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

Cushing’s Disease Ectopic ACTH

High ACTH Cushing’s

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

ACTHIndependentCT abdo

Adrenal Surgery

ACTH dependent1st 8mg O/N DST or HDDST2nd CRH Test if above test negative

CRH Test

PituitaryMRI

Pituitary Surgery

IPSS

Ectopic ACTH•CT thorax, abdo•Thyroid U/S•Octreotide Scan

Continue search for ectopic source

Remove ectopic source

< 1.1pM >2.2pM

1.1-2.2pM

No StimPositiveStim

Conclusive(>0.8-1.0cm)

Inconclusive

>2 basal

>3 CRH <1.5 basal<2 CRH

Conclusive

No CRH stimNo DXM suppressionStim by CRH or

DXM suppresses

Case

• 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

• 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

• 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

PNa (mEq/L)130 135 140 145

0

5

ADH(pM)

Thirst↓ ECFv

Normal Serum [Na] (135-145 mEq/L) Closely Guarded

Diabetes Insipidus

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

Polyuria: > 3 L/d + Polydipsia: > 3.5 L/d

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

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 Chicken or the Egg? (Egg)

The Polyuria or the Polydipsia?

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

1 6 11 POD #

50

100

150

PNa(mEq/L)

50

100

400

U/O(cc/h)

U/O #1

U/O #2

1 6 11 POD #

50

100

150

PNa(mEq/L)

50

100

400

U/O(cc/h)

Na #1

U/O #1

1 6 11 POD #

50

100

150

PNa(mEq/L)

50

100

400

U/O(cc/h)

Na #2

U/O #2

1 6 11 POD #

50

100

150

PNa(mEq/L)

50

100

400

U/O(cc/h)

Na #1

Na #2U/O #1

U/O #2

#1 DI#2 Normal

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 : q12hIf on steroids (decadron, solucortef, etc.) do capillary blood glucose bid

If urine output > 400cc/hour:Serum OSM & urine OSM now and then q12hSerum 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 > 148Serum sodium < 130Urine 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)