Hypopituitarism

Evolution of anterior pituitary hormone deficiencies

GH- FSH/LH vs ACTH – TSH – Prolactin if pathology tumour pressure/surgery/radiation

(prolactin )

Implication – ignoring genetic defectsIsolated deficit – “only” seen in case of GH If TSH/Prolactin deficient =MPHDNote “meaning” if normal TSH/low FT4 on screening investigation

Case History

• 50 year old freelance journalist

• Diagnosed as having nasopharyngeal ca

• Surgery & XRT Oct ‘99

• 3000cGy in 15 fractions (2 courses)

And then?• Jan 02 - GP found Na 122 - kept under review by

oncologists

• Nov 02 - abnormal TFTs - started Thyroxine 50mcg increased to 100mcg

• Feb 03 - patient felt worse - still tired, feeling cold, aches & pains, lightheaded, loss of balance

• May 03 - referred to an endocrinologist

Results

Jan 02 Feb 02 Mar 02 Nov 02 Nov 02

Nanmol/L

124* 124* 127*

TSHmU/L

4.21* 3.24 3.60* 3.89*

T4pmol/L

59(50-150)

61(50-150)

8*(9-26)

9(9-26)

What do the TFTs suggest?

SECONDARY HYPOTHYROIDISM

What is the patient’s low sodium

due to?• SST - 0 min - Cortisol 57nmol/L*

- 30 min - Cortisol 197nmol/L*

ACTH DEFICIENT

Why did thyroxine exacerbate his symptoms?

• Thyroxine introduced before hydrocortisone in cortisol deficiency can lead to acute cortisol deficiency

**POTENTIALLY FATAL**• Consider cortisol deficiency

– in a patient who has received a large dose of radiation particularly if

• sodium • TSH deficient• symptoms worsen with thyroxine therapy

Evolution of anterior pituitary hormone deficiencies

Isolated deficiencies of anterior pituitary hormones

due to pathologies other than genetic – do exist!

If present – may point to underlying pathology

Isolated gonadotrophin deficiency-Haemochromatosis

Isolated ACTH deficiency -Lymphocytic hypophysitis

Timing of onset of hypopituitarism

• Childhood

GHD - growth

FSH/LH – puberty

• Adult

Normal height/secondary sex characteristics

Diabetes Insipidus

Implication• Site of lesion is hypothalamic/ high stalk

• Pathology of lesion much more likely to be cranopharyngioma vs pituitary adenoma

• Presence of DI provides no information about anterior pituitary function except that ACTH status must be normal for DI to be manifested

Hypopituitarism

Causes• Pituitary Adenoma

– Functioning– Non-Functioning

• Pituitary Surgery• Pituitary Radiotherapy

– Conventional– Stereotactic

• Medical Therapy– DA drugs– Pegvisomant– Anti-adrenal drugs

Hypopituitarism

Non-adenomatous causes

• Intracranial tumours

– Craniopharyngiomas

– Meningioma

– Glioma

– Chordoma

– Metastasis-breast cancer

• Non-pituitary radiotherapy

• Infiltrative disorders

• Sheehan’s syndrome

• Pituitary apoplexy

• TBI

• Empty Sella syndrome

• Lymphocytic hypophysitis

• Genetic diseases

Investigation for Hypopituitarism

• Gonadotrophin status– FSH,LH,T/E2

– GnRH test x

• TSH– TSH, FT4– TRH test x

• Prolactin– Prolactin

How is ACTH diagnosed?

• UK SoE Survey

598 Clinical Members

81 Respondents

ITT 9.00am Cortisol (>400 nmol/L)

SST No Tests (NoT)

Glucagon

D

Reynolds et al, Clin End (2006)

ITT SST NoT Glucagon 9C

Definitive testing of HPA Axis Post- Surgery

31% 44% - 2.5% 2.5%

Long term Assessment

XRT 7% 65% - 4% 18%

Non – XRT 9% 36% 29% - 18%

Reynolds et al, Clin End (2006)

SST

93.8% - 250 µg 4.7% - 1µg

IV vs IM – (50-50)

Interpretation of Results• 67% - 30 min cortisol• 17% - 60 min cortisol• 7 % - increment cortisol• 9% - combinations

Reynolds et al, Clin End (2006)

Interpretation of Results

SST• Adequate peak cortisol response 250 – 650 nmol/l• Peak cortisol >550nmol/l at 30 min (51%)

ITT• Adequate peak cortisol response 400 – 600 nmol/l• Peak cortisol > 550nmol/l (47%)

Reynolds et al, Clin End (2006)

Glucorticoid Replacement

If patients symptomless but had failed chosen test of HPA axis

• 28% - still treated with glucocorticoid replacement• 38% - retested before treatment• 24% - recommended glucocorticoid cover when

unwell or ‘stressed’• 6% recommend patient carry steroid card• 4% - individual basis

Reynolds et al, Clin End (2006)

Glucocorticoid replacement

Hydrocortisone• 20mg/day (56%)• 67% - 10/5/5• Higher doses by 25%• Lower doses by 13%

General Trends• More SST – Less ITT• Lower replacement doses of HC

Reynolds et al, Clin End (2006)

• ACTH– Morning Cortisol (<100 – 300nmol/l)– ITT/ Glucagon/Synacthen

Investigation for Hypopituitarism

• GH Status– Provocative GH tests, IGF-1– IGFBP-3/ALSx

0

2

4

6

8G

H P

eak

(

g/L

)

GHD0 GHD1 GHD2 GHD3

P <0.0001

Toogood et al. Clin. Endocrinol. 1994

Severe Adult GHD (ITT)

How many tests to diagnose GHD in severe adult GHD

103 patients - documented or potential HP disease

- normal BMI

- ITT & AST

35 controls

Lissett et al (1999)

Pituitary Hormone Deficits

10092.383.376.8

- AST 320.51.02.46.8

- ITT 650.50.752.47.5

Median PeakGH (mU/l)

35136 1569Patient numbers

Controls321

66.6ConcordanceBetween tests (%)

OGHD

Lissett et al (1999)

Mean GH response (mU/l)

0.1 1 10 100

Difference between ITT and AST (mU/l)

0.1

1

10

100 Spearmans Rank correlation = 0.88,

P <0.0001

Magnitude of difference between each individuals GH

response to ITT and AST plotted against mean GH value

Lissett et al (1999)

Implications

Adults

• GHDO/GHD1 patients require 2 GH

stimulation tests vs only 1 required in

GHD2/GHD3 patients

Specificity of GH stimulation test

The debate about 2 tests vs. 1 test also

assumes that the information gained from

each of the tests is the same and

independent of the nature of the

pathophysiology

To investigate the role of the GHRH + AST in

the diagnosis of radiation-induced GHD in

comparison with the “Gold Standard”, the ITT.

Study Objectives

(Darzy et al, 2003)

(Darzy et al, 2003)

Subjects and Methods

* 58 adult patients (37 males), age 22.9(16-53.7)yr.

* All received cranial irradiation for non-pituitary brain tumour or leukaemia ( age 1.3-49 years ).

* Endocrine deficit other than GH present in 11 patients

* All patients had hormone replacement optimised before testing

(Darzy et al, 2003)

33 sex and age matched control group.

* GHRH+AST and ITT in all normals and patients

* Patients were tested 11.8 (1.5 – 32.8) yr post irradiation.

* Tests on two separate mornings.

(Darzy et al, 2003)

Pea

k G

H r

espo

nses

(µ

g /

L).

-20

0

20

40

60

80

100

120

N

NP

P

GHRH+AST ITT GHRH+AST ITT

N = normal controlsP = patients

P < 0.05

P < 0.05

55

23.8

14.5

4.8

(Darzy et al, 2003)

The peak GH responses to the ITT and time after irradiation

Pe

ak G

H r

esp

onse

s to

the

ITT

(µ

g / L

)

0

20

40

60Normalsn = 33

Normal < 6yr 6-12yr 12-18yr >18yr

(Darzy et al, 2003)

The peak GH responses to the GHRH + AST and time after irradiation

Time interval since irradiation (yr)

Pea

k G

H r

espo

nses

to th

e co

mbi

ned

GH

RH

+ A

ST

(µ

g / L

)

0

20

40

60

80

100

120

Normals

< 6 yr

6 - 12 12 - 18

> 18

(Darzy et al, 2003)

The discordancy ratio and time after irradiation

Time interval since irradiation

Dis

cord

ancy

Rat

io

(pea

k G

H to

the

GH

RH

+A

ST

/ IT

T)

0

10

20

30

<6yr 6-12yr 12-18yr >18yrNormals

Median BED 58.3 58.3 48.82 54.4

Patients and Methods

• Centrally measured IGF-I data from the KIMS

European database were analysed

• Patients with adult onset GHD and 2 or more

anterior pituitary hormone deficits were

included

• Patients with childhood onset GHD and cured

acromegaly were excluded

Patients and Methods

• Baseline IGF-I measurements from;

- 376 females (median age 48, range 21

to 77 years) and - 434 males (median age 52, range 21 to 80 years)

• The cohort was stratified into six gender based age ranges

• IGF-I & IGF-I SDS were determined

for each group

Percentage of patients with severe adult-onset GHD with IGF-I levels

within the normal age related range

Age Range (Years)

Number per group

%

21 -30 24 8.3

31 -40 74 31.1

41 -50 123 41.5

51 -60 93 49.5

61 -70 51 52.9

71 -80 11 54.5

Females

Percentage of patients with severe adult-onset GHD with IGF-I levels

within the normal age related range

Males

Age Range

(Years)

Number

per group

%

21-30 30 26.7

31-40 62 62.9

41-50 102 61.8

51-60 149 73.1

61-70 75 60.0

71-80 16 75.0

Box and whisker plots representing IGF-I SDS in females with AO-GHD

Age Range (Years)

21-30 31-40 41-50 51-60 61-70 71-80

IGF

-I SD

S

-10

-8

-6

-4

-2

0

2

4

Box and whisker plots representing IGF-I SDS in males with AO-GHD

Age Range (Years)

21-30 31-40 41-50 51-60 61-70 71-80

IGF

-I SD

S

-8

-6

-4

-2

0

2

4

Summary

• These data demonstrate;

– a large overlap of IGF-I SDS between

normal and severely GHD adults

– overlap of IGF-I between normal and severely

GHD adults is predominantly limited to the

lower half of the normal range

GHD2/GHD3 = 1 GH Provocative test

vs.

IGF-1

GHD0/GHD1 = 2 GH Provocative tests

vs.

1GH Provocative test

plus IGF-1

GH stimulation tests

• ITT/Arginine/Glucagon

• Arginine + GHRH

• GHRH + GHRP

• Clonidine? GHRH? – No

– Age

– BMI/Fat Mass

– Availability

Diabetes Insipidus

• 24 hour urine output > 3 litres

• 8 hour fluid deprivation test

Radiology – MRI Scan

• Absent PP high signal

• Microadenoma vs Macrodenoma

– Risk of hypopituitarism

• Stalk interruption

• Type and site of lesion

• Evolution

Pituitary hormone deficiencies

Treatment

• FSH/LH– Sex Steriods– Fertility-Gonadotrophins

• TSH– T4 (threshold)

• ACTH– Hydrocortisone (tds)– Cortisol profiles– Emergency advice

• DI– Desmopressin

• GH– GH

10 males – partial ACTH

• Base line plasma cortisol > 200nmol/l

• Peak stimulated cortisol<500nmol/l

10 matched controls

Cross-over randomised protocol – HC

10mgs BD vs 5 mgs BD vs no treatment

Partial ACTH - Glucorticoid replacement

D

D

Agha et al Clin End.2004

Pts, n=10 Controls, n=10 P-value

Age (years) 43.9±10.8 38.9±12.2 0.34BMI (kg/m2) 31.1±4.5 30.8±4.3 0.88CBG (mg/l) 41.7±7.1 44.9±4.6 0.25Baseline cortisol 273.9±61.8 357.3±84.4 0.021Peak stimulated cortisol 432.9±58.9

Results presented as mean±SD. BMI, body mass index; CBG, corticosteroid-binding globulin

Agha et al 2004

500

400

300

200

100

0 2 4 6 8 10

Time

Co

rtis

ol

Agha et al 2004

FDHDNTControl

Open-label randomised study

• 135 patents – 32 weeks

• Depot GH vs Daily GH vs no treatment

• Dose GH titrated to maintain IGF-1

within age-adjusted normal range

Long-acting GH preparation in patients with GHD

Hoffman et al (2005)

1- death - “Adrenal crisis”- On Depot GH

Two other serious and three non-serious cases of “adrenal crisis or insufficiency”

• 3 cases on daily GH vs 3 cases – depot GH• All had ACTH deficiency and were on

glucocorticoid replacement

Adverse events

Hoffman et al (2002)

• Ignorance – glucocorticoid dosage not during

intercurrent illness• Influence of Gh-IGF-1 axis on II β HSD driving

cortisol-cortisone shuttle in favour of “cortisone”• GH ↓ Cortisol-B-G

At Risk• Steroid card/Emergency Pack• Borderline ACTH D not receiving glucocorticoid replacement

(Giavoli et al,2004)

• Sub-optimal glucocorticoid replacement

Risk of Cortisol deficiency on GH replacement

66 adult GHD patients

• 17 euthyroid/49 hypothyroid on T4

• 6 month GH replacement study – 2 dose regimes

• Normalisation of IGF-1 in 67% patients – independent of GH dose

• Significant ↓in FT4 and reverse T3 levels

• No change in TSH, FT3, thyroxine BG levels

GH replacement and thyroid function in adult GHD patients

Porretti et al (2002)

• 8/17 euthyroid subjects and 9/49 central hypothyroid patients showed FT4 levels below normal range at end of study despite adequate substitution at baseline. Altogether 17/66 patients worsened thyroid function

* Monitor thyroid – function carefully

Porretti et al (2002)