1. TSH SECRETING TUMORS: AN UPDATE AND THE ISRAELI EXPERIENCE Rosane Abramof Ness Sapir Medical Center

2. TSH-Secreting Pituitary Adenomas Rare cause of hyperthyroidism Rare cause of hyperthyroidism Originate from pituitary thyrotrophs just 2 ectopic case (nasopharynx) reported. Originate from pituitary thyrotrophs just 2 ectopic case (nasopharynx) reported. First case documented in 1960 (TSH measured by bioassay) First case documented in 1960 (TSH measured by bioassay) Hamilton et al reported the first case of TSH-oma proved by measuring RIA in 1970. Hamilton et al reported the first case of TSH-oma proved by measuring RIA in 1970.

3. Epidemiology Prevalence: 1/1,000,000 Prevalence: 1/1,000,000 0.5-1% of all pituitary tumors. 0.5-1% of all pituitary tumors. 336 cases published (7/2004). 336 cases published (7/2004). Since 1990 the number of reported cases has tripled. Since 1990 the number of reported cases has tripled. TSH-omas are equally frequent in men and women. TSH-omas are equally frequent in men and women. Familial cases have been reported only as part of the multiple neoplasia type 1 syndrome (MEN1) Familial cases have been reported only as part of the multiple neoplasia type 1 syndrome (MEN1)

4. Pathology The majority of TSH-secreting adenomas (75%) secrete TSH alone, often accompanied by unbalanced hypersecretion of its alpha-subunit (a- GSU) The majority of TSH-secreting adenomas (75%) secrete TSH alone, often accompanied by unbalanced hypersecretion of its alpha-subunit (a- GSU) Mixed adenomas: with concomitant hypersecretion of other pituitary hormones are found in 25% of cases. The most frequent are cosecretion of GH and PRL with its respective syndromes. Mixed adenomas: with concomitant hypersecretion of other pituitary hormones are found in 25% of cases. The most frequent are cosecretion of GH and PRL with its respective syndromes. The somatotroph and lactotroph cells share with thyrotropes common transcription factors such as Prop-1 and Pit-1. The somatotroph and lactotroph cells share with thyrotropes common transcription factors such as Prop-1 and Pit-1. Rare cases of mixed TSH/gonadotropin adenomas Rare cases of mixed TSH/gonadotropin adenomas

5. TSH-oma Mostly macroadenomas that show invasiveness into the surrounding structure. Mostly macroadenomas that show invasiveness into the surrounding structure. Extrasellar extension in the supra- and/or parasellar area is present in the majority of cases. Extrasellar extension in the supra- and/or parasellar area is present in the majority of cases. The occurrence of invasive macroadenomas is particularly high among patients with previous thyroid ablation by surgery or radioiodine. The occurrence of invasive macroadenomas is particularly high among patients with previous thyroid ablation by surgery or radioiodine. Microadenomas < 1 cm reported in less than 15% although they are increasingly recognized. Microadenomas < 1 cm reported in less than 15% although they are increasingly recognized. 1974-1986: 1/11 (9%) 1974-1986: 1/11 (9%) 1987-2001: 8/32 (25%) 1987-2001: 8/32 (25%) Valdes Socin H et al. European Journal of Endocrinology 2003; 148: 433-442.

6. Etiology Molecular mechanisms leading to TSH-oma are presently unknown. Molecular mechanisms leading to TSH-oma are presently unknown. Derive from the clonal expansion of a single initially transformed cell. Derive from the clonal expansion of a single initially transformed cell. Candidate genes: Ras, gsp,mutation in TRH receptor gene, dopamine D2 receptor gene- NEGATIVE Candidate genes: Ras, gsp,mutation in TRH receptor gene, dopamine D2 receptor gene- NEGATIVE Pit-1 mutations: NEGATIVE Pit-1 mutations: NEGATIVE Loss of function of antioncogenes: p53 (found in 1 tumor), MENIN- NEGATIVE Loss of function of antioncogenes: p53 (found in 1 tumor), MENIN- NEGATIVE Somatic mutations of thyroid hormone receptor beta may be responsible for the defect in negative regulation of TSH secretion in some TSH-omas (few cases and not confirmed by all studies) Somatic mutations of thyroid hormone receptor beta may be responsible for the defect in negative regulation of TSH secretion in some TSH-omas (few cases and not confirmed by all studies)

7. Cell Cultures Somatostatin (SRIH): almost all TSH-omas express a variable number of SRIH receptor. Somatostatin (SRIH): almost all TSH-omas express a variable number of SRIH receptor. Highest SRIH-binding site density found in mixed GH/TSH adenomas. Highest SRIH-binding site density found in mixed GH/TSH adenomas. Dopamine receptors: large heterogeneity of TSH response to dopamine agonists. Dopamine receptors: large heterogeneity of TSH response to dopamine agonists.

8. Clinical Findings Hyperthyroidism (TSH: N- , FT4 , FT3  ) Hyperthyroidism (TSH: N- , FT4 , FT3  ) Neurologic symptoms associated to pressure effects of the pituitary adenoma (visual field defects, headaches) Neurologic symptoms associated to pressure effects of the pituitary adenoma (visual field defects, headaches) Symptoms due to associated hypersecretion. Symptoms due to associated hypersecretion. Loss of anterior pituitary function Loss of anterior pituitary function

9. Thyrotoxicosis with Inappropriately high TSH levels Mouse ab interfering with TSH assay Mouse ab interfering with TSH assay Central hyperthyroidism : Central hyperthyroidism :  Pituitary tumor: TSH secreting.  Resistance to thyroid hormone (RTH)

10. Resistance to Thyroid Hormone Autosomal dominant disorder characterized by reduced responsiveness of target tissues to thyroid hormone due to a mutation in the thyroid hormone receptor beta. Autosomal dominant disorder characterized by reduced responsiveness of target tissues to thyroid hormone due to a mutation in the thyroid hormone receptor beta. First reported in 1967. First reported in 1967. Variable severity of hormonal resistance in different tissues. Variable severity of hormonal resistance in different tissues.

11. Differential diagnosis between TSH secreting adenomas (TSH-omas) and resistance to thyroid hormones (RTH) (16 TSHomas 64 RTH) ParameterTSH-omas RTH P Female/Male ratio 1.3 1.4 NS Familial cases 0 % 84 % <0.0001 TSH mU/L 3.0 ±0.5 2.3 ±0.3 NS FT4 pmol/L 38.8 ±4.0 29.9 ±2.4 NS FT3 pmol/L 14.0 ±1.2 11.3 ±0.9 NS SHBG nmol/L 117 ±1861 ±4 <0.0001 Lesions at CT or MRI 100 % 6 % <0.0001 High  -GSU levels 69 % 3 % <0.0001 High  -GSU/TSH m.r. 81 % 2 % <0.0001 Blunted TSH response to TRH test 94 % 2 % <0.0001 Abnormal TSH response to T3 suppression a 100 %100 % b NS Werner & Ingbar/s The Thyroid (eighth Edition) p560

12. A Pituitary Tumor in a Patient with Thyroid Hormone Resistance: A Diagnostic Dilemma Safer et al Thyroid 2001

13. Localization Localization MRI MRI Pituitary scintigraphy with radiolabeled octreotide (octreoscan) Pituitary scintigraphy with radiolabeled octreotide (octreoscan) PET : (11)C-Methionine PET PET : (11)C-Methionine PET Petrosal sinus sampling (PSS) Petrosal sinus sampling (PSS)

14. Treatment Surgery Surgery Radiation therapy Radiation therapy Somatostatin analogues Somatostatin analogues Dopamine agonists Dopamine agonists

15. Surgical Treatment First therapeutic approach First therapeutic approach Normalization of TFT’s and disappearance of tumor in 33-44% of patients. Normalization of TFT’s and disappearance of tumor in 33-44% of patients. Normalization of TFT’s in 25% Normalization of TFT’s in 25% Unsuccessful in 25% Unsuccessful in 25%

16. Pituitary Radiotherapy Pituitary Radiotherapy TreatmentNoCured%Improved% No change % Surgery alone 129333334 Irradiation alone 6335017 Surgery and irradiation 57354223

17. Criteria of Cure Remission from hyperthyrodism Remission from hyperthyrodism Disappearance of neurological signs Disappearance of neurological signs Normalization of FT4 and FT3 Normalization of FT4 and FT3 Normalization of TSH Normalization of TSH undetectable TSH one week after neurosurgery undetectable TSH one week after neurosurgery Normalization of alpha- GSU Normalization of alpha- GSU Positive T3 suppression test with undetectable TSH and no response to TRH Positive T3 suppression test with undetectable TSH and no response to TRH May be transient No predictive value  Poor predictive value  Biochemical remission may be transient. Poor predictive value  Good prognostic value  Lack of sensitivity (good sign)  Optimal sensitivity and specificity. C/I in elderly of patients with IHD

18. Medical Therapy Somatostatin analogues: Somatostatin analogues: TSH reduction (> 50%) 90% Alpha-GSU reduction 93% Thyroid hormone normalization 96% Goiter size reduction 20% Tumor mass shrinkage (>20%) 45% Resistance 4% Discontinuation of therapy (s/e) 7% Beck-Peccoz and Persani. Medical Management of Thyrotropin-Secreting Pituitary Adenomas. Pituitary 2002 : 83-88

19. Chanson, P. et. al. Ann Intern Med 1993;119:236-240 Individual levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) during short-term (1 to 2 weeks) octreotide therapy in patients with TSH- secreting adenomas

20. Dopamine Agonists No long term effect in obtaining normalization of TFT’s or tumor shrinkage No long term effect in obtaining normalization of TFT’s or tumor shrinkage Effective in cases of TSH-PRL co secretion Effective in cases of TSH-PRL co secretion

21. TSH-secreting tumors: The Israeli Experience Ness-Abramof R, Ishay A, Greenman Y, Harel G and Shimon I.

22. Patient’s Characteristics No : 9 No : 9 Sex: 4 M/ 5 F Sex: 4 M/ 5 F Age 44 ± 18 years (range: 18-80 y) Age 44 ± 18 years (range: 18-80 y) Goiter: 5/7 pts Goiter: 5/7 pts Symptoms of TX: 5/9 (tremor, PAF) Symptoms of TX: 5/9 (tremor, PAF) Duration of symptoms before diagnosis : Duration of symptoms before diagnosis : 2.5 y ± 1.7 ( range 0.5- 4 years) 2.5 y ± 1.7 ( range 0.5- 4 years)  Duration of follow up: 9.4 ± 5.5 years (range 1.5-16 )

23. Laboratory tests TSH 5.0 mU/L ± 1.5 (nl: 0.3-4) TSH 5.0 mU/L ± 1.5 (nl: 0.3-4) (range: 3-8.6 mU/L) (range: 3-8.6 mU/L) FT4 45.7 pmol/L ± 17.5 (nl: 10-20) FT4 45.7 pmol/L ± 17.5 (nl: 10-20) (range 24.3 - > 77 pmol/L) (6/9 pts) (range 24.3 - > 77 pmol/L) (6/9 pts) TT4 228 ± 23.3 nmol/L (nl: 53-143) ( 2/9 pts) TT4 228 ± 23.3 nmol/L (nl: 53-143) ( 2/9 pts) T3T 5.49 nmol/L ± 3.8 (nl: 1-2.8) T3T 5.49 nmol/L ± 3.8 (nl: 1-2.8) (range 3.1- 13 nmol/L) (6/9 pts) (range 3.1- 13 nmol/L) (6/9 pts)

24. Laboratory tests Alpha subunits: normal 3/3 patients Alpha subunits: normal 3/3 patients Alpha subunit/ TSH molar ratio: normal Alpha subunit/ TSH molar ratio: normal TRH test: TRH test: Normal response 1/5 (20%) Abnormal response 4/5 (80%)

25. Characteristics of Pituitary Tumors Size of adenoma: 25.7 ± 14 mm Size of adenoma: 25.7 ± 14 mm (range: 9-41 mm ) (range: 9-41 mm ) Intrasellar 1/9 Intrasellar 1/9 Extrasellar extension 8/9 Extrasellar extension 8/9 Suprasellar 7/8 Suprasellar 7/8 Cavernous sinus 3/6 Cavernous sinus 3/6 Sphenoid sinus 2/6 Sphenoid sinus 2/6

26. Visual Fields: Normal 5 pts (55%) Visual Fields: Normal 5 pts (55%) Abnormal 4 pts (45%) Abnormal 4 pts (45%) (bitemporal hemianopsia) (bitemporal hemianopsia) Hypopituitarism: 2/9 hypogonadism Hypopituitarism: 2/9 hypogonadism 1/9 on OC 1/9 on OC Diabetes insipidus: 0/9 Diabetes insipidus: 0/9 Co secretion of hormone: 2/9 (22%) GH Co secretion of hormone: 2/9 (22%) GH

27. Primary Medical Therapy Pt 1: Lanreotide 30 mg –1 year Pt 1: Lanreotide 30 mg –1 year Normalization of TFT’s but no tumor shrinkage (tumor size 16 mm) Pt 2: Bromocriptine - 1 year Pt 2: Bromocriptine - 1 year No effect No effect Pt 7: Lanreotide 30 mg q3 weeks: Pt 7: Lanreotide 30 mg q3 weeks: Normalization of TFT, tumor shrinkage (1 year) 10 mm→ 4 mm (60%)

30. Surgical Therapy 8 patients 8 patients ( 2/8 had 2 surgeries) ( 2/8 had 2 surgeries) ( The patient with a microadenoma didn’t have surgery) Approach: Approach: Transphenoidal: 7/8 Transfrontal: 1/8 Hypopituitarism: 3/7 Hypopituitarism: 3/7 Hypogonadism : 2/7 Hypogonadism : 2/7 Adrenal insufficiency : 1/7 Diabetes insipidus: 0/7 Adrenal insufficiency : 1/7 Diabetes insipidus: 0/7 Normalization of TFT’s: 1 pt (transient) Abnormal TFT’s : 5 pts (2 patients were treated perioperatively) Residual tumor: 8 pts

31. Post Operative Therapy Radiation therapy: 3 patients Radiation therapy: 3 patients (2 due to residual tumor and 1 tumor regrowth) (2 due to residual tumor and 1 tumor regrowth) Medical therapy (7 pts) Medical therapy (7 pts) Lanreotide: 3 pts (Somatuline 30mg, Autogel 60 mg) Autogel 60 mg) Octreotide: LAR: 3 pts (dose 30 mg) s.c: 2 pts (dose 100mic/day) s.c: 2 pts (dose 100mic/day) Dopamine agonists: 2 pts (1 s/e, 1 ineffective) (1 patients lost to f/u)

32. Chronic Somatostatin Analogue Therapy (post surgical and primary therapy) Duration of therapy: 4.6 ± 4.3 years Duration of therapy: 4.6 ± 4.3 years (range: 1.5-14 years) (range: 1.5-14 years)  Normalization of TFT’s: 8/8 patients Tumor shrinkage: 2/8 patients Tumor shrinkage: 2/8 patients (10mm→4 mm) (12mm → 9 mm) Tumor growth : 0/8 patients Tumor growth : 0/8 patients Central hypothyroidism: 2/8 patients Central hypothyroidism: 2/8 patients Side effects: cholelithiasis (1) abdominal pain:(4) Side effects: cholelithiasis (1) abdominal pain:(4)

33. Conclusions Surgical therapy was not curative. Surgical therapy was not curative. Somatostatin analogues were highly effective in normalizing thyroid function tests (100%) Somatostatin analogues were highly effective in normalizing thyroid function tests (100%) No tumor growth during somatostatin analogue therapy was observed. No tumor growth during somatostatin analogue therapy was observed. The role of somatostatin analogues as primary therapy for TSH secreting tumors, particularly microadenomas needs to be further evaluated. The role of somatostatin analogues as primary therapy for TSH secreting tumors, particularly microadenomas needs to be further evaluated.

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35. The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients  Proportion of microadenoma X macroadenoma 1974-1986: 1/11 (9%) 1987-2001: 8/32 (25%)  Medical therapy with somatostatin analogues was the first line therapy in 26 patients (19 had surgery)  TSH levels were reduced by more than 50% in 23/26 patients (normalization of TFT 22/26 – 85%)  Tumor shrinkage of more than 20% was observed in 5/13 cases (36%). Valdes Socin H et al. European Journal of Endocrinology 2003; 148: 433-442. Valdes Socin H et al. European Journal of Endocrinology 2003; 148: 433-442.