH, disorders (excess/Hyper)
Treatment:
Goals? (2)
Non-pharmacological? (2)
Drugs? (3)

A
  • Reduce GH levels/block GH action
  • Treat the symptoms and conditions (hypertension, diabetes, arthritis…)
  1. Surgery: Effective and can completely cure acromegaly. But, removing large
    adenomas is a bit of a challenge.
  2. 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

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13
Q

GH, disorders (Excess/Hyper)
Pharmacological treatment:

A

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

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14
Q

Hormones of Adrenal Gland? (4)

A

Steroidal:
* Aldosterone- Mineralocorticoids (Mineral Balance)
* Cortisol- Glucocorticoids (Glucose Metabolism)
* Dehydroepiandosterone- Androgens (Masculinisation)

Catecholamines (Sympathetic activation):
* Adrenaline/Noradrenaline

Adrenal gland sits on top of kidneys

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15
Q

Corticosteroids biosynthesis:
Zone-specific steroidogenesis

A

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

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16
Q

Cortisol/Corticosteroids

A
  • 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

High Physiological levels:
* Anti-inflammatory/immunosuppressive
effects
* Permissive, integrated role for other
endocrine hormones (growth, stress, blood glucose)
Several Biological functions

Stress response: Conversion of protein to
glucose, with a negative nitrogen balance

17
Q

Anti-inflammatory effect of Corticosteroids/glucocorticoids

A
  • 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)

18
Q

Anti-inflammatory effect of
corticosteroids/glucocorticoids? (genomic pathway)

A

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

19
Q

Immunosuppressive effect of
Corticosteroids/Glucocorticoids?

A

CS inhibits the humoral factors involved
in the inflammatory response and
suppresses all immune cells’ maturation,
differentiation, and proliferation

20
Q

Corticosteroid analogues and clinical uses

A

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)

21
Q

What is Cushing’s syndrome? (excess glucocorticoids)

A

Excess Cortisol
(also excess aldosterone & excess adrenal androgens)

Cushing’s disease:
- ACTH-secreting pituitary tumour

22
Q

Cushing’s syndrome (signs and symptoms):

A
  1. Altered fat deposition
    *Truncal obesity
    * “Buffalo hump”
    * round face
  2. 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
  3. Loss of collagen and immunosuppression
    * Poor wound healing
    * Easy bruising
    * Infections (skin)
  4. Mental changes
    * Cognitive difficulties
    * Emotional instability
    * Depression
    * Sleep disturbances
  5. Altered glucose metabolism and utilisation
    * Hyperglycaemia, insulin resistance (diabetes)
  6. Excess aldosterone (mineralocorticosteroid activity)
    * Sodium (water) retention, hypokalaemia
    * hypertension
  7. Altered bone metabolism
    * arthritis
23
Q

Cushing’s syndrome- Diagnosis

A
  • 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

24
Q

Cushing’s syndrome (excess glucocorticoids)

A
  • Ectopic (10%)- eg: Bronchial tumour
  • Secondary cause (80%)- Pituitary tumour
  • Primary Cause (10%)- Adrenal carcinoma/adenoma)
25
Q

Corticosteroids (excess/hyper)
Treatment:

A

1.Surgery or radiation
2. Steroidogenesis inhibition
Specific enzyme inhibitors
=metyrapone, ketoconazole

26
Q

Corticosteroids biosynthesis inhibitors:
Metyrapone

A
  • Competitive inhibitor of CYP11B1 (11β-hydroxylase), which leads to a reduction in the conversion of 11-deoxycortisol to cortisol
  • Minimally affect aldosterone biosynthesis
  • Used to test the anterior pituitary function (negative feedback, HPA axis)
  • Contraindicated in patients with adrenal cortical insufficiency
  • Side effects include hypotension, dizziness,
    headache, sedation, skin rash, hirsutism
  • Interact with acetaminophen and phenytoin
27
Q

Corticosteroids biosynthesis inhibitors:
Ketoconazole

A
  • Potent inhibitor of CYP17A1 (17α hydroxylase),CYP11B1/B2 (11β hydroxylase).
  • Also inhibits cholesterol-side chain cleavage and adrenal C17-20 lyase enzymes.
  • Blocks the biosynthesis of cortisol, aldosterone and adrenal androgens
  • Side effect includes hepatitis, gastrointestinal discomfort, skin rashes, adrenal insufficiency
  • Contraindicated with concomitant use of other hepatotoxic drugs and in acquired QTc
    prolongation.
28
Q

Adrenal insufficiency – Addison’s disease
Symptoms?

A

(Autoimmune disease or by HIV or TB) –not producing sufficient cortisol, aldosterone and androgens

Hair Loss
Blurred vision
Abdominal pain
Decreased appetite
Darkening of the skin
Weight Loss
Hypoglycaemia
Postural Hypotension

  • ACTH production increased, as did MSH
    (share the same precursor as ACTH)
    → Increase melanin content in skin
29
Q

Aldosterone (mineralocorticoid)
(Recollect CVS/BP regulation RAAS)

A
  • Aldosterone secretion from adrenal glands is stimulated by increased plasma [K+] and RAAS system; largely independent of the HPA axis (ACTH)
  • Aldosterone acts on distal convoluted
    tubule (DCT) to increase sodium and water reabsorption, and potassium excretion

Deficiency in the enzyme required for the synthesis of aldosterone: Hypoaldosteronism
-Hyperkalaemia, Hyponatremia, Hypovolemia, Hypotension and others

Excess aldosterone level:
Primary hyperaldosteronism (Conn’s syndrome)
An abnormally large amount of aldosterone produced- common cause = tumour
* Results in the initial retention of Na+, hence increased water retention →
increased K+ elimination, hypokalaemia, weakness.
* High blood volume-Increase venous return- cardiac output- increase blood
pressure (HYPERTENSION)
* Hypokalaemia → renal damage → polyuria

Treatment (Surgery, aldosterone receptor antagonist)
e.g. spironolactone and eplerenone to prevent insertion of pumps
(Na+/K+ ATPase) and channels (ENaC) in late DCT and CD.

Kidney, DCT
Increased
-Sodium reabsorption
-Water reabsorption
-Potassium excretion inurine

30
Q

Androgens

A

Dehydroepiandrosterone (DHEA) and its derivatives are steroid hormone that
regulates the development and maintenance of MALE characteristics (masculinisation)

Secretion – Regulated by the level of ACTH (but no feedback axis to ACTH/CRH)

Deficiency in the enzyme required for synthesis of DHEA: Hypoandrogenism
Loss of energy, erectile dysfunction, libido, loss of muscle and bone mass and others

Excess DHEA level: Predominately in women
Excess hair (pubic and auxiliary hair growth),
masculinisation