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