Hypopituitarism

1
Hypopituitarism
2
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

3
Case History

• 50 year old freelance journalist
• Diagnosed as having nasopharyngeal ca
• Surgery XRT Oct 99
• 3000cGy in 15 fractions (2 courses)

4
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

5
Results
Jan 02
Feb 02
Mar 02
Nov 02
Nov 02
Na
124
124
127
nmol/L
TSH
4.21
3.24
3.60
3.89
mU/L
T4
59
61
8
9
pmol/L
(50-150)
(50-150)
(9-26)
(9-26)
6
What do the TFTs suggest?

• SECONDARY HYPOTHYROIDISM
• What is the patients low sodium
• due to?
• SST - 0 min - Cortisol 57nmol/L - 30 min -
  Cortisol 197nmol/L
• ACTH DEFICIENT

7
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

8
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

9
Timing of onset of hypopituitarism

• Childhood
• GHD - growth
• FSH/LH puberty
• Adult
• Normal height/secondary sex characteristics

10
(No Transcript)
11
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

12
Hypopituitarism

• Causes
• Pituitary Adenoma
• Functioning
• Non-Functioning
• Pituitary Surgery
• Pituitary Radiotherapy
• Conventional
• Stereotactic

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

13
Hypopituitarism

• Non-adenomatous causes
• Intracranial tumours
• Craniopharyngiomas
• Meningioma
• Glioma
• Chordoma
• Metastasis-breast cancer
• Non-pituitary radiotherapy
• Infiltrative disorders

• Sheehans syndrome
• Pituitary apoplexy
• TBI
• Empty Sella syndrome
• Lymphocytic hypophysitis
• Genetic diseases

14
Investigation for Hypopituitarism

• Gonadotrophin status
• FSH,LH,T/E2
• GnRH test x
• TSH
• TSH, FT4
• TRH test x
• Prolactin
• Prolactin

15
How is ACTH diagnosed?

• UK SoE Survey
• 598 Clinical Members
• 81 Respondents
• ITT 9.00am Cortisol (gt400 nmol/L)
• SST No Tests (NoT)
• Glucagon

Reynolds et al, Clin End (2006)
16
Reynolds et al, Clin End (2006)
17
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)
18
Interpretation of Results

• SST
• Adequate peak cortisol response 250 650 nmol/l
• Peak cortisol gt550nmol/l at 30 min (51)
• ITT
• Adequate peak cortisol response 400 600 nmol/l
• Peak cortisol gt 550nmol/l (47)

Reynolds et al, Clin End (2006)
19
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)
20
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)
21
Investigation for Hypopituitarism

• ACTH
• Morning Cortisol (lt100 300nmol/l)
• ITT/ Glucagon/Synacthen

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

22
Severe Adult GHD (ITT)
Toogood et al. Clin. Endocrinol. 1994
23
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)
24
Pituitary Hormone Deficits
Controls
3
2
1
O
GHD
Patient numbers
35
13
6
15
69
Median Peak GH (mU/l)
- ITT
65
0.5
0.75
2.4
7.5
- AST
32
0.5
1.0
2.4
6.8
Concordance Between tests ()
76.8
100
92.3
83.3
66.6
Lissett et al (1999)
25
Magnitude of difference between each individuals
GH response to ITT and AST plotted against mean
GH value
Lissett et al (1999)
26

• Implications
• Adults
• GHDO/GHD1 patients require 2 GH
  stimulation tests vs only 1 required in
  GHD2/GHD3 patients

27
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
28
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)
29
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)
30
33 sex and age matched control group. GHRHAST
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)
31
120
N normal controls
P patients
100
80
N
60
55
Peak GH responses (µg / L).
40
N
P
23.8
20
14.5
P lt 0.05
P
4.8
0
P lt 0.05
-20
GHRHAST ITT GHRHAST ITT
(Darzy et al, 2003)
32
The peak GH responses to the ITT and time after
irradiation
60
Normals
n 33
40
Peak GH responses to the ITT (µg / L)
20
0
(Darzy et al, 2003)
Normal lt 6yr 6-12yr 12-18yr gt18yr
33
The peak GH responses to the GHRH AST
and time after irradiation
120
Normals
100
lt 6 yr
80
Peak GH responses to the combined
GHRH AST (µg / L)
60
12 - 18
6 - 12
gt 18
40
20
0
Time interval since irradiation (yr)
(Darzy et al, 2003)
34
The discordancy ratio and time after irradiation
30
20
(peak GH to the GHRHAST / ITT)
Discordancy Ratio
10
0
Median BED 58.3 58.3 48.82 54.4
lt6yr 6-12yr 12-18yr
gt18yr
Normals
(Darzy et al, 2003)
Time interval since irradiation
35
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
36
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
37
Percentage of patients with severe adult-onset
GHD with IGF-I levels within the normal age
related range
Females



38
Percentage of patients with severe adult-onset
GHD with IGF-I levels within the normal age
related range
Males



39
Box and whisker plots representing IGF-I SDS in
females with AO-GHD
40
Box and whisker plots representing IGF-I SDS in
males with AO-GHD
41
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

42
GHD2/GHD3 1 GH Provocative test vs.
IGF-1 GHD0/GHD1 2 GH Provocative
tests vs. 1GH Provocative
test plus IGF-1
43
GH stimulation tests

• ITT/Arginine/Glucagon
• Arginine GHRH
• GHRH GHRP
• Clonidine? GHRH? No
• Age
• BMI/Fat Mass
• Availability

44
Diabetes Insipidus

• 24 hour urine output gt 3 litres
• 8 hour fluid deprivation test

45
Radiology MRI Scan

• Absent PP high signal
• Microadenoma vs Macrodenoma
• Risk of hypopituitarism
• Stalk interruption
• Type and site of lesion
• Evolution

46
Pituitary hormone deficiencies

• Treatment
• FSH/LH
• Sex Steriods
• Fertility-Gonadotrophins
• TSH
• T4 (threshold)

• ACTH
• Hydrocortisone (tds)
• Cortisol profiles
• Emergency advice
• DI
• Desmopressin
• GH
• GH

47
Partial ACTH - Glucorticoid replacement

• 10 males partial ACTH
• Base line plasma cortisol gt 200nmol/l
• Peak stimulated cortisollt500nmol/l
• 10 matched controls
• Cross-over randomised protocol HC
• 10mgs BD vs 5 mgs BD vs no treatment

Agha et al Clin End.2004
48
Pts, n10 Controls, n10 P-value Age
(years) 43.910.8 38.912.2 0.34 BMI
(kg/m2) 31.14.5 30.84.3 0.88 CBG
(mg/l) 41.77.1 44.94.6 0.25 Baseline
cortisol 273.961.8 357.384.4 0.021 Peak
stimulated cortisol 432.958.9 Results presented
as meanSD. BMI, body mass index CBG,
corticosteroid-binding globulin
Agha et al 2004
49
FD
500
HD
NT
Control
400
300
Cortisol
200
100
0
2
4
6
8
10
Time
Agha et al 2004
50
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)
51
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)
52
Risk of Cortisol deficiency on GH replacement

• Ignorance glucocorticoid dosage not ? during
• intercurrent illness
• Influence of Gh-IGF-1 axis on II ß 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

53
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)
54
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