Pituitary Pituitary Function and Function and
PathologyPathologyDr Duncan FowlerDr Duncan Fowler
The Ipswich HospitalThe Ipswich Hospital
OverviewOverview AnatomyAnatomy Physiology Physiology Assessment of pituitary function: Assessment of pituitary function:
static and dynamic testsstatic and dynamic tests Clinical scenario’s:Clinical scenario’s: Cushing’s DiseaseCushing’s Disease AcromegalyAcromegaly ProlactinomaProlactinoma ApoplexyApoplexy
Learning ObjectivesLearning Objectives
Describe pituitary anatomy and Describe pituitary anatomy and endocrine physiologyendocrine physiology
Describe methods for assessing Describe methods for assessing pituitary function using static and pituitary function using static and dynamic testingdynamic testing
Describe the new standard for the Describe the new standard for the measurement of growth hormone & measurement of growth hormone & its effects on clinical criteriaits effects on clinical criteria
Be are of the importance of Be are of the importance of screening for macroprolactinscreening for macroprolactin
Hypothalamo-pituitary Hypothalamo-pituitary anatomyanatomy
Hypothalamus is the part of the Hypothalamus is the part of the diencephalon associated with visceral, diencephalon associated with visceral, autonomic, endocrine affective and autonomic, endocrine affective and emotional behaviouremotional behaviour
Ventral portion forms the infundibulumVentral portion forms the infundibulum Posterior to this is the median eminence Posterior to this is the median eminence
– the final point of convergence of – the final point of convergence of pathways from the CNS on the endocrine pathways from the CNS on the endocrine system and is vascularised by the system and is vascularised by the primary capillaries of the hypothalamo-primary capillaries of the hypothalamo-hypophyseal portal vesselshypophyseal portal vessels
Sella turcicaSella turcica
TerminologyTerminology AdenohypophysisAdenohypophysis = anterior pituitary = anterior pituitary
controlled by releasing and inhibiting controlled by releasing and inhibiting factors released from nerves in the factors released from nerves in the median eminence into the hypophyseal median eminence into the hypophyseal portal vessels which carry them to the portal vessels which carry them to the pituitary pituitary
NeurohypophysisNeurohypophysis = posterior pituitary. = posterior pituitary. It is an extension of the CNS. Its function It is an extension of the CNS. Its function is controlled by direct neural connection is controlled by direct neural connection to the hypothalamusto the hypothalamus
PresentationPresentation
Hormonal hypersecretion e.g. Hormonal hypersecretion e.g. AcromegalyAcromegaly
Hormonal deficiency e.g Hormonal deficiency e.g amenorrhoeaamenorrhoea
Local pressure effects: Local pressure effects: headaches, visual field loss – headaches, visual field loss – bitemporal hemianopia – bump bitemporal hemianopia – bump into thingsinto things
Identical Identical chain but chain but specific specific chain – non chain – non covalently associatedcovalently associated
Luteinising hormone (LH)Luteinising hormone (LH) Follicular stimulating hormone (FSH)Follicular stimulating hormone (FSH) Thyroid stimulating hormone (TSH)Thyroid stimulating hormone (TSH) (human chorionic gonadotrophin – (human chorionic gonadotrophin –
hCG)hCG)
Potential for cross reaction e.g. Potential for cross reaction e.g. hyperemesishyperemesis
Control of Control of anterior pituitary anterior pituitary
functionfunction
Stimulators of TSHStimulators of TSH
Pulsatile release (~9 x/24 hours) – Pulsatile release (~9 x/24 hours) – amplitude at nightamplitude at night
Secretion stimulated by thyrotrophin Secretion stimulated by thyrotrophin releasing hormone (TRH) released releasing hormone (TRH) released into the hypohyseal portal vessels in into the hypohyseal portal vessels in the median eminencethe median eminence
(TRH also stimulates prolactin (TRH also stimulates prolactin release and in some circumstances release and in some circumstances growth hormone)growth hormone)
Inhibitors of TSHInhibitors of TSH
Thyroid hormones directly inhibit Thyroid hormones directly inhibit TSH (and to a lesser extent TRH) TSH (and to a lesser extent TRH) releaserelease
This can prevent the action of This can prevent the action of TRH which is basis for TRH testTRH which is basis for TRH test
Dopamine and somatostatin Dopamine and somatostatin inhibit release ?physiologically inhibit release ?physiologically important but useful clinically for important but useful clinically for TSHomasTSHomas
Stimulators of LH/FSHStimulators of LH/FSH
Pulsatile secretionPulsatile secretion Stimulated by pulsatile secretion of Stimulated by pulsatile secretion of
gonadotrophin secreting hormone gonadotrophin secreting hormone (GnRH) into the hypophyseal portal (GnRH) into the hypophyseal portal vesselsvessels
GnRH release is complex and very GnRH release is complex and very susceptible to stress and changes to susceptible to stress and changes to nutrition and energy homeostasis e.g. nutrition and energy homeostasis e.g. hypothalamic hypogonadotrophic hypothalamic hypogonadotrophic hypogonadism seen in weight loss or hypogonadism seen in weight loss or extreme exerciseextreme exercise
Inhibitors of LH/FSHInhibitors of LH/FSH Oestradiol and progesterone inhibit LH Oestradiol and progesterone inhibit LH
release directly and via GnRH but in the release directly and via GnRH but in the follicular phase oestradiol becomes follicular phase oestradiol becomes stimulatory inducing a surge of LH and stimulatory inducing a surge of LH and ovulation (positive feedback)ovulation (positive feedback)
Inhibin from the ovary inhibits FSH Inhibin from the ovary inhibits FSH releaserelease
In the late follicular phase inhibin and In the late follicular phase inhibin and oestradiol inhibit FSH releaseoestradiol inhibit FSH release
In men equally complex but more staticIn men equally complex but more static
Stimulators of ACTHStimulators of ACTH
ACTH is a single chain peptide ACTH is a single chain peptide cleaved from POMC along with MSH cleaved from POMC along with MSH and and endorphin (hence pigmentation endorphin (hence pigmentation in Addison’s) in Addison’s)
Secreted in pulsatile fashion in Secreted in pulsatile fashion in response to corticotrophin releasing response to corticotrophin releasing hormone (CRH) – determines set point hormone (CRH) – determines set point around which cortisol feedback worksaround which cortisol feedback works
Circadian rhythm with superimposed Circadian rhythm with superimposed effects of stresseffects of stress
Inhibitors of ACTHInhibitors of ACTH
Feedback from cortisol mainly directly on Feedback from cortisol mainly directly on pituitary but also on CRH releasepituitary but also on CRH release
Other adrenal androgens whose Other adrenal androgens whose secretions are enhanced by ACTH do secretions are enhanced by ACTH do not not have a feedback effect e.g. in congenital have a feedback effect e.g. in congenital adrenal hyperplasiaadrenal hyperplasia
Feedback can be imitated by synthetic Feedback can be imitated by synthetic glucocorticoids e.g. Dexamethasone glucocorticoids e.g. Dexamethasone (used in suppression testing – tumorous (used in suppression testing – tumorous corticotrophs less susceptible to corticotrophs less susceptible to feedback)feedback)
Stimulators of GH Stimulators of GH releaserelease
Growth hormone releasing hormone Growth hormone releasing hormone (GHRH) stimulates synthesis/release of (GHRH) stimulates synthesis/release of GH in pulsatile fashion – mostly at nightGH in pulsatile fashion – mostly at night
Ghrelin may have a role in Ghrelin may have a role in secretionsecretion GH exerts its effects directly and via IGF-1 GH exerts its effects directly and via IGF-1
production by the liverproduction by the liver Hypoglycaemia stimulates GH release Hypoglycaemia stimulates GH release
(basis of ITT for GH deficiency)(basis of ITT for GH deficiency) Amino acids stimulate GH release Amino acids stimulate GH release
(arginine can be used if ITT (arginine can be used if ITT contraindicated)contraindicated)
Inhibitors of GH releaseInhibitors of GH release
Somatostatin inhibits GH releaseSomatostatin inhibits GH release Feedback from GH and IGF-1 Feedback from GH and IGF-1
inhibit GH release at pituitary and inhibit GH release at pituitary and hypothalamic levelhypothalamic level
Free fatty acids inhibit GH releaseFree fatty acids inhibit GH release Glucose inhibits GHRH and GH Glucose inhibits GHRH and GH
release (basis of GH suppression release (basis of GH suppression test for acromegaly)test for acromegaly)
Stimulators of prolactin Stimulators of prolactin releaserelease
Released in pulsatile fashion especially at Released in pulsatile fashion especially at nightnight
No direct stimulatory factor No direct stimulatory factor Prolactin release is under tonic Prolactin release is under tonic
inhibitory controlinhibitory control Oestrogens cause hyperplasia of Oestrogens cause hyperplasia of
lactotrophs (hence care with COC with lactotrophs (hence care with COC with prolactinomas) & enhance prolactin prolactinomas) & enhance prolactin releaserelease
TRH causes release of prolactin as well as TRH causes release of prolactin as well as TSH but this is not physiologicalTSH but this is not physiological
Inhibitors of prolactin Inhibitors of prolactin releaserelease
Dopamine tonically inhibits releaseDopamine tonically inhibits release Impeding the hypophyseal portal Impeding the hypophyseal portal
circulation causes enhanced circulation causes enhanced prolactin release in contrast to other prolactin release in contrast to other pituitary hormones. Prolactin can pituitary hormones. Prolactin can rise to 2000 mU/l due to this ‘stalk rise to 2000 mU/l due to this ‘stalk effect’effect’
Dopamine antagonist drugs e.g. Dopamine antagonist drugs e.g. metoclopramide, tricyclic metoclopramide, tricyclic antidepressants can stimulate antidepressants can stimulate prolactin releaseprolactin release
Static Pituitary Static Pituitary TestsTests
ProlactinProlactin TFT’sTFT’s LH/FSH and testosterone/oestradiol LH/FSH and testosterone/oestradiol
– but timing important– but timing important IGF-1 (for GH)IGF-1 (for GH) Cortisol – random samples not Cortisol – random samples not
usually helpful –usually done 9amusually helpful –usually done 9am Serum and urine osmolality (plus Serum and urine osmolality (plus
additional tests to investigate additional tests to investigate SIADH)SIADH)
ProlactinProlactin
If in doubt measure basal If in doubt measure basal prolactin on 3 occasionsprolactin on 3 occasions
MacroprolactinMacroprolactin Non-bioactive prolactin: monomer of prolactin Non-bioactive prolactin: monomer of prolactin
and IgG molecule with prolonged clearance and IgG molecule with prolonged clearance raterate
Accounts for 10-30% of hyperprolactinaemiaAccounts for 10-30% of hyperprolactinaemia Some but not all assay systems claim to detect Some but not all assay systems claim to detect
macroprolactin but there are doubtsmacroprolactin but there are doubts Treat sera with polyethylene glycol to Treat sera with polyethylene glycol to
precipitate out immunoglobulins then re assay precipitate out immunoglobulins then re assay for prolactinfor prolactin
Screening recommended for all Screening recommended for all hyperprolactinaemic sera (hyperprolactinaemic sera (Clin Endo 71,466Clin Endo 71,466))
Clinical relevanceClinical relevance Macroprolactin is not biologically active – Macroprolactin is not biologically active –
people with it have normal gonadal functionpeople with it have normal gonadal function If someone with gonadal dysfunction due to If someone with gonadal dysfunction due to
another cause is found to have another cause is found to have “hyperprolactinaemia” due to “hyperprolactinaemia” due to macroprolactin:macroprolactin:
inappropriate dopamine agonist treatmentinappropriate dopamine agonist treatment imaging of the pituitary undertaken imaging of the pituitary undertaken
revealing incidentalomas (found in up to revealing incidentalomas (found in up to 10%) and unnecessary investigation and 10%) and unnecessary investigation and treatmenttreatment
Prevalence of Prevalence of macroprolactinaemiamacroprolactinaemia
Clin Endo 71;702 (2009)Clin Endo 71;702 (2009) 1330 hospital workers in Japan 1330 hospital workers in Japan
screened for hepatitis Bscreened for hepatitis B 49 of 1330 (3.7%) had macroprolactin 49 of 1330 (3.7%) had macroprolactin 15 (30.6%) of these 49 had 15 (30.6%) of these 49 had
hyperprolactinaemia – all had normal hyperprolactinaemia – all had normal monomeric prolactin on PEG monomeric prolactin on PEG precipitationprecipitation
29 of 1281 (2.26%) without 29 of 1281 (2.26%) without macroprolactin had (true) macroprolactin had (true) hyperprolactinaemiahyperprolactinaemia
Of the 44 hyperprolactinaemias, Of the 44 hyperprolactinaemias, 15 had macroprolactinaemia (34%)15 had macroprolactinaemia (34%)
Nobody had macroprolactinaemia Nobody had macroprolactinaemia and raised free prolactinand raised free prolactin
All sera with macroprolactin All sera with macroprolactin showed complexes of prolactin and showed complexes of prolactin and IgG – most had anti PRL Abs, with IgG – most had anti PRL Abs, with others showing a variety of others showing a variety of prolactin complexesprolactin complexes
Total PRL-free PRL/total PRL x 100 : if >57% = macroprolactinaemia
IgG bound100%
Anti PRL Abs76%
Glycosylated PRL20% (?relevant)
Of the 12 sera without Of the 12 sera without antiPRL AbsantiPRL Abs
Suggests non covalent binding of IgG to prolactin and/or other proteins or aggregation of PRL
Covalent disulfide bonds may be involved
TFT’s - Lack of elevation of TFT’s - Lack of elevation of TSH in the presence of low TSH in the presence of low
T4 T4 Indicates pituitary or hypothalamic Indicates pituitary or hypothalamic
cause of hypothyroidism – or sick cause of hypothyroidism – or sick euthyroid syndromeeuthyroid syndrome
Same pattern can occur in 1Same pattern can occur in 1stst few few months of treatment of months of treatment of thyrotoxicosis: T4 and T3 can be thyrotoxicosis: T4 and T3 can be reduced below normal by reduced below normal by carbimazole yet TSH remains carbimazole yet TSH remains suppressedsuppressed
Sick euthyroid syndromeSick euthyroid syndrome Any severe non thyroidal illness can causeAny severe non thyroidal illness can cause fT4 lowfT4 low fT3 is low or undetectable – reduced more fT3 is low or undetectable – reduced more
than T4than T4 TSH is usually normal but may be lowTSH is usually normal but may be low Reverse T3 is normal or elevated Reverse T3 is normal or elevated Preferential production of rT3, reduced Preferential production of rT3, reduced
binding globulins and circulating thyroid binding globulins and circulating thyroid homone binding inhibitorshomone binding inhibitors
Clinical judgement but more common Clinical judgement but more common than 2º hypothyroidismthan 2º hypothyroidism
TFT’s - Elevated fT4 and TFT’s - Elevated fT4 and fT3 with failure of fT3 with failure of
suppression of TSH suppression of TSH Discordant T4 and T3Discordant T4 and T3 Interfering antibodies – no Interfering antibodies – no
clinical signsclinical signs AmiodaroneAmiodarone Familial dysalbuminaemic Familial dysalbuminaemic
hyperthyroxinaemiahyperthyroxinaemia
TFT’s - Elevated fT4 and TFT’s - Elevated fT4 and fT3 with failure of fT3 with failure of
suppression of TSH suppression of TSH OtherOther Intermittent T4 therapyIntermittent T4 therapy Resistance to thyroid hormone*Resistance to thyroid hormone* TSH secreting tumour*TSH secreting tumour* Acute psychiatric illnessAcute psychiatric illness
TSHoma vs hormone TSHoma vs hormone resistanceresistance
TSHomaTSHoma PRTHPRTH
Clinically Clinically toxictoxic
YesYes VariableVariable
Family Family historyhistory
NoNo YesYes
subunitsubunit HighHigh NormalNormal
subunit/TSH subunit/TSH molar ratiomolar ratio
High (>1)High (>1) NormalNormal
TRH testTRH test BluntedBlunted NormalNormal
TSH TSH response:T3 response:T3 suppression suppression testtest
No changeNo change decreasedecrease
Peripheral Peripheral actionaction
HighHigh NormalNormal
GonadotophinsGonadotophins
In menstruating females tests not In menstruating females tests not usually neededusually needed
Day 21 progesterone gives Day 21 progesterone gives information on ovulationinformation on ovulation
High prolactin can suppress High prolactin can suppress gonadotrophin secretiongonadotrophin secretion
In males if 9am testosterone is In males if 9am testosterone is normal then gonadotrophin normal then gonadotrophin secretion is adequatesecretion is adequate
Growth hormoneGrowth hormone
Random tests not helpful due to Random tests not helpful due to pulsatile secretionpulsatile secretion
Need dynamic testing or IGF-1Need dynamic testing or IGF-1
GH assaysGH assays
Evolved from polyclonal RIA’s to Evolved from polyclonal RIA’s to 2 site monoclonal antibody non-2 site monoclonal antibody non-isotopic assays with enhanced isotopic assays with enhanced sensitivitysensitivity
Accurately quantify previously Accurately quantify previously undetectable valuesundetectable values
Do we need age and gender Do we need age and gender dependent reference ranges ?dependent reference ranges ?
Growth Hormone Units – Growth Hormone Units – a mess!a mess!
Previous standard not pure & contained a Previous standard not pure & contained a number of isoforms: 22kD, 20kD and number of isoforms: 22kD, 20kD and dimers/oligomersdimers/oligomers
UKNEQAS showed between method variation UKNEQAS showed between method variation increasing from 1994 to 1998 from 17 to increasing from 1994 to 1998 from 17 to 30% - most negatively biased assay reported 30% - most negatively biased assay reported values ½ that of most positively biasedvalues ½ that of most positively biased
In past: UK used mU/l and US mcg/l In past: UK used mU/l and US mcg/l Various conversion factors between 2 and 3 Various conversion factors between 2 and 3
usedused No simple conversion factor suitableNo simple conversion factor suitable
New standardNew standard
EU legislation means all lab results EU legislation means all lab results must be traceable to a defined must be traceable to a defined material (98/79/EC)material (98/79/EC)
Since 2001 new international standard Since 2001 new international standard in use (IS98/574): 22kD GH of >95% in use (IS98/574): 22kD GH of >95% puritypurity
Now we should use mcg/l of IS98/574 Now we should use mcg/l of IS98/574 We should not use mIU/l but assigned We should not use mIU/l but assigned
conversion factor is 3.0 IU/mgconversion factor is 3.0 IU/mg Criteria need to be looked at againCriteria need to be looked at again
9am cortisol9am cortisol
‘‘normal’ cortisol concentration normal’ cortisol concentration does not exclude dysfunctiondoes not exclude dysfunction
>500 nmol/l makes deficiency >500 nmol/l makes deficiency unlikely (unless v sick)unlikely (unless v sick)
<100 nmol/l likely to be abnormal. <100 nmol/l likely to be abnormal. Coincident ACTH can helpCoincident ACTH can help
Need further testingNeed further testing Salivary cortisol may become more Salivary cortisol may become more
importantimportant
Posterior PituitaryPosterior Pituitary
Paired serum and urine osmolality Paired serum and urine osmolality on risingon rising
Normal serum osmolality 280-295 Normal serum osmolality 280-295 mosmol/kg and concentrated urine mosmol/kg and concentrated urine (ratio >2:1) excludes DI(ratio >2:1) excludes DI
In DI serum osmolality is raised and In DI serum osmolality is raised and urine ratio is <2.0 (but still may be urine ratio is <2.0 (but still may be more than serum in mild cases)more than serum in mild cases)
Most need water deprivation testMost need water deprivation test
SIADH – syndrome of SIADH – syndrome of inappropriate ADH inappropriate ADH
secretionsecretion11stst described 1967 described 1967
Essential criteria:Essential criteria:
1.1. Plasma osmolality <270 mOsm/kgPlasma osmolality <270 mOsm/kg
2.2. Inappropriate urinary conc (>100 Inappropriate urinary conc (>100 mOsm/kg)mOsm/kg)
3.3. Clinical euvoloaemiaClinical euvoloaemia
4.4. High urinary Na (>40 mmol/l) with High urinary Na (>40 mmol/l) with normal salt and water intakenormal salt and water intake
5.5. Hypothyroidism & glucocorticoid Hypothyroidism & glucocorticoid deficiency excludeddeficiency excluded
Not fully understoodNot fully understood
4 types depending on pattern of ADH 4 types depending on pattern of ADH releaserelease
Why do patients continue to drink Why do patients continue to drink despite plasma osmolality below despite plasma osmolality below thirst threshold ?thirst threshold ?
Hyponatraemia is limited by ‘escape Hyponatraemia is limited by ‘escape from antidiuresis’: urine flow rises from antidiuresis’: urine flow rises and urine osmolality falls and and urine osmolality falls and sodium stabilises in hyponatraemic sodium stabilises in hyponatraemic rangerange
Causes of SIADHCauses of SIADH
1.1. TumoursTumours
2.2. Pulmonary diseasePulmonary disease
3.3. CNS diseaseCNS disease
4.4. Drugs: Phenothiazines, TCA’s, Drugs: Phenothiazines, TCA’s, chlorpropamide, ecstasy, chlorpropamide, ecstasy, carbamazepine, carbamazepine, cyclophosphamide, SSRI’s, cyclophosphamide, SSRI’s, othersothers
Cerebral Salt Wasting Cerebral Salt Wasting SyndromeSyndrome
Seen following cerebral insults e.g. Seen following cerebral insults e.g. head injury, SAH, tumours, surgeryhead injury, SAH, tumours, surgery
Causes: hyponatraemia, diuresis, Causes: hyponatraemia, diuresis, natriuresis, hypovolaemianatriuresis, hypovolaemia
Originally thought to be part of SIADHOriginally thought to be part of SIADH In neurosurgery commoner than SIADHIn neurosurgery commoner than SIADH May be due to May be due to brain natriuretic brain natriuretic
peptidepeptide Resolves in 2 weeks but responds well Resolves in 2 weeks but responds well
to salineto saline
CSWS vs SIADHCSWS vs SIADH
CSWSCSWS SIADHSIADH
Plasma NaPlasma Na LowLow LowLow
Plasma ureaPlasma urea HighHigh Low or Low or normalnormal
BPBP Low/post lowLow/post low NormalNormal
CVPCVP LowLow NormalNormal
Urinary NaUrinary Na HighHigh HighHigh
Urinary Urinary VolumeVolume
IncreasedIncreased DecreasedDecreased
ThirstThirst IncreasedIncreased NormalNormal
Approach to the Approach to the hyponatraemic patienthyponatraemic patient
Identify clinical signs of Identify clinical signs of underlying disease e.g. Addison’sunderlying disease e.g. Addison’s
Identify ECF statusIdentify ECF status Measure urinary sodium and Measure urinary sodium and
osmolalityosmolality Check TFT’s (and cortisol +/- Check TFT’s (and cortisol +/-
synacthen)synacthen) CXR – for fluid status and CXR – for fluid status and
underlying diseaseunderlying disease
Dynamic Dynamic Pituitary TestsPituitary Tests
Dynamic tests - Dynamic tests - principlesprinciples
If you think gland is under active If you think gland is under active – try to stimulate it– try to stimulate it
If you think gland is over active – If you think gland is over active – try to suppress ittry to suppress it
ACTH Adrenal AxisACTH Adrenal Axis
UnderactivityUnderactivity ITTITT Synacthen test – only assesses adrenal Synacthen test – only assesses adrenal
function directly – pituitary function function directly – pituitary function impliedimplied
OveractivityOveractivity Dexamethasone suppression testDexamethasone suppression test Urinary free cortisolUrinary free cortisol CRHCRH IPSSIPSS
GH/IGF-1 AxisGH/IGF-1 Axis
UnderactivityUnderactivity ITTITT Other stimulation tests e.g. Other stimulation tests e.g.
glucagon, arginineglucagon, arginine
OveractivityOveractivity Glucose tolerance testGlucose tolerance test
Thyroid AxisThyroid Axis Very rarely need dynamic testsVery rarely need dynamic tests TRH test usually adds little –TRH test usually adds little –
responses vary in 2º hypothyroidism responses vary in 2º hypothyroidism and there are easier ways to diagnose and there are easier ways to diagnose hyperthyroidismhyperthyroidism
If TSHoma suspected can do TRH test If TSHoma suspected can do TRH test and T3 suppression test (administer and T3 suppression test (administer T3 - 80-100mcg for 8-10 days - and in T3 - 80-100mcg for 8-10 days - and in TSHoma TSH fails to suppress, but TSHoma TSH fails to suppress, but suppression seen in thyroid hormone suppression seen in thyroid hormone resistance)resistance)
Gonadal AxisGonadal Axis
Dynamic testing rarely done in Dynamic testing rarely done in adult practiceadult practice
GnRH test assesses reserve of GnRH test assesses reserve of LH/FSH secretion – not usually LH/FSH secretion – not usually helpfulhelpful
ProlactinProlactin
No dynamic testsNo dynamic tests
VasopressinVasopressin
Underactivity (DI)Underactivity (DI) Water deprivation testWater deprivation test
The testsThe tests
ACTH/Adrenal axisACTH/Adrenal axis
Insulin Tolerance TestInsulin Tolerance Test
IndicationsIndications Assess ACTH/cortisol reserveAssess ACTH/cortisol reserve Assess GH reserveAssess GH reserve
ContraindicationsContraindications
Ischaemic heart diseaseIschaemic heart disease Epilepsy or unexplained blackoutsEpilepsy or unexplained blackouts Severe longstanding Severe longstanding
hypoadrenalism (liver glycogen hypoadrenalism (liver glycogen depleted)depleted)
Glycogen storage diseaseGlycogen storage disease Hypothyroidism – untreated can Hypothyroidism – untreated can
give subnormal resultsgive subnormal results
PrecautionsPrecautions
ECG must be normalECG must be normal 9am cortisol must be >100 9am cortisol must be >100
nmol/lnmol/l Serum F4 must be normal Serum F4 must be normal
(replace 1(replace 1stst if low) if low) Have resuscitation facilities, 20% Have resuscitation facilities, 20%
glucose and IV hydrocortisone glucose and IV hydrocortisone availableavailable
ProcedureProcedure
Fast from midnightFast from midnight IV insulin bolus: 0.15 U/kg (0.3 U/kg for IV insulin bolus: 0.15 U/kg (0.3 U/kg for
Cushing’s and acromegaly)Cushing’s and acromegaly) If not hypoglycaemic at 45 mins repeat If not hypoglycaemic at 45 mins repeat
the dosethe dose Give IV glucose if severe and prolonged Give IV glucose if severe and prolonged
hypoglycaemia (>20 mins), LOC or fits – hypoglycaemia (>20 mins), LOC or fits – stimulus has been adequatestimulus has been adequate
Give lunch and sweet drink at the end Give lunch and sweet drink at the end of the test -consider hydrocortisoneof the test -consider hydrocortisone
SamplingSampling
Use BM sticks as guide onlyUse BM sticks as guide only Lab glucose, cortisol and GH at Lab glucose, cortisol and GH at
0,30,45,60,90 and 120mins 0,30,45,60,90 and 120mins (extend if dose repeated)(extend if dose repeated)
Normal response (Bart’s)Normal response (Bart’s)
Lab glucose must fall to <2.2 mmol/lLab glucose must fall to <2.2 mmol/l Serum cortisol rises by more than Serum cortisol rises by more than
170 nmol/l to at least 580 nmol/l170 nmol/l to at least 580 nmol/l GH rises to > 15 mcg/lGH rises to > 15 mcg/l Severe GHD needed for NICE criteria Severe GHD needed for NICE criteria
for adult GH replacement < 3 mcg/lfor adult GH replacement < 3 mcg/l GHD that qualifies for GH treatment GHD that qualifies for GH treatment
in children <7 mcg/lin children <7 mcg/l
Synacthen test vs ITTSynacthen test vs ITT
DisadvantagesDisadvantages Does not measure the whole axisDoes not measure the whole axis Can be misleading after acute pituitary Can be misleading after acute pituitary
insultinsult Cannot measure GH responseCannot measure GH response
Advantages Advantages Simpler, safer, cheaperSimpler, safer, cheaper Usually good enough in chronic Usually good enough in chronic
situation (we tend to say >6 weeks but situation (we tend to say >6 weeks but Synacthen test becomes abnormal after Synacthen test becomes abnormal after 8-12 days)8-12 days)
Alternatives to ITT for Alternatives to ITT for GHDGHD
GlucagonGlucagon Arginine Arginine Arginine plus GHRHArginine plus GHRH Clonidine – in children but not Clonidine – in children but not
adultsadults
These other tests less well These other tests less well validated and only used if ITT validated and only used if ITT contraindicatedcontraindicated
Is ITT for GHD Is ITT for GHD always needed ?always needed ?
Which patients do not need Which patients do not need a GH stimulation test a GH stimulation test
JCEM 87; 477-485 (2002)JCEM 87; 477-485 (2002)Pituitary hormone Pituitary hormone deficitsdeficits
% with peak GH % with peak GH <2.5 mcg/l<2.5 mcg/l
00 4141
11 6767
22 8383
33 9696
44 9999
If multiple pituitary axes If multiple pituitary axes deficientdeficient
If 3 or more axes affected then If 3 or more axes affected then test for GHD not needed – test for GHD not needed – accuracy compares well with GH accuracy compares well with GH stimulation testingstimulation testing
The other axes are easier to test: The other axes are easier to test: TSH, ACTH, gonadotrophins and TSH, ACTH, gonadotrophins and vasopressinvasopressin
IGF-1 is not reliable for IGF-1 is not reliable for GHDGHD
IGF-1 may be normal in presence IGF-1 may be normal in presence of severe GHD – it is in about a of severe GHD – it is in about a thirdthird
Low IGF-1 also occurs in Low IGF-1 also occurs in malnutrition, poorly controlled malnutrition, poorly controlled diabetes, oral and high dose diabetes, oral and high dose transdermal oestrogen, transdermal oestrogen, hypothyroidism and hepatic hypothyroidism and hepatic insufficiencyinsufficiency
Short Synacthen TestShort Synacthen Test
Cortisol response to 250mcg of Cortisol response to 250mcg of tetracosactrin IV or IM (massively tetracosactrin IV or IM (massively supraphysiological)supraphysiological)
Fasting at 9amFasting at 9am Cortisol at 0, 30, 60 minCortisol at 0, 30, 60 min Normal response is rise by 170 nmol/l to Normal response is rise by 170 nmol/l to
>580>580 To tell 1º vs 2º measure ACTH (or long To tell 1º vs 2º measure ACTH (or long
test)test) 1 mcg test more sensitive to subtle 1 mcg test more sensitive to subtle
adrenal dysfunction but not used routinelyadrenal dysfunction but not used routinely
Dexamethasone Dexamethasone Suppression testsSuppression tests
Overnight – simple but less specific – 1mg at Overnight – simple but less specific – 1mg at midnight then measure cortisol at 9am: <50 midnight then measure cortisol at 9am: <50 nmol/l is normal (? true for modern assays)nmol/l is normal (? true for modern assays)
Low dose 48 hour – can be done as Low dose 48 hour – can be done as outpatient – 0.5mg every 6 hours: <50nmol/l outpatient – 0.5mg every 6 hours: <50nmol/l is 98% sensitiveis 98% sensitive
High dose 48 hour – to differentiate High dose 48 hour – to differentiate pituitary from ectopic ACTH - 2mg every 6 pituitary from ectopic ACTH - 2mg every 6 hours – become redundant as performance hours – become redundant as performance of test is less than the pre-test likelihood of of test is less than the pre-test likelihood of pituitary diseasepituitary disease
Dexamethasone Dexamethasone Suppression testsSuppression tests
Catches Catches Rely on patient compliance if done at Rely on patient compliance if done at
homehome Malabsorption of dexamethasoneMalabsorption of dexamethasone Drugs that increase hepatic clearance of Drugs that increase hepatic clearance of
dexamethasone e.g. carbamazepine, dexamethasone e.g. carbamazepine, phenytoinphenytoin
Need to stop exogenous oestrogen for 4-6 Need to stop exogenous oestrogen for 4-6 weeks to allow cortisol binding globulin to weeks to allow cortisol binding globulin to return to basal values (assays measure return to basal values (assays measure total cortisol but only free is active)total cortisol but only free is active)
GH axisGH axis
DeficiencyDeficiency
Stimulation tests such as ITTStimulation tests such as ITT
Excess – glucose Excess – glucose tolerance testtolerance test
AKA growth hormone suppression testAKA growth hormone suppression test Done in same way as test for diabetes/glucose Done in same way as test for diabetes/glucose
intoleranceintolerance Fasting then 75g glucose load (Polycal Fasting then 75g glucose load (Polycal
preferred – Lucozade keeps changing! ) then preferred – Lucozade keeps changing! ) then sit and do nothing sit and do nothing – no exercise, smoking, – no exercise, smoking, coffee !coffee !
Normal response is suppression to <0.14 Normal response is suppression to <0.14 mcg/lmcg/l
In acromegaly GH will not fall < 1 mcg/l (?still In acromegaly GH will not fall < 1 mcg/l (?still true – need to re-evaluate with new assays)true – need to re-evaluate with new assays)
False positives False positives
Failure of normal suppression but no Failure of normal suppression but no acromegalyacromegaly
Diabetes mellitusDiabetes mellitus Liver diseaseLiver disease Renal diseaseRenal disease AdolescenceAdolescence Anorexia nervosaAnorexia nervosa
False negatives can also occurFalse negatives can also occur
New assay dataNew assay data
Suggest we need to look again at Suggest we need to look again at diagnostic cut offsdiagnostic cut offs
25% of patients subsequently 25% of patients subsequently proven to have acromegaly proven to have acromegaly suppressed to <1 mcg/lsuppressed to <1 mcg/l
Posterior pituitaryPosterior pituitary
Water deprivation testWater deprivation test
Diagnosis of diabetes insipidusDiagnosis of diabetes insipidus Differential diagnosis of thirst Differential diagnosis of thirst
polyuria and nocturiapolyuria and nocturia
Precautions Precautions
Need to watch for dehydrationNeed to watch for dehydration Thyroid function and adrenal Thyroid function and adrenal
reserve must be normal or reserve must be normal or replacedreplaced
Close rapid liaison with lab is Close rapid liaison with lab is vital – results are needed quickly vital – results are needed quickly – ensure lab know the test is – ensure lab know the test is going ongoing on
Procedure Procedure
Allow fluids until 07.30 but no tea, Allow fluids until 07.30 but no tea, coffee or smokingcoffee or smoking
No food or fluid from 07.30No food or fluid from 07.30 Weigh patient and work out 97% Weigh patient and work out 97%
of weightof weight Directly supervise patient to avoid Directly supervise patient to avoid
cheatingcheating 8 hours water deprivation unless 8 hours water deprivation unless
stopping earlystopping early
WeightWeight
Weigh basally and at 4,6,7 and 8 Weigh basally and at 4,6,7 and 8 hours hours
If >3% weight lost send urgent If >3% weight lost send urgent serum osmolality serum osmolality
if >300 mosmol/kg give DDAVP if >300 mosmol/kg give DDAVP and allow to drink and allow to drink
If <300 mosmol/kg patient was If <300 mosmol/kg patient was probably fluid overloaded at the probably fluid overloaded at the start of the teststart of the test
Biochemical monitoringBiochemical monitoring
Hourly urine vols and osmolalityHourly urine vols and osmolality Hourly serum osmolalityHourly serum osmolality Record results on proformaRecord results on proforma
Give 2mcg desmopressin Give 2mcg desmopressin IM:IM:
If weight falls >3% and serum If weight falls >3% and serum osmolality >300osmolality >300
If serum osmolality >300 and If serum osmolality >300 and urine osmolality <600urine osmolality <600
Then measure urine vols and Then measure urine vols and osmolalities for further 2-4 hours osmolalities for further 2-4 hours (allow to eat and drink)(allow to eat and drink)
InterpretationInterpretation If urine osmolality <600 and serum If urine osmolality <600 and serum
osmolality > 300 after 8 hours of fluid osmolality > 300 after 8 hours of fluid deprivation then diagnosis is DI. deprivation then diagnosis is DI.
Assuming urine concentrates to >600 Assuming urine concentrates to >600 after DDAVP administration diagnosis is after DDAVP administration diagnosis is cranial DI. If this does not occur cranial DI. If this does not occur diagnosis is nephrogenic DI.diagnosis is nephrogenic DI.
Urine osmolality >600 in context of Urine osmolality >600 in context of normal serum osmolality after 8 hours normal serum osmolality after 8 hours excludes DI and no need for DDAVP excludes DI and no need for DDAVP administration.administration.
Consider psychogenic polydipsia if basal Consider psychogenic polydipsia if basal serum osmolality is <260 in presence of serum osmolality is <260 in presence of low urine osmolality.low urine osmolality.
Prolonged WDT (Miller and Prolonged WDT (Miller and Moses)Moses)
For mild DI where serum fails to For mild DI where serum fails to concentrate to >300 after 8 hours concentrate to >300 after 8 hours water deprivationwater deprivation
Unless symptoms very mild do Unless symptoms very mild do standard WDT 1standard WDT 1stst
Patient nil by mouth from 6pm the Patient nil by mouth from 6pm the night before – so patient starts night before – so patient starts more dehydrated more dehydrated
Otherwise interpretation the sameOtherwise interpretation the same
Clinical Clinical Scenario’sScenario’s
Investigation of suspected Investigation of suspected Cushing’sCushing’s
Clinical featuresClinical features
Proportion (%)Proportion (%)
Obesity/wt gainObesity/wt gain 9595
Facial plethoraFacial plethora 9090
Round faceRound face 9090
Thin skinThin skin 8585
Hypertension Hypertension 7575
HirsutismHirsutism 7575
Easy bruisingEasy bruising 6565
Glucose intoleranceGlucose intolerance 6060
Terminology Terminology
Cushing’s syndromeCushing’s syndrome – the – the biochemical syndrome of cortisol biochemical syndrome of cortisol excessexcess
Cushing’s diseaseCushing’s disease – the specific – the specific cause of the Cushing’s syndrome cause of the Cushing’s syndrome is a pituitary adenomais a pituitary adenoma
How picked upHow picked up
Can be floridCan be florid Can be subtle – probably many Can be subtle – probably many
are missed in hypertension, sleep are missed in hypertension, sleep apnoea and diabetes clinicsapnoea and diabetes clinics
Needs to be ruled out before Needs to be ruled out before bariatric surgerybariatric surgery
Process Process
1.1. Prove cortisol excessProve cortisol excess
2.2. Decide if ACTH dependent or Decide if ACTH dependent or ACTH independentACTH independent
3.3. If ACTH dependent – decide if If ACTH dependent – decide if pituitary or ectopic ACTHpituitary or ectopic ACTH
Bear in mindBear in mind
Proportion Proportion (%)(%)
Female:maleFemale:male
Cushing’s Cushing’s diseasedisease
7070 3.5:13.5:1
Ectopic ACTHEctopic ACTH 1010 1:11:1
Unknown Unknown ACTHACTH
55 5:15:1
Adrenal Adrenal adenomaadenoma
1010 4:14:1
Adrenal CaAdrenal Ca 55 1:11:1
Macronod Macronod hyperplhyperpl
<2<2 1:11:1
Pigmented Pigmented nodnod
<2<2 1:11:1
McCune-McCune-AlbrightAlbright
<2<2 1:11:1
Diagnosing Diagnosing hypercortisolaemiahypercortisolaemia
LDDST – 3-8% with Cushing’s suppress (if high LDDST – 3-8% with Cushing’s suppress (if high suspicion do DS-CRH test- 15 mins post CRH suspicion do DS-CRH test- 15 mins post CRH cortisol >38 nmol/l=CS). False positives more cortisol >38 nmol/l=CS). False positives more commoncommon
Overnight DST – less specific with more false Overnight DST – less specific with more false positivespositives
24 hour UFC – need repeated tests as single 24 hour UFC – need repeated tests as single measurements have low sensitivity. Collections measurements have low sensitivity. Collections often incompleteoften incomplete
Midnight cortisol – plasma or salivary – look for Midnight cortisol – plasma or salivary – look for loss of diurnal variation. Midnight plasma cortisol loss of diurnal variation. Midnight plasma cortisol excludes Cushing’s but needs admission. Salivary excludes Cushing’s but needs admission. Salivary cortisol : renewed interestcortisol : renewed interest as sens and spec 95-as sens and spec 95-98% and is surrogate for plasma free cortisol98% and is surrogate for plasma free cortisol
Establish the cause Establish the cause
Measure ACTH:Measure ACTH: < 5 pg/ml = ACTH independent< 5 pg/ml = ACTH independent >15 pg/ml = ACTH dependent>15 pg/ml = ACTH dependent
ACTH IndependentACTH Independent
Image adrenal glandsImage adrenal glands
ACTH dependentACTH dependent
Remember 70%+ will be pituitary Remember 70%+ will be pituitary – more in females– more in females
Don’t rely on imaging to tell Don’t rely on imaging to tell pituitary from ectopicpituitary from ectopic
Pituitary MRI often normal in Pituitary MRI often normal in Cushing’s Disease (up to 40%) – Cushing’s Disease (up to 40%) – adenoma’s smalladenoma’s small
Dynamic testsDynamic tests
High dose DSTHigh dose DST: 80% of patients with : 80% of patients with Cushing’s show cortisol suppression of > Cushing’s show cortisol suppression of > 50%. Adds little and not needed if >30% 50%. Adds little and not needed if >30% suppression on low dosesuppression on low dose
CRH testCRH test – measure cortisol and ACTH – measure cortisol and ACTH response to ovine or human CRH. In response to ovine or human CRH. In Cushing’s disease CRH responsiveness Cushing’s disease CRH responsiveness persists (20% rise) unlike ectopic. persists (20% rise) unlike ectopic. Responses variable but sensitivity 86-93% Responses variable but sensitivity 86-93% for Cushing’s diseasefor Cushing’s disease
IfIf
ACTH dependent Cushing’s ACTH dependent Cushing’s proven with typical responses on proven with typical responses on DST and CRH and 6mm lesion or DST and CRH and 6mm lesion or more on MRI then reasonable to more on MRI then reasonable to operateoperate
Otherwise more info neededOtherwise more info needed
Inferior petrosal sinus Inferior petrosal sinus samplingsampling
Inferior petrosal sinus Inferior petrosal sinus samplingsampling
Sample gradient of ACTH from the Sample gradient of ACTH from the pituitary to the periphery pituitary to the periphery
Site cannulae under venographic screeningSite cannulae under venographic screening Cushing’s disease:Cushing’s disease: Basal central:peripheral ratio of 2:1Basal central:peripheral ratio of 2:1 CRH stimulated ratio of 3:1CRH stimulated ratio of 3:1 ‘‘Gold standard’ but not perfect: false Gold standard’ but not perfect: false
positives and negatives (<10%) describedpositives and negatives (<10%) described Only 70% accurate for lateralisation in Only 70% accurate for lateralisation in
adultsadults
OverallOverall
Measure ACTH
< 5pg/ml >15 pg/ml
Adrenal imagingPituitaryMRI
+/- CRH+/- High dose DST
Adenoma surgery
No adenoma IPPS
Clinical Case – Mr MJClinical Case – Mr MJ
Age 57Age 57 Seen in diabetes clinicSeen in diabetes clinic Hypertensive and obese (BMI Hypertensive and obese (BMI
>50)>50) Somewhat Cushingoid in Somewhat Cushingoid in
appearance but no striaeappearance but no striae
Initial screenInitial screen
24 hour UFC: 24 hour UFC: 1189 nmol/d 1189 nmol/d 855 nmol/d855 nmol/d
Reference range 40-305 nmol/dReference range 40-305 nmol/d
Prolactin 133, testo 2.9, IGF -1 Prolactin 133, testo 2.9, IGF -1 20.4, TSH 1.7 fT4 1520.4, TSH 1.7 fT4 15
Confirming Cushing’s Confirming Cushing’s Syndrome – Syndrome –
48 hour low dose DST48 hour low dose DST Cortisol: 515 nmol/l → 376 nmol/l Cortisol: 515 nmol/l → 376 nmol/l
(27% reduction) (27% reduction)
Confirming ACTH Confirming ACTH dependencedependence
Basal ACTH 63 ng/lBasal ACTH 63 ng/l
Confirming pituitary source Confirming pituitary source – high dose DST– high dose DST
519 nmol/l → 75 nmol/l519 nmol/l → 75 nmol/l
Confirming pituitary source Confirming pituitary source – CRH test– CRH test
00 1515 3030 4545 6060 9090 120120
CortCortisolisol
361361 442442 565565 559559 524524 476476 429429
ACTACTHH
6868 190190 199199 163163 133133 8282 6666
ImagingImaging
Showed small adenoma on CT Showed small adenoma on CT then MRIthen MRI
In view of evidence (and patients In view of evidence (and patients obesity) IPPS not doneobesity) IPPS not done
Transphenoidal SurgeryTransphenoidal Surgery
Adenoma with ACTH staining removedAdenoma with ACTH staining removed 30 kg weight loss30 kg weight loss Diabetes resolvedDiabetes resolved BP easier to controlBP easier to control Initial synacthen test abnormal – Initial synacthen test abnormal –
subsequently normalised so now off subsequently normalised so now off hydrocortisone replacement and hydrocortisone replacement and remains well with no signs of remains well with no signs of recurrencerecurrence
Treatment – Treatment – transsphenoidal transsphenoidal
surgery surgery
Treatment – Treatment – transsphenoidal surgery transsphenoidal surgery
up to 90% remission rate in up to 90% remission rate in microadenomas, less if no microadenomas, less if no obvious tumour or large tumourobvious tumour or large tumour
Patients require steroid cover Patients require steroid cover afterwards – if they don’t they are afterwards – if they don’t they are not cured !not cured !
Complication rate 14% with Complication rate 14% with mortality of 2%mortality of 2%
AdrenalectomyAdrenalectomy
Cures all forms of ACTH Cures all forms of ACTH independent Cushing’s syndromeindependent Cushing’s syndrome
Bilateral adrenalectomy for Bilateral adrenalectomy for ACTH dependent Cushing’s but ACTH dependent Cushing’s but risk of Nelson’s syndromerisk of Nelson’s syndrome
RadiotherapyRadiotherapy
Primary radiotherapy: long term Primary radiotherapy: long term remission of 37%remission of 37%
Usually used 2Usually used 2ndnd line after line after surgery: 88% remission but can surgery: 88% remission but can take 5 years – usually results in take 5 years – usually results in other pituitary hormone deficits other pituitary hormone deficits (GH>hypogonad>hypothyroid>A(GH>hypogonad>hypothyroid>ACTH)CTH)
Medical therapy -Medical therapy -metyraponemetyrapone
inhibits 11inhibits 11 hydroxylase so blocks: hydroxylase so blocks: 11deoxycortisol11deoxycortisolcortisolcortisol
11 deoxycortisol levels rise: in some 11 deoxycortisol levels rise: in some assays 11 deoxycortisol cross reacts assays 11 deoxycortisol cross reacts with cortisol. Can result in with cortisol. Can result in unnecessary increase in treatmentunnecessary increase in treatment
ACTH levels rise but do not usually ACTH levels rise but do not usually overcome blockovercome block
Rise in adrenal androgens causes Rise in adrenal androgens causes hirsutismhirsutism
Medical therapy - Medical therapy - ketoconazoleketoconazole
Antifungal agentAntifungal agent Inhibits several enzymes in steroid Inhibits several enzymes in steroid
synthesis pathwaysynthesis pathway Also reduces adrenal androgens so Also reduces adrenal androgens so
no hirsutism (and cholesterol)no hirsutism (and cholesterol) Can be hepatotoxicCan be hepatotoxic Interacts with simvastatinInteracts with simvastatin Anaesthetic agent etomidate works Anaesthetic agent etomidate works
similarlysimilarly
Monitoring treatmentMonitoring treatment
Cortisol day curves (mean Cortisol day curves (mean cortisol between 150 and 300 cortisol between 150 and 300 nmol/l corresponds with a nmol/l corresponds with a normal cortisol production rate) normal cortisol production rate) – beware cross reactivity with 11 – beware cross reactivity with 11 deoxycortisol if on metyraponedeoxycortisol if on metyrapone
24 hour UFC’s24 hour UFC’s
AcromegalyAcromegaly
DiagnosisDiagnosis
GH suppression testGH suppression test IGF-1IGF-1
TreatmentTreatment
Surgery- cure up to 90% micro, <60% Surgery- cure up to 90% micro, <60% macromacro
Radiotherapy – can take several years to Radiotherapy – can take several years to workwork
Dopamine agonists –effective in up to Dopamine agonists –effective in up to 30%30%
Somatostatin analogues- effective in Somatostatin analogues- effective in 66%. Can be used pre-op to shrink & 66%. Can be used pre-op to shrink & soften – can shrink by 40% soften – can shrink by 40%
Pegvisomant - GH receptor antagonistPegvisomant - GH receptor antagonist
Monitoring Monitoring
IGF-1: in ref rangeIGF-1: in ref range GH suppression test: nadir <1 mcg/lGH suppression test: nadir <1 mcg/l GH day curve: mean <2.5 mcg/l GH day curve: mean <2.5 mcg/l
normalises mortality (but used old normalises mortality (but used old polyclonal immunoassays)polyclonal immunoassays)
Controversial ! What if there is Controversial ! What if there is discordance ?discordance ?
Can’t monitor GH if on pegvisomantCan’t monitor GH if on pegvisomant
Issues Issues Probably need age, gender and BMI Probably need age, gender and BMI
specific GH cut offs (GH levels are specific GH cut offs (GH levels are lower with increasing age and BMI. lower with increasing age and BMI. Females have higher GH nadir)Females have higher GH nadir)
Others things affect GH suppression Others things affect GH suppression e.g renal failure, diabetese.g renal failure, diabetes
Other things affect IGF-1 levels e.g. Other things affect IGF-1 levels e.g. malnutrition, liver disease, malnutrition, liver disease, hypothyroidismhypothyroidism
Changes in IGF-1 normative dataChanges in IGF-1 normative data
Discordance between GHST Discordance between GHST and IGF-1and IGF-1
Most commonly normal IGF-1 but Most commonly normal IGF-1 but high GHhigh GH
Repeat tests after 3 months – usually Repeat tests after 3 months – usually doesn’t helpdoesn’t help
Somatostain analogues have less Somatostain analogues have less effect on GHST than IGF-1effect on GHST than IGF-1
Most people would follow IGF-1 Most people would follow IGF-1 result but watch closely for result but watch closely for recurrence if GH suppression is recurrence if GH suppression is abnormal (evidence of increased abnormal (evidence of increased recurrence rate)recurrence rate)
Clinical CaseClinical Case
30 year old female30 year old female Noticed blurred visionNoticed blurred vision Optican found visual field defect – Optican found visual field defect –
confirmed as bitemporal by confirmed as bitemporal by ophthalmologistophthalmologist
6 months amennorrhoea6 months amennorrhoea On questioning – increased shoe On questioning – increased shoe
size and had to change wedding size and had to change wedding ring twice. Sweating more.ring twice. Sweating more.
On examinationOn examination
Clinically acromegalic with Clinically acromegalic with prominent nasal bridge and jawprominent nasal bridge and jaw
Large handsLarge hands Large tongue with indentation Large tongue with indentation
due to teethdue to teeth
Initial resultsInitial results
IGF1 IGF1 105nmol/l 105nmol/l (13-50)(13-50) Prolactin Prolactin 1154 miu/l1154 miu/l (<500)(<500) Cortisol Cortisol 353 nmol/l353 nmol/l SSTSST 367→535→646 nmol/l367→535→646 nmol/l fT4fT4 9 pmol/l9 pmol/l (9-23)(9-23) TSHTSH 1.77 miu/l1.77 miu/l (0.25-5)(0.25-5) Oestradiol Oestradiol 160 pmol/l160 pmol/l (100-(100-
750)750)
GH Suppression TestGH Suppression Test
BasalBasal 40 40 minmin
70 70 minmin
100 100 minmin
130 130 minmin
GHGH
(mcg/(mcg/l)l)
11.411.4 10.810.8 10.110.1 9.79.7 9.99.9
GlucoGlucosese
(mM)(mM)
4.74.7 5.85.8 5.75.7 5.75.7 5.25.2
ImagingImaging
Large pituitary tumour touching Large pituitary tumour touching the chiasmthe chiasm
Treatment PlanTreatment Plan
Not curable with surgeryNot curable with surgery Pre-op octreotide (to shrink Pre-op octreotide (to shrink
tumour and soften it) then tumour and soften it) then surgerysurgery
Followed up with octreotide and Followed up with octreotide and radiotherapyradiotherapy
May need pegvisomantMay need pegvisomant
Prolactinoma Prolactinoma
Commonest functioning pituitary Commonest functioning pituitary tumourtumour
Present earlier and also more Present earlier and also more common in women – die to common in women – die to amenorrhoeaamenorrhoea
In men may just present with In men may just present with local pressure effectslocal pressure effects
Many causes of high Many causes of high prolactinprolactin
ProlactinomaProlactinoma Drugs: DA antagonists, Drugs: DA antagonists,
neuroleptics, antidepressantsneuroleptics, antidepressants Non functioning tumour (<2000)Non functioning tumour (<2000) Pregnancy/lactationPregnancy/lactation HypothyroidismHypothyroidism Renal failure Renal failure PCOSPCOS
Lab issuesLab issues
Remember macroprolactin – Remember macroprolactin – screen all samplesscreen all samples
Prolactin levels can be very high Prolactin levels can be very high (>100,000) so if clinical (>100,000) so if clinical suspicion high but prolactin suspicion high but prolactin levels normal look for hook effect levels normal look for hook effect by diluting samplesby diluting samples
Features - hormonalFeatures - hormonal
GalactorrhoeaGalactorrhoea Menstrual disturbanceMenstrual disturbance Reduced libido/erectile Reduced libido/erectile
dysfunctiondysfunction Osteoporosis (long term)Osteoporosis (long term)
Features - massFeatures - mass
HeadachesHeadaches Visual field lossVisual field loss HypopituitarismHypopituitarism Cranial nerve palsiesCranial nerve palsies CSF leak (rare)CSF leak (rare)
If prolactin high but on If prolactin high but on drug known to increase drug known to increase
prolactinprolactin DilemmaDilemma Consider if timing fitsConsider if timing fits Can drug be withdrawn or Can drug be withdrawn or
changed ?changed ? Often end up doing MRI but Often end up doing MRI but
incidentalomas are commonincidentalomas are common
ProlactinomaProlactinoma
If PRL >2000 very likely If PRL >2000 very likely prolactinoma, if >5000 definitely prolactinoma, if >5000 definitely soso
If unsure if functioning or not If unsure if functioning or not can treat and rescancan treat and rescan
Prolactin levels will fall with Prolactin levels will fall with medical therapy anyway – more medical therapy anyway – more so if not prolactinomaso if not prolactinoma
Medical management – Medical management – Dopamine agonistsDopamine agonists
BromocriptineBromocriptine CabergolineCabergoline Quinagolide – being used more as Quinagolide – being used more as
no known risk of heart valve no known risk of heart valve fibrosisfibrosis
Clinical case – Mr JFClinical case – Mr JF 42 year old man with erectile 42 year old man with erectile
dysfunctiondysfunction No other symptomsNo other symptoms 10 year old child10 year old child Prolactin 23,000 with negative Prolactin 23,000 with negative
macroprolactin screenmacroprolactin screen Testosterone 2.0 nmol/l, LH <0.1 U/LTestosterone 2.0 nmol/l, LH <0.1 U/L fT4 23 TSH 2.43, SST normal, IGF-1 fT4 23 TSH 2.43, SST normal, IGF-1
18.118.1 MRI: macroadenoma but away from MRI: macroadenoma but away from
chiasmchiasm
On CabergolineOn Cabergoline
Prolactin now 686Prolactin now 686 Testosterone no better Testosterone no better Started on testosterone Started on testosterone
replacement – gel then Nebido and replacement – gel then Nebido and erectile problems resolvederectile problems resolved
Pituitary lesion smallerPituitary lesion smaller fT4 11 TSH 2.86 so started on fT4 11 TSH 2.86 so started on
thyroxine in case secondary thyroxine in case secondary hypothyroidismhypothyroidism
Pituitary Pituitary ApoplexyApoplexy
Pituitary ApoplexyPituitary Apoplexy
Acute infarction or haemorrhage of Acute infarction or haemorrhage of the pituitarythe pituitary
Usually an adenoma is presentUsually an adenoma is present Acute headache (retro-orbital), visual Acute headache (retro-orbital), visual
disturbance, altered mental function, disturbance, altered mental function, cranial nerve palsies & endocrine cranial nerve palsies & endocrine dysfunctiondysfunction
Can occur post partum in Can occur post partum in nontumorous glands – Sheehan’s nontumorous glands – Sheehan’s SyndromeSyndrome
ManagementManagement
Endocrine emergencyEndocrine emergency Send off baseline bloods – cortisol, Send off baseline bloods – cortisol,
TFT’s, IGF1, LH/FSH, testo/oestradiol, TFT’s, IGF1, LH/FSH, testo/oestradiol, prolactinprolactin
Urgent steroid replacement with high Urgent steroid replacement with high dose hydrocortisone or dexamethasonedose hydrocortisone or dexamethasone
Urgent discussion with neurosurgeons – Urgent discussion with neurosurgeons – if compression of chiasm or cranial if compression of chiasm or cranial nerve palsy surgery is indicatednerve palsy surgery is indicated
Learning ObjectivesLearning Objectives
Describe pituitary anatomy and Describe pituitary anatomy and endocrine physiologyendocrine physiology
Describe methods for assessing Describe methods for assessing pituitary function using static and pituitary function using static and dynamic testingdynamic testing
Describe the new standard for the Describe the new standard for the measurement of growth hormone & measurement of growth hormone & its effects on clinical criteriaits effects on clinical criteria
Be are of the importance of Be are of the importance of screening for macroprolactinscreening for macroprolactin