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Hypopituitarism
Evolution of anterior pituitary
hormone deficiencies
GH- FSH/LH vs ACTH – TSH – Prolactin
if pathology tumour pressure/surgery/radiation (prolactin )
Implication – ignoring genetic defects
Isolated deficit – “only” seen in case of GH
If TSH/Prolactin deficient =MPHD
Note “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
Na
nmol/L
124* 124* 127*
TSH
mU/L
4.21* 3.24 3.60* 3.89*
T4
pmol/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
8
GH
Pea
k
(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 Peak
GH (mU/l)
351361569Patient numbers
Controls321
66.6Concordance
Between tests (%)
OGHD
Lissett et al (1999)
Mean GH response (mU/l)
0.1 1 10 100
Difference betweenITT 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)
Peak G
H r
esponses
(µg /
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
Peak G
H r
esponses to t
he
ITT
(µ
g/ L
)
0
20
40
60Normals
n = 33
Normal < 6yr 6-12yr 12-18yr >18yr
(Darzy et al, 2003)
The peak GH responses to the GHRH + ASTand time after irradiation
Time interval since irradiation (yr)
Peak G
H r
espon
ses to t
he c
om
bin
ed
GH
RH
+ A
ST
(µg
/ 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
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)
Numberper 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
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
Age Range(Years)
Numberper 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
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 0.34
BMI (kg/m2) 31.1±4.5 30.8±4.3 0.88
CBG (mg/l) 41.7±7.1 44.9±4.6 0.25
Baseline cortisol 273.9±61.8 357.3±84.4 0.021
Peak 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
FD
HDNT
Control
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)