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 02Feb 02Mar 02Nov 02 Na nmol/L 124* 127* TSH mU/L 4.21*3.243.60*3.89* T4 pmol/L 59 (50-150) 61 (50-150) 8* (9-26) 9

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. 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

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 Sheehan’s syndrome Pituitary apoplexy TBI Empty Sella syndrome Lymphocytic hypophysitis Genetic diseases

14. Investigation for Hypopituitarism Gonadotrophin status –FSH,LH,T/E 2 –GnRH test x TSH –TSH, FT4 –TRH test x Prolactin –Prolactin

15. How is ACTH diagnosed? UK SoE Survey 598 Clinical Members 81 Respondents ITT9.00am Cortisol (>400 nmol/L) SST No Tests (NoT) Glucagon D Reynolds et al, Clin End (2006)

16. ITTSSTNoTGlucagon9C Definitive testing of HPA Axis Post- Surgery 31%44%-2.5% Long term Assessment XRT7%65%-4%18% Non – XRT 9%36%29%-18% 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 >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)

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. ACTH –Morning Cortisol (<100 – 300nmol/l) –ITT/ Glucagon/Synacthen Investigation for Hypopituitarism GH Status –Provocative GH tests, IGF-1 –IGFBP-3/ALS x

22. Toogood et al. Clin. Endocrinol. 1994 Severe Adult GHD (ITT)

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 10092.383.3 76.8 - AST 320.51.02.46.8 - ITT 650.50.752.47.5 Median Peak GH (mU/l) 35136 15 69 Patient numbers Controls 321 66.6 Concordance Between tests (%) OGHD 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. 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)

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

30. (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.

31. (Darzy et al, 2003) Peak GH responses (µg / L). -20 0 20 40 60 80 100 120 N N P P GHRH+AST ITT N = normal controls P = patients P < 0.05 55 23.8 14.5 4.8

32. (Darzy et al, 2003) The peak GH responses to the ITT and time after irradiation Peak GH responses to the ITT ( µg / L) 0 20 40 60 Normals n = 33 Normal 18yr

33. (Darzy et al, 2003) The peak GH responses to the GHRH + AST and time after irradiation Time interval since irradiation (yr) Peak GH responses to the combined GHRH + AST (µg / L) 0 20 40 60 80 100 120 Normals < 6 yr 6 - 12 12 - 18 > 18

34. (Darzy et al, 2003) The discordancy ratio and time after irradiation Time interval since irradiation Discordancy Ratio (peak GH to the GHRH+AST / ITT) 0 10 20 30 18yrNormals Median BED 58.3 58.3 48.82 54.4

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 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

38. 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 % 21-303026.7 31-406262.9 41-5010261.8 51-6014973.1 61-707560.0 71-801675.0

39. Box and whisker plots representing IGF-I SDS in females with AO-GHD Age Range (Years) 21-3031-4041-5051-6061-7071-80 IGF-I SDS -10 -8 -6 -4 -2 0 2 4

40. Box and whisker plots representing IGF- I SDS in males with AO-GHD Age Range (Years) 21-3031-4041-5051-6061-7071-80 IGF-I SDS -8 -6 -4 -2 0 2 4

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 > 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. 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

48. Pts, n=10Controls, n=10P-value Age (years)43.9±10.838.9±12.20.34 BMI (kg/m 2 )31.1±4.530.8±4.30.88 CBG (mg/l)41.7±7.144.9±4.60.25 Baseline cortisol273.9±61.8357.3±84.40.021 Peak stimulated cortisol432.9±58.9 Results presented as mean±SD. BMI, body mass index; CBG, corticosteroid-binding globulin Agha et al 2004

49. 500 400 300 200 100 0246810 Time Cortisol Agha et al 2004 FD HD NT Control

50. 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)

51. 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)

52. 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

53. 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)

54. 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)