Download Hypopituitarism

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
Na
nmol/L
TSH
mU/L
T4
pmol/L
Jan 02
Feb 02
Mar 02 Nov 02 Nov 02
124*
124*
127*
4.21*
3.24
3.60*
3.89*
59
61
8*
(50-150) (50-150) (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
• Sheehan’s syndrome
– Craniopharyngiomas
• Pituitary apoplexy
– Meningioma
• TBI
– Glioma
• Empty Sella syndrome
– Chordoma
• Lymphocytic hypophysitis
– Metastasis-breast cancer
• Genetic diseases
• Non-pituitary radiotherapy
• Infiltrative disorders
Investigation for Hypopituitarism
• Gonadotrophin status
– FSH,LH,T/E2
– GnRH test x
• TSH
– TSH, FT4
– TRH test x
• Prolactin
– Prolactin
How is ACTH
D
diagnosed?
• UK SoE Survey
598 Clinical Members
81 Respondents
ITT
SST
Glucagon
9.00am Cortisol (>400 nmol/L)
No Tests (NoT)
Reynolds et al, Clin End (2006)
ITT
SST
NoT
Glucagon
9C
31%
44%
-
2.5%
2.5%
XRT
7%
65%
-
4%
18%
Non – XRT
9%
36%
29%
-
18%
Definitive
testing of
HPA Axis
Post- Surgery
Long term
Assessment
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)
Investigation for Hypopituitarism
• ACTH
– Morning Cortisol (<100 – 300nmol/l)
– ITT/ Glucagon/Synacthen
• GH Status
– Provocative GH tests, IGF-1
– IGFBP-3/ALSx
Severe Adult GHD (ITT)
8
P <0.0001
GH Peak ( m g/L)
6
4
2
0
GHD0
GHD1
GHD2
GHD3
Toogood et al. Clin. Endocrinol. 1994
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
GHD
O
1
2
3
Controls
Patient numbers
69
15
6
13
35
7.5
6.8
2.4
2.4
0.75
1.0
0.5
0.5
65
32
76.8
66.6
83.3
92.3
100
Median Peak
GH (mU/l)
- ITT
- AST
Concordance
Between tests (%)
Lissett et al (1999)
Magnitude of difference between each individuals GH
response to ITT and AST plotted against mean GH value
100
Spearmans Rank correlation = 0.88,
P <0.0001
10
Difference between
ITT and AST (mU/l)
1
0.1
0.1
1
10
100
Mean GH response (mU/l)
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
Study Objectives
To investigate the role of the GHRH + AST in
the diagnosis of radiation-induced GHD in
comparison with the “Gold Standard”, the ITT.
(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)
120
N = normal controls
P = patients
Peak GH responses (µg / L).
100
80
N
60
55
40
N
23.8
20
P
14.5
P < 0.05
P < 0.05
0
P 4.8
-20
GHRH+AST
ITT
GHRH+AST
ITT
(Darzy et al, 2003)
The peak GH responses to the ITT and time after irradiation
Peak GH responses to the ITT (µg / L)
60
Normals
n = 33
40
20
0
Normal
< 6yr
6-12yr 12-18yr >18yr
(Darzy et al, 2003)
Peak GH responses to the combined
GHRH + AST (µg / L)
The peak GH responses to the GHRH + AST
and time after irradiation
120
Normals
100
< 6 yr
80
60
12 - 18
6 - 12
> 18
40
20
0
Time interval since irradiation (yr)
(Darzy et al, 2003)
The discordancy ratio and time after irradiation
30
20
10
0
Median BED 58.3
Normals
<6yr
58.3
48.82
54.4
6-12yr 12-18yr >18yr
Time interval since irradiation
(Darzy et al, 2003)
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
Females
Age Range
(Years)
21 - 30
31 - 40
41 - 50
51 - 60
61 - 70
71 - 80
Number
per group
24
74
123
93
51
11
%
8.3
31.1
41.5
49.5
52.9
54.5
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
4
2
0
-2
-4
IGF-I SDS
-6
-8
-10
21-30
31-40
41-50
51-60
61-70
Age Range (Years)
71-80
Box and whisker plots representing IGFI SDS in males with AO-GHD
4
2
0
-2
IGF-I SDS
-4
-6
-8
21-30
31-40
41-50
51-60
61-70
Age Range (Years)
71-80
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
• ACTH
– Hydrocortisone (tds)
• FSH/LH
– Cortisol profiles
– Sex Steriods
– Emergency advice
– Fertility-Gonadotrophins
Treatment
• TSH
– T4 (threshold)
• DI
– Desmopressin
• GH
– GH
Partial ACTH D - Glucorticoid
replacement
10 males – partial ACTH D
• 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
Agha et al Clin End.2004
Age (years)
BMI (kg/m2)
CBG (mg/l)
Baseline cortisol
Peak stimulated cortisol
Pts, n=10
Controls, n=10
P-value
43.9±10.8
31.1±4.5
41.7±7.1
273.9±61.8
432.9±58.9
38.9±12.2
30.8±4.3
44.9±4.6
357.3±84.4
0.34
0.88
0.25
0.021
Results presented as mean±SD. BMI, body mass index; CBG, corticosteroid-binding globulin
Agha et al 2004
FD
HD
NT
Control
500
Cortisol
400
300
200
100
0
2
4
6
8
10
Time
Agha et al 2004
Long-acting GH preparation in
patients with GHD
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
Hoffman et al (2005)
Adverse events
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
Hoffman et al (2002)
Risk of Cortisol deficiency on
GH replacement
• 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
GH replacement and thyroid
function in adult GHD patients
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
Porretti et al (2002)
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