Endocrine Flashcards
calcium homeostasis process
- detection of low plasma calcium by parathyroid gland cell
- release of PTH from cell by exocytosis
also postively regulated by Vit D
negatively regulated by calcitonin
PTH effects on calcium and phosphate
- increased bone resorption: immediate action on Ob expressing RANKL activating Oc -> bone resorption relating Ca into ECF
- Active reabsorption of calcium and magnesium from the distal convoluted tubule. Decreases reabsorption of phosphate.
- Increases intestinal calcium absorption by increasing activated vitamin D. Activated vitamin D increases calcium absorption
Vitamin D effects on calcium and phosphate
Increases renal tubular reabsorption and gut absorption of calcium
Increases osteoclastic activity
Increases renal phosphate reabsorption in the proximal tubule
Calcitonin effects on calcium
Inhibits osteoclast activity
Inhibits renal tubular absorption of calcium
Triiodothyronine T3
Major hormone active in target cells
Thyroxine T4
Most prevalent form in plasma, pro hormone
removal of iodine group by deiodinase enzymes to produce active T3
Process of thyroid hormone synthesis
- TSH activates cAMP
- Trapping of iodide ions converted into iodine
- iodine added onto tyrosine residues on thyroglobulin by thyroid peroxidase to make diff types of thyroid hormone
- Colloid containing thyroglobulin resorbed into follicular cell
- T3 and T4 secreted
In blood, T4 is bound to
thyroxine-binding globulin (TBG) and transthyretin (TTA), with a small amount bound to albumin
negative feedback loop of thyroid hormone
hypothalamus releases TRH
TRH acts on pituitary releasing TSH
TSH acts on thyroid releasing T3 and T4
T3 and T4 inhibit TSH release at pituitary and TRH release at hypothalamus
thyroid hormone functions
growth development, basal metabolic rate, mental process, thermogenesis in brown adipose tissue
Causes of primary hyperthyroidism
Graves, toxic multi nodular goitre, thyroiditis, toxic nodule
toxic multi nodular goitre
- multiple nodules on goitre
- overactive nodules
can get lid lag or lid retraction but no other thyroid eye disease features
thyroiditis
temporary overactivity of thyroid- thyroid damage & release all hormone already formed
- followed by period of inactivity- hypothyroidism
- trigger: preggo, infection, drugs eg. amiodarone
Endocrine hyper(hypo)tension:
caused by excess (lack):
- aldosterone from ZG
- cortisol or precursors from ZF
- catecholamines from medulla
physiological factors that control BP
vascular tone, ECF volume, cardiac output
symptoms of hyperthyroidism
– Weight loss despite good appetite (often very hungry) – Tiredness – Tremor – Hot, sweaty – Palpitations – Diarrhoea: watery – Light/absent menses – Mood: irritable, anxiety – Muscle weakness
examination findings in hyperthyroidism
– Agitated, talk fast
– Warm, sweaty
– Tremor
– Heart Rate (HR), may be in Atrial Fibrillation (AF)
– Smooth goitre (Graves) vs MNG vs single nodule vs no goitre (thyroiditis)
– Bruit (murmur over stethoscope) heard over goitre almost diagnostic of Graves
Graves eye signs
– Redness – Gritty sensation – Dry or watery eyes – Pain on eye movement – Swelling around the eyes – Proptosis (pushed forward appearance of eyes) – Double vision – Loss of colour vision
all eye signs except _ suggest Graves
lid retraction and lid lag- thyrotoxicosis
thyroid function tests indications in hyperthyroidism
TRAbs (TSH Receptor Antibodies) significantly positive indicates Graves
– TPO (thyroid peroxidase) antibodies less specific- more in hypothyroidism
– If TRAbs are negative, do scintigraphy (often technetium rather than radio-iodine uptake
antithyroid drugs
– Carbimazole and propylthiouracil (PTU)
– Decrease production of thyroid hormone (block TPO)
– Not for thyroiditis (high T4 levels are due to release of hormone stores from damaged gland, but gland is not actually overactive)
– Rare side effect of agranulocytosis (<1/500)
propanalol in hyperthyroidism treatment
good for tremor and raised HR (symptomatic)
radioactive iodine in hyperthyroidism
– Risk of long term hypothyroidism
– Avoid pregnancy for 6 months.
– Restrict contact with children under 12 and pregnant women
– Don’t share bed with partner for 4 days
surgery in hyperthyroidism
– Risk of long term hypothyroidism or damage to recurrent laryngeal nerve and parathyroid glands (control calcium)
Graves eye disease mechanism
B cells produce TSH receptor antibodies
TSH receptor antibodies bind to TSH receptors in retro-orbital connective tissue
T cells produced inflammatory cytokine which causes swelling in muscles and tissue behind the eye= increased pressure
the distinction between active and inactive thyroid eye disease
only active disease responds to steroids
assessed with Clinical Activity Score- pain, redness, change in function, swelling
management of Graves eye disease
- achieve euthyroidism- can have active eye disease without thyroid being overactive
- smoking cessation
- topical lubricants
- selenium (antioxidant)
- steroids and other immunosuppression
further steps once active eye disease settles:
- elective decompression- resolve residual proptosis
- squint surgery if EOM restriction
- eyelid surgery if residual swelling or retraction
surgical decompression of the eye is done if
evidence of optic neuropathy and raised intraocular pressure
management for Graves
1st: ATDs
I131 or surgery for relapse
I131 and smoking can increase risk of
Graves eye disease
the initial and usually definitive imaging modality for thyroid nodule assessment
ultrasound
99mTc Pertechnetate scan nodules
Increased uptake/functionality – “hot” nodule
No uptake/non-functioning – “cold” nodule (more likely to be metastatic)
I-123: imaging of active thyroid tissue
harmless to thyroid
determine activity of the thyroid
ectopic thyroid tissue
When is CT/MRI used in the imaging of the thyroid?
Staging of suspected metastatic thyroid cancer
Assessment of metastatic thyroid cancer following treatment or on surveillance
Assessment of patients with suspected recurrence where ultrasound is negative
histological assessment of thyroid lesions is provided by
fine-needle aspiration or core biopsy
histology vs cytology
histology= solid tissue from biopsy stained, tissue architecture and cytological features cytology= aspiration using needle and smeared onto slide
multi nodular goitre histology
dilated follicles, cholesterol clefts and foamy macrophages
produced by multiple episodes of thyroid trying to produce more product- involuting
Graves disease histology
cells have more columnar appearance, papillary architecture with scalloping
Hashimotos thyroiditis histology
Lymphoid predominant inflammation, follicular cell oncocytic change and variable degrees of gland destruction
Follicular adenoma histology
Completely encapsulated (with fibrotic tissue) lesion
Made up of thyroid follicles- collapsed colloid
Clonal population but benign
when does a follicular adenoma become a follicular carcinoma?
If capsular or vascular invasion then becomes follicular carcinoma
what 3 features are papillary carcinomas diagnosed on?
- intraneuclear inclusions
- clear nuclei & nuclear irregularity
- nuclear grooves
psammoma bodies
laminated calcified bodies characteristic in papillary carcinoma
Cell to colloid ratio is a good indicator of
malignancy, colloid is reassuring
key cytological features in multinodular goitre
lots of colloid, variably sized folloicles
key cytological features in papillary carcinoma
Papillary structures, nuclear grooves & inclusions
key cytological features in medullary carcinoma
dispersed small cells
Signs of hypercalcaemia
Painful Bones
Renal Stones
Thrones- Constipation, Indigestion
Abdominal Groans - GI symptoms: Nausea, Vomiting,
Psychiatric Moans – Effects on nervous system: lethargy, fatigue, memory loss, psychosis, depression
extracellular calcium measured in either
serum- anti-coagulated or plasma- unclotted
calcium concentration is made up of 2 components, 1 of which is actively regulated:
- ionised- physiologically active, actively regulated
- calcium bound to albumin
Measuring both albumin and total calcium is required to
assess extracellular ionised Ca2+ status
ALP function
promotes mineralisation by increasing the local concentration of inorganic phosphate ions
& by hydrolysing pyrophosphate, a key inhibitor of mineralisation
pagets disease is due to
overactive osteoclasts
Rising Ca2+ ->
feeds back to the parathyroid glands and suppresses PTH secretion (negative feedback loop)
what is calcitonin secreted by?
parafollicular or C-cells of the thyroid gland
Vitamin D synthesis
LIVER: cholecalciferol (VitD3) converted by 25-hydroxylase into 25 hydroxy-Vitamin D
KIDNEY: 25 hydroxy-Vitamin D converted by 1a- hydroxylase into 1,25 OH Vitamin D (calcetriol)- ACTIVE
Renal 1α-hydroxylase is regulated by
PTH, calcium can affect the activity
mechanism of Vit D action in the intestine
a calcium-binding protein (calbindin- D9k) is synthesised which promotes absorption of both calcium and phosphate
Calcitriol limitation of action
Calcitriol stimulates 24-hydroxlase (promotes its own inactivation)
– Calcitriol can switch off PTH gene transcription via VDR in parathyroid cells, limiting PTH action
Factitious hypercalcaemia
Raised [calcium] due to high plasma [albumin] e.g.
o Venous stasis o Dehydration o IV albumin
Primary hyperparathyroidism
presents more mildly than hypercalcemia seen in
malignancy
primary hyperparathyroidism definition and biochemical features
Primary - one parathyroid gland (or more) produces excess PTH. This may be asymptomatic or can lead to hypercalcaemia.
high calcium, low phosphate, mild raised ALP, PTH can be normal or high
secondary hyperparathyroidism definition and biochemical features
Secondary - there is increased secretion of PTH in response to low calcium because of kidney, liver, or bowel disease.
low calcium, high phosphate, low Vitamin D, high PTH
tertiary hyperparathyroidism definition and biochemical features
Tertiary - there is autonomous secretion of PTH, usually because of chronic kidney disease (CKD).
normal- high calcium, high PTH, low Vitamin D
muscle contractions in hypercalcemia
slow muscle contractions caused by less excitable neurons secondary to hypercalcemia
- seen in primary and tertiary hyperparathyroidism
Parathyroid imaging scan
Sestamibi- radionucleotide scan
treatment of primary hyperparathyroidism
rehydration, drugs to lower calcium levels
removal of parathyroid adenoma
drugs to treat hypercalcemia
o Bisphosphonates (inhibit osteoclast action and bone resorption); after re-hydration this is key drug for longer- term control o Furosemide (inhibits distal Ca2+ reabsorption; requires care and patient must be hydrated first) o Calcitonin (inhibits osteoclast action); tolerance may develop but useful for immediate, short-term management o Glucocorticoids (inhibit vitamin D conversion to calcitriol; can prolong calcitonin action)
calcimimetics
bind to Ca2+ sensor and inhibit PTH release. Restricted use (e.g. parathyroid carcinomas, advanced CKD)
PTHrP
secreted by solid tumours
PTHrP shares similar actions but is distinct (PTH itself is suppressed)
• Where PTHrP is the cause= humoral hypercalcaemia of malignancy
how can some tumours can synthesise calcitriol?
haematological malignancies (esp. Hodgkin’s lymphoma) possess 1-OHase activity and synthesise calcitriol
multiple myeloma
abundance of plasma cells- protein electrophoresis helps to identify Ig type with helps management
pepper pot skull & fractures
biochemical findings in malignant hypercalcemia
high calcium and phophate
suppressed PTH
ALP very high
GGT normal unless liver metastases
FHH
Familial hypocalciuric hypercalcaemia- low calcium in urine but high in blood
Ca2+ sensor on parathyroid glands less sensitive to Ca2+ suppression of PTH
• Altered ‘set-point’
biochemical findings in FHH
PTH high normal or slightly raised
plasma ionised calcium mild increase and low urine calcium excretion
sarcoidosis
small patches of red and swollen tissue- granulomatous disease
• ↑[calcium] with n[PTH]
• Hydroxylation of vit D in granulomas
Chvostek’s sign
tapping over parotid causes facial muscles to twitch- hyperexcitability, hypocalcemia
Trousseau’s sign
carpal spasm if the brachial artery occluded by inflating the blood pressure cuff and maintaining pressure above systolic
wrist flexion and fingers are drawn together- hypocalcemia
factitious hypocalcemia
Consequence of low plasma [albumin] e.g.:
• Acute phase response (low albumin)
• Malnutrition or malabsorption (protein deficiency in diet)
• Liver disease (reduced liver synthesis albumin)
• Nephrotic syndrome (albumin lost in urine)
clinical features of vitamin D deficiency
Osteomalacia (defective mineralisation), symptoms related to hypocalcemia
biochemical features of vitamin D deficiency
Low 25-D3 and 1,25-D3 (usually) • Low Ca2+ (may be normal in early stages) • High PTH (2y hyperparathyroidism) • Phosphate tends to be low • Often raised ALP
Causes of hypoparathyroidism
- iatrogenic- accidental parathyroidectomy
- radiation therapy
- autoimmune
- congenital: DiGeorge syndrome
biochemical features of hypoparathyroidism
Low Ca2+
• Inappropriately low PTH
• Phosphate may be increased
treatment of hypocalcemia
IV calcium in acute situations
oral calcium or Vit D
Vit D IM if malabsorption or rapid replenishment
active form if renal function impairment
DEXA scan
assess bone mineral density, good for osteoporosis
osteoporosis histology and biochemistry
normal for both
loss of thirst (adipsia) can occur with
hypothalamic damage, this is difficult to treat- fixed fluid intake
causes of polydipsia and polyuria
hypothalamus- primary, inhibitory/stimulatory lesions can affect this
pituitary-cranial DI, lack fo ADH
kidney- resistance to ADH (nephrogenic DI)
V1A receptors
vasopressin receptor that maintains blood volume and circulation- blood vessels
V2 receptors
appropriate retention of water, maintain osmolality- kidney
AVP receptor affinity
V2» V1> OT
vaptans act on which receptor
V2 selective
site of action of AVP
late distal tubule and collecting duct
AVP mechanism
increase water permeability by increasing apical AQP2 (move vesicles with AQP2 to cell surface)
basolateral AQP3/4 on collecting duct cell
less sensitive than AQP2 to ADH
causes of polyuria
DI (cranial or nephrogenic), psychogenic polydipsia, osmotic diuresis (hyperglycemia -DM), renal impairment (unusual)
Osmotic diuresis
substances that are not easily reabsorbed by the renal tubules are retained in the lumen, resulting an increase in osmotic pressure- increase in urination rate
water deprivation test
evaluate patients who have polydipsia Method: prevent patient drinking water ask the patient to empty their bladder hourly urine and plasma osmolalities
results of water deprivation test in psychogenic polydipsia
low starting plasma osmolality showing that the patient can concentrate their urine
results of water deprivation test in cranial DI
high starting and end plasma osmolality, low post-DDVAP plasma osmolality
results of water deprivation test in nephrogenic DI
high starting and end plasma osmolality, high post-DDVAP plasma osmolality
causes of cranial DI
idiopathic post head injury pituitary surgery craniopharyngiomas histiocytosis X
gestational DI
vasopressinase degrades AVP but not DDVAP, resolve 1w post party
causes of nephrogenic DI
- genetic: the more common form affects the vasopression (ADH) receptor, the less common form results from a mutation in the gene that encodes the aquaporin 2 channel
- electrolytes: hypercalcaemia, hypokalaemia
- lithium desensitizes the kidney’s ability to respond to ADH in the collecting ducts
- demeclocycline
treatment of cranial DI
central diabetes insipidus can be treated with desmopressin (DDVAP)
treatment of nephrogenic DI
thiazides (low ECF volume, increase water resorption at PCT but less at DCT), low salt/protein diet
first line investigations in hyponatremia
- dehydration- identify if urine is site of excess salt loss
- oedema
SIADH
hyponatraemia secondary to the dilutional effects of excessive water retention
causes of SIADH
- intracranial lesions/disease- affect intracranial pathway near hypothalamus
- intrathoracic disease esp infections- affect baroreceptor pathway: pain
- neoplasm esp lung/mediastinal
drug causes of SIADH
sulfonylureas SSRIs, tricyclics carbamazepine vincristine cyclophosphamide
Management of SIADH
- correction must be done slowly to avoid precipitating central pontine myelinolysis
- fluid restriction (1000ml/d to <800 if needed)
- demeclocycline
- ADH (vasopressin) receptor antagonists have been developed
how does aldosterone deficiency (Addisons) cause hyponatremia?
- Aldo reduced but ADH normal
- non osmotic ADH stimuli: reduced vol, nausea, pain
- reduced GC effects- impair water loss
metabolic products that stimulate GH secretion
amino acids eg. arginine- inhibit somatostatin release
demeclocycline
reduces the responsiveness of the collecting tubule cells to ADH
GHRH- where is it synthesised and released from?
the arcuate nucleus, and released from neurosecretory terminals at the median eminence
GHRH function
stimulate GH synthesis and release form stored pools
somatostatin synthesised in
periventricular nucleus
somatostatin function
inhibits secretion of GH from somatotrophs and inhibits the secretion of GHRH
GH negative regulation
- glucocorticoids- initial stimulatory effect but later suppressed
- IGF-1 and somatostatin
GH postitive regulation
- thyroid hormone
- catecholamines
- ghrelin
- oestrogen- decreased IGF-1 production
hypothyroidism in childhood effect on growth
poor growth, blunting of GH
responses to stimuli & reduced pituitary GH levels
growth hormone secretion type
Growth hormone secretion is pulsatile and has circadian rhythm
peak in slow wave sleep
which gender has higher growth hormone secretion?
female
GH levels in obesity
GH levels are lower in obesity and are restored by massive weight loss
exercise and GH
exercise- stimulant for GH secretion, occurs around 10-15 mins after start
may be mediated by Ach, adrenaline and endogenous opioids
GH signalling process
- One GH molecule binds to 2 GHR molecules leading to dimerisation of receptors
- Activation of receptor-associated Janus kinase, followed by STAT phosphorylation
- Translocates to nucleus and acts as a transcription factor
- Insulin-like growth factor-1 (IGF-1) gene activation
direct effects of GH
- inhibits glycogen synthesis in muscle
- anabolic- acts to increase blood pressure
- increasing lipolysis and gluconeogenesis
indirect effects of GH
Most growth promoting effects of GH due to IGF-1- autocrine/paracrine effect probably most responsible fro linear growth
where is IGF-1 secreted from?
liver and other tissue
what is puberty growth driven by?
in puberty growth is driven by GH and sex steroid, high amount of growth hormone is important in growth spurts.
what is childhood growth driven by?
GH and thyroxine
causes of short stature and poor growth in childhood
nutrition Chronic disease Genetic conditions (Turner syndrome, Trisomy 21, Noonan syndrome, skeletal dysplasias) Steroids Hypothyroidism Psychosocial deprivation
Central causes of short stature and poor growth in childhood
Pituitary abnormalities
- GH deficiency
- TSH deficiency: hypothyroidism
- Gonadotrophin deficiency: poor pubertal growth
These can be caused by tumours, irradiation, trauma, or genetic reasons
adult GH deficiency symptoms
decreased energy, social isolation, depressed mood
adult GH deficiency clinical features
increased body fat, decreased muscle mass, decreased bone density, increased risk of fracture
Impaired cardiac function
Decreased insulin sensitivity and impaired glucose tolerance
what other abnormalities does adult GH deficiency present with?
pituitary hormone abnormalities due to new adult pituitary tumours (macroadenomas, craniopharyngiomas)
GH excess present before epiphyses have fused
gigantism
GH excess present after growing ends of long bones have fused:
acromegaly
acromegaly symptoms
facial change, soft tissue swelling, acral enlargement, excessive sweating, carpal tunnel syndrome, tiredness and lethargy, headaches, oligo- or amenorrhea, infertility
why are people with acromegaly susceptible to malignancy?
increased GH -> increased IGF-1 -> encourage growth of malignancies
first line treatment of acromegaly
transpheniodal surgery to remove tumour (may use medical therapy to shrink tumour first)
drugs in treatment of acromegaly
Somatostatin analogues (octreotide, lantreotide) Long-acting GH receptor antagonist – pegvisomant. A modified recombinant GH molecule which prevents GH receptor dimerisation Dopamine agonists (if concurrent high prolactin – works in <10%)
tests of GH deficiency
gold standary: insulin tolerance test- hypoglycaemia stimulus for GH production
- arginine, clonidine
- glucagon
- overnight GH sampling
GH impact on insulin
Growth hormone has anti-insulin activity, because it suppresses the abilities of insulin to stimulate uptake of glucose in peripheral tissues and enhance glucose synthesis in the liver.
tests of GH excess
glucose tolerance test
what does the ITT show in GH deficiency?
lower GH peak and overall response
what does the GTT show in GH excess?
GH levels should drop but it stays the same
signs of puberty in examination of girls
breast staging, pubic hair, ancillary hair, acne, body habitus
signs of puberty in examination of boys
testicular volumes, genital stage, pubic hair, axillary hair, acne, facial hair, body habitus
breast buds
signs of estrogen production
pubertal testicular volume
prepubertal= <4ml
takes 2 years to go from 4 -> 10ml
male puberty start range and duration
Normal range start = 9-14 yrs
takes 5 years
female puberty start range and duration
Normal range start = 8 - 13 yrs
takes 2.5 years
compare pubertal height gain of male and female
male= 25 cm
female growth after menses= ~6cm
what is adrenarche?
Onset of production of adrenal androgens – 2 years or more – prior to onset of puberty.
Due to maturation of adrenal cortex – zona reticularis
clinical features of adrenarche
Axillary and/or pubic hair, greasy hair & skin, acne, body odour
pathological diagnoses associated with adrenarche
androgen secreting tumour or late onset CAH
slow growth and thin?
Slow growth and fat?
Rapid growth in childhood?
- Chronic disease e.g Coelaic disease, IBD
- Endocrine problem e.g. hypothyroidism
- Sex steroid exposure e.g. precocious puberty
central precocious puberty
Central activation of pubertal axis
Gonadal enlargement
Normal sequence of events
precocious pseudopuberty
Peripheral activation of sex steroids Not centrally activated Incomplete pubertal sequence No gonadal enlargement eg. CAH, ovarian tumour
obesity impact on growth rate
increased linear growth rate but don’t end up as taller adult, just get there sooner
congenital and acquired hypopituitarism causes
Congenital – single or multiple pituitary deficiencies or SOD
Acquired - craniopharyngioma
GHRH acts on
GnRH acts on
somatotrophs
gonadotrophs
CRH acts on
TRH acts on
corticotrophs
thyrotrophs
DA inhibits
somatostatin inhibits
lactotrophs
somatotrophs, thyrotrophs
posterior pituitary hormones
oxytoxcin and vasopressin stored and released
2 classes of steroid hormones
- corticosteroids, glucocorticoids, adrenal androgens
- sex steroids, androgens, oestrogen, progesterone
classical genomic mechanism of steroid hormones
‘Classical’ receptors in the cytoplasm activated by steroid binding - translocate to nucleus
Gene transcription & protein synthesis
Slow action
non-genomic mechanism of steroid hormones
Non-classical’ receptors, activated by steroid binding, e.g. ion channels in the plasma membrane
• Intra-cellular signalling pathways, e.g. calcium/inositol
• Rapid signalling
why are steroid hormones more water soluble than cholesterol?
the first step of steroid hormone synthesis in removal of the hydrophobic 6 carbon side chain
cytochrome P450 role in steroid synthesis
cholesterol side chain cleavage/ modification to convert it into pregnenolone
steroid dehyrogenases/reductase role in steroid synthesis
interconversion of active and inactive forms of steroid
cortisol activation and inactivation
in liver and peripheral tissues
11b-HSD2 converts between cortisol and cortisone
cortisol transport
bound cortisol and inactive cortisol travel to target tissues and are reactivated in target tissue
the adrenal gland is located around the __ vertebra
12th thoracic
adrenal cortex blood supply
arteries supply a subcapsular plexus of arterioles
• capillary sinusoids extend through the cortex separating chords of cells
adrenal medulla blood supply
receives long cortical arteries & capillaries from cortex
medulla and cortex drain via
the central medullary vein
adrenocortical hormones synthesised by different parts of adrenal cortex
zona glomerulosa= Aldo
zona fasciculata= cortisol
zona reticularis= androgens
what increases secretion of Aldo?
angiotensin II
plasma potassium
ACTH
Aldo functions
Stimulates the reabsorption of sodium from the distal tubules, with a consequant excretion of potassium
what increases secretion of cortisol?
ACTH from the pitutary gland, itself stimulated by CRH released by the hypothalamus
stress
cortisol function
- increases gluconeogenesis, lipolysis and proteolysis
- Inhibits inflammatory and immune responses
- increases insulin resistance
- permits normal response to angiotensin II and catecholamines byup-regulating alpha-1 receptors on arterioles
- inhibits bone formation
what increases secretion of adrenal androgens?
ACTH and HPA axis
adrenal androgen function
intracrine conversion to testosterone and oestradiol in peripheral tissues- external sexual characteristics
stimulatory factors for CRH
- serotonin
- acetylcholin
- encephalin
ADH potentiates CRH
inhibitory factors for CRH
alpha adrenergic agonists
GABA, endorphin
dopamine
cortisol
cortisol diurnal pattern
high on waking 6-10am
lowest at middle of night
how does CRH stimulate ACTH secretion from anterior pituitary corticotrophs?
CRH stimulates production of POMC which is then cleaved to ACTH and other peptides-> released into peripheral blood
how is cholesterol passage across the mitochondrial lipid membrane regulated?
Steroid acute regulatory (StAR) protein ‘chaperones’ cholesterol across the mitochondrial membrane- rate limiting step in production of steroid hormones
what stimulates increased StAR protein activity?
ANGII or ACTH stimulation
Which hormones levels rise as plasma glucose falls?
glucagon (from α cells of the pancreas) adrenaline noradrenaline growth hormone cortisol
dual action of cortisol to increase plasma glucose
anabolic- increase liver gluconeogenesis
catabolic- proteolysis and lipolysis in peripheral muscle and fat
difference between Cushing’s disease and syndrome
disease- pituitary tumour
syndrome- adrenal or ectopic tumours
phenotype of cortisol excess
hypertension, hypokalaemia, high plasma cortisol, low plasma Aldo & renin activity
difference in biochemical results between Cushing’s disease and syndrome
disease= high ACTH, high cortisol
syndrome (non-pituitary)= low ACTH, high cortisol
what is renin released in response to?
JG cell baroreceptors
• reduced ECF & renal perfusion pressure
Macula densa cell Na+ sensing and carotid arch baroreceptors
• activates sympathetic innervation of JG apparatus
rapid effects of RAS and aldo
increase vasconstriction, increase Aldo and catecholamine synthesis, increase Na and water reabsorption
long term effects of RAS and Also
increased smooth cell hyperplasia and hypertrophy
increased aldo synthase enzyme expression and glomerulosa cell proliferation
increased thirst, salt appetite, ADH release
Trophic Factors for RAS and Aldo
high plasma K+
low plasma Na+
Angiotensin II (RAS)
aldosterone direct damage to heart
left ventricular hypertrophy, cardiac fibrosis- not consequence of hypertenison
mineralacorticoid receptor antagonists in HF therapy
beneficial, blocks Aldo action in kidney and other tissues- prevent myocardial remodeller, Na retention and vascular dysfunction
endocrine causes class as which type of hypertension?
secondary
Conn’s syndrome
unilateral aldosterone producing adenoma
phenotype of primary aldosteronism
high Aldo- MR activation:
- hypernatremia, hypokalaemia, ECF expansion
- hypertension, low renin
treatment of Conn’s
surgical:
- venous sampling and/or CT scan then:
unilateral adrenalectomy
Bilateral adrenal hyperplasia phenotype is the most common
type of primary aldosteronism
primary aldosteronism- examples
Conn’s syndrome
Bilateral adrenal hyperplasia
glucocorticoid remediable aldosteronism
treatment of Bilateral adrenal hyperplasia
pharmacological:
- anti-hypertensives eg. MR antagonists eg. spironolactone
glucocorticoid remediable aldosteronism
autosomal dominant (chromo 8) ACTH driven hyperaldosteronism
GRA hybrid gene
Unequal meiotic exchange 11β-OHase promoter (ACTH-driven, much more active) aldo synthase coding region
phenotype of GRA
high aldosterone, MR activation,
- high Na+, low K+, ECF expansion,
- hypertension in neonate, low renin (RAS)
treatment of GRA
suppress pituitary ACTH secretion
- synthetic glucocorticoid (Dex)- feedback and inhibit ACTH
secondary hyperaldosteronism examples
renin secreting JG tumour
renal arterial sclerosis
renin secreting JG tumour
renin hyper secretion- increased RAS, severe hypertension
renal arterial stenosis
low perfusion pressure, renin secretion, ↑RAAS, hypertension
phenotype of secondary hyperaldosteronism
high plasma renin, high aldosterone MR activation, high Na+, low K+, ECF expansion, hypertension
treatment of renin secreting JG tumour
surgical removal of tumour or kidney
treatment of renal arterial stenosis
anti-hypertensive, e.g. MR blockers, statins, anti-platelet agents; balloon angioplasty +/- stent
presentation of Cushing’s syndrome/disease
– weight gain, stretch marks, easy bruising, proximal muscle weakness
– diabetes mellitus (high plasma glucose), menstrual irregularities, depression
how does elevated plasma cortisol cause hypertension?
- GC potentiate catecholamine action in heart & vasculature
- inhibit vascular NO production by eNOS
- inappropriately active kidney MR
how does 11β-HSD-2 protect MR receptors from inappropriate activation?
11β-HSD-2 protects kidney MR from inappropriate activation by cortisol by converting it to inactive cortisone
apparent MR excess
Autosomal recessive ‘loss of function’ mutation in 11β-HSD2
- ↓conversion of cortisol to cortisone
conditions of GC hyperactivity
Cushing’s Syndrome, Cushing’s Disease, ectopic ACTH, steroids, Apparent Mineralocorticoid Excess, drugs, liquorice
Phenotype of GC hyperactivity:
- high local kidney cortisol, low RAS MR activation, high Na+, low K+ ECF expansion, hypertension
How do drugs & liquorice ingestion cause GC excess?
carbenoxolone, glycyrrhizinic acid inhibitors of kidney 11β-HSD2
- ↓conversion of cortisol to cortisone
treatment of apparent MR excess
pharmacological: MR antagonists (spironolactone, eplerenone)
treatment of drugs & liquorice ingestion:
altered drug treatment
stop eating liquorice
pheochromocytoma
– chromaffin cell tumour
– secrete catecholamines
– noradrenaline and/or adrenaline
symptoms of pheochromocytoma
Palpitations, Headache, Episodic sweating
– racing heart, anxiety (~50%),
– hypertension – sustained/paroxysmal (~50%)
– diabetes mellitus (~40%)
diagnosis and treatment of pheochromocytoma
– 24 hour urinary metanephrines & catecholamines
– α-blockers, β-blockers, surgical resection
aldosterone renin ratio
both renin and aldosterone should be low in hypertension (= expected feedback)
ARR = mass concentration of aldosterone divided by plasma renin activity (recommended screening tool for primary hyperaldosteronism)
high maybe aldosterone secreting adenoma
Patients with hypertension should always be suspected of
primary hyperaldosteronism
APCCs (aldo producing cell clusters)
somatic mutations in genes that allow cells to depolarise and produce aldo at a lower potential
APAs follow
APPCs
second hit consisting of cell proliferation and nodule formation
Zone-specific expression of __ determines aldosterone production in the adrenal zona glomerulosa
aldosterone synthase
Zone-specific expression of ___ determines cortisol production in the adrenal zona fasciculata
17α-OHase & 11ß-OHase
Zone-specific expression of ___ determines DHEA production in the adrenal zona reticularis
17α-OHase & 17, 20 lyase
which cytochrome P450 complexes are important in sex steroid hormone synthesis?
- 17a -OHase/17, 20 lyase (CYP17A1) - adrenal cortex ZR & testis, ovary
- Aromatase (CYP19A1)- convert testosterone to oestradiol
- present in ovary AND peripheral oestrogen targets
steroid dehydrogenase
interconvert steroids
• 3β-HSDs: adrenal, testis, ovary
• 17β-HSDs: testis, ovary
• 5 a-reductases: testis & peripheral tissues
DHEA and androstenedione are made in
both male and female gonads
17β-HSD3- location and function
found in ovaries and testes Leydig cells
converts androstenedione to weak C19 androgen testosterone that needs to be activated further in sertoli cells
3β-HSDs
converts pregnenalone into progesterone in corpus luteum
5α-reductase
In testis Sertoli cells 5α-reductase converts testosterone to strong androgen 5α-dihydrotestosterone
aromatase in ovary and peripheral tissues
• In ovary & peripheral tissues, aromatase converts testosterone to strong oestrogen oestradiol (C18)
sex steroid feedback loop
GnRH from HP preoptic nucleus
Acts on anterior pituitary gonadotrophs: – FSH – LH FSH and LH stimulate sex steroid hormone production in gonads – androgens (male), – oestrogens (female) – ALSO inhibins (male & female)
Hormonal feedback on pituitary & hypothalamus regulates synthesis
Leydig and Sertoli cell role in hormone synthesis
Steroidogenic Leydig cells = make testosterone
Sertoli cells = ‘nursery’ cells for sperm production make inhibin & ABP (androgen binding protein)
compartmentalisation of male sex steroid production
LH stimulates testosterone (T) production by Leydig cells
• FSH promotes inhibin & androgen- binding protein (ABP) in Sertoli cells
• T moves from Leydig to Sertoli cells
• T converted to DHT & binds to ABP in luminal fluid of the seminiferous tubules
T from Leydig cells & inhibin from Sertoli cells feedback on GnRH, LH & FSH
– & – in seminiferous tubules promote sperm production & maturation
High testosterone & DHT
what is testosterone bound to in plasma?
Testosterone transported in plasma to peripheral targets bound (98%) to
sex hormone-binding globulin (SHBG)
androgens regulate
primary male repro function and secondary male sex characteristics
essential for male sex determination and genital development
androgen insensitivity syndorme
46,XY
due to mutated testosterone receptor:
Arrested testis development; lack of testosterone & anti-mullerian hormone
- mullerian duct fails to regress
partial insensitivity- androgen insensitivity syndorme
male external genitalia & body shape & mild spermatogenic defect after puberty
complete insensitivity- androgen insensitivity syndorme
Female external genitalia & body shape, female internal organs undeveloped or absent
natural mutation in the aromatase gene leads to
failure to convert testosterone to oestradiol
oestrogen deficiency affects
bone maturation:
– tall and long arms
– bone epiphyses did not close – Loss of bone mass
– osteoporosis
compartmentalisation of female sex steroid production
LH stimulates production of androstenedione & testosterone in thecal cells of the primary follicle
• Androgens move from thecal to granulosa cells
• FSH stimulates androgen conversion to estrogens by aromatase
Estradiol & inhibin from granulosa cells feed back on GnRH + LH & FSH release from HP & pituitar
– regulates the proliferative phase of the female menstrual cycle
oestradiol
what is oestradiol bound to in plasma?
SHBG
what can increased SHBG lead to?
lower free sex hormone availability
role of oestrogen
Female genital development & differentiation
• Secondary female sex characteristics
Estrogen from the primary ovarian follicle promotes endometrial growth during the follicular or ‘proliferative’ phase
role of progesterone
Made in the corpus luteum promotes endometrial secretion & vascularisation during the luteal or ‘secretory’ phase
• Prepares uterus for implantation of a fertilised egg
• Without implantation falling progesterone initiates menstruation
luteal-placental shift in pregnancy
Hormones decline: hCG from embryo & progesterone from corpus luteum
To maintain pregnancy, placenta begins to produce:
progesterone from cholesterol and oestrogen from DHEA (fetal adrenal)
causes of Addison’s disease
primary adrenal insufficiency- destruction of adrenal gland by tuberculosis, cancer metastases, autoimmune disease
why does skin pigmentation occur in Addisons?
high ACTH binds to a-MSH receptor on melanocytes (agonist)
presentation of Addisons
symptoms of all adrenocortical zones
- hyperpigmentation, hypotension, extreme fatigue,
weight loss and decreased appetite, hypoglycaemia, salt craving, abdominal pain
phenotype of Addison’s
low plasma aldo= lack of MR activation
- low Na+, high K+, reduced ECF, hypotension,
- Low plasma cortisol, low glucose, high ACTH (lack of cortisol feedback)
treatment of Addisons
Fluid & hormone replacement synthetic glucocorticoid (hydrocortisone, prednisone) synthetic mineralocorticoid (fludrocortisone)
Hypopituitarism- secondary adrenal insufficiency causes
- partial or complete loss of anterior lobe pituitary function
- tumour, pituitary apoplexy, suppression by long-term corticosteroids - lack of pituitary ACTH secretion & adrenocortical trophic stimulation
presentation of hypopituitarism
malfunction of ZF & ZR, reduced cortisol & androgen secretion
- RAS and Aldo secretion largely unaffected
- same as for Addison disease and include fatigue, weakness, weight loss, nausea, vomiting, and diarrhea, but there is usually less hypovolemia
phenotype of hypopituitarism
- low plasma ACTH & cortisol due to pituitary & adrenal failure - Increased vasopressin release from posterior pituitary
- ECV expansion low Na+, low K+ (dilutional hyponatraemia)
treatment of hypopituitarism
- hormone replacement, transsphenoidal decompression/tumour removal - synthetic glucocorticoid (hydrocortisone, prednisone), thyroxine, etc.
what is congenital adrenal hyperplasia?
Inherited condition present at birth (congenital) in which the adrenal gland is larger than usual (hyperplasia)
form of primary adrenal insufficiency
Usually caused by an inherited defect in gene for any steroidogenic enzyme
Inactivating mutations partial or complete
inheritance of CAH
Autosomal recessive (both parents carriers) Heterozygote ‘carriers’ usually asymptomatic (may affect immune system)
genotype of CAH affected individuals
Affected individuals usually compound heterozygotes:
both alleles altered, but different mutations inherited from mother & father
Genuine homozygotes seen from consanguineous marriage
most common type of CAH
steroid 21-hydroxylase (90-95%)
21-OHase pseudogene
actually 2 genes but 1 has been inactivated and non functional- in meiosis mutations can be swapped into the functional one
less common types of CAH
11b hydoxylase
17a hydroxylase
3b-HSD
StAR
StAR lipoid CAH
fat imported into the cytoplasm of adrenocortical cell but can’t be imported across mitochondrial membrane where steroid are made
accumulating fat= lipotoxic
presentation in all CAH syndromes
block in cortisol synthetic pathway: reduced cortisol, plasma glucose and feedback on CRH-ACTH
elevated ACTH: adrenal stimulation and hyperplasia
intermediate accumulation and reduced hormone
which intermediates would accumulate after the block in 21-hydroxylase pathway?
reduced cortisol and Aldo with increased ACTH
increased progesterone and 17 a-OH progesterone, increased DHEA and androstenedione
diagnosis of CAH
Usually soon after birth
Less severe CAH not apparent until puberty
Prenatal diagnosis possible now affected genes identified
effects of partial inactivation of 21-hydroxyl CAH
↓ Cortisol, ↓ feedback, ↑ACTH
Symptoms reflect mainly a lack of cortisol (enough aldo still made)
• Increased androgens
– virilisation in boys; masculinisation in girls
why are there fertility problems in complete 21-hydroxylase CAH?
increased DHEA and androstenedione lead to increased feedback on pituitary-> reduced LH and FSH
most common cause of ambiguous genitalia is
due to prenatal masculinaisation of genetical female infants
treatment of partial block 21-OH CAH
– replace cortisol function – feed-back inhibit ACTH ‘drive’ – reduce ACTH-driven androgens Monitoring: – glucocorticoid replacement – monitor 17-OH progesterone and androgens
treatment of complete block 21-OH CAH
– replace cortisol & mineralocorticoid – reduce ACTH-driven androgens – normalise plasma Na+, ECF & bp Monitoring: – glucocorticoid & mineralocorticoid – monitor 17-OH progesterone and androgens
untreated 21-OH CAH left untreated in females
ambiguous genitalia
single urethral/vaginal orifice (no separation)
fused labia & enlarged clitoris
late onset 21-OH CAH
mild inactivating mutation – less severe than in affected neonates
– usually presents after puberty in women
– following upsurge in ACTH & adrenal steroid secretion (adrenarche)
excess adrenal androgen results in
PCOS, hirsutisme, infertility
treatment of late onset 21-OH CAH
hydrocortisone replacement: titrate GC replacement
monitor 17-OH progesterone and androgen levels
hormonal pattern in 11b-OH CAH
reduced/no cortisol (partial), increased ACTH
increased substrates: deoxycortisol and DOC in ZF and excess adrenal androgens
why can hypertension present in 11-OH CAH?
hypertension due to weak MR activity of DOC at MR receptor
clinical clue that patient has 11OH-CAH instead of 21-OH CAH
treatment of 11-OH CAH
lifelong glucocorticoid replacement
monitor 17-OH progesterone & androgen levels
• also measure plasma Na+ concentration
symptoms in Addisonian crisis
Reduced consciousness
Hypotension
Hypoglycaemia, hyponatraemia, hyperkalemia
Patients can be very unwell
Primary Addison’s is associated with – whereas secondary adrenal insufficiency is not
hyperpigmentation
Chromogranin A
widely accepted biomarker for the assessment of neuro-endocrine tumors
Synaptophysin
integral part of the neuroendocrine secretory granule membrane
recognised by monoclonal antibody in NET (pathology)
flushing and diarrhoea are signs of
hormonal excess
carcinoid syndrome
collection of symptoms some people get when a neuroendocrine tumour, usually one that has spread to the liver, releases hormones such as serotonin into the bloodstream
how is serotonin measure?
serotonin itself can’t be measured so 5HIAA must be measured in 24h urine collection
serotonin causes the symptoms:
flushing, diarrhoea, acute bronchospasm, right heart failure- serotonin sticks to 5HT receptors on heart valves
why does serotonin cause right heart disease?
serotonin is usually cleared in the enterohepatic circulation but liver disease overrides the enterohepatic circulation allowing serotonin to get into right heart
what aspects of right heart disease does serotonin cause?
valve fibrosis RHF elevated JVP peripheral oedema hepatic congestion
‘pulsatile liver’
tricuspid regurgitation as result of valve fibrosis and if really bad then can be felt in liver
Clinical characteristics of NETs
Rare • Significant majority arise in GI system (including pancreas) • Usually slow growing • Wide spectrum of disease activity • Often metastatic at presentation • Prolonged survival is possible
presentation of liver NETs
liver → present w/ pain from enlargement of capsule, abnormal LFTs
presentation of large/small bowel NETs
terminal ileum if tumour is in large/small bowel → bowel obstruction
↳ abdominal distention, vomiting
presentation of pancreatic NETs
usually picked up on CT- abdominal pain
presentation of stomach NETs
iron deficiency anemia- blood loss, indigestion
hormonal presentation of pancreatic NET
increased: insulin- hypoglycemia glucagon- diabetes and usual rash gastrin- heartburn, pectin ulcers VIP- diarrhoea (profuse, watery, hypokalemia
treatment options for NETs
active surveillance
surgery (bowel/ pancreatic/ hepatic)
somatostatin analogue therapy
radionucleotide therapy
when is radionucleotide therapy useful for NETs?
symptom control when SA no longer fully effective
can target relatively ischaemic central core of metastatic deposits
transarterial chemoemolisation
deprive mass of blood supply
only targets cancer deposits in liver
destructive therapy so potential for rapid release of hormones from dying cells
MEN type 1 mutation
defect in MEN1 gene- menin
tumour suppressor gene
MEN inheritance
autosomal dominant
Clinical features of MEN type 1
Parathyroid (95%): hyperparathyroidism due to parathyroid hyperplasia
Pituitary (70%)
Pancreas (50%): e.g. insulinoma, gastrinoma (leading to recurrent peptic ulceration)
Also: adrenal and thyroid
screening of MEN1
Annual calcium and PTH
• Annual fasting gut hormones
– Chromogrannin A, insulin-glucose, gastrin glucagon, pancreatic polypeptide
• 3 yearly MRI of pituitary and now pancreas
• Consideration for CT / MRI of chest and thymus
MEN type 2
defect in MEN2 producing ret- proto-oncogene gene
Clinical features of MEN type 2A
Medullary thyroid cancer (70%)
Parathyroid (60%)
Phaeochromocytoma
Pheochromocytoma crisis
increased adrenaline leading to heart attack and multi organ failure
Clinical features of MEN type 2B
Hyperparathyroidism Medullary thyroid cancer Phaeochromocytoma Marfanoid body habitus Neuromas, musculoskeletal abnormalities (tall, thin)
Most common presentation of MEN1
hypercalcemia
how does glucocorticoid deficiency cause hyponatremia?
reduced GC effects- impair water loss
central effect- body retains more water
renal effect- reduced renal water excretion
reduced glucose is a non-osmotic ADH stimulus
DILUTIONAL HYPONATREMIA
triple phase response after pituitary surgery
early diabetes insipidus dipping into SIADH and then return of diabetes insipidus
reasoning behind triple phase response following pituitary surgery
level of hypothalamus-pituitary damage
AVP neurones may recover posterior pituitary- temp DI
partially processed forms released from pituitary stalk- SIADH
AVP neurones die quickly in hypothalamus- permanent DI
leptin production and action
It is produced by adipose tissue and acts on satiety centres in the hypothalamus and decreases appetite.
Leptin stimulates the release of
melanocyte-stimulating hormone (MSH) and corticotrophin-releasing hormone (CRH)
Low levels of leptin stimulates the release of
neuropeptide Y (NPY)
ghrelin is produced by
the P/D1 cells lining the fundus of the stomach and epsilon cells of the pancreas
ghrelin levels
increase before meals and decrease after meals
causes of secondary obesity
Hypothyroidism
• Cushing’s syndrome - usually iatrogenic
• Hypothalamic disease
• Others
› Drugs (oestrogen, beta blockers, tricyclic antidepressants, sodium valproate)
› Insulinoma, GH deficiency Genetic Disorders: e.g. Prader Willi syndrome
thyroxine deficiency is characterised by which fat distribution?
generalised
which hormonal abnormalities can lead to apple shaped fat distribution?
androgen and cortisol excess
GH deficiency
which hormonal abnormalities can lead to pear shaped fat distribution?
oestrogen excess
leptin in obesity
leptin resistance in obesity- no signal to tell you that you’re full
what is the overnight dexamethasone suppression test?
using synthetic glucocorticoid to suppress pituitary ACTH secretion & cortisol production from adrenal cortex (negative feedback)
low dose dexamethasone suppression test
suppresses pituitary ACTH secretion and cortisol production in normal individuals, but not from a pituitary adenoma (Cushing’s Disease)
high dose dexamethasone suppression test
part-inhibits ACTH secretion from a pituitary adenoma, but not from a cortisol-producing adrenal adenoma or an ectopic ACTH-producing tumour (Cushing’s syndrome)
What is the synacthen test?
quantifies adrenal function or lack of function (insufficiency)
short synacthen test
synthetic ACTH will stimulate healthy adrenal glands to produce cortisol and the cortisol level should at least double. A failure of cortisol to rise (less than double the baseline) indicates primary adrenal insufficiency (Addison’s disease).
long synacthen test
In primary adrenal failure there is no cortisol response as the adrenals no longer function.
In adrenal atrophy (secondary adrenal insufficiency), the prolonged ACTH eventually gets the adrenals going again and cortisol rises.
triggers of Addisonian crisis
- can be the first presentation of Addisons Disease
- triggered by infection, trauma or other acute illness in someone with established Addisons.
- can present in someone on long term steroids suddenly withdrawing those steroids.
Rotterdam criteria
for PCOS
anovulation, elevated levels of androgenic hormones, and/or enlarged ovaries containing at least 12 follicles each- transvaginal USS
DIDMOAD is
the association of cranial Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness (also known as Wolfram’s syndrome)
damage to the pituitary stalk can lead to
cranial diabetes insipidus
stops the transport of oxytocin and vasopressin
what can impair t4 absorption?
PPIs eg omeprazole/lansoprazole
H2 antagonists eg ranitidine
Iron, calcium, aluminium
Don’t take T4 <4h after these
Increased T4 requirement if
start oestrogen (OCP, HRT) or anticonvulsants
