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Efficacy of the long-acting octreotide formulation (sandostatin-LAR) in patients with TSH-secreting pituitary adenomas after incomplete surgery and octreotide treatment failure Chun-Fang ZHANG*, Dan LIANG* and Li-Yong ZHONG*# * Endocrine branch, Beijing Tiantan Hospital affiliated to Capital Medical University, Beijing, 100050, China. # Correspondence to: Li-Yong ZHONG, Endocrine branch, Beijing Tiantan Hospital affiliated to Capital Medical University, No. 6, Tiantanxili, Dongcheng District, Beijing, 100050, China. E-mail: [email protected]. Tel: +86-10-67096618 Abstract Background: To report the efficacy and safety of Sandostatin-LAR in patients with TSH-secreting pituitary adenomas after incomplete surgery and Octreotide treatment failure. Methods: Fifteen patients with thyroid-stimulating hormone (TSH)-secreting pituitary adenomas (8 male and 7 female), who previously underwent incomplete surgical resection and/or adjuvant radiotherapy (n = 12) and failure of Octreotide treatment (n = 15), followed between 2007 and 2010 in Beijing Tiantan Hospital were included in this study. All patients received 1- to 2-months of Sandostatin-LAR treatment after the above combination of treatment. Paired samples t-Test was used to analysis the variables. Results: After two-month duration of Sandostatin-LAR treatment, the mean serum FT4 (16.02 ± 1.72 pM) and FT3 (2.87 ± 0.43 pM) levels of 15 patients significantly decreased compared with those after Octreotide-treatment (FT4, 35.36 ± 7.42 pM, P < 0.001; FT3, 17.85 ± 7.22 pM, P < 0.001). Mean TSH levels stayed in the normal range after Sandostatin-LAR treatment (0.72 ± 0.21 mU/L) and were significantly lower than the pretreatment value (5.27 ± 1.04 mU/L, P < 0.001), post-surgery value (3.37 ± 0.31 mU/L, P < 0.001) and post-octreotide-treatment value (4.52 ± 0.41 mU/L, P < 0.001). In these patients with TSH-secreting pituitary adenomas there was no evidence of tachyphylaxis. Conclusions: Sandostatin-LAR may be a useful and safe therapeutic tool to facilitate the medical treatment of TSH-secreting pituitary adenomas in patients who underwent incomplete surgery or need long-term somatostatin analog therapy. Keywords: pituitary adenomas; TSH; Sandostatin-LAR; Octreotide; surgery Introduction Pituitary adenomas are tumors that occur in the pituitary gland, and account for about 15%-20% of intracranial neoplasms [1]. Classification of pituitary tumors is based on plasma hormone levels or immunohistochemical staining. Diagnosis of pituitary adenoma can be made, or at least suspected, by a constellation of related symptoms, and confirmed by testing hormone levels and by radiographic imaging of the pituitary. Surgery is a common treatment for pituitary tumors. Although many pituitary tumors are successfully resected, functional adenomas may not be cured by surgery. Management of pituitary tumors has improved in the past decade since the introduction of novel therapeutic agents. As a result, several treatment options are now available. Dopamine agonists are the preferred treatment for both symptomatic microprolactinomas (less than 10 mm in their largest diameter) and macroprolactinomas (10 mm or more); these drugs result in normalization of hormone levels and tumor shrinkage in most treated patients. New formulations (such as cabergoline and parenteral bromocriptine) with prolonged duration of action offer improved compliance with treatment and cure rates [2]. Thyroid-stimulating hormone (TSH)-secreting pituitary adenomas account for less than 1% of functioning pituitary tumors [3] and are occasionally manifested as hyperthyroidism [4] and usually doesn't cause symptoms. However, tumor patients with clinical manifestation of hyperthyroidism are tended to be misdiagnosed as primary hyperthyroidism and pretreated with antithyroid drug therapy. The pituitary tumor will increase in size after application of antithyroid drug prior to surgical resection and it is difficult for subsequent surgery to remove the tumor completely. Up to now, the literature contains little information about the current management of patients with TSH-secreting pituitary adenomas or about the usefulness of the somatostatin analogue octreotide in such cases. In this study, we applied long-acting Octreotide formulation (Sandostatin-LAR, Octreotide Acetate Microspheres for Injection) in patients with TSH-secreting pituitary adenomas after incomplete surgery and failure of Octreotide treatment. Our study demonstrated the effectiveness of treating patients with long-acting Octreotide formulation increase the possibility of clinical remission. METHODS Patients Diagnosis of TSH-secreting pituitary adenomas was based on clinical findings (tumoral syndrome and/or thyrotoxicosis), biochemical evidence of unsuppressed TSH levels contrasting with elevated serum thyroid hormone concentrations and the identification of an adenoma by pituitary magnetic resonance imaging (MRI). Additional diagnostic tools were dynamic response of TSH and a subunit (aSU) to thyrotropin-releasing hormone (TRH), tri-iodothyronine (T3) suppression test in questionable cases, and measurement of prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and adrenocorticotropin (ACTH) levels. All the diagnosis was confirmed by pathology and immunohistochemistry after surgery.The tumors are composed of choromophobic cells and exhibit sinusoidal growth pattern. By IHC, the tumor cells are positive for TSHβ and aSU. The tumors are also sometimes multihormonal with positive staining for GH and PRL. In this article, we follow the guidelines and classification scheme for pituitary gland tumors that was released by the World Health Organization (WHO) in 2004 [5]. Fifteen patients with TSH-secreting pituitary adenomas from Beijing Tiantan Hospital affiliated to Capital Medical University between 2007 and 2010 were included in this study (seven women and eight men; mean ± SE age, 41 ± 0.65 year). Ten patients presented pure TSH-secreting tumors, three had a mixed TSH-GH-secreting adenoma and two had a mixed TSH-PRL-secreting adenoma. On a computed tomography scan or nuclear magnetic resonance imaging, three of these patients had giant adenomas (maximal diameter > 40mm), eleven had macroadenomas (maximal diameter > 10mm), and one had microadenoma. All patients had previously been treated with transsphenoidal incomplete surgical resection (n = 9), transfrontal incomplete surgical resection (n = 6), and post-surgically been treated with radiotherapy (n = 12; 45 to 50 Gy, 5 to 6 weeks) and Octreotide (n = 15). All patients showed uncontrolled hyperthyroidism after 1 to 2 months of Octreotide treatment before this study. The individual characteristics of each patient are summarized in Table 1. Treatment The present study was approved by the institutional ethics committee of the Capital Medical University (Beijing, China), and each patient gave written informed consent. The diagnosis of TSH-secreting pituitary adenomas was based on physical examination, elevated free thyroid hormone concentrations in the presence of normal or elevated TSH levels, and pituitary adenoma. After incomplete surgical resection (n = 15) and post-surgical radiotherapy (n = 12), all patients received subcutaneous injection (sc) of Octreotide for a period of 1 month. However, in all patients (n = 15), TSH, T3, T4, FT3, or FT4 levels were in the abnormal range during treatment with Octreotide (0.1 mg/8hr) for one to two months. All patients then received im injections of Sandostatin-LAR 20 mg/month for the next two months. Specimen collection and hormone detection For serum TSH, T3, T4, FT3, and FT4 assay, venous blood was collected (8 am of the day) at diagnosis, post-surgery (1 week), post-Octreotide treatment (1 or 2 month) and Sandostatin-LAR treatment (1 and 2 months). Serum was extracted and stored at -80℃ until further use. Hormones were measured by radioimmunoassay with kit (No, REF 2K47-20; Abbott Laboratories, Middletown VA. USA) according to the protocol. The reference range for T3: 0.89-2.44 nM; T4: 62.68-150.84 nM; FT3: 2.63-5.70 pM; FT4: 9.00-19.04 pM; TSH: 0.35-4.94 mU/L. Statistical analysis All data were expressed as mean ± standard deviation (SD). Paired samples t-Test (SPSS 14.0 statistical software, SPSS, Chicago, IL, USA) was used to assess the effects of Sandostatin-LAR on T3, T4, FT3, FT4 and TSH levels in patients with pituitary adenomas. P value of < 0.05 was considered statistically significant. RESULTS Clinical evaluation All patients (n = 15) received incomplete surgical resection of the tumors after first diagnosed as described in Table 2. Twelve patients received radiotherapy after incomplete surgical resection. Two to three months after surgery and radiotherapy, symptoms of hyperthyroidism recurred for all patients and treatment with 0.1mg/8hr sc Octreotide injection were applied subsequently. However, significant symptoms of hyperthyroidism were not effectively controlled after 1 to 2 months of Octreotide administration. Sandostatin-LAR was used for these Octreotide treatment failure cases. During Sandostatin-LAR administration, clinical signs improved and all patients were euthyroid after 2 months of the i.m. Sandostatin-LAR treatment. All patients continued monthly i.m. injections of Sandostatin-LAR after cured both clinically and biologically. Hormonal evaluation and treatment effects In this cohort of 15 patients with TSH-secreting pituitary adenomas, the mean basal serum FT4 and FT3 levels were 61.51 ± 15.33 pM (mean ± SD) and 36.76 ± 10.46 pM, respectively, before any treatment was started. One week post-surgery, the serum FT4 and FT3 decreased to 30.22 ± 6.29 pM and 17.28 ± 5.59 pM, respectively, but 14 out of 15 cases remained abnormal (Table 3, Figure 1C, 1D). No suppression of FT4 and FT3 levels were seen in the 15 cases treated by Octreotide. Neither a tumoral shrinkage nor an improved surgical outcome was obtained in those patients (remission group: 0/15, failure group: 15/15). After Sandostatin-LAR treatment, mean serum FT4 (16.02 ± 1.72 pM) and FT3 (2.87 ± 0.43 pM) levels significantly decreased compared with those post-Octreotide-treatment (FT4, 35.36 ± 7.42 pM, P < 0.001, Figure 1C; FT3, 17.85 ± 7.22 pM, P < 0.001; Figure 1D). Fourteen patients were considered to be euthyroid (normal FT4 and FT3 concentrations) during the 2-month treatment with Sandostatin-LAR. In one patient FT4 level remained abnormal at the 2-months evaluation (Figure 1D). The mean serum TSH value at diagnosis was 5.27 ± 1.04 mU/L and fell to 4.52 ± 0.41 mU/L after two months of octreotide treatment (Table 3). After a 2-month period of monthly im injections of Sandostatin-LAR, the mean TSH value recorded on two months after the last injection was 0.72 ± 0.21 mU/L. Mean TSH levels stayed in the normal range after Sandostatin-LAR treatment (0.72 ± 0.21 mU/L) and were significantly lower than the pretreatment value (5.27 ± 1.04 mU/L, P < 0.001), post-surgery value (3.37 ± 0.31 mU/L, P < 0.001) and post-octreotide-treatment value (4.52 ± 0.41 mU/L, P < 0.001; Figure 1E). In these patients with TSH-secreting pituitary adenomas there was no evidence of tachyphylaxis. The tumor sizes decreased significantly after two months of Sandostatin-LAR (0.03 ± 0.00 cm3) treatment compared with two months after octreotide treatment (0.62 ± 0.03 cm3) and postsurgery (0.63 ± 0.02 cm3, P < 0.001; Figure 2). Safety and tolerability of Sandostatin-LAR Sandostatin-LAR is generally well tolerated by all the patients. Biochemical examination including liver and kidney function, blood routine examination and blood lipid and glucose concentration were taken regularly and none of the patients expressed abnormal. Clinical manifestation including gastrointestinal disturbances and injection site reactions were also considered. Three out of 15 (20%) patients receiving Sandostatin-LAR experienced nausea and abdominal discomfort. One patient (6.7%) had moderate discomfort at the injection site. Symptoms are, however, generally mild and none of the patients require treatment withdrawal because of side effects. Follow-up All patients were followed-up for a mean period of 1.87 years (range 1.2-3.0 years). At the last follow-up examination, 13 patients fulfilled all the biochemical criteria for remission and none had evidence of regrowth of the pituitary adenoma. The remaining two patients are currently under long-acting Sandostatin-LAR with acceptable biochemical control of the disease. In summary, at the last follow-up, Hypersecretion and residual tumors were well controlled by Sandostatin-LAR treatment in all patients after incomplete surgery and failure of Octreotide treatment. DISCUSSION TSH-secreting pituitary adenomas are rare, frequently are macroadenomas at diagnosis and thus present with mass effect symptoms, together with variable symptoms and signs of hyperthyroidism [6]. Pituitary surgery is considered the first therapeutic approach in patients with TSH-secreting pituitary adenomas [7] to restore euthyroidism in hyperthyroid patients and to eliminate the symptoms of mass effect in patients with macroadenomas. Pituitary surgery led to normalization of thyroid hormone levels and complete tumor removals in 44% of the patients, produced normalization of thyroid hormone secretion despite incomplete tumor removals in 25% of the patients, and was unsuccessful in 29% [6, 8]. Radiation therapy, as an adjuvant therapy, has been considered the most appropriate methods for patients not in remission after surgery [9]. However, the percent remission of hyperthyroidism is low after radiotherapy or stereotactic radiosurgery [4, 6]. Since somatostatin analogs [10] has been allowed to be medical treatment with patients with TSH-dependent hyperthyroidism related to TSH-secreting pituitary tumors, medical treatment of TSH-secreting adenomas has been widely improved [11]. Somatostatin analogs allow the control of thyroid function and tumoral mass in all patients with TSH-secreting adenomas when surgery and/or radiotherapy have failed [9, 12, 13]. Octreotide, a synthetic somatostatin analog with a half-life of between 80–110 min, is administered sc two or three times daily or continuously using portable pumps. To avoid drawbacks of Octreotide such as multiple daily injections or the use of portable pumps, Sandostatin-LAR, a long-acting octreotide formulation of the somatostatin analog octreotide has been used. It consists of octreotide acetate encapsulated with a biodegradable polymer (Sandostatin-LAR), and this depot formulation is injected im every 4 weeks. In this study, we applied used Sandostatin-LAR as a Long-Acting Octreotide Formulation in patients with persistent TSH-dependent hyperthyroidism after incomplete tumor removal of adenomas with/without adjuvant radiation therapy and failure of Octreotide treatment. The first noticeable finding of our study was that in our population of patients with TSH-secreting pituitary adenomas, who underwent incomplete surgery and failure of Octreotide treatment, Sandostatin-LAR decreased mean TSH, FT4, and FT3 levels in the normal range (n = 13), and long-term treatment maintained euthyroidism in the other two patients. Postoperative radiotherapy is generally applied after incomplete surgery. However, secreting pituitary adenoma is moderately sensitive to radiotherapy and the efficacy needs a few months to show up. It takes conventional radiotherapy one year or more to show maximize therapeutic effects and ten years for patients to return to normal hormone levels [14]. It is reported that radiotherapy decreased only 31% of the TSH levels in patients with TSH adenoma, but cannot reduce the TSH level to normal. It is undeniable that, in our study radiotherapy may contribute to the final treatment effect after two months of Sandostatin-LAR administration. However, postoperative radiotherapy alone cannot achieve cure rate of 87% within 5-6 months. The second important finding in this series was that Sandostatin-LAR was well tolerated throughout the study. Minor digestive problems (nausea, mild abdominal pain, and softened stools) or moderate discomfort at the injection site, lasting less than 48 h, were reported by three and one patients, respectively, and did not require interruption of the treatment. In this study, gallbladder echographies did not reveal the occurrence of gallstones in any patient during Sandostatin-LAR treatment as also reported by Kuhn et al. [15]. On the other hand, after two-month treatment with multiple daily s.c. injections of Octreotide, the patients noted the convenience of monthly injections and continued i.m. Sandostatin-LAR at the end of the study. In conclusion, this study shows the efficacy and safety of Sandostatin-LAR in patients with TSH-secreting pituitary adenomas that were responsive to Sandostatin-LAR, who were previously treated with incomplete surgery and/or pituitary radiotherapy and failure of Octreotide treatment. Sandostatin-LAR may be a useful and safe therapeutic tool to facilitate the medical treatment of TSH-secreting pituitary tumors in patients who underwent incomplete surgery or need long-term somatostatin analog therapy. Authors’ disclosures of potential conflicts of interest The authors indicated no potential conflicts of interest. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. LIU L, LIU ZX, LIU YS, LIU JF, ZENG Y, ZENG ZC, et al. Applied anatomy for pituitary adenoma resection. Chinese Medical Journal 2011; 124(15):2269-2274. PMID: 21933555 Shimon I, Melmed S. Management of pituitary tumors. Ann Intern Med 1998, 129(6):472-483. PMID: 9735086 Mandell, F. B, Stoller, K. J, Michota, A F. The Cleveland Clinic Foundation intensive review of internal medicine. Lippincott Williams & Wilkins: Hagerstwon, MD; 2009: 341-342. Chanson P, Weintraub BD, Harris AG. Octreotide therapy for thyroid-stimulating hormone-secreting pituitary adenomas. A follow-up of 52 patients. Ann Intern Med 1993, 119(3):236-240. PMID: 8323093 DeLellis RA, Lloyd RV, Heitz PU, Eng C, Eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004: 236-237. Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC, Weintraub BD. Thyrotropin-secreting pituitary tumors. Endocr Rev 1996, 17(6):610-638. PMID: 8969971 McCutcheon IE, Weintraub BD, Oldfield EH. Surgical treatment of thyrotropin-secreting pituitary adenomas. J Neurosurg 1990, 73(5):674-683. PMID: 2213157 Sanno N, Teramoto A, Osamura RY. Long-term surgical outcome in 16 patients with thyrotropin pituitary adenoma. J Neurosurg 2000, 93(2):194-200. PMID: 10930003 Caron P, Arlot S, Bauters C, Chanson P, Kuhn JM, Pugeat M, et al. Efficacy of the long-acting octreotide formulation (octreotide-LAR) in patients with thyrotropin-secreting pituitary adenomas. J Clin Endocrinol Metab 2001, 86(6):2849-2853. PMID: 11397898 Losa M, Magnani P, Mortini P, Persani L, Acerno S, Giugni E, et al. Indium-111 pentetreotide single-photon emission tomography in patients with TSH-secreting pituitary adenomas: correlation with the effect of a single administration of octreotide on serum TSH levels. Eur J Nucl Med 1997, 24(7):728-731. PMID: 9211757 Socin HV, Chanson P, Delemer B, Tabarin A, Rohmer V, Mockel J, et al: The changing spectrum of TSH-secreting pituitary adenomas. diagnosis and management in 43 patients. Eur J Endocrinol 2003, 148(4):433-442. PMID: 12656664 Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 2007, 21(2):277-305. PMID: 17574009 Hofland LJ, Lamberts SW: The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev 2003, 24(1):28-47. PMID: 12588807 Barrande G, Pittino-Lungo M, Coste J, Ponvert D, Bertagna X, Luton JP , et al. Hormonal and metabolic effect s of radiotherapy in acromegaly. Long-term result s in 128 patient s followed in a single center. J Clin Endocrinol Metab 2000, 85:3779-3785. PMID: 11061538 15. Kuhn JM, Arlot S, Lefebvre H, Caron P, Cortet-Rudelli C, Archambaud F et al. Evaluation of the treatment of thyrotropin-secreting pituitary adenomas with a slow release formulation of the somatostatin analog lanreotide. J Clin Endocrinol Metab 2000, 85(4):1487-1491. PMID: 10770186 Table 1. Clinical characteristics of the 15 patients with a TSH-secreting pituitary adenoma at first diagnosis At first diagnosis Patient Age Follow no. (yr) Tumor size TSH Sex up (yr) T3 (nM) T4 (nM) FT3 (pM) FT4 (pM) (0.89-2.44) (62.68-150.84) (2.63-5.70) (9.00-19.04) (mm3) (mU/L) (0.350-4.94) 1 38 M 1.5 4.59 12.29 308.88 > 46.08 > 77.22 3.0 × 2.8 × 3.1 2 45 F 2.0 4.46 8.12 > 308.88 20.25 45.53 2.2 × 2.0 × 3.0 3 46 M 1.7 8.44 2.66 141.46 5.45 15.94 1.6 × 2.0 × 2.1 4 42 M 2.2 4.66 11.26 288.76 42.08 71.12 3.5 × 2.9 × 3.2 5 33 F 1.2 4.37 9.37 288.76 38.33 58.32 1.0 × 1.6 × 1.2 6 26 F 1.5 5.44 10.37 268.04 41.22 62.33 2.5 × 2.6 × 3.1 7 33 M 2.0 5.59 11.28 287.78 42.09 76.22 4.3 × 3.8 × 3.1 8 44 F 2.5 4.69 9.79 274.18 39.67 66.22 2.4 × 3.0 × 3.2 9 32 M 2.3 6.68 12.38 309.77 45.18 76.12 2.6 × 3.2 × 3.0 10 48 F 1.2 5.19 9.19 268.77 41.18 68.34 3.5 × 3.2 × 3.6 11 37 M 1.6 5.00 8.87 288.56 39.17 57.22 5.2 × 4.7 × 5.0 12 42 F 1.5 4.87 10.28 297.76 39.07 67.12 2.4 × 2.7 × 3.2 13 49 M 1.7 5.01 8.97 267.66 36.06 57.21 3.1 × 2.6 × 2.7 14 51 F 2.1 5.24 9.05 288.76 37.18 66.32 5.5 × 5.0 × 8.0 15 37 M 3.0 4.88 8.64 256.67 38.36 57.46 1.8 × 2.1 × 2.6 FT3, free T3; FT4, free T4. Table 2. Treatments of the 15 patients with a TSH-secreting pituitary adenoma Treatment Patient Pathological Primary no. Sandostatin Radiotherapy Octreotide# staining LAR* treatment 1 TSS + 0.1mg, 2months 20mg, 2 months TSH 2 TSS - 0.1mg, 1months 20mg, 2 months TSH 3 TSS + 0.1mg, 1months 20mg, 2 months TSH 4 TFS + 0.1mg, 1months 20mg, 2 months TSH 5 TSS - 0.1mg, 1months 20mg, 2 months TSH 6 TSS + 0.1mg, 1months 20mg, 2 months TSH+GH 7 TFS + 0.1mg, 1months 20mg, 2 months TSH+GH 8 TSS + 0.1mg, 1months 20mg, 2 months TSH 9 TFS - 0.1mg, 2months 20mg, 2 months TSH+GH 10 TFS + 0.1mg, 1months 20mg, 2 months TSH+PRL 11 TFS + 0.1mg, 1months 20mg, 2 months TSH 12 TSS + 0.1mg, 1months 20mg, 2 months TSH 13 TSS + 0.1mg, 1months 20mg, 2 months TSH 14 TFS + 0.1mg, 1months 20mg, 2 months TSH+PRL 15 TSS + 0.1mg, 1months 20mg, 2 months TSH TSS, transsphenoidal surgery; TFS, transfrontal surgery; TSH, thyroid-stimulating hormone; GH, growth hormone; PRL, prolactin; #Dose of every 8 hours, duration of Octreotide treatment. *Monthly dose, duration of Sandostatin-LAR treatment. Five to six weeks of treatment of radiotherapy (45-50Gy). Table 3. Serum hormones before and after treatments Hormonal At first 1 week evaluation diagnosis postsurgery TSH (mU/L) 5.27 ± 1.04 3.37 ± 0.31 Octreotide Sandostatin-LAR Normal range T3 (nM) 9.50 ± 2.30 1 month 2 months 1 month 2 months 1.67 ± 4.52 ± 1.02 ± 0.72 ± 0.82 0.41 0.43 0.21 2.42 ± 6.29 ± 1.53 ± 1.08± 0.69 1.57 0.44 0.30 0.35-4.94 4.64 ± 0.87 0.89-2.44 275.65 ± 216.38 ± 185.96 ± 233.19 ± 128.19 ± 111.87 ± 43.11 36.99 38.38 46.02 37.37 17.97 36.76 ± 17.28 ± 3.90 ± 17.85 ± 3.40 ± 2.87 ± 10.46 5.59 1.07 7.22 0.63 0.43 61.51 ± 30.22 ± 23.35 ± 35.36 ± 18.83 ± 16.02 ± 15.33 6.29 4.11 7.42 3.31 1.72 T4 (nM) 62.68-150.84 FT3 (pM) 2.63-5.70 FT4 (pM) 9.00-19.04 All data, Mean ± SD. Figures and figure legends Figure 1. Changes in serum T3 (A), T4 (B), FT4 (C), FT3 (D) and TSH (E) concentrations in 15 patients with TSH-secreting pituitary adenoma at diagnosis, one-week after surgery, after octreotide and Sandostatin-LAR treatments. The red line with red spot indicates the mean of the hormone in 15 patients. Figure 2. Treatment effects of Sandostatin-LAR. (A) Coronal (a, c) and sagittal (b, d) magnetic resonance imaging (MRI) in patient 1 displaying a tumor mass before treatment with surgery (a, b) and after treatment with surgery (c, d). (B) Comparison of tumor sizes of 15 patients with TSH-secreting pituitary adenoma at diagnosis, after surgery, after octreotide treatment and Sandostatin-LAR treatment. The red line indicates the mean of the 15 tumor sizes. Tumor sizes decreased significantly two months after Sandostatin-LAR treatment compared with two months after octreotide treatment and postsurgery. Number 1 to 15 indicates patient 1 to 15.