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