Inappropriate Secretion Of TSH Research Articles

A challenging case of a pituitary macroadenoma and toxic thyroid adenoma with inappropriate TSH secretion.

Thyroid-stimulating hormone-secreting pituitary adenomas (TSHomas) are rare, accounting for less than 1% of all pituitary adenomas. We present a case of hyperthyroidism secondary to a likely TSHoma and coexisting functional thyroid adenoma. Laboratory errors and familial abnormalities in thyroid function tests were ruled out, and a diagnosis of the toxic thyroid adenoma was confirmed on a thyroid uptake scan. However, the triiodothyronine suppression test was contraindicated due to the patient's cardiovascular disease, and the thyrotropin-releasing hormone stimulation test, measurement of glycoprotein hormone alpha-subunit, and genetic testing were unavailable. Magnetic resonance imaging of the brain revealed a suprasellar pituitary macroadenoma measuring 40 mm × 20.3 mm × 17 mm. The patient was initiated on carbimazole; however, thyroid stimulating hormone and thyroxine levels remained elevated. The patient declined trans-sphenoidal surgery and was treated with radioactive iodine to manage the toxic thyroid adenoma, leading to reduced thyroxine levels and symptom improvement. Unfortunately, the patient passed away before long-acting somatostatin analogs became available. This case highlights the diagnostic and therapeutic challenges involved in managing thyrotoxicosis with dual etiology. Hyperthyroidism can have multiple etiologies, which can coexist in the same patient. Persistent discordant thyroid function tests warrant further investigation. The gold standard for diagnosis of TSHomas remains immunohistochemical analysis of the tumor tissue.

Syndrome of inappropriate secretion of TSH, it's complicated

Syndrome of inappropriate secretion of TSH, it's complicated

A reference center study in thyrotropin-secreting pituitary adenomas: clinicopathological, therapeutic and long-term follow-up outcomes.

This study aims to analyze the clinicopathological features, diagnostic steps, and therapeutic results of TSHomas and to reveal the effective factors on remission. The clinical, radiological, and pathological features and surgical and endocrinological results of 41 TSHoma cases followed between 2005 and 2022 were retrospectively analyzed. The factors affecting the surgical cure were investigated by comparing the groups with and without remission. A total of 41 patients (23 male,18 female) were included in the study and the mean age was 42 (31.5-49). Palpitation and headache were the most common complaints. The time from the onset of symptoms to diagnosis was 8 (3-20) months. There were 8 patients with a preoperative clinical and biochemical diagnosis of TSH + GH co-secretion. In the TRH stimulation test, a blunted TSH response was obtained in 18 patients (90.0%). Complete suppression could not be obtained in any of the patients who underwent the T3 suppression test. The median maximum tumor diameter was 19.0 mm (6.8-41). There was microadenoma in 4 (9.8%) patients and macroadenoma in 37 patients (92.8%). Remission was achieved in 31 (75.6%) of 40 patients who underwent endoscopic transsphenoidal surgery (eTSS). The Ki-67 labeling index was 2% (1.00-4.00) in the entire patient group. Preoperative use of antithyroid drugs appears to be significantly associated with surgical cure. Diagnosis of TSHoma is still full of challenges and dynamic tests remain important. Recognition and good management of inappropriate TSH secretion states affect subsequent surgical outcomes.

An undiagnosed TSH-secreting pituitary macroadenoma found during pregnancy.

SummaryThyroid stimulating hormone (TSH)-secreting pituitary adenoma (TSHoma) is an uncommon cause of thyrotoxicosis, and is even rarer when found during pregnancy. Our patient presented with thyrotoxicosis accompanied by an inappropriately normal TSH level at 10 weeks of gestation during work-up of surgical termination of pregnancy (STOP). Subsequent investigations performed after STOP confirmed the presence of a TSH-secreting pituitary macroadenoma. She was initially treated with anti-thyroid drugs for biochemical control, followed by trans-sphenoidal surgery after STOP had been performed. Her thyroid function completely normalized after the trans-sphenoidal surgery. Our case illustrated the importance of recognizing the syndrome of inappropriate TSH secretion and highlighted several pregnancy-related aspects in the diagnosis and management of TSHoma during pregnancy.Learning pointsThis case report illustrates the need to raise awareness in recognizing the syndrome of inappropriate TSH secretion.Illustrate the different hormone tests available for reaching the diagnosis of TSH-secreting pituitary adenoma.Highlight the physiological changes in the thyroid status during pregnancy and the importance of using trimester-specific reference ranges for assessment of thyroid function during pregnancy.Describe the challenges in the management of TSH-secreting pituitary adenoma during pregnancy.

The Differential Diagnosis of Discrepant Thyroid Function Tests: Insistent Pitfalls and Updated Flow-Chart Based on a Long-Standing Experience.

Background: Discrepant thyroid function tests (TFTs) are typical of inappropriate secretion of TSH (IST), a rare entity encompassing TSH-secreting adenomas (TSHoma) and Resistance to Thyroid Hormone (RTHβ) due to THRB mutations. The differential diagnosis remains a clinical challenge in most of the cases. The objective of this study was to share our experience with patients presenting with discrepant TFTs outlining the main pitfalls in the differential diagnosis.Methods: medical records of 100 subjects with discrepant TFTs referred to Thyroid Endocrine Centers at the University of Milan were analyzed, retrospectively. Patients were studied by dynamic testing (TRH test, T3-suppression test, or a short course of long-acting somatostatin analog, when appropriate), THRB sequencing, and pituitary imaging.Results: 88 patients were correctly diagnosed as RTHβ with (n = 59; 16 men, 43 women) or without THRB variants (n = 6; 2 men, 4 female) or TSHoma (n = 23; 9 men, 14 women). We identified 14 representative subjects with an atypical presentation or who were misdiagnosed. Seven patients, with spurious hyperthyroxinemia due to assays interference were erroneously classified as RTHβ (n = 4) or TSHoma (n = 3). Three patients with genuine TSHomas were classified as laboratory artifact (n = 2) or RTHβ (n = 1). Two TSHomas presented atypically due to coexistent primary thyroid diseases. In one RTHβ a drug-induced thyroid dysfunction was primarily assumed. These patients experienced a mean diagnostic delay of 26 ± 14 months. Analysis of the investigations which can differentiate between TSHoma and RTHβ showed highest accuracy for the T3-suppression test (100% specificity with a cut-off of TSH <0.11 μUI/ml). Pituitary MRI was negative in 6/26 TSHomas, while 11/45 RTHβ patients had small pituitary lesions, leading to unnecessary surgery in one case.Conclusions: Diagnostic delay and inappropriate treatments still occur in too many cases with discrepant TFTs suggestive of central hyperthyroidism. The insistent pitfalls lead to a significant waste of resources. We propose a revised flow-chart for the differential diagnosis.

MON-465 Novel Thyroid Hormone β Mutation L266s Causes Atrial Fibrillation &amp; Cerebral Infarction

Background: Resistance against thyroid hormone β (RTHβ) is characterized by reduced tissue sensitivity to thyroid hormone. Patients with RTHβ resistance typically demonstrate increases in FT3 and FT4 accompanied by inappropriately elevated TSH. Mutations in the TRβ gene are the most common genetic disorder in thyroid hormone resistance and result in impaired thyroid receptor functions due to a dominant negative effect. Here, we describe a case with a novel TRβ mutation, presenting atrial fibrillation and cerebral infarction.Clinical case: A 55-year-old man presented chronic atrial fibrillation and tachycardia as the onset of cerebral infarction. Because blood tests revealed 5.6 pg/ml FT3 (reference range: 2.36–4.06), 3.39 ng/ml FT4 (0.71–1.5), 0.98 TSH μIU/ml (0.541–4.261), and negative TRAb, suggesting inappropriate secretion of TSH (SITSH). He was referred to our department for further investigation. All three test kits, including LUMIPULSE, ECLusys, and TOSOH, showed an unsuppressed TSH value despite hyperthyroxinemia, demonstrating genuine SITSH. His family history was unclear, but his father had died of heart disease. A pituitary MRI suggested microadenoma, but TSH-secreting pituitary adenoma was excluded because of a negative α subunit and responsiveness to a TRH stimulation test. The TRβ gene was analyzed with informed consent from the patient, and a novel mutation replacing the 266th amino acid serine (TCG) with leucine (TTG) in the 8th exon was found, confirming the diagnosis of RTHβ. Tachycardia and atrial fibrillation were considered to be caused by thyrotoxicosis in heart, which dominantly expresses TRα rather than TRβ. Therefore, β-blockers and anticoagulants, were continued.Conclusion: This is the first report of a case of RTHβ with the TRβ L266S mutation. This novel mutation is located in the thyroid hormone-binding area of the TRβ gene, suggesting that reduced hormone binding may cause thyroid hormone resistance.

Diagnosing Thyrotropin-Secreting Pituitary Adenomas by Short-Term Somatostatin Analogue Test.

Background: Diagnosis of thyrotropin (TSH)-secreting pituitary adenomas (TSHoma) before surgery remains a challenge, especially for microadenomas. We aimed to establish a short-term somatostatin analogue (SSA) test to differentiate TSHomas from other causes of syndromes of inappropriate secretion of TSH (IST), mainly resistance to thyroid hormone β (RTHβ). Materials and Methods: We first evaluated the sensitivity and specificity of SSA test in a training cohort (TSHoma, n = 32; RTHβ, n = 20). The test was then validated in an independent cohort (TSHoma, n = 9; RTHβ, n = 2). We finally applied the SSA test in 12 perceptively enrolled IST cases with negative imaging findings and absent thyroid hormone receptor beta (THRB) mutations or mixed hormone imbalances. Results: Both TSHoma and RTHβ patients showed a decrease of TSH at the start of the SSA test, but the velocity of the TSH suppression slowly decreased in RTHβ patients after 2 hours. The suppression ratio of TSH at 24 hours versus 2 and 0 hours was significantly greater in TSHoma patients compared with RTHβ patients (70.58% ± 18.6% vs. 6.01% ± 25.41%, p < 0.0001, 79.83% ± 12.79% vs. 51.16% ± 13.62%, p < 0.0001, respectively). The 24- versus 2-hour suppression ratio showed the best diagnostic accuracy at a cut point of 44.46% in the training cohort, with a sensitivity of 95.00%, a specificity of 93.75%, and a positive predictive value (PPV) of 88.89%. The accuracy was confirmed in the validation cohort. Three out of 12 patients in the prospective cohort showed a TSH suppression ratio greater than 44.46% and all developed microadenomas during follow-up. Conclusions: A short-term SSA test provides an alternative diagnostic approach for TSHomas. A positive SSA test result is suggestive for a TSHoma even before positive findings become apparent on pituitary imaging. However, studies including larger number of patients, especially those with RTHβ, are needed to confirm our findings.

MON-612 Familial Dysalbuminemic Hyperthyroxinemia Cases in Five Unrelated Japanese Families and the Influences on Free T4 Measurement

Familial dysalbuminemic hyperthyroxinemia (FDH) is caused by abnormal human serum albumin (HSA) with an increased thyroxine (T4) affinity leading to euthyroid hyperthyroxinemia. In Japanese FDH patients with the HSAR218P mutation, not only one-step but also two-step immunoassays for free T4 (FT4) can yield false-positive results. Therefore, it is difficult to distinguish FDH from syndrome of inappropriate secretion of TSH, even when multiple assays are used. Patient 1 was a 29-year-old pregnant woman. A radiographic examination and hormone stimulation test were not performed. We suspected that the patient had FDH because of her family history such as abnormal thyroid function and hyperthyroxinemia (Total T4 level was greater than the measurement sensitivity). Genetic analysis using direct sequencing for HSA revealed that she was consistent with FDH. She experienced a normal delivery. Other patients were performed the thyroid test with Chief complaints of infertility or depression and their thyroid function abnormalities were pointed out. Thyroid function tests revealed elevated FT4 and FT3 levels; their TSH level was within the reference range in all patients. To investigate T4 to HSA binding, gel filtration high-performance liquid chromatography was used for the biochemical analyses. Furthermore, FT4 was measured in FDH patients using one-step method LUMIPULSE (Fujirebio) using T3 as an antigen and an anti-T4 antibody as a label. The genomic analysis revealed a heterozygous missense mutation in HSA(R218P). In FDH patient sera, the albumin effluent corresponded to the peaks for total T4 (TT4); approximately 60% of the T4 in the effluent was detected as FT4. Mean FT4 level measured with LUMIPULSE was 1.28 ng/dL within the reference value range. In the FDH patients, a relatively larger quantity of T4 was bound to abnormal HSA. This bound T4 was measured as FT4 during the analysis. When thyroid function abnormality without clinical findings is observed, it is considered preferable to understand the antigen and antibody to be used and to select measurement method.

SAT-612 An Anti-Idiotype Antibody to T3 Measurements: A Misleading Cause of Inappropriate TSH Secretion

Background: Measurements of thyrotropin (TSH), total and free thyroxine (TT4,FT4), triiodothyronine (TT3,FT3) are widely used diagnostic methods for thyroid function evaluation. However, some serum samples demonstrate a nonspecific binding with assay reagents that can interfere with the measurement of these hormones. Several steps can be taken to identify results that may reflect the presence of interfering factors including: 1) discrepancies between current values and previous results using the same methods; 2) clues from the clinical setting; 3) the pattern of discrepant and non-discrepant thyroid profile results (1,2) Clinical case: A 67-year-old woman admitted with generalized muscle weakness for one week. On physical examination she had left facial palsy (LMN), dysarthria, motor power grade 1 in her lower extremities and grade 3 in her upper extremities, her deep tendon reflex was diminished and her peripheral sensation was decreased as glove and stocking pattern. She was also experiencing normal anal sphincter tone and perianal sensation. She was diagnosed with hypertension and she was prescribed atenolol for treatment. She was clinically euthyroid. Provisional clinical diagnosis was Guillain-Barre syndrome. Because her laboratory profile showed hyponatremia, the following thyroid function tests were ordered: TSH 7.090 mIU/L (0.27-4.20 normal range [NR]); FT3 13.33 pg/ml (2.00-4.40 NR); FT4 1.37 ng/dl (0.93-1.70 NR) tested by one-step electrochemiluminescent immunoassay (ECLIA,Roche platform,Cobas®);anti-thyroid peroxidase antibody (16.25 IU/ml, normal); anti-thyroglobulin antibody (<10 IU/ml); serum morning cortisol concentration, normal. The thyroid profile was repeated on new samples from the same patient 3 and 7 days later. The results confirmed mildly elevated TSH with high FT3 concentration but normal FT4. Then, the thyroid profile also was processed in a different laboratory using a different technique (Abbott® platform). Using this platform, the FT3, FT4 and TSH were all within reference ranges. To confirm that the sample contained an interfering, an aliquot also was sent to Roche for further analysis. The results showed that the patient had antibodies to anti-idiotype of both the T3 and FT3 assays. Conclusion To avoid misdiagnosis or inappropriate treatment decisions, when there are discrepancies between the clinical setting and the thyroid function tests, the clinician should always consider that there is a substance interfering with the assay.

Dynamic changes of central thyroid functions in the management of Cushing's syndrome.

The aim of this study was to determine the frequency of central thyroid dysfunctions in Cushing's syndrome (CS). We also aimed to evaluate the frequency of hyperthyroidism due to the syndrome of the inappropriate secretion of TSH (SITSH), which was recently defined in patients with insufficient hydrocortisone replacement after surgery. We evaluated thyroid functions (TSH and free thyroxine [fT4]) at the time of diagnosis, during the hypothalamo-pituitary-adrenal axis recovery, and after surgery in 35 patients with CS. The patients were separated into two groups: ACTH-dependent CS (group 1, n = 20) and ACTH-independent CS (group 2, n = 15). Patients' clinical and laboratory findings were evaluated in five visits in the outpatient clinic of the endocrinology department. The frequency of baseline suppressed TSH levels and central hypothyroidism were determined to be 37% (n = 13) and 26% (n = 9), respectively. A negative correlation was found between baseline cortisol and TSH levels (r = -0.45, p = 0.006). All patients with central hypothyroidism and suppressed TSH levels showed recovery at the first visit without levothyroxine treatment. SITSH was not detected in any of the patients during the postoperative period. No correlation was found between prednisolone replacement after surgery and TSH or fT4 levels on each visit. Suppressed TSH levels and central hypothyroidism may be detected in CS, independent of etiology. SITSH was not detected in the early postoperative period due to our adequate prednisolone replacement doses.

DIAGNOSIS OF ENDOCRINE DISEASE: Diagnostic approach to TSH-producing pituitary adenoma.

Thyrotropin (TSH)-secreting adenomas (TSHomas) are the rarest form of pituitary adenomas, and most endocrinologists will see few cases in a lifetime, if any. In most cases, the diagnostic approach is complicated and cases may be referred after being presented as a syndrome of inappropriate TSH secretion or as a pituitary mass. This review aims to cover the past, present and possible future diagnostic approaches to TSHomas, including different clinical presentations, laboratory assessment and imaging advances. The differential diagnoses will be discussed, as well as possible coexisting disorders. By evaluating the existing reports and reviews describing this rare condition, this review aims to present a clinically practical suggestion on the diagnosic workup for TSHomas, Major advances and scientific breakthroughs in the imaging area in recent years, facilitating diagnosis of TSHomas, support the belief that future progress within the imaging field will play an important role in providing methods for a more efficient diagnosis of this rare condition.

Thyrotropin-secreting pituitary adenomas: epidemiology, diagnosis, and management.

Inappropriate secretion of TSH was first described in 1960 in a patient with evidence of hyperthyroidism and expanded sella on imaging. It was later found that a type of pituitary adenoma that secretes TSH (thyrotropinoma) was the underlying cause. The objective of the present review article is to summarize data on the epidemiology, pathogenesis, diagnosis, and management of thyrotropinomas. The prevalence of thyrotropinomas is lower than that of other pituitary adenomas. Early diagnosis is now possible thanks to the availability of magnetic resonance imaging and sensitive laboratory assays. As a corollary, many patients now present earlier in the course of their disease and have smaller tumors at the time of diagnosis. Treatment also has evolved over time. Transsphenoidal surgery is still considered definitive therapy. Meanwhile, radiation therapy, including radiosurgery, is effective in achieving tumor control in the majority of patients. In the past, radiation therapy was used as second line treatment in patients with residual or recurrent tumor after surgery. However, the availability of somatostatin analogs, which can lead to normalization of thyroid function as well as shrink these tumors, has led to an increase in the role of medical therapy in patients who are not in remission after pituitary surgery. In addition, dopamine agonists have shown some efficacy in the management of these tumors. Better understanding of the molecular pathogenesis of thyrotropinomas may lead to rationally designed therapies for patients with thyrotropinomas.

Syndrome of inappropriate secretion of TSH: Differential diagnosis in 61 patients

Objective To analyze the diagnostic approaches to differentiate thyrotropin(TSH)-secreting pituitary adenomas(TSHoma)and resistance to thyroid hormone(RTH). Methods This was a retrospective single center study. All patients with insuppressible TSH despite elevated free-T4 and free-T3 levels from 2004 to 2014 were enrolled. Results Twenty-seven patients were diagnosed as TSHoma, 20 as RTH, and 14 remained undetermined. Palpitation was observed in 54% patients as the main symptom. There was no significant difference in gender, serum levels of sex hormone-binding globulin, and free thyroid hormones between patients with TSHoma and RTH. The ages of patients at diagnosis and disease onset were older in TSHoma patients than RTH patients[(45.59±11.32 vs 31.80±11.32)years, P=0.012; (42.16±12.53 vs 23.30±15.77)years, P<0.01]. The course of disease was shorter in TSHoma patients than RTH patients[(3.44±4.55 vs 8.50±9.95)years, P=0.049]. Five RTH patients showed pituitary adenoma by MRI. TSHoma patients showed blunt TSH response to thyrotropin hormone releasing hormone(TRH)stimulation while RTH patients showed normal TRH stimulation[(2.35±1.61 vs 9.48±2.94)fold, P<0.01]. TSHoma patients showed significantly suppressed serum TSH by somatostatin analogs as compared with RTH patients[(77.02±13.43)%vs(52.33±15.02)%, P<0.01]. Twelve RTH patients had thyroid hormone receptor beta (TRβ) mutation. Conclusion A later age of disease onset and shorter disease course suggested TSHoma other than RTH. TRH stimulating test was the most accurate test to distinguish RTH and TSHoma as compared with pituitary MRI, somatostatin suppression test, and TRβ mutation analysis. (Chin J Endocrinol Metab, 2015, 31: 925-931) Key words: Thyrotropin-secreting pituitary adenoma; Resistance to thyroid hormones

TSH-secreting pituitary adenoma: benefits of pre-operative octreotide.

SummaryTSH-secreting pituitary adenomas are rare and the optimal investigation and management is uncertain. We describe a case of a 43 year-old woman with a TSH-secreting pituitary adenoma, highlighting diagnostic testing and our use, pre-operatively of somatostatin analogue therapy, which induced biochemical euthyroidism and a reduction in tumour size.Learning points The differential diagnosis of the syndrome of inappropriate TSH secretion is non-thyroidal illness, medications, assay interference due to heterophilic antibodies, thyroid hormone resistance and TSH-secreting pituitary adenoma.TRH stimulation test and triiodothyronine suppression test assist in differentiating thyroid hormone resistance and TSH-secreting pituitary adenoma.Somatostatin analogue therapy can induce biochemical euthyroidism and reduce tumour size.

Clinical significance of fluctuations in thyroid hormones after surgery for Cushing's syndrome.

Patients with Cushing's syndrome (CS) frequently develop hyperthyroidism after surgery due to SITSH (syndrome of inappropriate secretion of TSH) and this SITSH contributed to the symptoms of steroid withdrawal syndrome (SWS). However, the duration of fluctuations in thyroid hormones after surgery for CS remains unknown. The aim of this prospective study was to investigate the clinical course of fluctuation in thyroid hormone level in CS patients after surgery. Thyroid hormone levels [free T3 (FT3), free T4 (FT4) and TSH] and serum cortisol levels were measured before and 1, 3, 6 and 12 months after surgery in 8 patients with active CS (3 pituitary CS and 5 adrenal CS). FT3 levels were above the normal range in 75% of patients up to 6 months after surgery, but returned to the normal range by 12 months. However, TSH levels were not suppressed below the normal range throughout the first 12 months after surgery. Serious symptoms of SWS appeared during the 6-month period after surgery, but disappeared with normalization of thyroid function at 12 months, which was not related to the recovery of function hypothalamus-pituitary-adrenal axis after CS surgery. Therefore, T3 toxicosis could result in deterioration of SWS after surgery for CS. These results indicate that physicians need to take T3 toxicosis into consideration in the pathological evaluation of SWS within 12 months after surgery for CS.

Evaluation and Management of Thyrotropin-Secreting Pituitary Adenomas

Thyrotropin (TSH)-secreting pituitary adenomas are uncommon pituitary neoplasms. They have been increasingly recognized with the advent of ultrasensitive TSH assays and advanced pituitary imaging. Clinically, patients may often present with signs and symptoms of hyperthyroidism. Some patients may present with tumor-related local mass effect, anterior hypopituitarism or syndromes related to co-secretion of other pituitary hormones. Their diagnosis and differential diagnosis from other causes of hyperthyroidism and ‘inappropriate TSH secretion’ often presents a clinical challenge. While trans-sphenoidal pituitary adenomectomy remains the therapeutic modality of choice, medical treatment with somatostatin receptor agonists or dopamine agonists is often needed as adjunctive therapy or perhaps as a potential alternative to surgery. Radiation therapy to the sella may be advised as a third-line therapy.

Clinical and genetic characteristics of a large monocentric series of patients affected by thyroid hormone (Th) resistance and suggestions for differential diagnosis in patients without mutation of Th receptor β.

The syndrome of resistance to thyroid hormone (RTH) is caused by a mutation of TH receptor β (TRβ) in 80% of cases. Patients without mutation (non-TR-RTH) may have a biochemical pattern that is difficult to differentiate from that of pituitary TSH-secreting adenoma (TSHoma). Herein, we report a large monocentric series of RTH focusing on patients with non-TR-RTH, to evaluate possible clinical or biochemical parameters able to distinguish them from TSHoma. We retrospectively reviewed the data of 99 consecutive patients with inappropriate TSH secretion (IST) syndrome referred to our Department between 1983 and 2011, identifying 68 patients with RTH and 31 patients with TSHomas. Patient records were reviewed for the main clinical, biochemical and imaging characteristics. Of our 68 patients with RTH, 16 (23·5%) did not show a TRβ mutation and did not have affected family members. Of these 16 patients, three developed a TSHoma, during follow-up. To distinguish non-TR-RTH from TSHoma, we identified appropriate cut-off values for the main biochemical parameters that demonstrated the greatest sensitivity and specificity (T3 suppression test, α-subunit/TSH molar ratio, α-subunit assay and TRH test) and we calculated the probability for each patient to develop a TSHoma. The application of the identified cut-offs could become a very useful tool in the challenging differential diagnosis between sporadic non-TR-RTH and TSHoma. It would then be possible to select the patients at higher risk of developing a TSHoma and therefore needing a closer follow-up.

Hyperthyroidism Due to Thyroid-Stimulating Hormone Secretion After Surgery for Cushing's Syndrome: A Novel Cause of the Syndrome of Inappropriate Secretion of Thyroid-Stimulating Hormone

Hyperthyroidism with the syndrome of inappropriate secretion of TSH (SITSH) occurred by a decrease in hydrocortisone dose after surgery for Cushing's syndrome. This is a novel cause of SITSH. The aim of this study was to describe and discuss 2 cases of SITSH patients that were found after surgery for Cushing's syndrome. We also checked whether SITSH occurred in 7 consecutive patients with Cushing's syndrome after surgery. A 45-year-old Japanese woman with ACTH-independent Cushing's syndrome and a 37-year-old Japanese man with ACTH-dependent Cushing's syndrome presented SITSH caused by insufficient replacement of hydrocortisone for postoperative adrenal insufficiency. When the dose of hydrocortisone was reduced to less than 20 mg/d within 18 days after surgery, SITSH occurred in both cases. We examined whether the change of the hydrocortisone dose induced the secretion of TSH. Free T₃ and TSH were normalized by the hydrocortisone dose increase of 30 mg/d, and these were elevated by the dose decrease of 10 mg/d. We also checked TSH and thyroid hormone levels of the 7 consecutive patients with Cushing's syndrome after surgery. Six (66.6 %) of 9 patients showed SITSH. This is the first report that insufficient replacement of hydrocortisone after surgery for Cushing's syndrome caused SITSH. Hyperthyroidism by SITSH as well as adrenal insufficiency can contribute to withdrawal symptoms of hydrocortisone replacement. We need to consider the possibility of SITSH for the pathological evaluation of withdrawal syndrome of hydrocortisone replacement.

Aberrant Expression of Thyroid Hormone Receptor β Isoform May Cause Inappropriate Secretion of TSH in a TSH-Secreting Pituitary Adenoma

Patients with TSH-secreting pituitary adenomas (TSHoma) show inappropriate secretion of TSH; serum TSH levels are not suppressed despite high serum free thyroid hormone levels. The mechanism of a defect in negative regulation of TSH in a TSHoma is still unclear. Recently, we cloned a novel thyroid hormone receptor β isoform (TRβ4) from a human pituitary library. To elucidate the clinical significance of TRβ4, we investigated the expression of this isoform in TSHoma. RT-PCR was performed to detect TRβ isoforms such as TRβ1, TRβ2, and TRβ4 using RNA obtained from surgically resected TSHoma. The effects of TRβ4 on the TSH gene expression were examined in the transient gene expression experiments. Quantitative analysis using a real-time PCR revealed that relative expression of TRβ4 to TRβ1+2 was higher in three TSHoma than in a prolactinoma or a nonfunctioning pituitary adenoma. TRβ4 construct did not mediate T(3)-dependent gene regulation but inhibited the negative regulation of TSHα mediated by TRβ1 or TRβ2. Aberrant expression of TRβ4 may partly contribute to the inappropriate secretion of TSH in a TSHoma.

Resistance to Thyroid Hormone Accompanied by Graves' Disease

Resistance to thyroid hormone (RTH) is characterized by elevated serum levels of thyroid hormones and normal or slightly increased serum thyrotropin (TSH) levels. Recently it has been suggested that chronic TSH stimulation in RTH activates intrathyroidal lymphocytes, leading to thyroid damage and autoimmune thyroid disease (AITD). Therefore, individuals with RTH have an increased likelihood of AITD compared to unaffected relatives. We here report a 33-year-old woman in whom we diagnosed Graves' disease and treated her with thiamazole (MMI). For two years, her TSH levels were suppressed when thyroid hormones were elevated and conversely they were increased when thyroid hormones levels were decreased. These findings were common for a clinical course during treatment for Graves' disease with anti-thyroid drug. However, three years after the initiation of MMI therapy, she had a normal or gradually elevated serum TSH level even though the level of thyroid hormones never decreased, indicating inappropriate secretion of TSH. We concluded she had RTH clinically, and we demonstrated by direct sequence analysis a mutation of the TRβ gene, causing replacement of a glycine (G) with arginine (R) at codon 251. The finding of an elevated TSH level without decreased thyroid hormones should suggest the presence of RTH during therapy of Graves' disease.