Pituitary Function and
Pathology
Dr Duncan Fowler
The Ipswich Hospital
Overview
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Anatomy
Physiology
Assessment of pituitary function: static and
dynamic tests
Clinical scenario’s:
Cushing’s Disease
Acromegaly
Prolactinoma
Apoplexy
Learning Objectives
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Describe pituitary anatomy and endocrine
physiology
Describe methods for assessing pituitary
function using static and dynamic testing
Describe the new standard for the
measurement of growth hormone & its
effects on clinical criteria
Be are of the importance of screening for
macroprolactin
Hypothalamo-pituitary anatomy
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Hypothalamus is the part of the diencephalon
associated with visceral, autonomic, endocrine
affective and emotional behaviour
Ventral portion forms the infundibulum
Posterior to this is the median eminence – the final
point of convergence of pathways from the CNS on
the endocrine system and is vascularised by the
primary capillaries of the hypothalamohypophyseal portal vessels
Sella turcica
Terminology
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Adenohypophysis = anterior pituitary
controlled by releasing and inhibiting factors
released from nerves in the median eminence
into the hypophyseal portal vessels which carry
them to the pituitary
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Neurohypophysis = posterior pituitary. It is an
extension of the CNS. Its function is controlled
by direct neural connection to the hypothalamus
Presentation of Pituitary Disease
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Hormonal hypersecretion e.g. Acromegaly
Hormonal deficiency e.g amenorrhoea
These can occur with or without:
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Local pressure effects: headaches, visual
field loss – bitemporal hemianopia – bump
into things
Sensitivity of the axes to damage
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With tumours and radiotherapy GH and gonadal
axes are more likely to be affected early with
thyoroid and adrenal axes less susceptible (one
reason why pituitary tumours present earlier in
women)
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With lymphocytic hypophysitis the opposite is
the case
Lymphocytic hypophysisitis
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Mainly occurs in women in late pregnancy or 1st
year after delivery
May be autoimmune (linked with Hashimoto’s
thyroiditis)
Posterior pituitary not affected
Can cause mass effect (enhances on MRI)
Life threatening ACTH deficiency can occur
Biopsy for definitive diagnosis if required
Variable natural history
Identical  chain but specific  chain
– non covalently associated
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Luteinising hormone (LH)
Follicular stimulating hormone (FSH)
Thyroid stimulating hormone (TSH)
(human chorionic gonadotrophin – hCG)
Potential for cross reaction e.g. hyperemesis
Control of anterior pituitary
function and biochemical testing
Physiological control
 Static testing
 Dynamic testing:
 If you think gland is under active – try to
stimulate it
 If you think gland is over active – try to
suppress it
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Thyroid Axis
Stimulators of TSH
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Pulsatile release (~9 x/24 hours) –
amplitude at night
Secretion stimulated by thyrotrophin
releasing hormone (TRH) released into the
hypohyseal portal vessels in the median
eminence
(TRH also stimulates prolactin release and
in some circumstances growth hormone)
Inhibitors of TSH
Thyroid hormones directly inhibit TSH
(and to a lesser extent TRH) release
 This can prevent the action of TRH
which is basis for TRH test
 Dopamine and somatostatin inhibit
release ?physiologically important but
useful clinically for TSHomas
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TFT’s and Pituitary Disease
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TSH does not behave as it “should” with
intact feedback loop
Abnormal T4 concentrations without
expected compensatory changes in TSH
TFT’s - Lack of elevation of TSH in
the presence of low T4
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Indicates pituitary or hypothalamic cause of
hypothyroidism – or sick euthyroid
syndrome
Same pattern can occur in 1st few months of
treatment of thyrotoxicosis: T4 and T3 can
be reduced below normal by carbimazole yet
TSH remains suppressed
Sick euthyroid syndrome
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Any severe non thyroidal illness can cause
fT4 low
fT3 is low or undetectable – reduced more than T4
TSH is usually normal but may be low
Reverse T3 is normal or elevated
Preferential production of rT3, reduced binding
globulins and circulating thyroid homone binding
inhibitors
Clinical judgement but more common than 2º
hypothyroidism
TFT’s - Elevated fT4 and fT3 with
failure of suppression of TSH
Discordant T4 and T3
 Interfering antibodies – no clinical signs
 Amiodarone
 Familial dysalbuminaemic
hyperthyroxinaemia
TFT’s - Elevated fT4 and fT3 with
failure of suppression of TSH
Other
 Intermittent T4 therapy
 Resistance to thyroid hormone*
 TSH secreting tumour*
 Acute psychiatric illness
TSHoma vs hormone resistance
TSHoma
PRTH
Clinically toxic
Yes
Variable
Family history
No
Yes
 subunit
High
Normal
 subunit/TSH
molar ratio
TRH test
High (>1)
Normal
Blunted
Normal
TSH response:T3 No change
suppression test
Peripheral action High
decrease
Normal
Thyroid Axis
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Very rarely need dynamic tests
TRH test usually adds little –responses vary
in 2º hypothyroidism and there are easier
ways to diagnose hyperthyroidism
If TSHoma suspected can do TRH test and
T3 suppression test (administer T3 - 80100mcg for 8-10 days - and in TSHoma TSH
fails to suppress, but suppression seen in
thyroid hormone resistance)
Gonadal Axis
Stimulators of LH/FSH
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Pulsatile secretion
Stimulated by pulsatile secretion of gonadotrophin
secreting hormone (GnRH) into the hypophyseal
portal vessels
GnRH release is complex and very susceptible to
stress and changes to nutrition and energy
homeostasis e.g. hypothalamic hypogonadotrophic
hypogonadism seen in weight loss or extreme
exercise
Inhibitors of LH/FSH
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Oestradiol and progesterone inhibit LH
release directly and via GnRH but in the
follicular phase oestradiol becomes
stimulatory inducing a surge of LH and
ovulation (positive feedback)
Inhibin from the ovary inhibits FSH release
In the late follicular phase inhibin and
oestradiol inhibit FSH release
In men equally complex but more static
Static testing of gonadotophins
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In menstruating females tests not usually
needed
Day 21 progesterone gives information on
ovulation
High prolactin can suppress gonadotrophin
secretion
In males if 9am testosterone is normal then
gonadotrophin secretion is adequate
Dynamic testing of gonadal axis
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Dynamic testing rarely done in adult
practice
GnRH test assesses reserve of LH/FSH
secretion – not usually helpful
Adrenal Axis
Stimulators of ACTH
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ACTH is a single chain peptide cleaved from
POMC along with MSH and  endorphin (hence
pigmentation in Addison’s)
Secreted in pulsatile fashion in response to
corticotrophin releasing hormone (CRH) –
determines set point around which cortisol
feedback works
Circadian rhythm with superimposed effects of
stress
Inhibitors of ACTH
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Feedback from cortisol mainly directly on pituitary
but also on CRH release
Other adrenal androgens whose secretions are
enhanced by ACTH do not have a feedback effect
e.g. in congenital adrenal hyperplasia
Feedback can be imitated by synthetic
glucocorticoids e.g. Dexamethasone (used in
suppression testing – tumorous corticotrophs less
susceptible to feedback)
Static testing - 9am cortisol
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‘normal’ cortisol concentration does not
exclude dysfunction
>390 nmol/l makes deficiency unlikely
(unless v sick)
<100 nmol/l likely to be abnormal.
Coincident ACTH can help
Need further testing
Salivary cortisol may become more
important
Dynamic testing of ACTH
Adrenal Axis
Underactivity
 ITT
 Synacthen test – only assesses adrenal function
directly – pituitary function implied
Overactivity
 Dexamethasone suppression test
 Urinary free cortisol
 CRH
 IPSS
Insulin Tolerance Test
Indications
 Assess ACTH/cortisol reserve
 Assess GH reserve
Contraindications
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Ischaemic heart disease
Epilepsy or unexplained blackouts
Severe longstanding hypoadrenalism (liver
glycogen depleted)
Glycogen storage disease
Hypothyroidism – untreated can give
subnormal results
Precautions
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ECG must be normal
9am cortisol must be >100 nmol/l
Serum fT4 must be normal (replace 1st if
low)
Have resuscitation facilities, 20% glucose
and IV hydrocortisone available
Procedure
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Fast from midnight
IV insulin bolus: 0.15 U/kg (0.3 U/kg for
Cushing’s and acromegaly)
If not hypoglycaemic at 45 mins repeat the dose
Give IV glucose if severe and prolonged
hypoglycaemia (>20 mins), LOC or fits – stimulus
has been adequate
Give lunch and sweet drink at the end of the test consider hydrocortisone
Sampling
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Use BM sticks as guide only
Lab glucose, cortisol and GH at
0,30,45,60,90 and 120mins (extend if dose
repeated)
Normal response (Bart’s)
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Lab glucose must fall to <2.2 mmol/l
Serum cortisol rises by more than 170 nmol/l
to at least 580 nmol/l
Short Synacthen Test
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Cortisol response to 250mcg of tetracosactrin IV or
IM (massively supraphysiological)
Fasting at 9am
Cortisol at 0, 30, 60 min
Normal response is rise by 170 nmol/l to >580
To tell 1º vs 2º measure ACTH (or long test)
1 mcg test more sensitive to subtle adrenal
dysfunction but not used routinely
Synacthen test vs ITT
Disadvantages
 Does not measure the whole axis
 Can be misleading after acute pituitary insult
 Cannot measure GH response
Advantages
 Simpler, safer, cheaper
 Usually good enough in chronic situation (we tend
to say >6 weeks but Synacthen test becomes
abnormal after 8-12 days)
Dexamethasone Suppression tests
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Overnight – simple but less specific – 1mg at
midnight then measure cortisol at 9am: <50
nmol/l is normal (? true for modern assays)
Low dose 48 hour – can be done as outpatient –
0.5mg every 6 hours: <50nmol/l is 98% sensitive
High dose 48 hour – to differentiate pituitary from
ectopic ACTH - 2mg every 6 hours – become
redundant as performance of test is less than the
pre-test likelihood of pituitary disease
Dexamethasone Suppression tests
Catches
 Rely on patient compliance if done at home
 Malabsorption of dexamethasone
 Drugs that increase hepatic clearance of
dexamethasone e.g. carbamazepine, phenytoin
 Need to stop exogenous oestrogen for 4-6 weeks to
allow cortisol binding globulin to return to basal
values (assays measure total cortisol but only free
is active)
Growth Axis
Stimulators of GH release
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Growth hormone releasing hormone
(GHRH) stimulates synthesis/release of
GH in pulsatile fashion – mostly at night
Ghrelin may have a role in secretion
GH exerts its effects directly and via IGF-1
production by the liver
Hypoglycaemia stimulates GH release
(basis of ITT for GH deficiency)
Amino acids stimulate GH release (arginine
can be used if ITT contraindicated)
Inhibitors of GH release
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Somatostatin inhibits GH release
Feedback from GH and IGF-1 inhibit GH
release at pituitary and hypothalamic level
Free fatty acids inhibit GH release
Glucose inhibits GHRH and GH release
(basis of GH suppression test for
acromegaly)
Static Testing of growth axis
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Random tests not helpful due to pulsatile
secretion
Need dynamic testing or IGF-1
GH assays
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Evolved from polyclonal RIA’s to 2 site
monoclonal antibody non-isotopic assays
with enhanced sensitivity
Accurately quantify previously undetectable
values
Do we need age and gender dependent
reference ranges ?
Growth Hormone Units – a mess!
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Previous standard not pure & contained a number
of isoforms: 22kD, 20kD and dimers/oligomers
UKNEQAS showed between method variation
increasing from 1994 to 1998 from 17 to 30% - most
negatively biased assay reported values ½ that of
most positively biased
In past: UK used mU/l and US mcg/l
Various conversion factors between 2 and 3 used
No simple conversion factor suitable
New standard
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EU legislation means all lab results must be
traceable to a defined material (98/79/EC)
Since 2001 new international standard in use
(IS98/574): 22kD GH of >95% purity
Now we should use mcg/l of IS98/574
We should not use mIU/l but assigned
conversion factor is 3.0 IU/mg
Criteria need to be looked at again
Dynamic testing of GH/IGF-1
Axis
Underactivity
 ITT
 Other stimulation tests e.g. glucagon,
arginine
Overactivity
 Glucose tolerance test
ITT for GH deficiency
Normal responses (Bart’s)
 GH rises to > 15 mcg/l
 Severe GHD needed for NICE criteria for
adult GH replacement < 3 mcg/l
 GHD that qualifies for GH treatment in
children <7 mcg/l
Alternatives to ITT for GHD
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Glucagon
Arginine
Arginine plus GHRH
Clonidine – in children but not adults
These other tests less well validated and
only used if ITT contraindicated
Is ITT for GHD always
needed ?
Which patients do not need a GH
stimulation test
JCEM 87; 477-485 (2002)
Pituitary hormone
deficits
0
% with peak GH <2.5
mcg/l
41
1
67
2
83
3
96
4
99
If multiple pituitary axes deficient
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If 3 or more axes affected then test for GHD
not needed – accuracy compares well with
GH stimulation testing
The other axes are easier to test: TSH,
ACTH, gonadotrophins and vasopressin
IGF-1 is not reliable for GHD
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IGF-1 may be normal in presence of severe
GHD – it is in about a third
Low IGF-1 also occurs in malnutrition,
poorly controlled diabetes, oral and high
dose transdermal oestrogen, hypothyroidism
and hepatic insufficiency
Excess – glucose tolerance test
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AKA growth hormone suppression test
Done in same way as test for diabetes/glucose
intolerance
Fasting then 75g glucose load (Polycal preferred –
Lucozade keeps changing! ) then sit and do
nothing – no exercise, smoking, coffee !
Normal response is suppression to <0.14 mcg/l
In acromegaly GH will not fall < 1 mcg/l (?still
true – need to re-evaluate with new assays)
False positives
Failure of normal suppression but no acromegaly
 Diabetes mellitus
 Liver disease
 Renal disease
 Adolescence
 Anorexia nervosa
False negatives can also occur
New assay data
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Suggest we need to look again at diagnostic
cut offs
25% of patients subsequently proven to have
acromegaly suppressed to <1 mcg/l
Prolactin
Stimulators of prolactin release
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Released in pulsatile fashion especially at night
No direct stimulatory factor
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Prolactin release is under tonic inhibitory
control
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Oestrogens cause hyperplasia of lactotrophs
(hence care with COC with prolactinomas) &
enhance prolactin release
TRH causes release of prolactin as well as TSH
but this is not physiological
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Inhibitors of prolactin release
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Dopamine tonically inhibits release
Impeding the hypophyseal portal circulation
causes enhanced prolactin release in
contrast to other pituitary hormones.
Prolactin can rise to 2000 mU/l due to this
‘stalk effect’
Dopamine antagonist drugs e.g.
metoclopramide, tricyclic antidepressants
can stimulate prolactin release
Static Testing - Prolactin
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If in doubt measure basal prolactin on 3
occasions
Indications to measure include:
 Galactorrhoea
 Amenorrhoea/hypogonadism
 Infertility
 Pituitary mass
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Macroprolactin
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Non-bioactive prolactin: monomer of prolactin
and IgG molecule with prolonged clearance rate
Mass >150kDa vs 23 kDa for monomeric
Accounts for 10-30% of hyperprolactinaemia
Some but not all assay systems claim to detect
macroprolactin but there are doubts
Treat sera with polyethylene glycol to precipitate
out immunoglobulins then re assay for prolactin
Screening recommended for all
hyperprolactinaemic sera (Clin Endo 71,466)
Clinical relevance
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Macroprolactin is not biologically active – people
with it have normal gonadal function
Presence of macroprolactin usually persists
If someone with gonadal dysfunction due to
another cause is found to have
“hyperprolactinaemia” due to macroprolactin:
inappropriate dopamine agonist treatment
imaging of the pituitary undertaken revealing
incidentalomas (found in up to 10%) and
unnecessary investigation and treatment
Prevalence of macroprolactinaemia
Clin Endo 71;702 (2009)
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1330 hospital workers in Japan screened for
hepatitis B
49 of 1330 (3.7%) had macroprolactin
15 (30.6%) of these 49 had
hyperprolactinaemia – all had normal
monomeric prolactin on PEG precipitation
29 of 1281 (2.26%) without macroprolactin
had (true) hyperprolactinaemia
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Of the 44 hyperprolactinaemias, 15 had
macroprolactinaemia (34%)
Nobody had macroprolactinaemia and
raised free prolactin
All sera with macroprolactin showed
complexes of prolactin and IgG – most had
anti PRL Abs, with others showing a variety
of prolactin complexes
Total PRL-free PRL/total PRL x 100 : if >57% =
macroprolactinaemia
IgG bound
100%
Anti PRL Abs
76%
Glycosylated PRL
20% (?relevant)
Of the 12 sera without antiPRL Abs
Covalent disulfide bonds may be involved
Suggests non covalent binding of IgG to prolactin and/or other proteins or aggregation of PRL
Prolactin
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No dynamic tests
Posterior Pituitary Vasopressin
Vasopressin control
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Complex release in response to osmotic status
and BP/circulating volume
Plasma osmolality is most important: to
maintain osmolality 284-295 mOsm/Kg
Other factors such as drinking (suppresses VP
release independent of osmolality)
VP regulates water reabsorption in distal
nephron via Aquaporins and regional blood flow
Hypovolaemia shifts release to left→ low Na
Static testing of Posterior
Pituitary
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Paired serum and urine osmolality on rising
Normal serum osmolality 280-295
mosmol/kg and concentrated urine (ratio
>2:1) excludes DI
In DI serum osmolality is raised and urine
ratio is <2.0 (but still may be more than
serum in mild cases)
Most need water deprivation test
Dynamic testing: Water
deprivation test
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Diagnosis of diabetes insipidus
Differential diagnosis of thirst polyuria and
nocturia
Precautions
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Need to watch for dehydration
Thyroid function and adrenal reserve must
be normal or replaced
Close rapid liaison with lab is vital – results
are needed quickly – ensure lab know the
test is going on
Procedure
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Allow fluids until 07.30 but no tea, coffee or
smoking
No food or fluid from 07.30
Weigh patient and work out 97% of weight
Directly supervise patient to avoid cheating
8 hours water deprivation unless stopping
early
Weight
Weigh basally and at 4,6,7 and 8 hours
 If >3% weight lost send urgent serum
osmolality
 if >300 mosmol/kg give DDAVP and allow
to drink
 If <300 mosmol/kg patient was probably
fluid overloaded at the start of the test
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Biochemical monitoring
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Hourly urine vols and osmolality
Hourly serum osmolality
Record results on proforma
Give 2mcg desmopressin IM:
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If weight falls >3% and serum osmolality
>300
If serum osmolality >300 and urine
osmolality <600
Then measure urine vols and osmolalities
for further 2-4 hours (allow to eat and drink)
Interpretation
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If urine osmolality <600 and serum osmolality >
300 after 8 hours of fluid deprivation then
diagnosis is DI.
Assuming urine concentrates to >600 after DDAVP
administration diagnosis is cranial DI. If this does
not occur diagnosis is nephrogenic DI.
Urine osmolality >600 in context of normal serum
osmolality after 8 hours excludes DI and no need
for DDAVP administration.
Consider psychogenic polydipsia if basal serum
osmolality is <260 in presence of low urine
osmolality.
Prolonged WDT (Miller and Moses)
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For mild DI where serum fails to
concentrate to >300 after 8 hours water
deprivation
Unless symptoms very mild do standard
WDT 1st
Patient nil by mouth from 6pm the night
before – so patient starts more dehydrated
Otherwise interpretation the same
Excess - SIADH
SIADH – syndrome of inappropriate
ADH secretion
1st described 1967
Essential criteria:
1.
Plasma osmolality <270 mOsm/kg
2.
Inappropriate urinary conc (>100 mOsm/kg)
3.
Clinical euvoloaemia
4.
High urinary Na (>40 mmol/l) with normal salt
and water intake
5.
Hypothyroidism & glucocorticoid deficiency
excluded
Not fully understood
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4 types depending on pattern of ADH
release
Why do patients continue to drink despite
plasma osmolality below thirst threshold ?
Hyponatraemia is limited by ‘escape from
antidiuresis’: urine flow rises and urine
osmolality falls and sodium stabilises in
hyponatraemic range
Causes of SIADH
1.
2.
3.
4.
Tumours
Pulmonary disease
CNS disease
Drugs: Phenothiazines, TCA’s,
chlorpropamide, ecstasy, carbamazepine,
cyclophosphamide, SSRI’s, others
Approach to the hyponatraemic
patient
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Identify clinical signs of underlying disease
e.g. Addison’s
Identify ECF status
Measure urinary sodium and osmolality
Check TFT’s (and cortisol +/- synacthen)
CXR – for fluid status and underlying
disease
Clinical Scenario’s
Investigation of suspected Cushing’s
Clinical features
Obesity/wt gain
Facial plethora
Round face
Thin skin
Hypertension
Hirsutism
Easy bruising
Glucose intolerance
Proportion (%)
95
90
90
85
75
75
65
60
Terminology
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Cushing’s syndrome – the biochemical
syndrome of cortisol excess
Cushing’s disease – the specific cause of the
Cushing’s syndrome is a pituitary adenoma
How picked up
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Can be florid
Can be subtle – probably many are missed
in hypertension, sleep apnoea and diabetes
clinics
Needs to be ruled out before bariatric
surgery
Process
1.
2.
3.
Prove cortisol excess
Decide if ACTH dependent or ACTH
independent
If ACTH dependent – decide if pituitary or
ectopic ACTH
Bear in mind
Cushing’s disease
Ectopic ACTH
Unknown ACTH
Adrenal adenoma
Adrenal Ca
Macronod hyperpl
Pigmented nod
McCune-Albright
Proportion (%)
70
10
5
10
5
<2
<2
<2
Female:male
3.5:1
1:1
5:1
4:1
1:1
1:1
1:1
1:1
Diagnosing hypercortisolaemia
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LDDST – 3-8% with Cushing’s suppress (if high suspicion
do DS-CRH test- 15 mins post CRH cortisol >38
nmol/l=CS). False positives more common
Overnight DST – less specific with more false positives
24 hour UFC – need repeated tests as single measurements
have low sensitivity. Collections often incomplete
Midnight cortisol – plasma or salivary – look for loss of
diurnal variation. Midnight plasma cortisol excludes
Cushing’s but needs admission. Salivary cortisol : renewed
interest as sens and spec 95-98% and is surrogate for
plasma free cortisol
Establish the cause
Measure ACTH:
 < 5 pg/ml = ACTH independent
 >15 pg/ml = ACTH dependent
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ACTH Independent
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Image adrenal glands
ACTH dependent
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Remember 70%+ will be pituitary – more in
females
Don’t rely on imaging to tell pituitary from
ectopic
Pituitary MRI often normal in Cushing’s
Disease (up to 40%) – adenoma’s small
Dynamic tests

High dose DST: 80% of patients with Cushing’s
show cortisol suppression of > 50%. Adds little and
not needed if >30% suppression on low dose

CRH test – measure cortisol and ACTH response
to ovine or human CRH. In Cushing’s disease
CRH responsiveness persists (20% rise) unlike
ectopic. Responses variable but sensitivity 86-93%
for Cushing’s disease
If
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ACTH dependent Cushing’s proven with
typical responses on DST and CRH and
6mm lesion or more on MRI then reasonable
to operate
Otherwise more info needed
Inferior petrosal sinus sampling
Inferior petrosal sinus sampling
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Sample gradient of ACTH from the pituitary to the
periphery
Site cannulae under venographic screening
Cushing’s disease:
Basal central:peripheral ratio of 2:1
CRH stimulated ratio of 3:1
‘Gold standard’ but not perfect: false positives and
negatives (<10%) described
Only 70% accurate for lateralisation in adults
Overall
Measure ACTH
< 5pg/ml
>15 pg/ml
Adrenal imaging
PituitaryMRI
+/- CRH
+/- High dose DST
Adenoma  surgery
No adenoma  IPPS
Clinical Case – Mr MJ




Age 57
Seen in diabetes clinic
Hypertensive and obese (BMI >50)
Somewhat Cushingoid in appearance but no
striae
Initial screen

24 hour UFC:
1189 nmol/d
855 nmol/d
Reference range 40-305 nmol/d

Prolactin 133, testo 2.9, IGF -1 20.4, TSH 1.7
fT4 15
Confirming Cushing’s Syndrome –
48 hour low dose DST

Cortisol: 515 nmol/l → 376 nmol/l (27%
reduction)
Confirming ACTH dependence

Basal ACTH 63 ng/l
Confirming pituitary source – high
dose DST

519 nmol/l → 75 nmol/l
Confirming pituitary source – CRH
test
0
15
30
45
60
90
120
Corti 361
sol
442
565
559
524
476
429
ACT
H
190
199
163
133
82
66
68
Imaging


Showed small adenoma on CT then MRI
In view of evidence (and patients obesity)
IPPS not done
Transphenoidal Surgery





Adenoma with ACTH staining removed
30 kg weight loss
Diabetes resolved
BP easier to control
Initial synacthen test abnormal –
subsequently normalised so now off
hydrocortisone replacement and remains
well with no signs of recurrence
Treatment –
transsphenoidal surgery
Treatment – transsphenoidal surgery



up to 90% remission rate in microadenomas,
less if no obvious tumour or large tumour
Patients require steroid cover afterwards – if
they don’t they are not cured !
Complication rate 14% with mortality of 2%
Adrenalectomy


Cures all forms of ACTH independent
Cushing’s syndrome
Bilateral adrenalectomy for ACTH
dependent Cushing’s but risk of Nelson’s
syndrome
Radiotherapy


Primary radiotherapy: long term remission
of 37%
Usually used 2nd line after surgery: 88%
remission but can take 5 years – usually
results in other pituitary hormone deficits
(GH>hypogonad>hypothyroid>ACTH)
Medical therapy -metyrapone




inhibits 11 hydroxylase so blocks:
11deoxycortisolcortisol
11 deoxycortisol levels rise: in some assays 11
deoxycortisol cross reacts with cortisol. Can
result in unnecessary increase in treatment
ACTH levels rise but do not usually
overcome block
Rise in adrenal androgens causes hirsutism
Medical therapy - ketoconazole






Antifungal agent
Inhibits several enzymes in steroid synthesis
pathway
Also reduces adrenal androgens so no
hirsutism (and cholesterol)
Can be hepatotoxic
Interacts with simvastatin
Anaesthetic agent etomidate works similarly
Monitoring treatment


Cortisol day curves (mean cortisol between
150 and 300 nmol/l corresponds with a
normal cortisol production rate) – beware
cross reactivity with 11 deoxycortisol if on
metyrapone
24 hour UFC’s
Acromegaly
Diagnosis


GH suppression test
IGF-1
Treatment





Surgery- cure up to 90% micro, <60% macro
Radiotherapy – can take several years to
work
Dopamine agonists –effective in up to 30%
Somatostatin analogues- effective in 66%.
Can be used pre-op to shrink & soften – can
shrink by 40%
Pegvisomant - GH receptor antagonist
Monitoring



IGF-1: in ref range
GH suppression test: nadir <1 mcg/l
GH day curve: mean <2.5 mcg/l normalises
mortality (but used old polyclonal immunoassays)
Controversial ! What if there is discordance ?
Can’t monitor GH if on pegvisomant
Issues




Probably need age, gender and BMI specific
GH cut offs (GH levels are lower with
increasing age and BMI. Females have
higher GH nadir)
Others things affect GH suppression e.g
renal failure, diabetes
Other things affect IGF-1 levels e.g.
malnutrition, liver disease, hypothyroidism
Changes in IGF-1 normative data
Discordance between GHST and
IGF-1




Most commonly normal IGF-1 but high GH
Repeat tests after 3 months – usually doesn’t
help
Somatostain analogues have less effect on
GHST than IGF-1
Most people would follow IGF-1 result but
watch closely for recurrence if GH
suppression is abnormal (evidence of
increased recurrence rate)
Clinical Case





30 year old female
Noticed blurred vision
Optican found visual field defect –
confirmed as bitemporal by ophthalmologist
6 months amennorrhoea
On questioning – increased shoe size and
had to change wedding ring twice. Sweating
more.
On examination



Clinically acromegalic with prominent nasal
bridge and jaw
Large hands
Large tongue with indentation due to teeth
Initial results







IGF1
Prolactin
Cortisol
SST
fT4
TSH
Oestradiol
105nmol/l
(13-50)
1154 miu/l
(<500)
353 nmol/l
367→535→646 nmol/l
9 pmol/l
(9-23)
1.77 miu/l
(0.25-5)
160 pmol/l
(100-750)
GH Suppression Test
Basal
40 min
70 min
100 min 130 min
GH
11.4
(mcg/l)
10.8
10.1
9.7
9.9
Glucose 4.7
(mM)
5.8
5.7
5.7
5.2
Imaging

Large pituitary tumour touching the chiasm
Treatment Plan




Not curable with surgery
Pre-op octreotide (to shrink tumour and
soften it) then surgery
Followed up with octreotide and
radiotherapy
May need pegvisomant
Prolactinoma



Commonest functioning pituitary tumour
Present earlier and also more common in
women – die to amenorrhoea
In men may just present with local pressure
effects
Many causes of high prolactin







Prolactinoma
Drugs: DA antagonists, neuroleptics,
antidepressants
Non functioning tumour (<2000)
Pregnancy/lactation
Hypothyroidism
Renal failure
PCOS
Lab issues


Remember macroprolactin – screen all
samples
Prolactin levels can be very high (>100,000)
so if clinical suspicion high but prolactin
levels normal look for hook effect by diluting
samples (however modern assays can
measure very high concentrations)
Features - hormonal




Galactorrhoea
Menstrual disturbance
Reduced libido/erectile dysfunction
Osteoporosis (long term)
Features - mass





Headaches
Visual field loss
Hypopituitarism
Cranial nerve palsies
CSF leak (rare)
If prolactin high but on drug known
to increase prolactin




Dilemma
Consider if timing fits
Can drug be withdrawn or changed ? Just a
few days is enough for oral medications
Often end up doing MRI but incidentalomas
are common
Prolactinoma



If PRL >2000 very likely prolactinoma, if
>5000 definitely so
If unsure if functioning or not can treat and
rescan
Prolactin levels will fall with medical therapy
anyway – more so if not prolactinoma
Medical management – Dopamine
agonists



Bromocriptine
Cabergoline
Quinagolide – being used more as no known
risk of heart valve fibrosis
Clinical case – Mr JF







42 year old man with erectile dysfunction
No other symptoms
10 year old child
Prolactin 23,000 with negative
macroprolactin screen
Testosterone 2.0 nmol/l, LH <0.1 U/L
fT4 23 TSH 2.43, SST normal, IGF-1 18.1
MRI: macroadenoma but away from chiasm
On Cabergoline





Prolactin now 686
Testosterone no better
Started on testosterone replacement – gel
then Nebido and erectile problems resolved
Pituitary lesion smaller
fT4 11 TSH 2.86 so started on thyroxine in
case secondary hypothyroidism
Pituitary Apoplexy
Pituitary Apoplexy




Acute infarction or haemorrhage of the
pituitary
Usually an adenoma is present
Acute headache (retro-orbital), visual
disturbance, altered mental function, cranial
nerve palsies & endocrine dysfunction
Can occur post partum in nontumorous
glands – Sheehan’s Syndrome
Management




Endocrine emergency
Send off baseline bloods – cortisol, TFT’s,
IGF1, LH/FSH, testo/oestradiol, prolactin
Urgent steroid replacement with high dose
hydrocortisone or dexamethasone
Urgent discussion with neurosurgeons – if
compression of chiasm or cranial nerve palsy
surgery is indicated
Learning Objectives




Describe pituitary anatomy and endocrine
physiology
Describe methods for assessing pituitary
function using static and dynamic testing
Describe the new standard for the
measurement of growth hormone & its
effects on clinical criteria
Be are of the importance of screening for
macroprolactin