Pituitary Insufficiency
William Harper, MD, FRCPC
Endocrinology & Metabolism
Assistant Professor of Medicine
McMaster University
Pituitary Disorders
• Mass effect
• Headaches
• CN II, III, IV, V1, V2, VI
• Pituitary hypersecretory Syndrome
• PRL, GH, ACTH, > > TSH
• Anterior Pituitary Dysfunction
• ACTH, TSH, LH/FSH > > GH
• Posterior Pituitary Dysfunction
• ADH
Mass Effect: H/A, CN II, EOM, V1, V2
(LR6SO4)3
V1
V2
H-P-A Axis
High ACTH Cushing’s
Cushing’s Disease
Ectopic ACTH
Establish hypercortisolism (Cushing’s syndrome)
• “Screening” tests
• 1 mg O/N DMST
• DXM 1 mg po 11PM  8AM plasma cortisol
• < 140 nM R/O Cushing’s Syndrome
» SEN 98% SPEC 71-80%
» < 50 nM SEN ~100% SPEC ? (Poor), still some cases missed!
• 24 UFC
• < 248 nM/d R/O Cushing’s Syndrome (SEN 95-100%)
• 248-840 nM/d Equivocal
• > 840 nM/d consistent with Cushing’s Syndrome (SPEC 98%)
Establish hypercortisolism (Cushing’s syndrome)
• “Confirmatory Tests”
• 24 UFC
• > 840 nM/d Establishes Cushing’s Syndrome on 2 or more
collections AND clear clinical findings of Cushing’s makes
diagnosis of Cushing’s with SPEC 98%
• Otherwise, need an additional confirmatory test.
• LDDST (Liddle Test)
• 2 baseline 24h urine for cortisol and 17-OH steroids
• DXM 0.5 mg q6h x 48h (8 doses)
• During 2nd day on DXM repeat 24h urine collection
– UFC > 100 nM/d or 17OHS > 11 uM/d indicates Cushing’s
– Historical gold standard but SEN 56-69%, SPEC 74-100%
• Plasma cortisol < 50 nM measured 2 or 6 hours after last dose
has SEN 90-100% and SPEC 97-100%
Clinical Suspicion
Screen Test: 24 UFC or 1mg O/N DST (+/- evening plasma/salivary cortisol)
Confirmatory Testing:
Repeat 24 UFC +/- CRH/DXM Test (+/- evening plasma/salivary cortisol)
ACTH
< 1.1pM
ACTH
Independent
CT abdo
>2.2pM
1.1-2.2pM
No Stim
CRH Test
Positive
Stim
Adrenal Surgery
Pituitary
MRI
Conclusive
(>0.8-1.0cm)
ACTH dependent
1st 8mg O/N DST or HDDST
2nd CRH Test if above test negative
Stim by CRH or
DXM suppresses
Inconclusive
IPSS
No CRH stim
No DXM suppression
Ectopic ACTH
•CT thorax, abdo
•Thyroid U/S
•Octreotide Scan
<1.5 basal
<2 CRH
Pituitary Surgery
Continue search for
ectopic source
Conclusive
Remove
ectopic source
Case
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49 year old female
Adie’s pupil x 2 years
L frontoparietal H/A
Neurologist ordered MRI
• Enlarged Pituitary!
• Subsequent Endo referral
• TSH 31.7 mU/L, FT4 6 pM  Hypothyroid!
• FSH 63 (menopausal)
Pituitary Hyperplasia
• Another cause of sellar mass!
• Physiological enlargement of pituitary
• Lactotroph Hyperplasia (pregnancy)
» Pregnancy, most common
• Thyrotroph, Gonadotroph Hyperplasia
» Primary gland failure
• Somatotroph, Corticotroph Hyperplasia
» GHRH or CRH secreting neuroendocrine tumors
Prolactinoma
• Most common pituitary tumor
• Dx: elevated PRL with size/level correlation (stalk-effect!)
• Treatment:
• Dopamine Agonist
» Bromocriptine, Cabergoline, Pergolide, Quinagolide
• TSSx
• XRT
• Treatment goals:
• Macroadenoma: shrink tumor (mass effect, H/A)
• Stop galactorrhea
• Reestablish menses/fertility
» OCP if fertility not wanted
Prolactinoma: pregnancy
• Microadenoma:
• 1.6% symptomatic growth
• Stop bromocriptine once conception achieved
• Macroadenoma
• 13-36% symptomatic growth during pregnancy
• Continue bromocriptine througout pregnancy
• Monitoring PRL useless
• Formal VF tests q3mos
• MRI if any change in vision
Anterior Pituitary Dysfunction
• Gold standard diagnosis = 3x bolus test
• Insulin  ACTH, GH (Insulin Tolerance Test)
• LHRH  LH, FSH
• TRH  TSH, PRL
• Done > 6 weeks post pituitary surgery
• ITT contraindicated: elderly, cardiac disease
• 8AM plasma cortisol
• 1 mcg ACTH stimulation testing
Diagnosis of AI
• 8AM Plasma Cortisol (Pcortisol at 8AM or during “Stress”):
< 83 nM  AI confirmed
< 138 nM  suggests AI present (SEN 36%, SPEC~100%)
> 552 nM  excludes AI (>552 nM @ anytime of day, SEN~100%)
[with possible exception of critically-ill patients]
Diagnosis of AI
• Short Cortrosyn/ACTH test
• Must be performed within a few days of starting exogenous
glucocorticoid Rx or else H-P-A axis will be suppressed by
steroid Rx
• Exogenous glucocorticoid must be dexamethasone (isn’t
picked up by the cortisol RIA)
Short Cortrosyn Test
• High (Standard) Dose:
• 250 ug IV or IM, measure cortisol t = 0, 30, 60 min
• Normal: any cortisol > 550 nM (even pre-injection t = 0)
• Rules out 1˚ AI (SEN 100%) but only 90% SEN for 2˚ AI
• Low Dose:
• 1 ug IV (can’t be IM), measure cortisol t = 0, 30 min
• t = 30 min cortisol > 500 nM rules out 1˚ or 2˚ AI
(exception is 2˚ AI of recent onset < 2wk)
• SEN 95% SPEC 96% ( > 600 nM SEN 100%, SPEC 83%)
• 1 ug dose stimulates maximal adrenal cortex secretion 30 min
after injection and in normal subjects results in a peak plasma
ACTH concentration 2X that seen in an ITT
Short Cortrosyn Test (cont’d)
• Criteria requiring a minimum cortisol increment (i.e. 2x
baseline or absolute rise of 250 nM) now considered
invalid
• High basal cortisol due to stress or normal diurnal
variation may represent near maximal stimulation with an
inability to increase secretion further in upwards of 20% of
normal patients
• Possible exception of critically-ill patients
Distinguish 1˚ from Central AI
Plasma ACTH
• Measure with basal cortisol during short ACTH test
• Primary AI: ACTH > 11 pM
• Central AI: ACTH < 2.2 pM
• Must measure BEFORE exogenous glucocorticoid
administration as will be suppressed almost immediately
• 2 phases of steroid feedback suppression on ACTH:
• Fast Phase (sec-min): membrane stabilizing effect
• Delayed phase (hrs-days): mediated by glucocorticoid receptor
Distinguish 1˚ from Central AI
Long Cortrosyn Test
• Rarely needed
• Done if plasma ACTH equivocal (2.2-11 pM) or result not
available (i.e. not sent before the initiation of exogenous
glucocorticoids)
• 250 ug IV infusion over 8h x 3d
• Plasma cortisols during infusion (0, 4, and 8h)
• 24h UFC day prior to and on 3 days with infusion
• 1˚AI: no response
• Central AI: some response
Anterior Pituitary Dysfn Rx
• Corticosteroids
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•
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Prednisone 5 mg qhs or qam to 5/2.5 mg daily
Cortef 20 mg qhs or qam to 20/10 mg daily
Medic-alert, 2-3x dose during acute-illness
Surgery: 50mg IV preop & q8h postop
• Levothyroxine
• Titrate dose to mid-normal FT4 not TSH
• Sex steroids
• Male: testosterone 100 mg/wk IM, androgel 5g/d
• Female: premenopausal OCP, postmenopausal HRT?
• Growth hormone?
Pituitary Apoplexy
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Acute pituitary hemorrhage
Sudden severe H/A, diploplia, visual loss
Shock due to adrenal crisis
Diagnosis: pituitary MRI or CT
Rx:
• urgent surgical decompression
• Solucortef 50 mg IV q8h
• Dopamine agonist if high PRL/known prolactinoma
Normal Serum [Na] (135-145 mEq/L) Closely Guarded
ADH
(pM)
↓ ECFv
Thirst
5
0
130
135
140
145
PNa (mEq/L)
Diabetes Insipidus
Polyuria: > 3 L/d
+
Polydipsia: > 3.5 L/d
Ddx
• Diabetes Mellitus
• Hypercalcemia
• Solute diuresis:
» Volume expansion 2° saline loading
» High-protein feeds (urea as osmotic agent)
» Post-obstructive diuresis
• Diabetes Insipidus:
» Central (CDI)
» Nephrogenic (NDI)
• Primary (Psychogenic) Polydipsia
Diabetes Insipidus Ddx
Central (CDI)
• Idiopathic
– autoimmune
• Neurosurgery, head trauma
• Cerebral hypoperfusion
• Tumor
– Craniopharyngioma, pituitary
adenoma, suprasellar
meningioma, pineal gland,
metastasis
• Infiltration
– Fe, Sarcoid, Histiocytosis X
•
•
•
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•
•
Nephrogenic (NDI)
X-linked recessive
Hypokalemia
Hypercalcemia (2° to HPT in
particular)
Renal disease: after ATN,
postobstructive uropathy, RAS,
renal transplant, amyloid,
Sickle cell anemia
Sjogren’s
Drugs:
– Lithium, 20% of chronic users
– Demeclocycline, amphotericin,
colchicine
Diabetes Insipidus
• Intact thirst & access to water
•
•
•
•
Hi-normal serum sodium (142-145 mEq/L)
Polydipsia (crave cold fluids)
Polyuria, Nocturia  sleep disturbance
1° treatment is pharmacological
• Impaired thirst or access to water:
• Hypernatremia
• Insufficiently concentrated urine
• 1° treatment is free water (enteral or IV D5W)
Diabetes Insipidus
• Healthy out-patients
• DI with Intact thirst or access to water
• Hi-normal serum sodium (142-145 mEq/L)
• Polydipsia (crave cold fluids)
• Polyuria, Nocturia  sleep disturbance
• 1˚ Psychogenic Polydipsia
• Low-normal serum sodium (135-137 mEq/L)
• Anxious middle-aged women
• Psychiatric illness, phenothiazine (dry mouth)
1˚ Polydipsia: “What came first?”
The Polyuria or the Polydipsia?
The Chicken or the Egg? (Egg)
Water Deprivation Test
• Hold water intake for 2-3h prior to coming in.
• Continue to hold water & Monitor:
• Urine volume, UOSM q1h
• Serum Na, OSM q2h
• If serum OSM/sodium do not rise above normal ranges &
UOSM reaches 600  1˚ Polydipsia
• If serum OSM reaches 295-300 mM & UOSM doesn’t ↑
• Diabetes Insipidus established
• Endogenous ADH should be maximal, check serum ADH
– 2 green rubber stopper tubes, pre-chilled, on ice, need biochemist
• Give DDAVP 10 ug IN
– CDI: UOSM ↑ by 100-800% (complete CDI), ↑ by 15-50% (partial CDI)
with absolute UOSM > 345mM
– NDI: UOSM ↑ by up to < 9%, sometimes ↑ as high as 45% but absolute
UOSM always < isotonic (290 mM)
Diabetes Insipidus
• Impaired thirst or access to water
• Elevated serum sodium/OSM
• UOSM < 500 mM, USG < 1.017
• If serum sodium/OSM not elevated
• Not DI!
• UOSM and USG are irrelevant
Pituitary Surgery/Trauma
• Triphasic response to surgery
• Phase 1: DI
• Axonal injury 2° surgery/swelling
• Begins after POD #1 (pre-existing DI can occur earlier)
• Lasts 1-5d
• Phase 2: SIADH
• Axonal necrosis of AVP secreting neurons with uncontrolled
AVP release
• Lasts 1-5 days
• Phase 3: DI
• Axonal death with cessation of AVP production
• Usually permanent
PNa
U/O
(mEq/L)
(cc/h)
400
150
U/O #1
100
100
50
U/O #2
1
6
11
POD #
50
PNa
U/O
(mEq/L)
(cc/h)
Na #1
400
150
U/O #1
100
100
50
50
1
6
11
POD #
PNa
U/O
(mEq/L)
(cc/h)
400
150
Na #2
100
100
50
U/O #2
1
6
11
POD #
50
#1 DI
#2 Normal
PNa
(mEq/L)
Na #1
U/O
(cc/h)
400
150
Na #2
U/O #1
100
100
50
U/O #2
1
6
11
POD #
50
PITUITARY SURGERY PROTOCOL
Immediately Postop (in recovery room):
Send serum for electrolytes, creatinine, blood sugar
Send urine for USG (specific gravity)
Then monitor:
Accurate I&O: fluid intake & urine output hourly (q1h) with complete tally
q12 hours (q12h)
Serum electrolytes and USG : q12h
If on steroids (decadron, solucortef, etc.) do capillary blood glucose bid
If urine output > 400cc/hour:
Serum OSM & urine OSM now and then q12h
Serum lytes, creatinine now and then q6h
USG now and then q4h
Call Endocrinology Service once serum electrolytes and USG results are back
for possible DDAVP and IV fluid orders
Call Endocrinology Service whenever:
Serum sodium > 148
Serum sodium < 130
Urine output > 400 cc/h (see above 3.)
Treatment of DI
• Rx Dehydration
• NS initially if ECFv contraction
• Then IV D5W or enteral free water to lower serum [Na]
» 1-2 mEq/h if Na > 160, symptomatic (coma, SZ), acute
» Otherwise 0.5-1.0 mEq/h
• Insensible losses? (0.5 L/d)
• Do NOT replace U/O if giving DDAVP
• DDAVP (Desmopressin)
• Reduces U/O and therefore simplifies fluid therapy
• Long t½: duration 8-12h, up to 24h
• Therefore use judiciously
» DDAVP 1ug IV/SC x 1
» Only repeat if breaks-thru again (i.e. becomes
hypernatremic with dilute polyuria)
» Once nasal mucosa stable can switch to intranasal
» Also oral form DDAVP now available
DDAVP: 1ug IV/SC = 10 ug IN = 0.1 mg PO
Treatment of DI
• AVP, Aqueous vasopressin (Pitressin)
• Only parenteral form, 5-10 U SC q2-4h
• Lasts 2-6h
• Can cause HTN, coronary vasospasm
• Chlorpropamide (OHA which stimulates AVP secretion)
• 100-500 mg po OD-bid
• Only useful for partial DI, can cause hypoglycemia
• HTCZ (induces volume contraction which diminishes free water excretion)
• 50-100 mg OD-bid
• Mainstay of Rx for chronic NDI
• Amiloride (blunts Lithium uptake in distal tubules & collecting ducts)
• 5-20 mg po OD-bid
• Drug of choice for Lithium induced DI
• Indomethacin 100-150 mg po bid-tid (PGs antagonize AVP action)
• Clofibrate 500 mg po qid (augments AVP release in partial CDI)
• Tegretol 200-600 mg po od (augments AVP release in partial CDI)