1. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Thyrotropin (TSH) secreting pituitary adenomas R4 변종규 / Prof. 진상욱

2. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y  Background  Pathophysiology  Clinical manifestation  Diagnostic procedures  Treatment & Follow up Contents

3. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Background Since 1960 more than 450 cases of TSHoma have been published, the prevalence of these adenomas being around one case per million. TSHomas account for about 0.5–3% of all pituitary adenomas The syndrome of ‘inappropriate secretion of TSH’ was the term coined originally to indicate two forms of central hyperthyroidism – Thyrotropin (TSH)-secreting pituitary adenomas (TSHomas) – Resistance to thyroid hormone action (RTH). Increase in the number of TSHomas diagnosed in the last 3 decades => due to both practitioner awareness and the introduction of ultrasensitive immunometric TSH assays P. Beck-Peccoz, A.Lania et al. Eur Thyroid J, 2:76-82, 2013 국내에서는 1986 년 첫 보고 이후 2011 년 까지 약 11 례 가 보고 됨.

4. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Pathophysiology  TSHomas usually benign tumors - Few patients- TSHoma into carcinoma with multiple metastases - These adenomas are often large and invasive lesions and very fibrous  TSH secretion - High concentrations circulating total or free thyroid hormones non-suppressed TSH levels - No response to TRH (no increase) - No response to exogenous thyroid hormone administration (no decrease)  70% of TSHoma : secrete only TSH hormone (mostly macroadenoma) - accompanied by hypersecretion of α-GSU (glycoprotein hormone α subunit )  25% of TSHoma : mixed adenoma, secrete other hormone - 15% : GH - 10% : prolactin  TSHomas express a variable number of somatostatin receptors - prompted the use of somatostatin analogs in TSHoma treatment. P. Beck-Peccoz, A.Lania et al. Eur Thyroid J, 2:76-82, 2013

5. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Clinical menifastations Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 597–606

6. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Clinical menifastations  Most of patients have long history of thyroid dysfunction - Increased circulating levels of both free T4 and T3, therefore associated with signs and symptoms of hyperthyroidism. - Misdiagnosed as Graves’ disease - 30% thyroidectomy or radioiodine thyroid ablation  Compression of the surrounding anatomical structures - Visual field defects, loss of vision, headache, hypopituitarism - Invasive macroadenomas is high among patients with previous thyroid ablation  Cardiotoxicosis include atrial fibrillation and/or cardiac failure  Occurrence of uni or multi nodular goiter is frequent - Progress to toxic goiter is infrequent Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 597–606

7. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Clinical menifastations  Progress to thyroid carcinomas documented in a few cases  Disorders of the gonadal axis are frequent - Menstrual disorders are present in all females with mixed TSH/PRL tumors and in one third of those with pure TSHoma - Central hypogonadism, delayed puberty and decreased libido have been described in male patients Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 597–606

8. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Diagnostic procedures  Elevated α-GSU/TSH molar ratio - 85% of patients elevated α-GSU and elevated α-GSU/TSH molar ratio >1 - Recent series of TSHomas, normal α-GSU levels were observed in more than 60% of the cases and more frequently in microadenomas than in macroadenomas Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 597–606

9. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Diagnostic procedures  Stimulatory and inhibitory test - T3 suppression test (80–100μg per day for 8–10 days) - elderly or Coronary artery disease (contraindication) - TRH stimulation test (200 μg intravenous)  Pituitary MRI and CT - Most TSHomas diagnosed at the stage of macroadenomas with frequent suprasellar extension or sphenoidal sinus invasion - Microadenomas are now reported with increasing frequency, about 15% of cases Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 597–606

10. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Differential diagnosis P. Beck-Peccoz, A.Lania et al. Eur Thyroid J, 2:76-82, 2013

11. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Treatment European Journal of Endocrinology (2007) 157 39–46

12. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Treatment  Primary objectives of the treatment - Removal of the pituitary tumor, restoration of euthyroidism  Surgery (1 st line therapy) Trans-sphenoidal or subfrontal adenomectomy - Operation may be difficult as the tumor may present a marked fibrosis  -> high expression of basic fibroblast growth factor - Locally invasive, involving the cavernous sinus, internal carotid artery. - Microadenoma : Complete removal of the tumor is achieved in the majority of patients - Macroadenoma : No more than 60% of patients may be cured.

13. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Treatment  Medical treatment 1. Somatostatin analogues (octreotide, lanreotide) - Reduction in TSH and α-GSU secretion in almost all cases. - Circulating thyroid hormone levels normalized in 90% of patients. - Goiter size was significantly reduced 1/5 cases. - Shrinkage of tumor improves visual defects. 2. Dopamine agonist (bromocriptine, cabergoline) - Dopamine type 2 receptors are present in most TSHomas - Bromocriptine reduced TSH levels in only 20% of patients tested. - Tumor shrinkage reported only in those with combined excess of TSH and PRL. P. Beck-Peccoz, A.Lania et al. Eur Thyroid J, 2:76-82, 2013

14. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y 3. Methimazole - After resection TSHoma, followed by octreotide, methimazole combination therapy - Control both TSH and thyroid hormone concentration. Sayaka F, Masaki T et al. Endocrine J 58(6): 485-490, 2011 => May cause TSH secretion from normal, non-adenomatous thyrotropes to be re-activated  Radiotherapy or radiosurgery - If surgery and medical treatment are contraindicated or declined, pituitary fractionated stereotaxic radiotherapy or radiosurgery might be considered. Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 597–606

15. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Criteria of cure P. Beck-Peccoz, L Persani. Thyroid disease manager: 2013

16. Towards Global Eminence K Y U N G H E E U N I V E R S I T Y Follow up Follow up No data on recurrence rates of TSHomas in patients judged cured after surgery or radiotherapy have been reported. Recurrence of the adenoma does not appear to be frequent, at least in the first years after successful surgery The patient should be evaluated clinically and biochemically 2 or 3 times the first year postoperatively, and then every year. Pituitary imaging should be performed every two or three years P. Beck-Peccoz, A.Lania et al. Eur Thyroid J, 2:76-82, 2013