Pituitary Function and Pituitary Function and PathologyPathologyDr Duncan FowlerDr Duncan Fowler

The Ipswich HospitalThe Ipswich Hospital

OverviewOverview

AnatomyAnatomy Physiology Physiology Assessment of pituitary function: static and Assessment of pituitary function: static and

dynamic testsdynamic tests Clinical scenario’s:Clinical scenario’s: Cushing’s DiseaseCushing’s Disease AcromegalyAcromegaly ProlactinomaProlactinoma ApoplexyApoplexy

Learning ObjectivesLearning Objectives

Describe pituitary anatomy and endocrine Describe pituitary anatomy and endocrine physiologyphysiology

Describe methods for assessing pituitary Describe methods for assessing pituitary function using static and dynamic testingfunction using static and dynamic testing

Describe the new standard for the Describe the new standard for the measurement of growth hormone & its measurement of growth hormone & its effects on clinical criteriaeffects on clinical criteria

Be are of the importance of screening for Be are of the importance of screening for macroprolactinmacroprolactin

Hypothalamo-pituitary anatomyHypothalamo-pituitary anatomy

Hypothalamus is the part of the diencephalon Hypothalamus is the part of the diencephalon associated with visceral, autonomic, endocrine associated with visceral, autonomic, endocrine affective and emotional behaviouraffective and emotional behaviour

Ventral portion forms the infundibulumVentral portion forms the infundibulum Posterior to this is the median eminence – the final Posterior to this is the median eminence – the final

point of convergence of pathways from the CNS on point of convergence of pathways from the CNS on the endocrine system and is vascularised by the the endocrine 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 factors controlled by releasing and inhibiting factors released from nerves in the median eminence released from nerves in the median eminence into the hypophyseal portal vessels which carry into the hypophyseal portal vessels which carry them to the pituitary them to the pituitary

NeurohypophysisNeurohypophysis = posterior pituitary. It is an = posterior pituitary. It is an extension of the CNS. Its function is controlled extension of the CNS. Its function is controlled by direct neural connection to the hypothalamusby direct neural connection to the hypothalamus

PresentationPresentation

Hormonal hypersecretion e.g. AcromegalyHormonal hypersecretion e.g. Acromegaly Hormonal deficiency e.g amenorrhoeaHormonal deficiency e.g amenorrhoea Local pressure effects: headaches, visual Local pressure effects: headaches, visual

field loss – bitemporal hemianopia – bump field loss – bitemporal hemianopia – bump into thingsinto things

Identical Identical αα chain but specific chain but specific ββ chain – non covalently associatedchain – non covalently 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 – hCG)(human chorionic gonadotrophin – hCG)

Potential for cross reaction e.g. hyperemesisPotential for cross reaction e.g. hyperemesis

Control of anterior Control of anterior pituitary functionpituitary function

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 into the releasing hormone (TRH) released into the hypohyseal portal vessels in the median hypohyseal portal vessels in the median eminenceeminence

(TRH also stimulates prolactin release and (TRH also stimulates prolactin release and in some circumstances growth hormone)in some circumstances growth hormone)

Inhibitors of TSHInhibitors of TSH

Thyroid hormones directly inhibit TSH Thyroid hormones directly inhibit TSH (and to a lesser extent TRH) release(and to a lesser extent TRH) release

This can prevent the action of TRH This can prevent the action of TRH which is basis for TRH testwhich is basis for TRH test

Dopamine and somatostatin inhibit Dopamine and somatostatin inhibit release ?physiologically important but release ?physiologically important but useful clinically for TSHomasuseful clinically for TSHomas

Stimulators of LH/FSHStimulators of LH/FSH

Pulsatile secretionPulsatile secretion Stimulated by pulsatile secretion of gonadotrophin Stimulated by pulsatile secretion of gonadotrophin

secreting hormone (GnRH) into the hypophyseal secreting hormone (GnRH) into the hypophyseal portal vesselsportal vessels

GnRH release is complex and very susceptible to GnRH release is complex and very susceptible to stress and changes to nutrition and energy stress and changes to nutrition and energy homeostasis e.g. hypothalamic hypogonadotrophic homeostasis e.g. hypothalamic hypogonadotrophic hypogonadism seen in weight loss or extreme hypogonadism seen in weight loss or extreme exerciseexercise

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 releaseInhibin from the ovary inhibits FSH release 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 cleaved from ACTH is a single chain peptide cleaved from POMC along with MSH and POMC along with MSH and ββ endorphin (hence endorphin (hence pigmentation in Addison’s) pigmentation in Addison’s)

Secreted in pulsatile fashion in response to Secreted in pulsatile fashion in response to corticotrophin releasing hormone (CRH) – corticotrophin releasing hormone (CRH) – determines set point around which cortisol determines set point around which cortisol feedback worksfeedback works

Circadian rhythm with superimposed effects of Circadian rhythm with superimposed effects of stressstress

Inhibitors of ACTHInhibitors of ACTH

Feedback from cortisol mainly directly on pituitary Feedback from cortisol mainly directly on pituitary but also on CRH releasebut also on CRH release

Other adrenal androgens whose secretions are Other adrenal androgens whose secretions are enhanced by ACTH do enhanced by ACTH do not not have a feedback effect have a feedback effect e.g. in congenital adrenal hyperplasiae.g. in congenital adrenal hyperplasia

Feedback can be imitated by synthetic Feedback can be imitated by synthetic glucocorticoids e.g. Dexamethasone (used in glucocorticoids e.g. Dexamethasone (used in suppression testing – tumorous corticotrophs less suppression testing – tumorous corticotrophs less susceptible to feedback)susceptible to feedback)

Stimulators of GH releaseStimulators of GH release

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 (arginine Amino acids stimulate GH release (arginine

can be used if ITT contraindicated)can be used if ITT contraindicated)

Inhibitors of GH releaseInhibitors of GH release

Somatostatin inhibits GH releaseSomatostatin inhibits GH release Feedback from GH and IGF-1 inhibit GH Feedback from GH and IGF-1 inhibit GH

release at pituitary and hypothalamic levelrelease at pituitary and hypothalamic level Free fatty acids inhibit GH releaseFree fatty acids inhibit GH release Glucose inhibits GHRH and GH release Glucose inhibits GHRH and GH release

(basis of GH suppression test for (basis of GH suppression test for acromegaly)acromegaly)

Stimulators of prolactin releaseStimulators of prolactin release

Released in pulsatile fashion especially at nightReleased in pulsatile fashion especially at night No direct stimulatory factor No direct stimulatory factor

Prolactin release is under tonic inhibitory Prolactin release is under tonic inhibitory controlcontrol

Oestrogens cause hyperplasia of lactotrophs Oestrogens cause hyperplasia of lactotrophs (hence care with COC with prolactinomas) & (hence care with COC with prolactinomas) & enhance prolactin releaseenhance prolactin release

TRH causes release of prolactin as well as TSH TRH causes release of prolactin as well as TSH but this is not physiologicalbut this is not physiological

Inhibitors of prolactin releaseInhibitors of prolactin release

Dopamine tonically inhibits releaseDopamine tonically inhibits release Impeding the hypophyseal portal circulation Impeding the hypophyseal portal circulation

causes enhanced prolactin release in causes enhanced prolactin release in contrast to other pituitary hormones. contrast to other pituitary hormones. Prolactin can rise to 2000 mU/l due to this Prolactin can rise to 2000 mU/l due to this ‘stalk effect’‘stalk effect’

Dopamine antagonist drugs e.g. Dopamine antagonist drugs e.g. metoclopramide, tricyclic antidepressants metoclopramide, tricyclic antidepressants can stimulate prolactin releasecan stimulate prolactin release

Static Pituitary TestsStatic Pituitary Tests

ProlactinProlactin TFT’sTFT’s LH/FSH and testosterone/oestradiol – but LH/FSH and testosterone/oestradiol – but

timing importanttiming important IGF-1 (for GH)IGF-1 (for GH) Cortisol – random samples not usually Cortisol – random samples not usually

helpful –usually done 9amhelpful –usually done 9am Serum and urine osmolality (plus additional Serum and urine osmolality (plus additional

tests to investigate SIADH)tests to investigate SIADH)

ProlactinProlactin

If in doubt measure basal prolactin on 3 If in doubt measure basal prolactin on 3 occasionsoccasions

MacroprolactinMacroprolactin Non-bioactive prolactin: monomer of prolactin Non-bioactive prolactin: monomer of prolactin

and IgG molecule with prolonged clearance rateand IgG molecule with prolonged clearance rate 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 precipitate Treat sera with polyethylene glycol to precipitate

out immunoglobulins then re assay for prolactinout immunoglobulins then re assay for 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 – people Macroprolactin is not biologically active – people with it have normal gonadal functionwith 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 macroprolactin:“hyperprolactinaemia” due to macroprolactin:

inappropriate dopamine agonist treatmentinappropriate dopamine agonist treatment imaging of the pituitary undertaken revealing imaging of the pituitary undertaken revealing

incidentalomas (found in up to 10%) and incidentalomas (found in up to 10%) and unnecessary investigation and treatmentunnecessary investigation and treatment

Prevalence of macroprolactinaemiaPrevalence of macroprolactinaemiaClin Endo 71;702 (2009)Clin Endo 71;702 (2009)

1330 hospital workers in Japan screened for 1330 hospital workers in Japan screened for hepatitis Bhepatitis 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 precipitationmonomeric prolactin on PEG precipitation

29 of 1281 (2.26%) without macroprolactin 29 of 1281 (2.26%) without macroprolactin had (true) hyperprolactinaemiahad (true) hyperprolactinaemia

Of the 44 hyperprolactinaemias, 15 had Of the 44 hyperprolactinaemias, 15 had macroprolactinaemia (34%)macroprolactinaemia (34%)

Nobody had macroprolactinaemia and Nobody had macroprolactinaemia and raised free prolactinraised free prolactin

All sera with macroprolactin showed All sera with macroprolactin showed complexes of prolactin and IgG – most had complexes of prolactin and IgG – most had anti PRL Abs, with others showing a variety anti PRL Abs, with others showing a variety of prolactin complexesof prolactin 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 antiPRL AbsOf the 12 sera without antiPRL 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 TSH in TFT’s - Lack of elevation of TSH in the presence of low T4 the presence of low T4

Indicates pituitary or hypothalamic cause of Indicates pituitary or hypothalamic cause of hypothyroidism – or sick euthyroid hypothyroidism – or sick euthyroid syndromesyndrome

Same pattern can occur in 1Same pattern can occur in 1stst few months of few months of treatment of thyrotoxicosis: T4 and T3 can treatment of thyrotoxicosis: T4 and T3 can be reduced below normal by carbimazole yet be reduced below normal by carbimazole yet TSH remains suppressedTSH remains suppressed

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 than T4fT3 is low or undetectable – reduced more than 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 binding Preferential production of rT3, reduced binding

globulins and circulating thyroid homone binding globulins and circulating thyroid homone binding inhibitorsinhibitors

Clinical judgement but more common than 2º Clinical judgement but more common than 2º hypothyroidismhypothyroidism

TFT’s - Elevated fT4 and fT3 with TFT’s - Elevated fT4 and fT3 with failure of suppression of TSH failure of suppression of TSH

Discordant T4 and T3Discordant T4 and T3 Interfering antibodies – no clinical signsInterfering antibodies – no clinical signs AmiodaroneAmiodarone Familial dysalbuminaemic Familial dysalbuminaemic

hyperthyroxinaemiahyperthyroxinaemia

TFT’s - Elevated fT4 and fT3 with TFT’s - Elevated fT4 and fT3 with failure of suppression of TSH failure of 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 resistanceTSHoma vs hormone resistanceTSHomaTSHoma PRTHPRTH

Clinically toxicClinically toxic YesYes VariableVariable

Family historyFamily history NoNo YesYes

αα subunitsubunit HighHigh NormalNormal

αα subunit/TSH subunit/TSH molar ratiomolar ratio

High (>1)High (>1) NormalNormal

TRH testTRH test BluntedBlunted NormalNormal

TSH response:T3 TSH response:T3 suppression testsuppression test

No changeNo change decreasedecrease

Peripheral actionPeripheral action HighHigh NormalNormal

GonadotophinsGonadotophins

In menstruating females tests not usually In menstruating females tests not usually neededneeded

Day 21 progesterone gives information on Day 21 progesterone gives information on ovulationovulation

High prolactin can suppress gonadotrophin High prolactin can suppress gonadotrophin secretionsecretion

In males if 9am testosterone is normal then In males if 9am testosterone is normal then gonadotrophin secretion is adequategonadotrophin secretion is adequate

Growth hormoneGrowth hormone

Random tests not helpful due to pulsatile Random tests not helpful due to pulsatile secretionsecretion

Need dynamic testing or IGF-1Need dynamic testing or IGF-1

GH assaysGH assays

Evolved from polyclonal RIA’s to 2 site Evolved from polyclonal RIA’s to 2 site monoclonal antibody non-isotopic assays monoclonal antibody non-isotopic assays with enhanced sensitivitywith enhanced sensitivity

Accurately quantify previously undetectable Accurately quantify previously undetectable valuesvalues

Do we need age and gender dependent Do we need age and gender dependent reference ranges ?reference ranges ?

Growth Hormone Units – a mess!Growth Hormone Units – a mess!

Previous standard not pure & contained a number Previous standard not pure & contained a number of isoforms: 22kD, 20kD and dimers/oligomersof isoforms: 22kD, 20kD and dimers/oligomers

UKNEQAS showed between method variation UKNEQAS showed between method variation increasing from 1994 to 1998 from 17 to 30% - most increasing from 1994 to 1998 from 17 to 30% - most negatively biased assay reported values ½ that of negatively biased assay reported values ½ that of most positively biasedmost 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 usedVarious conversion factors between 2 and 3 used No simple conversion factor suitableNo simple conversion factor suitable

New standardNew standard

EU legislation means all lab results must be EU legislation means all lab results must be traceable to a defined material (98/79/EC)traceable to a defined material (98/79/EC)

Since 2001 new international standard in use Since 2001 new international standard in use (IS98/574): 22kD GH of >95% purity(IS98/574): 22kD GH of >95% purity

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 does not normal’ cortisol concentration does not exclude dysfunctionexclude dysfunction

>500 nmol/l makes deficiency unlikely >500 nmol/l makes deficiency unlikely (unless v sick)(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 on risingPaired serum and urine osmolality on rising Normal serum osmolality 280-295 Normal serum osmolality 280-295

mosmol/kg and concentrated urine (ratio mosmol/kg and concentrated urine (ratio >2:1) excludes DI>2:1) excludes DI

In DI serum osmolality is raised and urine In DI serum osmolality is raised and urine ratio is <2.0 (but still may be more than ratio is <2.0 (but still may be more than serum in mild cases)serum in mild cases)

Most need water deprivation testMost need water deprivation test

SIADH – syndrome of inappropriate SIADH – syndrome of inappropriate ADH secretionADH secretion

11stst 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 mOsm/kg)Inappropriate urinary conc (>100 mOsm/kg)

3.3. Clinical euvoloaemiaClinical euvoloaemia

4.4. High urinary Na (>40 mmol/l) with normal salt High urinary Na (>40 mmol/l) with normal salt and water intakeand water intake

5.5. Hypothyroidism & glucocorticoid deficiency Hypothyroidism & glucocorticoid deficiency excludedexcluded

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 despite Why do patients continue to drink despite plasma osmolality below thirst threshold ?plasma osmolality below thirst threshold ?

Hyponatraemia is limited by ‘escape from Hyponatraemia is limited by ‘escape from antidiuresis’: urine flow rises and urine antidiuresis’: urine flow rises and urine osmolality falls and sodium stabilises in osmolality falls and sodium stabilises in hyponatraemic rangehyponatraemic range

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, carbamazepine, chlorpropamide, ecstasy, carbamazepine, cyclophosphamide, SSRI’s, otherscyclophosphamide, SSRI’s, others

Cerebral Salt Wasting SyndromeCerebral Salt Wasting Syndrome

Seen following cerebral insults e.g. head Seen following cerebral insults e.g. head injury, SAH, tumours, surgeryinjury, SAH, tumours, surgery

Causes: hyponatraemia, diuresis, natriuresis, Causes: hyponatraemia, diuresis, natriuresis, hypovolaemiahypovolaemia

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 peptide brain natriuretic peptide Resolves in 2 weeks but responds well to Resolves in 2 weeks but responds well to

salinesaline

CSWS vs SIADHCSWS vs SIADH

CSWSCSWS SIADHSIADH

Plasma NaPlasma Na LowLow LowLow

Plasma ureaPlasma urea HighHigh Low or normalLow or normal

BPBP Low/post lowLow/post low NormalNormal

CVPCVP LowLow NormalNormal

Urinary NaUrinary Na HighHigh HighHigh

Urinary VolumeUrinary Volume IncreasedIncreased DecreasedDecreased

ThirstThirst IncreasedIncreased NormalNormal

Approach to the hyponatraemic Approach to the hyponatraemic patientpatient

Identify clinical signs of underlying disease Identify clinical signs of underlying disease e.g. Addison’se.g. Addison’s

Identify ECF statusIdentify ECF status Measure urinary sodium and osmolalityMeasure urinary sodium and osmolality Check TFT’s (and cortisol +/- synacthen)Check TFT’s (and cortisol +/- synacthen) CXR – for fluid status and underlying CXR – for fluid status and underlying

diseasedisease

Dynamic Pituitary Dynamic Pituitary TestsTests

Dynamic tests - principlesDynamic tests - principles

If you think gland is under active – try to If you think gland is under active – try to stimulate itstimulate it

If you think gland is over active – try to If you think gland is over active – try to suppress itsuppress it

ACTH Adrenal AxisACTH Adrenal Axis

UnderactivityUnderactivity ITTITT Synacthen test – only assesses adrenal function Synacthen test – only assesses adrenal function

directly – pituitary function implieddirectly – pituitary function implied

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. glucagon, Other stimulation tests e.g. glucagon,

argininearginine

OveractivityOveractivity Glucose tolerance testGlucose tolerance test

Thyroid AxisThyroid Axis

Very rarely need dynamic testsVery rarely need dynamic tests TRH test usually adds little –responses vary TRH test usually adds little –responses vary

in 2º hypothyroidism and there are easier in 2º hypothyroidism and there are easier ways to diagnose hyperthyroidismways to diagnose hyperthyroidism

If TSHoma suspected can do TRH test and If TSHoma suspected can do TRH test and T3 suppression test (administer T3 - 80-T3 suppression test (administer T3 - 80-100mcg for 8-10 days - and in TSHoma TSH 100mcg for 8-10 days - and in TSHoma TSH fails to suppress, but suppression seen in fails to suppress, but suppression seen in thyroid hormone resistance)thyroid hormone resistance)

Gonadal AxisGonadal Axis

Dynamic testing rarely done in adult Dynamic testing rarely done in adult practicepractice

GnRH test assesses reserve of LH/FSH GnRH test assesses reserve of LH/FSH secretion – not usually helpfulsecretion – not usually helpful

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 hypoadrenalism (liver Severe longstanding hypoadrenalism (liver

glycogen depleted)glycogen depleted) Glycogen storage diseaseGlycogen storage disease Hypothyroidism – untreated can give Hypothyroidism – untreated can give

subnormal resultssubnormal results

PrecautionsPrecautions

ECG must be normalECG must be normal 9am cortisol must be >100 nmol/l9am cortisol must be >100 nmol/l Serum F4 must be normal (replace 1Serum F4 must be normal (replace 1 stst if low) if low) Have resuscitation facilities, 20% glucose Have resuscitation facilities, 20% glucose

and IV hydrocortisone availableand IV hydrocortisone available

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 the doseIf not hypoglycaemic at 45 mins repeat the dose Give IV glucose if severe and prolonged Give IV glucose if severe and prolonged

hypoglycaemia (>20 mins), LOC or fits – stimulus hypoglycaemia (>20 mins), LOC or fits – stimulus has been adequatehas been adequate

Give lunch and sweet drink at the end of the test Give lunch and sweet drink at the end of the test -consider hydrocortisone-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 (extend if dose 0,30,45,60,90 and 120mins (extend if dose repeated)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 170 nmol/l Serum cortisol rises by more than 170 nmol/l

to at least 580 nmol/lto at least 580 nmol/l GH rises to > 15 mcg/lGH rises to > 15 mcg/l Severe GHD needed for NICE criteria for Severe GHD needed for NICE criteria for

adult GH replacement < 3 mcg/ladult GH replacement < 3 mcg/l GHD that qualifies for GH treatment in GHD that qualifies for GH treatment in

children <7 mcg/lchildren <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 insultCan be misleading after acute pituitary insult Cannot measure GH responseCannot measure GH response

Advantages Advantages Simpler, safer, cheaperSimpler, safer, cheaper Usually good enough in chronic situation (we tend Usually good enough in chronic situation (we tend

to say >6 weeks but Synacthen test becomes to say >6 weeks but Synacthen test becomes abnormal after 8-12 days)abnormal after 8-12 days)

Alternatives to ITT for GHDAlternatives to ITT for GHD

GlucagonGlucagon Arginine Arginine Arginine plus GHRHArginine plus GHRH Clonidine – in children but not adultsClonidine – in children but not adults

These other tests less well validated and only These other tests less well validated and only used if ITT contraindicatedused if ITT contraindicated

Is ITT for GHD always Is ITT for GHD always needed ?needed ?

Which patients do not need a GH Which patients do not need a GH stimulation test stimulation test

JCEM 87; 477-485 (2002)JCEM 87; 477-485 (2002)Pituitary hormone deficitsPituitary hormone deficits % with peak GH <2.5 % with peak GH <2.5

mcg/lmcg/l

00 4141

11 6767

22 8383

33 9696

44 9999

If multiple pituitary axes deficientIf multiple pituitary axes deficient

If 3 or more axes affected then test for GHD If 3 or more axes affected then test for GHD not needed – accuracy compares well with not needed – accuracy compares well with GH stimulation testingGH stimulation testing

The other axes are easier to test: TSH, The other axes are easier to test: TSH, ACTH, gonadotrophins and vasopressinACTH, gonadotrophins and vasopressin

IGF-1 is not reliable for GHDIGF-1 is not reliable for GHD

IGF-1 may be normal in presence of severe IGF-1 may be normal in presence of severe GHD – it is in about a thirdGHD – it is in about a third

Low IGF-1 also occurs in malnutrition, Low IGF-1 also occurs in malnutrition, poorly controlled diabetes, oral and high poorly controlled diabetes, oral and high dose transdermal oestrogen, hypothyroidism dose transdermal oestrogen, hypothyroidism and hepatic insufficiencyand hepatic insufficiency

Short Synacthen TestShort Synacthen Test

Cortisol response to 250mcg of tetracosactrin IV or Cortisol response to 250mcg of tetracosactrin IV or IM (massively supraphysiological)IM (massively 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 >580Normal response is rise by 170 nmol/l to >580 To tell 1º vs 2º measure ACTH (or long test)To tell 1º vs 2º measure ACTH (or long test) 1 mcg test more sensitive to subtle adrenal 1 mcg test more sensitive to subtle adrenal

dysfunction but not used routinelydysfunction but not used routinely

Dexamethasone Suppression testsDexamethasone Suppression 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 outpatient – Low dose 48 hour – can be done as outpatient – 0.5mg every 6 hours: <50nmol/l is 98% sensitive0.5mg every 6 hours: <50nmol/l is 98% sensitive

High dose 48 hour – to differentiate pituitary from High dose 48 hour – to differentiate pituitary from ectopic ACTH - 2mg every 6 hours – become ectopic ACTH - 2mg every 6 hours – become redundant as performance of test is less than the redundant as performance of test is less than the pre-test likelihood of pituitary diseasepre-test likelihood of pituitary disease

Dexamethasone Suppression testsDexamethasone Suppression tests

Catches Catches Rely on patient compliance if done at homeRely on patient compliance if done at home Malabsorption of dexamethasoneMalabsorption of dexamethasone Drugs that increase hepatic clearance of Drugs that increase hepatic clearance of

dexamethasone e.g. carbamazepine, phenytoindexamethasone e.g. carbamazepine, phenytoin Need to stop exogenous oestrogen for 4-6 weeks to Need to stop exogenous oestrogen for 4-6 weeks to

allow cortisol binding globulin to return to basal allow cortisol binding globulin to return to basal values (assays measure total cortisol but only free values (assays measure total cortisol but only free is active)is active)

GH axisGH axis

DeficiencyDeficiency

Stimulation tests such as ITTStimulation tests such as ITT

Excess – glucose tolerance testExcess – glucose tolerance 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 preferred – Fasting then 75g glucose load (Polycal preferred –

Lucozade keeps changing! ) then Lucozade keeps changing! ) then sit and do sit and do nothing nothing – no exercise, smoking, coffee !– no exercise, smoking, coffee !

Normal response is suppression to <0.14 mcg/lNormal response is suppression to <0.14 mcg/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 acromegalyFailure of normal suppression but no acromegaly 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 diagnostic Suggest we need to look again at diagnostic cut offscut offs

25% of patients subsequently proven to have 25% of patients subsequently proven to have acromegaly suppressed to <1 mcg/lacromegaly suppressed to <1 mcg/l

Posterior pituitaryPosterior pituitary

Water deprivation testWater deprivation test

Diagnosis of diabetes insipidusDiagnosis of diabetes insipidus Differential diagnosis of thirst polyuria and Differential diagnosis of thirst polyuria and

nocturianocturia

Precautions Precautions

Need to watch for dehydrationNeed to watch for dehydration Thyroid function and adrenal reserve must Thyroid function and adrenal reserve must

be normal or replacedbe normal or replaced Close rapid liaison with lab is vital – results Close rapid liaison with lab is vital – results

are needed quickly – ensure lab know the are needed quickly – ensure lab know the test is going ontest is going on

Procedure Procedure

Allow fluids until 07.30 but no tea, coffee or Allow fluids until 07.30 but no tea, coffee or smokingsmoking

No food or fluid from 07.30No food or fluid from 07.30 Weigh patient and work out 97% of weightWeigh patient and work out 97% of weight Directly supervise patient to avoid cheatingDirectly supervise patient to avoid cheating 8 hours water deprivation unless stopping 8 hours water deprivation unless stopping

earlyearly

WeightWeight

Weigh basally and at 4,6,7 and 8 hours Weigh basally and at 4,6,7 and 8 hours If >3% weight lost send urgent serum If >3% weight lost send urgent serum

osmolality osmolality if >300 mosmol/kg give DDAVP and allow if >300 mosmol/kg give DDAVP and allow

to drink to drink If <300 mosmol/kg patient was probably If <300 mosmol/kg patient was probably

fluid overloaded at the start of the testfluid overloaded at the start 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 IM:Give 2mcg desmopressin IM:

If weight falls >3% and serum osmolality If weight falls >3% and serum osmolality >300>300

If serum osmolality >300 and urine If serum osmolality >300 and urine osmolality <600osmolality <600

Then measure urine vols and osmolalities Then measure urine vols and osmolalities for further 2-4 hours (allow to eat and drink)for further 2-4 hours (allow to eat and drink)

InterpretationInterpretation If urine osmolality <600 and serum osmolality > If urine osmolality <600 and serum osmolality >

300 after 8 hours of fluid deprivation then diagnosis 300 after 8 hours of fluid deprivation then diagnosis is DI. is DI.

Assuming urine concentrates to >600 after DDAVP Assuming urine concentrates to >600 after DDAVP administration diagnosis is cranial DI. If this does administration diagnosis is cranial DI. If this does not occur diagnosis is nephrogenic DI.not occur diagnosis is nephrogenic DI.

Urine osmolality >600 in context of normal serum Urine osmolality >600 in context of normal serum osmolality after 8 hours excludes DI and no need osmolality after 8 hours excludes DI and no need for DDAVP administration.for DDAVP administration.

Consider psychogenic polydipsia if basal serum Consider psychogenic polydipsia if basal serum osmolality is <260 in presence of low urine osmolality is <260 in presence of low urine osmolality.osmolality.

Prolonged WDT (Miller and Moses)Prolonged WDT (Miller and Moses)

For mild DI where serum fails to For mild DI where serum fails to concentrate to >300 after 8 hours water concentrate to >300 after 8 hours water deprivationdeprivation

Unless symptoms very mild do standard Unless symptoms very mild do standard WDT 1WDT 1stst

Patient nil by mouth from 6pm the night Patient nil by mouth from 6pm the night before – so patient starts more dehydrated before – so patient starts more dehydrated

Otherwise interpretation the sameOtherwise interpretation the same

Clinical Scenario’sClinical Scenario’s

Investigation of suspected Cushing’sInvestigation of suspected Cushing’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 biochemical – the biochemical syndrome of cortisol excesssyndrome of cortisol excess

Cushing’s diseaseCushing’s disease – the specific cause of the – the specific cause of the Cushing’s syndrome is a pituitary adenomaCushing’s syndrome is a pituitary adenoma

How picked upHow picked up

Can be floridCan be florid Can be subtle – probably many are missed Can be subtle – probably many are missed

in hypertension, sleep apnoea and diabetes in hypertension, sleep apnoea and diabetes clinicsclinics

Needs to be ruled out before bariatric Needs to be ruled out before bariatric surgerysurgery

Process Process

1.1. Prove cortisol excessProve cortisol excess

2.2. Decide if ACTH dependent or ACTH Decide if ACTH dependent or ACTH independentindependent

3.3. If ACTH dependent – decide if pituitary or If ACTH dependent – decide if pituitary or ectopic ACTHectopic ACTH

Bear in mindBear in mind

Proportion (%)Proportion (%) Female:maleFemale:male

Cushing’s diseaseCushing’s disease 7070 3.5:13.5:1

Ectopic ACTHEctopic ACTH 1010 1:11:1

Unknown ACTHUnknown ACTH 55 5:15:1

Adrenal adenomaAdrenal adenoma 1010 4:14:1

Adrenal CaAdrenal Ca 55 1:11:1

Macronod hyperplMacronod hyperpl <2<2 1:11:1

Pigmented nodPigmented nod <2<2 1:11:1

McCune-AlbrightMcCune-Albright <2<2 1:11:1

Diagnosing hypercortisolaemiaDiagnosing hypercortisolaemia

LDDST – 3-8% with Cushing’s suppress (if high suspicion LDDST – 3-8% with Cushing’s suppress (if high suspicion do DS-CRH test- 15 mins post CRH cortisol >38 do DS-CRH test- 15 mins post CRH cortisol >38 nmol/l=CS). False positives more commonnmol/l=CS). False positives more common

Overnight DST – less specific with more false positivesOvernight DST – less specific with more false positives 24 hour UFC – need repeated tests as single measurements 24 hour UFC – need repeated tests as single measurements

have low sensitivity. Collections often incompletehave low sensitivity. Collections often incomplete Midnight cortisol – plasma or salivary – look for loss of Midnight cortisol – plasma or salivary – look for loss of

diurnal variation. Midnight plasma cortisol excludes diurnal variation. Midnight plasma cortisol excludes Cushing’s but needs admission. Salivary cortisol : renewed Cushing’s but needs admission. Salivary cortisol : renewed interestinterest as sens and spec 95-98% and is surrogate for as sens and spec 95-98% and is surrogate for plasma free cortisolplasma 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 – more in Remember 70%+ will be pituitary – more in femalesfemales

Don’t rely on imaging to tell pituitary from Don’t rely on imaging to tell pituitary from ectopicectopic

Pituitary MRI often normal in Cushing’s Pituitary MRI often normal in Cushing’s Disease (up to 40%) – adenoma’s smallDisease (up to 40%) – adenoma’s small

Dynamic testsDynamic tests

High dose DSTHigh dose DST: 80% of patients with Cushing’s : 80% of patients with Cushing’s show cortisol suppression of > 50%. Adds little and show cortisol suppression of > 50%. Adds little and not needed if >30% suppression on low dosenot needed if >30% suppression on low dose

CRH testCRH test – measure cortisol and ACTH response – measure cortisol and ACTH response to ovine or human CRH. In Cushing’s disease to ovine or human CRH. In Cushing’s disease CRH responsiveness persists (20% rise) unlike CRH responsiveness persists (20% rise) unlike ectopic. Responses variable but sensitivity 86-93% ectopic. Responses variable but sensitivity 86-93% for Cushing’s diseasefor Cushing’s disease

IfIf

ACTH dependent Cushing’s proven with ACTH dependent Cushing’s proven with typical responses on DST and CRH and typical responses on DST and CRH and 6mm lesion or more on MRI then 6mm lesion or more on MRI then reasonable to operatereasonable to operate

Otherwise more info neededOtherwise more info needed

Inferior petrosal sinus samplingInferior petrosal sinus sampling

Inferior petrosal sinus samplingInferior petrosal sinus sampling

Sample gradient of ACTH from the pituitary to the Sample gradient of ACTH from the pituitary to the periphery 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 positives and Gold standard’ but not perfect: false positives and

negatives (<10%) describednegatives (<10%) described Only 70% accurate for lateralisation in adultsOnly 70% accurate for lateralisation in adults

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 >50)Hypertensive and obese (BMI >50) Somewhat Cushingoid in appearance but no Somewhat Cushingoid in appearance but no

striaestriae

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 20.4, TSH 1.7 Prolactin 133, testo 2.9, IGF -1 20.4, TSH 1.7 fT4 15fT4 15

Confirming Cushing’s Syndrome – Confirming Cushing’s Syndrome – 48 hour low dose DST48 hour low dose DST

Cortisol: 515 nmol/l → 376 nmol/l (27% Cortisol: 515 nmol/l → 376 nmol/l (27% reduction)reduction)

Confirming ACTH dependenceConfirming ACTH dependence

Basal ACTH 63 ng/lBasal ACTH 63 ng/l

Confirming pituitary source – high Confirming pituitary source – high dose DSTdose DST

519 nmol/l → 75 nmol/l519 nmol/l → 75 nmol/l

Confirming pituitary source – CRH Confirming pituitary source – CRH testtest

00 1515 3030 4545 6060 9090 120120

CortisCortisolol

361361 442442 565565 559559 524524 476476 429429

ACTACTHH

6868 190190 199199 163163 133133 8282 6666

ImagingImaging

Showed small adenoma on CT then MRIShowed small adenoma on CT then MRI In view of evidence (and patients obesity) In view of evidence (and patients obesity)

IPPS not doneIPPS 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 remains hydrocortisone replacement and remains well with no signs of recurrencewell with no signs of recurrence

Treatment – Treatment – transsphenoidal surgery transsphenoidal surgery

Treatment – transsphenoidal surgery Treatment – transsphenoidal surgery

up to 90% remission rate in microadenomas, up to 90% remission rate in microadenomas, less if no obvious tumour or large tumourless if no obvious tumour or large tumour

Patients require steroid cover afterwards – if Patients require steroid cover afterwards – if they don’t they are not cured !they don’t they are not cured !

Complication rate 14% with mortality of 2%Complication rate 14% with mortality of 2%

AdrenalectomyAdrenalectomy

Cures all forms of ACTH independent Cures all forms of ACTH independent Cushing’s syndromeCushing’s syndrome

Bilateral adrenalectomy for ACTH Bilateral adrenalectomy for ACTH dependent Cushing’s but risk of Nelson’s dependent Cushing’s but risk of Nelson’s syndromesyndrome

RadiotherapyRadiotherapy

Primary radiotherapy: long term remission Primary radiotherapy: long term remission of 37%of 37%

Usually used 2Usually used 2ndnd line after surgery: 88% line after surgery: 88% remission but can take 5 years – usually remission but can take 5 years – usually results in other pituitary hormone deficits results in other pituitary hormone deficits (GH>hypogonad>hypothyroid>ACTH)(GH>hypogonad>hypothyroid>ACTH)

Medical therapy -metyraponeMedical therapy -metyrapone

inhibits 11inhibits 11ββ hydroxylase so blocks: hydroxylase so blocks: 11deoxycortisol11deoxycortisol→→ cortisolcortisol

11 deoxycortisol levels rise: in some assays 11 11 deoxycortisol levels rise: in some assays 11 deoxycortisol cross reacts with cortisol. Can deoxycortisol cross reacts with cortisol. Can result in unnecessary increase in treatmentresult in unnecessary 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 hirsutismRise in adrenal androgens causes hirsutism

Medical therapy - ketoconazoleMedical therapy - ketoconazole

Antifungal agentAntifungal agent Inhibits several enzymes in steroid synthesis Inhibits several enzymes in steroid synthesis

pathwaypathway Also reduces adrenal androgens so no Also reduces adrenal androgens so no

hirsutism (and cholesterol)hirsutism (and cholesterol) Can be hepatotoxicCan be hepatotoxic Interacts with simvastatinInteracts with simvastatin Anaesthetic agent etomidate works similarlyAnaesthetic agent etomidate works similarly

Monitoring treatmentMonitoring treatment

Cortisol day curves (mean cortisol between Cortisol day curves (mean cortisol between 150 and 300 nmol/l corresponds with a 150 and 300 nmol/l corresponds with a normal cortisol production rate) – beware normal cortisol production rate) – beware cross reactivity with 11 deoxycortisol if on cross reactivity with 11 deoxycortisol if on metyraponemetyrapone

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% macroSurgery- cure up to 90% micro, <60% macro Radiotherapy – can take several years to Radiotherapy – can take several years to

workwork Dopamine agonists –effective in up to 30%Dopamine agonists –effective in up to 30% Somatostatin analogues- effective in 66%. Somatostatin analogues- effective in 66%.

Can be used pre-op to shrink & soften – can Can be used pre-op to shrink & soften – can shrink by 40% 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 normalises GH day curve: mean <2.5 mcg/l normalises

mortality (but used old polyclonal immunoassays)mortality (but used old polyclonal immunoassays)

Controversial ! What if there is discordance ?Controversial ! What if there is discordance ?

Can’t monitor GH if on pegvisomantCan’t monitor GH if on pegvisomant

Issues Issues

Probably need age, gender and BMI specific Probably need age, gender and BMI specific GH cut offs (GH levels are lower with GH cut offs (GH levels are lower with increasing age and BMI. Females have increasing age and BMI. Females have higher GH nadir)higher GH nadir)

Others things affect GH suppression e.g Others things affect GH suppression e.g renal failure, diabetesrenal failure, diabetes

Other things affect IGF-1 levels e.g. Other things affect IGF-1 levels e.g. malnutrition, liver disease, hypothyroidismmalnutrition, liver disease, hypothyroidism

Changes in IGF-1 normative dataChanges in IGF-1 normative data

Discordance between GHST and Discordance between GHST and IGF-1IGF-1

Most commonly normal IGF-1 but high GHMost commonly normal IGF-1 but high GH Repeat tests after 3 months – usually doesn’t Repeat tests after 3 months – usually doesn’t

helphelp Somatostain analogues have less effect on Somatostain analogues have less effect on

GHST than IGF-1GHST than IGF-1 Most people would follow IGF-1 result but Most people would follow IGF-1 result but

watch closely for recurrence if GH watch closely for recurrence if GH suppression is abnormal (evidence of suppression is abnormal (evidence of increased recurrence rate)increased 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 ophthalmologistconfirmed as bitemporal by ophthalmologist 6 months amennorrhoea6 months amennorrhoea On questioning – increased shoe size and On questioning – increased shoe size and

had to change wedding ring twice. Sweating had to change wedding ring twice. Sweating more.more.

On examinationOn examination

Clinically acromegalic with prominent nasal Clinically acromegalic with prominent nasal bridge and jawbridge and jaw

Large handsLarge hands Large tongue with indentation due to teethLarge tongue with indentation due 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 (100-750)(100-750)

GH Suppression TestGH Suppression Test

BasalBasal 40 min40 min 70 min70 min 100 min100 min 130 min130 min

GHGH

(mcg/l)(mcg/l)11.411.4 10.810.8 10.110.1 9.79.7 9.99.9

GlucoseGlucose

(mM)(mM)4.74.7 5.85.8 5.75.7 5.75.7 5.25.2

ImagingImaging

Large pituitary tumour touching the chiasmLarge pituitary tumour touching the chiasm

Treatment PlanTreatment Plan

Not curable with surgeryNot curable with surgery Pre-op octreotide (to shrink tumour and Pre-op octreotide (to shrink tumour and

soften it) then surgerysoften it) then surgery Followed up with octreotide and Followed up with octreotide and

radiotherapyradiotherapy May need pegvisomantMay need pegvisomant

Prolactinoma Prolactinoma

Commonest functioning pituitary tumourCommonest functioning pituitary tumour Present earlier and also more common in Present earlier and also more common in

women – die to amenorrhoeawomen – die to amenorrhoea In men may just present with local pressure In men may just present with local pressure

effectseffects

Many causes of high prolactinMany causes of high prolactin

ProlactinomaProlactinoma Drugs: DA antagonists, neuroleptics, Drugs: DA antagonists, neuroleptics,

antidepressantsantidepressants Non functioning tumour (<2000)Non functioning tumour (<2000) Pregnancy/lactationPregnancy/lactation HypothyroidismHypothyroidism Renal failure Renal failure PCOSPCOS

Lab issuesLab issues

Remember macroprolactin – screen all Remember macroprolactin – screen all samplessamples

Prolactin levels can be very high (>100,000) Prolactin levels can be very high (>100,000) so if clinical suspicion high but prolactin so if clinical suspicion high but prolactin levels normal look for hook effect by diluting levels normal look for hook effect by diluting samplessamples

Features - hormonalFeatures - hormonal

GalactorrhoeaGalactorrhoea Menstrual disturbanceMenstrual disturbance Reduced libido/erectile dysfunctionReduced libido/erectile dysfunction 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 drug known If prolactin high but on drug known to increase prolactinto increase prolactin

DilemmaDilemma Consider if timing fitsConsider if timing fits Can drug be withdrawn or changed ?Can drug be withdrawn or changed ? Often end up doing MRI but incidentalomas Often end up doing MRI but incidentalomas

are commonare common

ProlactinomaProlactinoma

If PRL >2000 very likely prolactinoma, if If PRL >2000 very likely prolactinoma, if >5000 definitely so>5000 definitely so

If unsure if functioning or not can treat and If unsure if functioning or not can treat and rescanrescan

Prolactin levels will fall with medical therapy Prolactin levels will fall with medical therapy anyway – more so if not prolactinomaanyway – more so if not prolactinoma

Medical management – Dopamine Medical management – Dopamine agonistsagonists

BromocriptineBromocriptine CabergolineCabergoline Quinagolide – being used more as no known Quinagolide – being used more as no known

risk of heart valve fibrosisrisk of heart valve fibrosis

Clinical case – Mr JFClinical case – Mr JF

42 year old man with erectile dysfunction42 year old man with erectile dysfunction 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 18.1fT4 23 TSH 2.43, SST normal, IGF-1 18.1 MRI: macroadenoma but away from chiasmMRI: macroadenoma but away from chiasm

On CabergolineOn Cabergoline

Prolactin now 686Prolactin now 686 Testosterone no better Testosterone no better Started on testosterone replacement – gel Started on testosterone replacement – gel

then Nebido and erectile problems resolvedthen Nebido and erectile problems resolved Pituitary lesion smallerPituitary lesion smaller fT4 11 TSH 2.86 so started on thyroxine in fT4 11 TSH 2.86 so started on thyroxine in

case secondary hypothyroidismcase secondary hypothyroidism

Pituitary ApoplexyPituitary Apoplexy

Pituitary ApoplexyPituitary Apoplexy

Acute infarction or haemorrhage of the Acute infarction or haemorrhage of the pituitarypituitary

Usually an adenoma is presentUsually an adenoma is present Acute headache (retro-orbital), visual Acute headache (retro-orbital), visual

disturbance, altered mental function, cranial disturbance, altered mental function, cranial nerve palsies & endocrine dysfunctionnerve palsies & endocrine dysfunction

Can occur post partum in nontumorous Can occur post partum in nontumorous glands – Sheehan’s Syndromeglands – Sheehan’s Syndrome

ManagementManagement

Endocrine emergencyEndocrine emergency Send off baseline bloods – cortisol, TFT’s, Send off baseline bloods – cortisol, TFT’s,

IGF1, LH/FSH, testo/oestradiol, prolactinIGF1, LH/FSH, testo/oestradiol, prolactin Urgent steroid replacement with high dose Urgent steroid replacement with high dose

hydrocortisone or dexamethasonehydrocortisone or dexamethasone Urgent discussion with neurosurgeons – if Urgent discussion with neurosurgeons – if

compression of chiasm or cranial nerve palsy compression of chiasm or cranial nerve palsy surgery is indicatedsurgery is indicated

Learning ObjectivesLearning Objectives

Describe pituitary anatomy and endocrine Describe pituitary anatomy and endocrine physiologyphysiology

Describe methods for assessing pituitary Describe methods for assessing pituitary function using static and dynamic testingfunction using static and dynamic testing

Describe the new standard for the Describe the new standard for the measurement of growth hormone & its measurement of growth hormone & its effects on clinical criteriaeffects on clinical criteria

Be are of the importance of screening for Be are of the importance of screening for macroprolactinmacroprolactin