Hypopituitarism
Evolution of anterior pituitary
        hormone deficiencies
GH- FSH/LH vs ACTH – TSH – Prolactin

if pathology tumour pre...
Case History

• 50 year old freelance journalist

• Diagnosed as having nasopharyngeal ca

• Surgery & XRT Oct „99

• 3000...
And then?
• Jan 02 - GP found Na 122 - kept under
  review by oncologists

• Nov 02 - abnormal TFTs - started Thyroxine
  ...
Results
         Jan 02   Feb 02   Mar 02 Nov 02 Nov 02

 Na      124*      124*              127*
nmol/L
TSH             ...
What do the TFTs suggest?

  SECONDARY HYPOTHYROIDISM

   What is the patient‟s low sodium
               due to?
• SST   ...
Why did thyroxine
 exacerbate his symptoms?
• Thyroxine introduced before
  hydrocortisone in cortisol deficiency can
  le...
Evolution of anterior pituitary
           hormone deficiencies

Isolated deficiencies of anterior pituitary hormones
due ...
Timing of onset of hypopituitarism

•   Childhood
          GHD - growth
          FSH/LH – puberty

•   Adult
     Normal...
Diabetes Insipidus
Implication
• Site of lesion is hypothalamic/ high stalk

• Pathology of lesion much more likely to be
...
Hypopituitarism
Causes
• Pituitary Adenoma        • Medical Therapy
  – Functioning              – DA drugs
  – Non-Functi...
Hypopituitarism
Non-adenomatous causes
• Intracranial tumours          • Sheehan‟s syndrome
   – Craniopharyngiomas       ...
Investigation for Hypopituitarism

• Gonadotrophin status
  – FSH,LH,T/E2
  – GnRH test x

• TSH
   – TSH, FT4
   – TRH te...
How is ACTH       D   diagnosed?

• UK SoE Survey
  598 Clinical Members
   81 Respondents

ITT              9.00am Cortis...
ITT   SST   NoT      Glucagon           9C

Definitive
testing of
HPA Axis
                31%   44%    -           2.5%  ...
SST
93.8% - 250 µg
 4.7% - 1µg
    IV vs IM – (50-50)

Interpretation of Results
• 67% - 30 min cortisol
• 17% - 60 min co...
Interpretation of Results

SST
• Adequate peak cortisol response 250 – 650 nmol/l
• Peak cortisol >550nmol/l at 30 min (51...
Glucorticoid Replacement
    If patients symptomless but had failed chosen
    test of HPA axis
•   28% - still treated wi...
Glucocorticoid replacement
Hydrocortisone
  • 20mg/day (56%)
  • 67% - 10/5/5
  • Higher doses by 25%
  • Lower doses by 1...
Investigation for Hypopituitarism

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

• GH Status...
Severe Adult GHD (ITT)
            8

                                       P <0.0001



            6
  g/L)
GH Peak (

...
How many tests to diagnose GHD in
          severe adult GHD


103 patients   - documented or potential
                 H...
Pituitary Hormone Deficits

GHD                  O      1      2      3       Controls

Patient numbers     69     15     ...
Magnitude of difference between each individuals GH
     response to ITT and AST plotted against mean GH value

          ...
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 ...
Study Objectives

To investigate the role of the GHRH + AST in
the diagnosis of radiation-induced GHD in
comparison with t...
Subjects and Methods

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

* All received cranial irradiation for non-pit...
33 sex and age matched control group.

* GHRH+AST and ITT in all normals and
  patients

* Patients were tested 11.8 (1.5 ...
120
                                                      N = normal controls
                              100
          ...
The peak GH responses to the ITT and time after irradiation
                                             60
              ...
The peak GH responses to the GHRH + AST
                          and time after irradiation

                            ...
The discordancy ratio and time after irradiation
      30




      20




      10




       0



           Median BED ...
Patients and Methods
• Centrally measured IGF-I data from the KIMS
  European database were analysed


• Patients with adu...
Patients and Methods

• Baseline IGF-I measurements from;
  - 376 females (median age 48, range 21
  to 77 years) and - 43...
Percentage of patients with severe
 adult-onset GHD with IGF-I levels
within the normal age related range
                ...
Percentage of patients with severe
 adult-onset GHD with IGF-I levels
within the normal age related range
                ...
Box and whisker plots representing
IGF-I SDS in females with AO-GHD

                    4


                    2


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

                     4



                     2
...
Summary
• These data demonstrate;

  – a large overlap of IGF-I SDS between
    normal and severely GHD adults

  – overla...
GHD2/GHD3   =   1 GH Provocative test
                        vs.
                      IGF-1

GHD0/GHD1   =   2 GH Provoc...
GH stimulation tests

• ITT/Arginine/Glucagon
• Arginine + GHRH
• GHRH + GHRP
• Clonidine? GHRH? – No
  – Age
  – BMI/Fat ...
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 interrupt...
Pituitary hormone deficiencies

Treatment                    • ACTH
• FSH/LH                       – Hydrocortisone (tds)
...
Partial ACTH D - Glucorticoid
               replacement
10 males – partial ACTH D
  • Base line plasma cortisol > 200nmol...
Pts, n=10             Controls, n=10        P-value

Age (years)                      43.9±10.8             38.9±12.2     ...
FD
           500                  HD
                                NT
                                Control
         ...
Long-acting GH preparation in
     patients with GHD
Open-label randomised study

• 135 patents – 32 weeks
• Depot GH vs D...
Adverse events

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

Two other serious and three non-serious ca...
Risk of Cortisol deficiency on
               GH replacement
• Ignorance – glucocorticoid dosage not  during
            ...
GH replacement and thyroid
    function in adult GHD patients
66 adult GHD patients

• 17 euthyroid/49 hypothyroid on T4
•...
Porretti et al (2002)

• 8/17 euthyroid subjects and 9/49 central
  hypothyroid patients showed FT4 levels
  below normal ...
Hypopituitarism Evolution of anterior pituitary hormone ...
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Hypopituitarism Evolution of anterior pituitary hormone ...

  1. 1. Hypopituitarism
  2. 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. 3. Case History • 50 year old freelance journalist • Diagnosed as having nasopharyngeal ca • Surgery & XRT Oct „99 • 3000cGy in 15 fractions (2 courses)
  4. 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. 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. 6. 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
  7. 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. 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. 9. Timing of onset of hypopituitarism • Childhood GHD - growth FSH/LH – puberty • Adult Normal height/secondary sex characteristics
  10. 10. 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
  11. 11. Hypopituitarism Causes • Pituitary Adenoma • Medical Therapy – Functioning – DA drugs – Non-Functioning – Pegvisomant • Pituitary Surgery – Anti-adrenal drugs • Pituitary Radiotherapy – Conventional – Stereotactic
  12. 12. 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
  13. 13. Investigation for Hypopituitarism • Gonadotrophin status – FSH,LH,T/E2 – GnRH test x • TSH – TSH, FT4 – TRH test x • Prolactin – Prolactin
  14. 14. How is ACTH D diagnosed? • UK SoE Survey 598 Clinical Members 81 Respondents ITT 9.00am Cortisol (>400 nmol/L) SST No Tests (NoT) Glucagon Reynolds et al, Clin End (2006)
  15. 15. ITT SST NoT Glucagon 9C Definitive testing of HPA Axis 31% 44% - 2.5% 2.5% Post- Surgery Long term Assessment XRT 7% 65% - 4% 18% Non – XRT 9% 36% 29% - 18% Reynolds et al, Clin End (2006)
  16. 16. 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)
  17. 17. 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)
  18. 18. 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)
  19. 19. 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)
  20. 20. Investigation for Hypopituitarism • ACTH – Morning Cortisol (<100 – 300nmol/l) – ITT/ Glucagon/Synacthen • GH Status – Provocative GH tests, IGF-1 – IGFBP-3/ALSx
  21. 21. Severe Adult GHD (ITT) 8 P <0.0001 6 g/L) GH Peak ( 4 2 0 GHD0 GHD1 GHD2 GHD3 Toogood et al. Clin. Endocrinol. 1994
  22. 22. 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)
  23. 23. Pituitary Hormone Deficits GHD O 1 2 3 Controls Patient numbers 69 15 6 13 35 Median Peak GH (mU/l) - ITT 7.5 2.4 0.75 0.5 65 - AST 6.8 2.4 1.0 0.5 32 Concordance 76.8 66.6 83.3 92.3 100 Between tests (%) Lissett et al (1999)
  24. 24. 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)
  25. 25. Implications Adults • GHDO/GHD1 patients require 2 GH stimulation tests vs only 1 required in GHD2/GHD3 patients
  26. 26. 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
  27. 27. 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)
  28. 28. 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)
  29. 29. 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)
  30. 30. 120 N = normal controls 100 P = patients Peak GH responses (µg / L). 80 N 60 55 40 N 23.8 P 20 14.5 P < 0.05 P 4.8 0 P < 0.05 -20 GHRH+AST ITT GHRH+AST ITT (Darzy et al, 2003)
  31. 31. The peak GH responses to the ITT and time after irradiation 60 Normals n = 33 Peak GH responses to the ITT (µg / L) 40 20 0 Normal < 6yr 6-12yr 12-18yr >18yr (Darzy et al, 2003)
  32. 32. The peak GH responses to the GHRH + AST and time after irradiation 120 Peak GH responses to the combined Normals 100 < 6 yr GHRH + AST (µg / L) 80 60 12 - 18 6 - 12 > 18 40 20 0 Time interval since irradiation (yr) (Darzy et al, 2003)
  33. 33. The discordancy ratio and time after irradiation 30 20 10 0 Median BED 58.3 58.3 48.82 54.4 Normals <6yr 6-12yr 12-18yr >18yr Time interval since irradiation (Darzy et al, 2003)
  34. 34. 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
  35. 35. 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
  36. 36. Percentage of patients with severe adult-onset GHD with IGF-I levels within the normal age related range Females Age Range Number % (Years) 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
  37. 37. Percentage of patients with severe adult-onset GHD with IGF-I levels within the normal age related range Males Age Range Number % (Years) 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
  38. 38. 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 71-80 Age Range (Years)
  39. 39. Box and whisker plots representing IGF- I 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 71-80 Age Range (Years)
  40. 40. 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
  41. 41. GHD2/GHD3 = 1 GH Provocative test vs. IGF-1 GHD0/GHD1 = 2 GH Provocative tests vs. 1GH Provocative test plus IGF-1
  42. 42. GH stimulation tests • ITT/Arginine/Glucagon • Arginine + GHRH • GHRH + GHRP • Clonidine? GHRH? – No – Age – BMI/Fat Mass – Availability
  43. 43. Diabetes Insipidus • 24 hour urine output > 3 litres • 8 hour fluid deprivation test
  44. 44. Radiology – MRI Scan • Absent PP high signal • Microadenoma vs Macrodenoma – Risk of hypopituitarism • Stalk interruption • Type and site of lesion • Evolution
  45. 45. Pituitary hormone deficiencies Treatment • ACTH • FSH/LH – Hydrocortisone (tds) – Sex Steriods – Cortisol profiles – Fertility-Gonadotrophins – Emergency advice • TSH • DI – T4 (threshold) – Desmopressin • GH – GH
  46. 46. 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
  47. 47. 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
  48. 48. FD 500 HD NT Control 400 Cortisol 300 200 100 0 2 4 6 8 10 Time Agha et al 2004
  49. 49. 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)
  50. 50. 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)
  51. 51. 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
  52. 52. 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)
  53. 53. 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

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