1. Department of Medical Sciences University of Milan, Italy Endocrinology and Diabetology Unit Fondazione Policlinico IRCCS Milan, Italy Paolo Beck-Peccoz TSH-secreting pituitary adenomas paolo.beckpeccoz@unimi.it

2. 0 50 100 150 200 Pure TSH-omas GH PRLFSH/LH 72.2% 16.0% 10.4% 1.4% Number of cases TSH-omas mixed tumor Beck-Peccoz et al., Endocrine Reviews 1996;17:610–638. Classification of TSH-secreting pituitary tumors

3. Euthyroid Thyroid Peripheral tissue Pituitary TSH T3 T4 Hypothalamus TRH RTH Peripheral tissue Pituitary TSH T3 T4 TRH Hypothalamus Thyroid Hyperthyroid Peripheral tissue Pituitary TSH T3 T4 TRH Hypothalamus Thyroid & TSH-oma

5. Positive MRI in RTH patients 9 out of 22 (40%) patients with RTH showed the presence of a pituitary lesion at MRI/CT scan Pituitary incidentaloma diagnosed in 8 cases Possible association between RTH and TSH-oma was suspected, but not yet proved, in only one 62-yr-old woman Nevertheless, the prevalence of pituitary incidentaloma appears higher in RTH patients (40%) than in the general population (20-30%)

6. Central Hyperthyroidism: serum levels of TSH and FT4 TSH mU/L Serum FT4 pmol/L 0.1 1 10 18 27 36 45 54 63 RTH (n=59) TSH-omas (n=13)

7. CIRCULATING FACTORS MAY INTERFERE WITH MEASUREMENT OF TSH OR TOTAL AND FREE THYROID HORMONES OVERESTIMATION OF SERUM LEVELS CENTRAL HYPERTHYROIDISM? Heterophylic Ab directed against mouse  -globulins: interference with monoclonal Ab used in the IRMA Anti-TSH Ab or Ab cross-reacting with TSH Anti-T4 and/or anti-T3 Ab Abnormal forms of albumin or transthyretin (FDH)

8. DIFFERENTIAL DIAGNOSIS BETWEEN TSH-OMAS AND RTH Age (years)11-84 0.1-80 NS Sex (F/M ratio) 1.28 1.17 NS TSH mU/L2.7±0.6 2.2±0.3 NS FT4 pmol/L 40.0±4.2 29.5±2.5 NS FT3 pmol/L14.5±1.4 11.7±1.0 NS SHBG nmol/L 113.0±17.2 62.0±4.0 <0.0001 Familial cases 0% 81% <0.0001 Lesions at CT scan or MRI 98% 10% <0.0001 High  -subunit levels 65% 2% <0.0001 High  -subunit/TSH m.r. 81% 2%<0.0001 Abnormal TSH response to TRH test 83% 4% <0.0001 Abnormal TSH response to T3 suppression test 100% 100% NS PARAMETER TSH-omas RTH P

9. TSH biological activity in various thyroid disorders RTH TSHomas 0 1 2 3 4 5 Circulating TSH B/I Persani et al., J Clin Endocrinol Metab. 1994; 78:1034–1039.

10. Net increments after TRH injection in RTH FT4 0 5 10 15 20 pmol/L * FT3 0 2.5 5 7.5 10 pmol/L * TSH 0 10 2030mU/L Controls RTH * P<0.01 vs controls controls Beck-Peccoz&Persani, Eur J Endocrinol, 1994; 131:331-340

11. DIFFERENTIAL DIAGNOSIS BETWEEN TSH-OMAS AND RTH Age (years)11-84 0.1-80 NS Sex (F/M ratio) 1.28 1.17 NS TSH mU/L2.7±0.6 2.2±0.3 NS FT4 pmol/L 40.0±4.2 29.5±2.5 NS FT3 pmol/L14.5±1.4 11.7±1.0 NS SHBG nmol/L 113.0±17.2 62.0±4.0 <0.0001 Familial cases 0% 81% <0.0001 Lesions at CT scan or MRI 98% 10% <0.0001 High  -subunit levels 65% 2% <0.0001 High  -subunit/TSH m.r. 81% 2%<0.0001 Abnormal TSH response to TRH test 83% 4% <0.0001 Abnormal TSH response to T3 suppression test 100% 100% NS PARAMETER TSH-omas RTH P

13. DIFFERENTIAL DIAGNOSIS BETWEEN TSH-OMAS AND RTH Age (years)11-84 0.1-80 NS Sex (F/M ratio) 1.28 1.17 NS TSH mU/L2.7±0.6 2.2±0.3 NS FT4 pmol/L 40.0±4.2 29.5±2.5 NS FT3 pmol/L14.5±1.4 11.7±1.0 NS SHBG nmol/L 113.0±17.2 62.0±4.0 <0.0001 Familial cases 0% 81% <0.0001 Lesions at CT scan or MRI 98% 10% <0.0001 High  -subunit levels 65% 2% <0.0001 High  -subunit/TSH m.r. 81% 2%<0.0001 Abnormal TSH response to TRH test 83% 4% <0.0001 Abnormal TSH response to T3 suppression test 100% 100% NS PARAMETER TSH-omas RTH P

14. DIFFERENTIAL DIAGNOSIS BETWEEN TSH-OMAS AND RTH Age (years)11-84 0.1-80 NS Sex (F/M ratio) 1.28 1.17 NS TSH mU/L2.7±0.6 2.2±0.3 NS FT4 pmol/L 40.0±4.2 29.5±2.5 NS FT3 pmol/L14.5±1.4 11.7±1.0 NS SHBG nmol/L 113.0±17.2 62.0±4.0 <0.0001 Familial cases 0% 81% <0.0001 Lesions at CT scan or MRI 98% 10% <0.0001 High  -subunit levels 65% 2% <0.0001 High  -subunit/TSH m.r. 81% 2%<0.0001 Abnormal TSH response to TRH test 83% 4% <0.0001 Abnormal TSH response to T3 suppression test 100% 100% NS PARAMETER TSH-omas RTH P

17. Acute somatostatin analog injection -50 -25 Variations (% of basal values) +25 0 +50 TSHFT4FT3 RTH TSH-omas Mannavola et al., Clin Endocrinol 2005; 62: 176-181

18. 2-3 months somatostatin analog administration -50 -25 Variations (% of basal values) +25 0 +50 TSHFT4FT3RTHTSH-omas Mannavola et al., Clin Endocrinol 2005; 62: 176-181

19. In summary: normal elevated SHBG and  -sub negativepositive Imaging NOYES Family members YESNO YESNO YESNO TRH test T3-suppression test TRH test post T3 TR  NO Molecular study FT3 & FT4 two step or TSH Ultrasensitive methods TSH- oma RTH

21. 0 5 10 15 20 25 30 35 40 45 50 All patientsPrevious thyroid ablation No thyroid ablation Percent of cases Intrasellar Extrasellar Invasive

22. Different therapeutical approaches None TH analogs TRIAC, DT4, GC1 (binds wtTR  >TR  ), HY1 (acts on TR  mut R320C) Cardiac selective blockers Inhibition of mutant gene expression Neurosurgery Radiotherapy SRIH analogs Octreotide Lanreotide SOM 230 RTH TSH-oma

23. Reduction of tumor mass complete 34% 29% 0% partial 34% 40% 51% absent 32% 31% 49% Resolution of clinical symptoms yes 57% 62% 95% no 43% 38% 5% Surgery Surgery +Rx SMS analogs (n=125) (n=57) (n=84) TSH producing adenomas: results of different therapeutic approaches

25. Results of chronic somatostatin analog treatment of TSH-secreting pituitary adenomas  TSH/  -GSU reduction92%  Thyroid hormone normalization95%  Vision improvement75%  Tumor mass shrinkage52%  True resistance4%  Discontinuation due to side effects 10%

26. 0 5 10 15 20 25 30 3540024612 24 TSH a-GSU FT4 FT3 GH Months Hormone levels Hormone levels after somatostatin analog in one patient with mixed GH/TSH adenoma IGF-I normalized after 2 months

27. ACKNOWLEDGEMENTS Luca Persani Deborah Mannavola Irene Campi Laura Fugazzola Guia Vannucchi Marco Bonomi Andrea Lania Sabrina Corbetta Giovanna Mantovani Carmela Asteria Krishna Chatterjee Samuel Refetoff Anna Spada